Datasets:

tomekkorbak

/

pii-pile-chunk3-1150000-1200000

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[ "Novel avilamycin derivatives with improved polarity generated by targeted gene disruption.", "\nThe oligosaccharide antibiotics avilamycin A and C are produced by Streptomyces viridochromogenes Tu57. ", "Both consist of a heptasaccharide chain, which is attached to a polyketide-derived dichloroisoeverninic acid moiety. ", "They show excellent antibiotic activity against Gram-positive bacteria. ", "Both molecules are modified by O-methylation at different positions, which contributes to poor water solubility and difficulties in galenical drug development. ", "In order to generate novel avilamycin derivatives with improved polarity and improved pharmacokinetic properties, we generated a series of mutants with one, two, or three mutated methyltransferase genes. ", "Based on the structure of the novel avilamycin derivatives, the exact function of three methyltransferases, AviG2, AviG5, and AviG6, involved in avilamycin biosynthesis could be assigned." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "Authorities arrested the operators of four Los Angeles-area trade schools for allegedly running an elaborate “pay-to-stay” scam in which foreign nationals used student visas to stay in the United States without actually going to school.", "\n\nThe schools appear to have tapped the booming Asian immigration population in Koreatown and the San Gabriel Valley. ", "Authorities say the suspects took in $6 million a year in tuition payments.", "\n\nHee Sun Shim, 51, of Beverly Hills; Hyung Chan Moon, 39; and Eun Young Choi, 35, were named in a 21-count indictment returned by a federal grand jury Tuesday.", "\n\nAuthorities say Shim operated three schools in Koreatown and a fourth in Alhambra that enrolled hundreds of foreign nationals in their schools so they could remain in the country knowing the students had no plans of attending.", "\n\n\nThe schools identified by investigators were Prodee University/Neo-America Language School; Walter Jay M.D. Institute; an Educational Center and the American College of Forensic Studies and Likie Fashion and Technology College in Alhambra.", "\n\n“Officials at several schools allegedly abused their responsibility to ensure that only legitimate foreign students were allowed to the stay in the country,” said Acting United States Attorney Stephanie Yonekura in a statement. “", "This type of fraud against the United States will be thoroughly examined to bring those responsible to justice and to protect the integrity of our immigration system.”", "\n\nShim, Moon and Choi were arrested by immigration agents and are expected to be arraigned Thursday. ", "Their charges include conspiring to commit immigration fraud, money laundering and encouraging illegal residence.", "\n\nThe arrests were the culmination of a four-year probe by Homeland Security Investigations.", "\n\n\nThe men’s scam was discovered when agents with Homeland Security’s Student and Exchange Visitor Program made a surprise visit to Prodee University’s main campus on Wilshire Boulevard in Koreatown. ", "The school had more than 900 students enrolled on its books, but officials say they found only three students in a single English-language class.", "\n\nA surprise check at American College of Forensic Studies had a similar result, authorities said. ", "Investigators found one student in one religion class though 300 foreign students were considered “active” at the school.", "\n\nThe key to the scam was an immigration document that allows shows a foreign national has been accepted into a government-certified school and will be attending it full time. ", "The “students” paid up to $1,800 for six month’s “tuition”to the men so they would appear to be enrolled and could remain in the United States, authorities said.", "\n\nThe men allegedly faked school transcripts and other student records, including school transfer papers when authorities questioned the length of a student’s stay.", "\n\n\nAuthorities said they plan to have each university’s Student and Exchange Visitor Program certification withdrawn. ", "Students enrolled in the schools have to reach out to exchange program officials to determine what to do next, the U.S. Attorneys Office said.", "\n\nFor more breaking news in California, follow @josephserna." ]

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[ "Q:\n\nWhy were rotary vane compressors never used in jet engines?", "\n\nIt seems like a rotary vane compressors have ideal characteristics for a jet engine. ", "They can generate high pressure ratios (up to maybe 10-12) compared to older axial compressors and I think they can have a high flow rate at ~90% energy efficiency. ", "They also seem simpler to construct/cheaper than axial compressors.", "\nI understand that modern axial compressors can generate a higher pressure ratio, but historically why didn't rotary vane compressors have a place over at least centrifugal compressors in earlier jet engines?", "\n\nA:\n\nThe most important characteristic for a jet engine compressor is high mass flow rate with light weight and if possible small size. ", "For the same size, the flow rate can be increased by operating the compressor at higher rpm. ", "But sliding components don't allow that.", "\nOnly the axial and centrifugal compressors can achieve sufficient flow rates, so they are used. ", "Centrifugal compressors achieve higher pressure ratio for weight, but are larger, so they were used in many early designs and now remain in small turboprops while larger engines use axial compressors for their compactness.", "\n\n" ]

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[ "Trends in Use of Midodrine in the ICU: A Single-Center Retrospective Case Series.", "\nMidodrine is an oral alpha-agonist approved for orthostatic hypotension. ", "The use of midodrine as a vasopressor sparing agent has steadily increased in the ICU despite limited evidence for its safety in that setting. ", "We describe the trends in use and reported side effects and complications of midodrine in multidisciplinary ICUs of a tertiary care institution. ", "Single-center retrospective case series. ", "Medical and surgical ICU patients from January 2011 to October 2016 at Mayo Clinic, Rochester. ", "Adult patients admitted to any ICU who received midodrine for hypotension were eligible. ", "None. ", "We reviewed the mean arterial pressures and cumulative vasopressor dose before and after midodrine administration and assessed for reported complications. ", "During the study period, a total of 1,119 patients were initiated on midodrine, 56% in surgical ICUs, 42% in medical ICUs, and 2% in a mixed medical and surgical neurology ICU. ", "There was a significant decrease in the number of patients on vasopressors 24 hours after initiation of midodrine (663 to 344; p < 0.001); among the patients that remained on vasopressors, there was a significant decrease in the median cumulative vasopressor dose (p = 0.002). ", "There was a significant increase in median mean arterial pressure 24 hours after initiation of midodrine among patients who were not on vasopressors (65-68; p < 0.01). ", "Asymptomatic bradycardia (heart rate < 50 beats/min) was the most common side effect (n = 172 patients, median 39 beats/min). ", "Two patients developed bowel ischemia after initiation of midodrine that prompted discontinuation of midodrine in one case. ", "Evaluating trends of utilization, the off-label use of midodrine has increased steadily over the years across ICUs. ", "Our results suggest that midodrine is being increasingly used as an adjunct to increase mean arterial pressure and facilitate weaning of vasopressors in the ICU. ", "Prospective trials are required to further establish the appropriate timing, efficacy, safety, and cost-effectiveness of midodrine use in ICU patients." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "Preview the Over40Handjobs.comMembers area http://www.rabbitsreviews.com/screenshots/various/over-40-handjobs1.jpghttp://www.rabbitsreviews.com/screenshots/various/over-40-handjobs2.jpghttp://www.rabbitsreviews.com/screenshots/various/over-40-handjobs3.jpghttp://www.rabbitsreviews.com/screenshots/various/over-40-handjobs4.jpg\n\nVideos\n\nFull Review\n\nA sitename like Over 40 Handjobs can be taken in a couple ways. ", "Perhaps it stars someone who has given at least 41 tuggies. ", "Maybe the ones giving the rubs and tugs are at least 41 years old. ", "It could even be argued that it refers to how the site boasts more than 40 scenes, all of which show the dick-stroking we know and love so much.", "\n\nAs it turns out, Over40Handjobs has more than 40 scenes in which there is at least one babe who is over 40 years old. ", "Judging by how good they are at what they do, they've probably stroked more than 40 dicks during their lifetime. ", "The chicks are always amazing at giving handjobs and it isn't uncommon to see them giving the guys titjobs, too.", "\n\nThere are both MILFs and grannies among the middle-aged babes. ", "You'll also see teens quite often, as a common motif in about half the material is that either a mom walked in on her daughter while the latter was yanking her boyfriend's crank, or the daughter walked in on mom while she was jerking off her man.", "\n\nIn both situations, the mom takes over and teaches the daughter how to really give a handjob. ", "The scenes starring only mature chicks are just as hot and, like the mother/daughter scenes, always end in copious amounts of cum shooting out of a clearly satisfied hunk's cock.", "\n\nThere are 119 episodes and they add a new only weekly. ", "The photos basically reenact what's in the movies, but they're taken from different angles and show different facial expressions on the models. ", "The lighting isn't always as clear as in the vids, though. ", "Each set can be saved in a Zip folder that is filled with high-res images.", "\n\nAs for the movies, you can go with full-length versions or opt for a series of clips instead. ", "If you prefer, you can stream the MP4s in an embedded player. ", "Newer movies offer HD footage, but the older ones are still average to great in quality.", "\n\nLive cams are linked to, but they cost extra. ", "If you want to enjoy some additional material that won't cost you a penny, you need to take a look at the bonus sites. ", "There's Simone Fox, Club Tug, See Mom Suck and four others. ", "At the end of the day, Over 40 Handjobs has really hot content that will appeal to those who like tugjobs from mature, mostly amateur, babes.", "\n\nPhotos\n\nYour membership includes\n\nWrite Your Review\n\n* Please include a pro and a con about the site. ", "Balance is essential in making a comment worthwhile. ", "Scores without comments will be deleted.", "\n\n* Watch out for ratings of zero and 100. ", "In our opinion, there is no such thing as a site that is absolutely perfect or completely worthless." ]

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[ "This invention relates generally to a punched tape system for controlling the operation of a machine. ", "Basically, punched tape control systems operate through the use of a closed loop punched or perforated tape which contains appropriately spaced perforations to convey information to control the various operations of the machine.", "\nPunched tape of the type utilized to control the operation of machines typically has a plurality of parallel tracks or channels. ", "One of these tracks or channels contains a plurality of sprocket holes which are engaged by a drive sprocket. ", "The rotation of the drive sprocket sequentially engages the sprocket holes to advance the tape through a tape reading station. ", "The tape contains perforations in the various channels to convey information which is sensed or read by the tape reader and the particular location of these data holes is converted by suitable circuitry to control the operation of the machine.", "\nOne problem with the prior systems is that the sprocket holes do not convey any information. ", "This reduces the number of available channels or tracks on the tape.", "\nA second problem can be best understood by considering the type of information contained on the tape. ", "If it is desired to have the machine advance stock material, under the prior systems it was often necessary to place a perforation in a particular track (or a series of perforations in a straight line transverse to the longitudinal axis of the tape) to start the advancing operation. ", "Then, when it was desired to terminate the advancing operation another perforation or series of perforations in a different track was necessary.", "\nThe alternate way of accomplishing the same result, according to the prior art, was to provide a sequence or series of perforations in a particular track to indicate the continuation of a given machine operation. ", "Thus a series of five consecutive perforations in a particular track or channel were utilized to indicate that the feeding operation was to continue for the length of time it took the tape to be advanced by the drive sprocket the equivalent of five sprocket holes.", "\nNone of the prior art systems for punched tape machine controls therefore, made optimum use of the available space on the tape. ", "None of the prior art systems made optimum use of the sprocket holes." ]

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[ "Compound archery bows include pulleys at the ends of the bow limbs. ", "The pulleys carry cables along with a bowstring, which are rigged to allow the bowstring to be drawn to launch an arrow. ", "Because the pulleys lie within the same approximate spatial plane as the bowstring, cables, and arrow, the arrow shaft will contact the cables during the arrow launching process, unless the cables are braced out of the path of the arrow. ", "Deflection rods or cable guards have been used for years to brace the cables out of the arrow path. ", "A typical cable guard extends from the bow riser and is laterally offset from the plane of the cables and bowstring.", "\nSome cable guards simply utilize a rod (often with a bend) for deflecting the cables. ", "A cable slide is often used in conjunction with these types of rod-type cable guards. ", "However, the frictional contact of the cables with the rod or cable slide reduced the speed by which the bowstring launches the arrow, which reduces, in turn, the arrow speed.", "\nRollers have been used to further reduce such frictional forces. ", "The rollers may be part of a guide or guard assembly that is mounted to the rod. ", "The guide assembly includes a pair of rollers positioned within a guide or guard structure. ", "The rollers have traditionally been arranged in a side-by-side manner, typically arranged coaxially. ", "The side-by-side arrangement of the rollers may induce additional torque and frictional forces on the cable that may have adverse effects on performance of the archery bow.", "\nThese and other problems are avoided and numerous advantages are provided by the apparatuses and methods described herein." ]

{ "pile_set_name": "USPTO Backgrounds" }

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[ "The Analysis of Influential Factors of Residents' Consumption based on Panel Data Model\n\nChun-lei HAN, Kong-lai ZHU, Jin-rui WANG\n\nAbstract\n\nInvestment, consumption and exports are regarded as the 'three carriages' to enhance the economic growth in which consumption is of great importance. ", "The influencing factors of consuming were analysed with the applications of EVIEWS6.0 and panel data model. ", "In the analysis, the level of consumption was treated as the dependent variable and per capita income and the price level as independent variables. ", "The data such as the per capita income, the level of consumption and the price level were extracted from the Chinese Statistical Yearbook published by Chinese National Statistical Bureau. ", "After the analysis, the results were compared among the eastern, central and western part of China. ", "Finally, the corresponding policies to improve the level of consumption were brought up. ", "Key words: panel data model; residents' consumption; average income; price index" ]

{ "pile_set_name": "Pile-CC" }

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[ "Using History to Analyze the Learning by Observing and Pitching In Practices of Contemporary Mesoamerican Societies.", "\nThe analysis of Indigenous learning practices in Mexico and the United States typically relies on ethnography, oral history, and participant observation as the methodology for understanding the socialization processes of Mesoamerican societies. ", "In this chapter, we consider the importance of using historical analysis as an added methodology for understanding the Indigenous learning practices by considering three case studies of Indigenous communities in Mexico, where a consideration of historical patterns have proven fruitful for understanding the contemporary Learning by Observing and Pitching In (LOPI) practices. ", "These communities include the Nahua people of the state of Puebla, the P'urhépecha communities of the state of Michoacán, and the Nahua people of the Texcoco area to the southeast of Mexico City. ", "We conclude that a consideration of the cultural patterns that have developed in Mesoamerican societies across time would benefit contemporary researchers as one component of their LOPI research." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "Het Keizer Karelplein in Nijmegen is de gevaarlijkste verkeerslocatie van Nederland. ", "Dat concludeert RTL Nieuws op basis van cijfers van de politie en Rijkswaterstaat.", "\n\nDe nieuwsrubriek onderzocht ruim 200.000 ongelukken in de periode van 2014 tot 2016. ", "Daaruit blijkt dat er in Nederland bijna 1200 plaatsen zijn waar in drie jaar tijd meer dan tien ongevallen waren. ", "Op deze zogenoemde black spots gebeurden in drie jaar tijd zo'n 17.000 ongelukken, met in totaal 2658 slachtoffers, zowel doden als gewonden.", "\n\nGemeentelijke wegen\n\nMeer dan de helft van de verkeersonveilige locaties bevindt zich volgens RTL op gemeentelijke wegen (624). ", "Rijkswegen kennen 507 gevaarlijke plekken, provinciale wegen 54. ", "Op rijkswegen gaat het veelal om materiële schade. ", "De gemeentelijke wegen zijn veel risicovoller: daar waren ruim 2000 slachtoffers.", "\n\nHet Keizer Karelplein in Nijmegen spant met 83 ongevallen in drie jaar tijd de kroon. ", "Andere onveilige plaatsen zijn bijvoorbeeld het A4-gedeelte van knooppunt De Nieuwe Meer in Amsterdam of de Ringbaan in Tilburg." ]

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[ "<?", "php\n/**\n * Zend Framework\n *\n * LICENSE\n *\n * This source file is subject to the new BSD license that is bundled\n * with this package in the file LICENSE.txt.", "\n * It is also available through the world-wide-web at this URL:\n * http://framework.zend.com/license/new-bsd\n * If you did not receive a copy of the license and are unable to\n * obtain it through the world-wide-web, please send an email\n * to license@zend.com so we can send you a copy immediately.", "\n *\n * @category Zend\n * @package Zend_Controller\n * @subpackage Router\n * @copyright Copyright (c) 2005-2015 Zend Technologies USA Inc. (http://www.zend.com)\n * @version $Id$\n * @license http://framework.zend.com/license/new-bsd New BSD License\n */\n\n/** Zend_Controller_Router_Route_Abstract */\n#require_once 'Zend/Controller/Router/Route/Abstract.php';\n\n/**\n * Module Route\n *\n * Default route for module functionality\n *\n * @package Zend_Controller\n * @subpackage Router\n * @copyright Copyright (c) 2005-2015 Zend Technologies USA Inc. (http://www.zend.com)\n * @license http://framework.zend.com/license/new-bsd New BSD License\n * @see http://manuals.rubyonrails.com/read/chapter/65\n */\nclass Zend_Controller_Router_Route_Module extends Zend_Controller_Router_Route_Abstract\n{\n\n /**\n * Default values for the route (ie. ", "module, controller, action, params)\n *\n * @var array\n */\n protected $_defaults;\n\n /**\n * Default values for the route (ie. ", "module, controller, action, params)\n *\n * @var array\n */\n protected $_values = array();\n\n /**\n * @var boolean\n */\n protected $_moduleValid = false;\n\n /**\n * @var boolean\n */\n protected $_keysSet = false;\n\n /**#@+\n * Array keys to use for module, controller, and action. ", "Should be taken out of request.", "\n *\n * @var string\n */\n protected $_moduleKey = 'module';\n protected $_controllerKey = 'controller';\n protected $_actionKey = 'action';\n /**#@-*/\n\n /**\n * @var Zend_Controller_Dispatcher_Interface\n */\n protected $_dispatcher;\n\n /**\n * @var Zend_Controller_Request_Abstract\n */\n protected $_request;\n\n /**\n * Get the version of the route\n *\n * @return int\n */\n public function getVersion()\n {\n return 1;\n }\n\n /**\n * Instantiates route based on passed Zend_Config structure\n *\n * @param Zend_Config $config\n * @return Zend_Controller_Router_Route_Module\n */\n public static function getInstance(Zend_Config $config)\n {\n $frontController = Zend_Controller_Front::getInstance();\n\n $defs = ($config->defaults instanceof Zend_Config) ? 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", "Assigns and returns an array of variables\n * on a successful match.", "\n *\n * If a request object is registered, it uses its setModuleName(),\n * setControllerName(), and setActionName() accessors to set those values.", "\n * Always returns the values as an array.", "\n *\n * @param string $path Path used to match against this routing map\n * @param boolean $partial\n * @return array An array of assigned values or a false on a mismatch\n */\n public function match($path, $partial = false)\n {\n $this->_setRequestKeys();\n\n $values = array();\n $params = array();\n\n if (!", "$partial) {\n $path = trim($path, self::URI_DELIMITER);\n } else {\n $matchedPath = $path;\n }\n\n if ($path !", "= '') {\n $path = explode(self::URI_DELIMITER, $path);\n\n if ($this->_dispatcher && $this->_dispatcher->isValidModule($path[0])) {\n $values[$this->_moduleKey] = array_shift($path);\n $this->_moduleValid = true;\n }\n\n if (count($path) && !", "empty($path[0])) {\n $values[$this->_controllerKey] = array_shift($path);\n }\n\n if (count($path) && !", "empty($path[0])) {\n $values[$this->_actionKey] = array_shift($path);\n }\n\n if ($numSegs = count($path)) {\n for ($i = 0; $i < $numSegs; $i = $i + 2) {\n $key = urldecode($path[$i]);\n $val = isset($path[$i + 1]) ? ", "urldecode($path[$i + 1]) : null;\n $params[$key] = (isset($params[$key]) ? (", "array_merge((array)$params[$key], array($val))) : $val);\n }\n }\n }\n\n if ($partial) {\n $this->setMatchedPath($matchedPath);\n }\n\n $this->_values = $values + $params;\n\n return $this->_values + $this->_defaults;\n }\n\n /**\n * Assembles user submitted parameters forming a URL path defined by this route\n *\n * @param array $data An array of variable and value pairs used as parameters\n * @param boolean $reset Weither to reset the current params\n * @param boolean $encode\n * @param boolean $partial\n * @return string Route path with user submitted parameters\n */\n public function assemble($data = array(), $reset = false, $encode = true, $partial = false)\n {\n if (!", "$this->_keysSet) {\n $this->_setRequestKeys();\n }\n\n $params = (!", "$reset) ? ", "$this->_values : array();\n\n foreach ($data as $key => $value) {\n if ($value !", "== null) {\n $params[$key] = $value;\n } elseif (isset($params[$key])) {\n unset($params[$key]);\n }\n }\n\n $params += $this->_defaults;\n\n $url = '';\n\n if ($this->_moduleValid || array_key_exists($this->_moduleKey, $data)) {\n if ($params[$this->_moduleKey] !", "= $this->_defaults[$this->_moduleKey]) {\n $module = $params[$this->_moduleKey];\n }\n }\n unset($params[$this->_moduleKey]);\n\n $controller = $params[$this->_controllerKey];\n unset($params[$this->_controllerKey]);\n\n $action = $params[$this->_actionKey];\n unset($params[$this->_actionKey]);\n\n foreach ($params as $key => $value) {\n $key = ($encode) ? ", "urlencode($key) : $key;\n if (is_array($value)) {\n foreach ($value as $arrayValue) {\n $arrayValue = ($encode) ? ", "urlencode($arrayValue) : $arrayValue;\n $url .= self::URI_DELIMITER . ", "$key;\n $url .= self::URI_DELIMITER . ", "$arrayValue;\n }\n } else {\n if ($encode) {\n $value = urlencode($value);\n }\n $url .= self::URI_DELIMITER . ", "$key;\n $url .= self::URI_DELIMITER . ", "$value;\n }\n }\n\n if (!", "empty($url) || $action !", "== $this->_defaults[$this->_actionKey]) {\n if ($encode) {\n $action = urlencode($action);\n }\n $url = self::URI_DELIMITER . ", "$action . ", "$url;\n }\n\n if (!", "empty($url) || $controller !", "== $this->_defaults[$this->_controllerKey]) {\n if ($encode) {\n $controller = urlencode($controller);\n }\n $url = self::URI_DELIMITER . ", "$controller . ", "$url;\n }\n\n if (isset($module)) {\n if ($encode) {\n $module = urlencode($module);\n }\n $url = self::URI_DELIMITER . ", "$module . 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[ "\r\n\r\nMatter of William O. v John A. (2017 NY Slip Op 04507)\r\n\r\n\r\n\r\n\n\nMatter of William O. v John A.\n\n\n2017 NY Slip Op 04507\n\n\nDecided on June 8, 2017\n\n\nAppellate Division, Third Department\n\n\nPublished by New York State Law Reporting Bureau pursuant to Judiciary Law § 431.", "\n\n\nThis opinion is uncorrected and subject to revision before publication in the Official Reports.", "\n\n\n\r\nDecided and Entered: June 8, 2017\r\n\n521643\r\n\r\n[*1]In the Matter of WILLIAM O., Appellant,\r\nvJOHN A. et al., ", "Respondents, et al., ", "Respondent. (", "And Another Related Proceeding.)", "\r\n\r\nCalendar Date: May 1, 2017\r\n\r\nBefore: McCarthy, J.P., Rose, Devine, Clark and Mulvey, JJ.", "\r\n\r\n\nSandra M. Colatosti, Albany, for appellant.", "\nPaul R. Corradini, Elmira, for respondents.", "\nPamela Doyle Gee, Big Flats, attorney for the children.", "\n\nClark, J.\r\n\r\nMEMORANDUM AND ORDER\nAppeal from an order of the Family Court of Chemung County (Hayden, J.), entered August 6, 2015, which, in two proceedings pursuant to Family Ct Act article 6, dismissed the petitions at the close of petitioner's proof.", "\nPetitioner (hereinafter the father) and respondent Michelle A. are the unmarried parents of three children (born in 2006, 2007 and 2009), all of whom are in the custody of their maternal grandparents, respondents John A. and Wanda A. (hereinafter the grandparents). ", "Pursuant to an order of custody and visitation\nentered on June 30, 2014, which is the subject of another appeal in this Court (Matter of William O. v Wanda A., ___ AD3d ___ [decided herewith]), Family Court continued the grandparents' legal and physical custody of the children and awarded the father visitation with the children on alternate weekends from 1:00 p.m. to 6:00 p.m. on Saturdays and Sundays, with such visits to be held within this state. ", "In January 2015, the father filed a petition seeking to modify the June 2014 order of custody and visitation and, shortly thereafter, in February 2015, he filed a second modification petition. ", "The matter proceeded to a hearing and, at the close of the father's proof, the grandparents moved to dismiss the petitions for failure to establish that there had been a change in circumstances since entry of the June 2014 order. ", "Family Court granted the motion [*2]and dismissed the petitions [FN1]. ", "The father now appeals.", "\nWe affirm. ", "At the hearing, the father testified that, although he had petitioned for \"full\" custody of the children, he was only seeking joint legal custody of the children and an expansion of his visitation. ", "For the reasons more fully discussed in our decision resolving the father's appeal from the June 2014 order of custody and visitation (Matter of William O. v Wanda A., supra), the portion of the father's appeal relating to a change in legal custody has not, as the grandparents and the attorney for the children contend, been rendered moot by the entry of a September 2016 order suspending the father's visitation (see Matter of Blagg v Downey, 132 AD3d 1078, 1079 [2015]; cf. ", "Hughes v Gallup-Hughes, 90 AD3d 1087, 1088 [2011]; compare Matter of Dalmida v Livermore, 134 AD3d 1306, 1306-1307 [2015]). ", "However, insofar as the father's modification petitions sought an expansion of visitation, any challenges related thereto have been rendered moot (see Matter of Hearst Corp. v Clyne, 50 NY2d 707, 714 [1980]; Matter of Audra Z. v Lina Y., 135 AD3d 1197, 1198 [2016]).", "\nAs to the merits, to survive a motion to dismiss, the father bore the burden of establishing that there had been a change in circumstances since entry of the June 2014 order significant enough to warrant a review of the issue of custody to ensure the continued best interests of the children (see Matter of Heasley v Morse, 144 AD3d 1405, 1406 [2016]; Matter of Engelhart v Bowman, 140 AD3d 1293, 1293 [2016]). ", "To that end, the father merely testified that, since entry of the June 2014 order, he had twice moved his residence to different areas within Pennsylvania. ", "He stated that he had most recently moved to a more spacious apartment that was closer to the grandparents' residence in Chemung County. ", "However, the father's move to a bigger and closer out-of-state residence was insufficient to constitute a change in circumstances warranting an inquiry into whether joint legal custody was in the children's best interests (see Matter of Washington v Bender, 59 AD3d 888, 889-890 [2009], lv denied 12 NY3d 710 [2009]). ", "Nor was the requisite change in circumstances established by the father's testimony that the grandparents referred to him by his first name in front of the children, did not permit the children to regularly call him on the telephone and would not share the children's medical and educational records with him, as some of this evidence was before Family Court at the time that the June 2014 order was entered.[FN2] Accordingly, as the father did not present sufficient proof to demonstrate the requisite change in circumstances, Family Court properly dismissed the father's modification petitions (see Matter of Tyrel v Tyrel, 132 AD3d 1026, 1027 [2015]; Matter of Fish v Fish, 112 AD3d 1161, 1161-1162 [2013]).", "\nThe father's remaining contentions do not warrant extended discussion. ", "By failing to challenge — at the hearing — Family Court's ruling precluding him from testifying as to certain hearsay statements allegedly made by one of the grandparents' other grandchildren, the father failed to preserve his argument that such testimony should have been permitted under a particular hearsay exception (see Matter of Thomas FF. ", "v Jennifer GG., ", "143 AD3d 1207, 1208 [2016]; [*3]Matter of Britiny U. [Tara S.], 124 AD3d 964, 965 [2015]). ", "Further, considering the children's relatively young ages at the time of the hearing and that the attorney for the children adequately conveyed their wishes to Family Court, we discern no abuse of discretion in Family Court's determination not to conduct a Lincoln hearing (see Matter of Leary v McGowan, 143 AD3d 1100, 1103 [2016]; Matter of VanBuren v Assenza, 110 AD3d 1284, 1285 [2013]). ", "The father's remaining arguments, to the extent not specifically addressed herein, have been examined and determined to be without merit.", "\nMcCarthy, J.P., Rose, Devine and Mulvey, JJ., ", "concur.", "\nORDERED that the order is affirmed, without costs.", "\nFootnotes\n\nFootnote 1: Roughly two hours after Family Court dismissed the instant modification petitions, the father filed an additional modification petition, which was also dismissed (Matter of William O. v John A., 148 AD3d 1258 [2017], lv denied ___ NY3d ___ [2017]).", "\r\n\nFootnote 2: As to the remaining allegations made in his petitions, the father failed to present any evidence to support such claims at the hearing.", "\r\n\n\n" ]

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[ "Q:\n\nas separator -- why no article?", "\n\nFrom Core Java Volume I—Fundamentals, 9th Edition by Cay S. Horstmann (2012):\n\nThe Java compiler itself is highly skilled in guessing the various meanings of the period character as separator between packages, subpackages, classes, inner classes, and methods and variables.", "\n\nHere is what the thing that they're talking about in the excerpt looks like:\n\npackage com.horstmann.corejava // an example of a Java package\n Employee.getSalary() // an example of a method call in Java\n\nI asked my American friend why there was no article in front of separator and his answer was, first of all, that the sentence sounded completely fine to him and that you could put a definite article there, but you don't need to. ", "As to why that was the case, no explanation followed.", "\nLater on, he added that this is more like saying what the role is, not what the thing itself is. ", "Alright, that makes total sense, but is there some sort of rule of thumb that can help you determine whether to use an article or leave it out altogether (whether we're talking about a role or not a role)? ", "Obviously, the author could have gone with the \"article\" possibility (I don't see anything wrong with that), but he evidently didn't choose to go that way. ", "There must have been something that prompted him to forgo sticking in an article. ", "So, I'm really curious as to what was going on in his head at that moment and what exactly prompted him to make the decision that he made.", "\nIf you have anything to say about this grammar problem, please feel free to share your thoughts and ideas.", "\n\nA:\n\nHere's the logic the way I see it.", "\nSee the sentence below:\n\nCan you talk to the manager, or person acting as manager, about this?", "\n\nThe entire phrase \"manager, or person acting as manager\" are all talking about a single thing (something that is a manager or its equivalent). ", " For example, this entire phrase could be the subject of a sentence.", "\n\nThe manager, or person acting as manager, is required to sign the visitor log.", "\n\nSo you only need one \"the\" in front of it, since there really is only one noun on a logical level. ", " You can repeat the \"the\" for clarity if you like, but it's not required because the first \"the\" is still \"in effect,\" so to speak.", "\nIt's similar to:\n\nI wanted the blue book, blue notepad, and blue pen.", "\nI wanted the blue book, notepad, and pen.", "\n\nThe first sentence is extra clear, though depending on the context the second sentence would usually mean the same.", "\n\nAlso, one other thing I can think of is that the writer of that sentence does not know if there will be one of or more than one of \"packages, subpackages, classes, inner classes, and methods and variables.\" ", " So ...\n\nSaying \"the separator between ...\" would say that the period character could be the only character to separate these items.", "\n\nSaying \"a separator between ...\" would say that the period character, in addition to other characters, could separate these items.", "\n\nIf there is a possibility that at times, you must use only period characters to separate these items, but at other times, you can use other characters, omitting the article lets the statement apply to the widest amount of cases.", "\n\n" ]

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[ "At least 80 dead in 6 states in thunderstorms, lightning on Sunday; more storms likely\n\nindia\n\nUpdated: May 14, 2018 22:27 IST\n\nAs many as 80 people have been killed in five states due to thunderstorms and lightning strikes since Sunday, with Uttar Pradesh alone recording 51 deaths, the Home Ministry said on Monday.", "\n\nUP officials said the toll in Uttar Pradesh later went up to 54. ", "Officials in Bihar too confirmed six deaths due to lightning in the wee hours of Monday.", "\n\nBihar’s disaster management department confirmed two deaths in Saran district and one each in Patna, Darbhanga, Khagaria and Rohtas. ", "Chief minister Nitish Kumar asked the disaster management department to provide ex gratia to the kin of the deceased.", "\n\nFourteen people died in West Bengal, 12 in Andhra Pradesh, two in Delhi and one in Uttarakhand, a ministry spokesperson said. ", "Of the 136 people injured in lightning strikes and thunderstorms, 123 were from Uttar Pradesh, 11 from Delhi and two from Uttarakhand.", "\n\nLightning strikes and thunderstorms hit 24 districts in Uttar Pradesh, six in West Bengal, three in Andhra Pradesh, two in Delhi and one in Uttarakhand, the spokesperson said. ", "Dust storms and thunderstorms wreaked havoc in Delhi and parts of Uttar Pradesh, West Bengal, Andhra Pradesh on Sunday, leaving behind a trail of destruction.", "\n\nHigh-velocity winds uprooted trees and affected road, rail and air services last evening at a number of places in north India, including the national capital. ", "Thunderstorms also occurred at isolated places in Himachal Pradesh, Uttarakhand, Punjab, Haryana, Chandigarh, Madhya Pradesh, Jharkhand, Assam, Meghalaya, Maharashtara, Karnataka, Kerala and Tamil Nadu, the India Meteorological Department (IMD) had said yesterday.", "\n\nThe India Meteorological Department said in its latest forecast the western disturbance that is bringing moisture from Eurasian water bodies and north and northwest India, including the hilly states of Jammu and Kashmir, Himachal and Uttarakhand, and in the plains of Punjab, Haryana and Uttar Pradesh, will continue to affect the weather in this region on Tuesday.", "\n\nSome parts of the hilly northern states can expect hail and isolated areas of Rajasthan could witness dust storms on Monday and Tuesday.", "\n\nResidents of Rajasthan and Uttar Pradesh can expect relief from strong, widespread thunderstorms by Wednesday but weaker thunderstorms, scattered rain and gusty winds may occur in some areas for the rest of the week.", "\n\nIn the south, Telangana, Rayalaseema, interior areas of south Karnataka and Tamil Nadu and Puducherry are likely to see thunderstorm activity on Monday. ", "On Tuesday the thunderstorm activity will be restricted to Odisha and south interior Karnataka.", "\n\nPrime Minister Narendra Modi said on Twitter that he had asked authorities to provide “all possible assistance” to the needy.", "\n\nTrail of destruction\n\nStorms are common at this time of the year, the beginning of the rainy season in South Asia, but the severity of the weather this year, and the human cost, have been unusual.", "\n\nA spokesperson of the Union home ministry said 42 were killed in Uttar Pradesh, 14 in West Bengal, 12 in Andhra Pradesh, two in Delhi and one in Uttarakhand. ", "The spokesperson added 83 people were injured in Uttar Pradesh, 11 in Delhi and two in Uttarakhand.", "\n\nTwenty-four districts in Uttar Pradesh, six in West Bengal, three in Andhra Pradesh, two in Delhi and one in Uttarakhand were hit by the lightning and thunderstorms, the spokesperson added.", "\n\nPrabhat Mohapatra, deputy special relief commissioner, told Reuters four people were killed in Odisha.", "\n\nDust storms and thunderstorms accompanied with high-velocity winds wreaked havoc on Sunday evening as they uprooted trees, knocked down power poles, grounded flights and disrupted trains across New Delhi and parts of Uttar Pradesh, West Bengal, Andhra Pradesh.", "\n\nThunderstorms also occurred at isolated places in Himachal Pradesh, Uttarakhand, Punjab, Haryana, Chandigarh, Madhya Pradesh, Jharkhand, Assam, Meghalaya, Maharashtara, Karnataka, Kerala and Tamil Nadu, the met department said on Sunday.", "\n\nThe devastation comes over 12 days after storms hit Uttar Pradesh, Rajasthan, Telangana, Uttarakhand and Punjab, killing 134 people and injuring over 400. ", "Uttar Pradesh was the worst affected accounting for 80 deaths, most of them in Agra district in the western part of the state.", "\n\nOn May 9, several parts of Uttar Pradesh were struck by a severe storm that left 18 dead and 27 others injured.", "\n\n(With agency inputs)" ]

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[ "Decomposition of water-soluble mononitrosyl iron complexes with dithiocarbamates and of dinitrosyl iron complexes with thiol ligands in animal organisms.", "\nEPR studies have shown that water-soluble mononitrosyl iron complexes with N-methyl-d-glucamine dithiocarbamate (MNIC-MGD) (3 micromol) injected to intact mice were decomposed virtually completely within 1h. ", "The total content of MNIC-MGD in animal urine did not exceed 30 nmol/ml. ", "In the liver, a small amount of MNIC-MGD were converted into dinitrosyl iron complexes (30 nmol/g of liver tissue). ", "The same was observed in intact rabbits in which MNIC-MGD formation was induced by endogenous or exogenous NO binding to NO traps, viz., ", "iron complexes with MGD. ", "In mice, the content of MNIC-MGD in urine samples did not change after bacterial lipopolysaccharide-induced expression of iNOS. ", "It was supposed that MNIC-MGD decomposition in intact animals was largely due to the release of NO from the complexes and its further transfer to other specific acceptors. ", "In mice with iNOS expression, the main contribution to MNIC-MGD decomposition was made by superoxide ions whose destructive effect is mediated by an oxidative mechanism. ", "This effect could fully compensate the augmented synthesis of MNIC-MGD involving endogenous NO whose production was supported by iNOS. ", "Water-soluble dinitrosyl iron complexes (DNIC) with various thiol-containing ligands and thiosulfate injected to intact mice were also decomposed; however, in this case the effect was less pronounced than in the case of MNIC-MGD. ", "It was concluded that DNIC decomposition was largely due to the oxidative effect of superoxide ions on these complexes." ]

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[ "Philadelphia, PA: Those suffering from chronic pain report significant improvements in health following the passage of medical cannabis access laws, according to data published in the journal Forum for Health Economics & Policy.", "\n\nResearchers affiliated with the University of Pennsylvania and the Perelman School of Medicine assessed the impact of medical cannabis legalization laws on self-reported health outcomes.", "\n\nInvestigators reported that pain patients were the group most likely to report health benefits following medical cannabis enactment. ", "They determined: “A MML (medical marijuana law) and protected dispensaries positively affected the health of individuals suffering from chronic pain by reducing the days not in good physical health, days not in good mental health, and days with health-related limitations. … [", "T]hese effects translate into reduction in the number of days with health-related issues between 14 percent and 23 percent.”", "\n\nThey concluded: “Individuals who report having pain that limits their daily activity see large health improvements. ", "This is the strongest evidence that a group with a high probability of pain medication use sees large benefits from medical marijuana laws.”", "\n\nSeparate studies – such as those here, here, and here – consistently report that pain patients reduce their use of opioids following access to medical cannabis therapy. ", "Among state-licensed medical cannabis registrants, two out of three report consuming cannabis to mitigate pain conditions.", "\n\nFull text of the study, “The impact of medical marijuana laws and dispensaries on self-reported health,” appears in Forum for Health Economics & Policy.", "\n\nShare this: Twitter\n\nFacebook\n\n" ]

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[ "Melioidosis is a tropical infection caused by inhalation, ingestion, or inoculation of the Gram-negative soil saprophyte and Tier 1 select agent Burkholderia pseudomallei. ", "Although increasingly recognized throughout the tropics, melioidosis is hyperendemic in northeast Thailand, where it is tied as the second leading infectious cause of death. ", "Even with appropriate antibiotic treatment, 40% of patients die, many from severe sepsis. ", "Of survivors, about 10% relapse, most in the first year. ", "As for other causes of sepsis, no successful immunomodulatory therapies exist. ", "Melioidosis is therefore a major public health threat in Thailand for which new therapies are urgently needed. ", "We have implemented a highly successful Thai-US collaboration to elucidate mechanisms of host defense in human melioidosis for nearly eight years. ", "Our whole exome sequencing studies of bacteremic patients have identified candidate genes and inflammatory pathways that may determine outcome in melioidosis. ", "Our collaborators on this proposal, Dr. Chaussabel and Dr. Lertmongkolchai, have analyzed the blood transcriptome to create signatures that distinguish melioidosis from other causes of sepsis and identify biological pathway activation that is unique to melioidosis. ", "While the human inflammatory response in melioidosis remains poorly understood, our preliminary results spotlight the promise of the application of advanced technologies to melioidosis. ", "We propose a Melioidosis ICIDR that intensifies existing international scientific relationships by applying state-of-the-art technologies to comprehensively elucidate the immunologic and inflammatory mechanisms underlying the pathogenesis of melioidosis and poor response to therapies. ", "We will augment our whole exome sequencing analyses with whole transcriptome RNA sequencing and high-throughput single cell polychromatic flow cytometry for sophisticated immunophenotyping of melioidosis patients. ", "Designed around a prospective, multi-center longitudinal cohort study of melioidosis with detailed clinical and biological phenotyping, and expert-supported in-country analysis of all resulting data, the proposal will directly enhance Thai melioidosis research capacity. ", "Our aims are to 1) identify host inflammatory changes in acute melioidosis that elucidate pathogenesis and predict death, 2) identify immunological mechanisms that permit relapse, and 3) validate newly identified genetic determinants of survival in melioidosis. ", "Beyond the scientific aims addressed in this application, the proposal establishes a unique and durable melioidosis research platform headquartered in the optimal location for clinical melioidosis research, with tremendous potential to impact the public health o Thais and global citizens alike." ]

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[ "Green labeo\n\nThe green labeo or mountain labeo (Labeo fisheri) is a species of freshwater fish in the family Cyprinidae. ", "It is found only in Sri Lanka, where it occurs in some of the streams in the basin of the Mahaweli River.", "\n\nDescription\nMaximum size 362 mm SL. ", "Caudal peduncle short. ", "Dorsoventral eyes are medium-sized. ", "Rostral fold well developed and overlapping upper lip. ", "Only maxillary. ", " barbels present. ", "Dorsal fin consist with 10–12 branched rays. ", "There are 37–39 scales on lateral line. ", "Adults with olive green body whitish venter. ", "All fins much darker than juveniles and with a reddish-orange tinge. ", "There is a black blotch at caudal peduncle, which is disappear in some specimen. ", "Juveniles and young adults with yellowish brown body and white venter. ", "Black blotch at caudal peduncle as in adults.", "\n\nEcology and Habitat\nIts habitat is clear, rocky, fast flowing mountain streams which are shaded by trees. ", "It feeds on algae on the substrate and is a fast swimming species. ", "It is threatened by the damming of streams for hydro-electric and irrigation schemes, as well as the deforestation of the rainforests it is found in, and the resulting siltation and increased turbidity of the streams. ", "It may already be extinct.", "\n\nReferences\n\nfisheri\nCategory:Cyprinid fish of Asia\nCategory:Freshwater fish of Sri Lanka\nCategory:Fish described in 1917\nCategory:Taxonomy articles created by Polbot" ]

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[ "Fuck the cheerleader game - Horny Cheerleader\n\nIf that happens, choose a different part of my body. ", "There are 6 different parts of my body to play with for fhck of the three levels. ", "Fuck the cheerleader game 2…Played the same as level 1.", "\n\nLevel 3…Is played the same way, but with one exception. ", "You must first choose one of the three objects on the bottom right of the screen. ", "Which one to use on which body part?", "\n\nCheerLeader Fuck - fuck horny Lena cheer chick in this sex game\n\nSauna Fuck Two hot girls are sweating at delicious hentai sauna, all naked and horny. ", "The girls invite y. Fuck Samus Aran When she is not doing her intergalactic missions she is finding incest men to st. ", "First Date Fuck This lucky guy got to fuck Kylie, so he thinks. ", "He calls her the next morning cheerlrader.", "\n\nVirtual Dildo Fuck She has her hands down south holding her pussy lips. ", "Spread her tight vagina wal. ", "Strip and Fuck Have the hot blonde girl slowly take her clothes off.", "\n\nThen fuck her with a spike. ", "The games are always free for you to play and we also have others adult games, porn games and more!" ]

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[ "Update 11/19/18: Given the concerns raised by our community, we decided not to move forward with any version of this challenge for now.", "\n\nUpdate — We’re pressing pause on the challenge and hope to relaunch in the next couple of weeks. ", "Read more here.", "\n\nToday we’re announcing our first Figma API Challenge — with $15K in prizes for the winners — to incentivize our community to create the best possible Figma to Sketch converter.", "\n\nThat’s right — we want to make it easier for everyone to export their design files straight to our competitor…not harder. ", "It may sound crazy, but Figma is committed to building an open design platform. ", "With this Challenge, we’re putting our money where our mouth is.", "\n\nDesigners work in many different ways — with an array of stakeholders and clients — and shouldn’t have to worry about switching between tools on projects. ", "We’ve had Sketch import available since we launched, so this is a natural evolution of Figma’s design ecosystem.", "\n\nSketch export is the first Figma API Challenge, where we invite designers and developers to experiment with Figma’s functionality. ", "After seeing the amazing things people made with our read API, we wanted to start rewarding people for open-sourcing what they create with the broader community 💪. ", "Stay tuned for future Challenges.", "\n\nEach submission to the challenge will be evaluated on both objective and subjective criteria. ", "Judges will look at how well exporters transfer two files of Figma objects into Sketch:\n\n1st file = basic level objects 2nd file = type, components, styles, and prototypes\n\nAlthough we expect the former to be easier to import — there’s a clear “right” and “wrong” way to do it — the latter file may be trickier. ", "Each of the objects in the second file don’t necessarily have a 1:1 relationship between Figma and Sketch, so the exporters will be judged subjectively. ", "How easy is the exporter to use? ", "How creative is its approach to porting the design over?", "\n\nThe judges will weight these different factors in their review and provide a total score. ", "For example, 5% of each submission’s score will be based on the quality of its code and GitHub documentation. ", "To see the full-breakdown of score weighting and judging criteria, go to the Figma API Challenge rules here.", "\n\nThe first place winner will receive $10K as a token of our appreciation, and the 2nd place winner will receive $5K.\n\nYou can work in teams of up to 3 to build the integration, and the contest is open to anyone over the age of 21 in most countries (see exceptions here). ", "Projects should be submitted via this Google form with a link to a GitHub repository containing a readme file and the MIT License.", "\n\nTo select the winners of this Challenge, we looked for judges who have both a strong design background and a history of building plugins, tools and resources for the community. ", "Here’s the roster:\n\nEmily is a Design Systems Engineer at GitHub where she works on Primer and is building out a React based component library. ", "She enjoys creating tools for designers and engineers, designing APIs and keeping up with all the new fancy things in the JavaScript world.", "\n\nRaph is an interaction designer at Google, formerly of Timeful, Jawbone and Massive Health. ", "With a background in behavior science, he is obsessed with system thinking and using design to nudge, cajole and create the architecture for people to succeed.", "\n\nCat is no stranger to helping designers build better experiences for the world. ", "With a focus on design accessibility, she’s the founder of Stark, a color-blind simulator and contrast checker, and Lyra, a symbol-to-speech app for autistic children. ", "Read more about her passion for design accessibility here.", "\n\nRoy is a Berlin-based designer who works at design agency IXDS. ", "He keeps himself busy with side projects like Sketch Runner and organizes events like the upcoming Design Tools Hackathon 2018 in Tel Aviv.", "\n\nThe Challenge will run from October 2nd, 2018 to November 16th, 2018 at 11:59pm (PST). ", "We can’t wait to see what our community comes up with. ", "DM me (I’m Figma’s online community manager) on Twitter if you have any additional questions!" ]

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[ "Q:\n\nwhat is the correct way to define a non-alphanumeric char in c++?", "\n\nSometimes I need to define a char which represents a non-alphanumeric char.", "\nWhat is the correct way to define its value in C++?", "\nIs using EOF or char_traits<char>::eof() a good choice?", "\n\nA:\n\nYou're reading too much in to the word char.", "\nAt the end of the day, it is little more than a size. ", " In this case, 8 bits. ", " Shorts are 16 (and you can wear them on the beach), ints can be 32 or something else, and longs can be 64 (or ints, or a quick conversation with the relevant authorities on the beach as to why you lost both pairs of shorts).", "\nThe correct way to define a value in C++ is basically down to what the maximum value that can be held. ", " char_traits::eof() is indeed a good constant, but out of context - means very little. ", " \n\n" ]

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[ "Q:\n\nfiltering list items based on user's search terms in javascript\n\nI am filtering (showing and hiding) a set of list items based on user's input. ", "check it out here: http://jsfiddle.net/m5dzG/2/ \nQuestion:\nTry inputing the word \"comparison\" you will see that the list hides except the ones that has the word \"comparison\" in them. ", "good so far... but if you hit space and add more terms like the word \"extrapolated\" that is exist in that string it will find list items that have either of those words. ", "What I want is AND not OR. ", "basically I want to show the list item that has both those words in it. ", "Because as you can imagine by putting more terms the list gets bigger not smaller.", "\nI think the problem is in my regular expression in this line \nvar search_text = jQuery('#search').val();\nvar rg= new RegExp('('+$.unique(search_text.split(\" \")).join(\"|\")+')',\"i\");\n\nany help would be appreciated.", "\nThanks\n\nA:\n\nTry this. ", " It should make a string like this: ^(?=.*?honda)(?=.*?accord). ", " This way, the string must have each of the terms somewhere in the string.", "\nvar search_text = jQuery('#search').val();\nvar rg= new RegExp('^(?=.*?'+$.unique(search_text.split(\" \")).join(\")(?=.*?\")+')',\"i\");\n\n" ]

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[ "Q:\n\nImplementation of Analog Matched Filter\n\nI have been reading about communication theory and I was wondering if matched filters can be implemented with analog parts and what they would look like?", "\nIf they can't be it seems like the matched filter construct is of only theoretical interest without any practical implementations. ", "\n\nA:\n\nAnalog matched filters are widely used in special cases where they have been in practice possible to construct. ", "Examples:\n\ndispersive delay line in chirp pulse compression radar; an acoustic surface wave filter\nintegrator to detect rectanqular DC pulses (actually a pulse lenght delay line and a subtractor are also needed if we haven't a clock which keep the integrator reset when no pulses are expected to arrive)\n\nFor arbitary complex pulses analog matched filters are impractical because the needed tolerances are not manageable.", "\nNOT ASKED, but maybe useful: Detection with correlator is mathematically equivalent with using a matched filter. ", "For example greenbacks were in first gasoline automates recognized this way in analog domain. ", "A candidate slided over a half transparent greenback image. ", "If there occurred a sudden peak in the total light penetration, the candidate at least had right greenback patterns.", "\nADD due a comment:\nThe questioner asked a link to an existing implementation. ", "Unfortunately I have no such weblink. ", "But I can include one version which should be plausible altough hopelessly impractical when compared the equivalent processing in digital domain.", "\nHere's a matched filter for 1 second long rectangular DC pulses. ", "The impulse response of such filter should be also one second long rectangular DC pulse.", "\nThat impulse response is possible to generate with an integrator. ", "The length 1s is achieved by subtracting the same input delayed by 1 second. ", "Subtraction and integration are possible to realize with a differential amplifier and integrator which are made of opamps. ", "In the next image they are built both with one opamp:\n\nIf the integration time constant is 1s (for ex. ", "R=100kOhm, C=10uF), one volt DC pulse would generate 1 volt high triangle pulse to the output.", "\nTo prevent integrator to drift to saturation there are discharging resistors Rd, drawn with dashed line. ", "Having R=100kOhm, I would try Rd = 500kOhm...1MOhm. ", "Discharging time constant 5...10s should not spoil the filtering of 1s pulses and surely wins at least the drift caused by non-idealities of modern high performance opamps.", "\n1 second linear delay is problematic. ", "If one accepts quite low system bandwidth - say 5kHz - a looped tape recorder can be used. ", "It unfortunately doesn't record DC, but the signal can be shifted upper with mixing:\n\nWhen the signal has been stored 1s, it's taken out and mixed back to 0Hz. ", "The written mixing method is AM, which is inefficient due the generated lower sideband + carrier. ", "But it's simple technically and the needed carrier frequency (more than 10kHz, say 12kHz) + both sidebands are still well recordable and possible to get separated (=filtered) from the leaked input signal at the output of the modulator.", "\nThe lowpass filter at the input of the whole system kills those signals which are out of the 5kHz bandwidth.", "\n\n" ]

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[ "Hungry elephant overturns vehicle in search of food\n\nHungry elephant overturns vehicle in search of food\n\nCOLOMBO: A tourist in Sri Lanka captured a terrific moment when an elephant tipped over a three-wheeler vehicle after being fed by an onlooker.", "\n\nThe video, filmed Sept. 14, shows the elephant approach the tuk tuk vehicle on a road between Arugam Bay and Yala.", "\n\nA man gets out of the tuk tuk and hand-feeds the elephant, which accepts the offering before swatting at the man with its trunk and overturning the vehicle.", "\n\nThe filmer explained the passenger, an Irish tourist, had been instructed by the driver to throw the food in a bid to get the elephant to clear the street, but he misunderstood and hand-fed the wild animal instead.", "\n\n“The elephant turned over the tuk tuk and took out all his bags searching for food. ", "Must be the luck of the Irish that he wasn’t injured,” the filmer wrote." ]

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[ "South Tyrone Hospital\n\nThe South Tyrone Hospital () is a local hospital in Dungannon, County Tyrone, Norther Ireland. ", "It is managed by the Southern Health and Social Care Trust.", "\n\nHistory\nThe hospital has its origins in the Dungannon Union Workhouse and Infirmary which was designed by George Wilkinson and opened in 1842. ", "A fever hospital was added in 1846. ", "The infirmary evolved to become South Tyrone Hospital and a red brick tower block was erected on the site in the 1960s.", "\n\nReferences\n\nCategory:Southern Health and Social Care Trust\nCategory:Health and Social Care in Northern Ireland hospitals\nCategory:Hospitals in County Tyrone" ]

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[ "\n\n## Dedication\n\nTO MY FATHER, RICK OLSEN, AND HIS BROTHER KENNY\n\n## Contents\n\n 1. ", "Dedication\n 2. ", "Introduction\n 3. _", "Meet Lazarus: The First Man in Medical History to Survive Lou Gehrig's Disease_\n 4. ", "CHAPTER 1\n 5. ", "Sophie's Choice\n 6. _", "How the FDA Let a Mother Save One Son . . . ", "and Left Her Other Son to Die_\n 7. ", "CHAPTER 2\n 8. ", "Five Thousand Miles for a Cure\n 9. _", "How One American Family Moved Overseas to Save Their Dying Son_\n 10. ", "CHAPTER 3\n 11. ", "What Steve Jobs Saw\n 12. _", "How the FDA Stops American Doctors from Using a Proven Cancer Treatment_\n 13. ", "CHAPTER 4\n 14. ", "Making Medical Miracles\n 15. _", "The Cutting-Edge Cancer Killers You Can't Get Yet_\n 16. ", "CHAPTER 5\n 17. ", "Inside Man\n 18. _", "How One Biotech CEO Came to Champion Right to Try_\n 19. ", "CHAPTER 6\n 20. ", "We Are the 99 Percent\n 21. _", "How Right to Try Has Taken America by Storm_\n 22. ", "CHAPTER 7\n 23. ", "Compassionate Use\n 24. _", "The Mythical Unicorn_\n 25. ", "CHAPTER 8\n 26. ", "Would You Use a Fifteen-Year-Old Cell Phone?", "\n 27. _", "How to Get American Medicine Back on Top_\n 28. ", "CHAPTER 9\n 29. ", "If You Have the Right to Die, You Should Have the Right to Try\n 30. ", "CHAPTER 10\n 31. ", "Where Do I Start?", "\n 32. _", "A Step-by-Step Guide to Seeking an Investigational Treatment_\n 33. ", "Afterword\n 34. _", "Everyone Deserves the Right to Try: An Update on Jenn McNary, Ted Harada, and Diego Morris_\n 35. _", "Acknowledgments_\n 36. _", "Notes_\n 37. _", "Index_\n 38. _", "Photographs_\n 39. ", "About the Author\n 40. ", "Credits\n 41. ", "Copyright\n 42. ", "About the Publisher\n\n# Guide\n\n 1. ", "Cover\n 2. ", "Contents\n 3. ", "Chapter 1\n\n## Introduction\n\n_Meet Lazarus: The First Man in Medical History to Survive Lou Gehrig's Disease_\n\n_\"Marco!\"_", "\n\n_\"Polo!\"_", "\n\nTed Harada dived under the glistening water of his backyard pool and swam toward the giggling voices of his three children, who scattered to escape their father's grasp.", "\n\nBut as soon as he was underwater, Ted felt his lungs tighten. ", "A sudden drowning sensation overcame him. ", "When he broke through the surface, he was gasping for air.", "\n\nHe looked back. ", "He had swum only a few feet. ", "What on earth was going on? ", "He had played this game with his kids hundreds of times. ", "Why was he having trouble breathing?", "\n\nHis wife, Michelle, called out, \"Ted, are you all right?\"", "\n\n\"Yeah, I'm fine,\" Ted told her.", "\n\nBut Ted was not fine. ", "It was late summer of 2009 and Ted had felt himself getting fatigued more easily of late. ", "Despite the fact that he was biking and exercising regularly, he found he was increasingly out of breath. ", "But nothing like this. ", "This was different.", "\n\nHe got out of the pool, dried off, and tried to put the incident out of his mind.", "\n\nA few months later, Ted went on a fall hike with a group of friends in the north Georgia mountains. ", "It was just a mile-long journey and not a particularly steep incline. ", "Ted had done hikes like this dozens of times before.", "\n\nBut after a few minutes, his left leg started shaking uncontrollably.", "\n\nHe stopped.", "\n\nHis friends came back and needled him.", "\n\n\"Come on, Ted, suck it up,\" they said.", "\n\n\"No, guys, I can't go any farther,\" he told them, bent over trying to calm his leg and catch his breath.", "\n\nThey became concerned.", "\n\n\"Ted, are you okay?\" ", "they asked.", "\n\n\"Honestly, I don't know.\"", "\n\nHis leg felt like rubber. ", "He had not told anyone about the incident at the pool.", "\n\n\"I guess it's just not my day,\" Ted finally told them. \"", "You guys go ahead.\"", "\n\nThey figured he was coming down with something and helped him back to the car. ", "Ted insisted they finish the climb and so they left him there.", "\n\nAlone in the car, he felt frustrated, scared, and lost.", "\n\n\"What's happening to me?\" ", "he thought.", "\n\nWhen he got home, he told Michelle what had happened. \"", "Ted, you need to go to a doctor and get checked out,\" she said. ", "He promised that he would. ", "But, like most people, he put it off. ", "Weeks went by, and Michelle kept reminding him. ", "So finally he gave in and made an appointment to see a doctor at his local family practice.", "\n\nAfter examining him, the doctor said Ted probably had asthma and prescribed an inhaler. ", "He used it for a month or so, but it had no effect.", "\n\nAs fall turned into winter, his bouts of breathlessness grew worse. ", "One day, while walking the dog, Ted noticed that he was walking with a limp. ", "His left leg was not keeping up with his right. ", "So he went to an orthopedist he had known for several years, Dr. Vincent Smith, to check out his left leg.", "\n\nDr. Smith confirmed the weakness in the leg, and took X-rays and an MRI. ", "They came back all clear.", "\n\n\"You might have a pinched nerve in your back,\" Dr. Smith told Ted. \"", "Let's get you to a neurosurgeon.\"", "\n\nWhen the neurosurgeon examined Ted, she found that he had weakness not only in his left leg, but also in his left arm and left hand. ", "She told Ted to come to the hospital the next day for an MRI of his brain and spinal cord.", "\n\n\"Maybe I'll need surgery,\" Ted thought.", "\n\nWhen he arrived, the neurosurgeon also conducted an MRA—a magnetic resonance angiogram—checking the blood vessels in Ted's brain to see if he's had a stroke. ", "But all the tests came back clear. ", "Nothing explained Ted's symptoms.", "\n\nThe neurosurgeon handed Ted a disk with all his test data on it and told him, \"Ted, there's definitely something wrong, but there's nothing I can do. ", "You need to go see a neurologist.\"", "\n\nNow Ted was really starting to get desperate. ", "He called the orthopedist, Dr. Smith, and asked if he could come back and see him that day. ", "Sensing the panic in Ted's voice, Dr. Smith found an opening for Ted that afternoon.", "\n\nWhen he arrived at the doctor's office, Ted told him, \"You told me to go to a neurosurgeon and she says she can't see anything, and that I need to go see a neurologist. ", "What's going on?\" ", "Dr. Smith popped the disk into his computer and spent forty-five minutes going through all the images with Ted, showing him that everything was as it should be.", "\n\n\"I'm gonna be honest, Ted,\" Dr. Smith told him. \"", "Whatever is going on with you is not common. ", "You need to go up to Emory University and see someone who is used to treating zebras. ", "We only see horses here. ", "You need a zebra doctor.\"", "\n\n\"A zebra doctor?\" ", "Ted thought.", "\n\nDr. Smith gave Ted the number for Emory's Department of Neurology. ", "Ted got into his car and called Emory from right there in the parking lot. ", "It was March, but the nurse who answered the phone told him their next opening was not until August.", "\n\n\"I can't wait five months to find out what is wrong with me,\" Ted told her.", "\n\nShe suggested he contact Dr. David Williams at the Peachtree Neurological Clinic. ", "Williams had done a fellowship at Emory and was highly recommended. ", "Ted called and made an appointment.", "\n\nA few days later, Dr. Williams saw Ted. ", "He reviewed the MRIs and the tests the other doctors had performed. ", "He examined Ted, testing the strength of his legs, arms, and hands. ", "He told Ted to get dressed while he went to the other room to review the MRIs again.", "\n\nWhen he returned, Ted's frustration bubbled up to the surface.", "\n\n\"Doc, just lay it out for me,\" Ted pleaded. \"", "I've spent eight months getting bounced around from doctor to doctor, and every doctor says there's something wrong but they don't know what's wrong. ", "I don't think I'm crazy. ", "This isn't just in my head. ", "What's happening to me?\"", "\n\n\"No, it's not in your head,\" Dr. Williams told him. \"", "You potentially have a very serious problem. ", "I need to do some more tests. ", "I'd like you to come in Thursday and I want you to bring your wife with you.\"", "\n\nBring his wife? ", "Ted had never had a doctor tell him to bring his wife to an appointment before.", "\n\n\"Why do I need to bring my wife with me?\" ", "Ted asked. \"", "Please, just tell me what you think is going on.\"", "\n\nDr. Williams told Ted that he could be suffering from motor neuron disease—a disorder that affects the cells that control muscle movement. ", "He needed to do another test to be sure.", "\n\nWhen Ted returned with Michelle on Thursday, Dr. Williams administered an EMG, or electromyogram—a test in which the doctor sticks needles into the muscles and measures the nerve waves from the spinal cord to the muscles. ", "When the results came back, they confirmed Ted's worst fears. ", "Dr. Williams found abnormalities in Ted's foot, left calf, left thigh, and left hand.", "\n\n\"I'm sorry\" Dr. Williams told him, \"but I am 80 to 90 percent sure you have ALS—Lou Gehrig's disease. ", "It's a fatal disease.\"", "\n\n\"How long have I got?\" ", "Ted asked him.", "\n\n\"I'm not looking to scare you,\" Dr. Williams told him. \"", "Some people live two to five years. ", "Others are slow progressors, and live eight to ten years.\" ", "He wrote Ted a prescription for a medication called Rilutek.", "\n\n\"It's the only approved drug to treat ALS,\" Dr. Williams told him. \"", "They've shown it can extend your life two to four months on average.\"", "\n\nTed's heart sank. ", "Two to four months? ", "That's it?", "\n\nDr. Williams told Ted that he should never accept a terminal diagnosis like this without getting a second opinion and gave him several choices. ", "He could get Ted into Emory University's ALS center, where he had done a fellowship under its director, Dr. Jonathan Glass. ", "He mentioned in passing that Emory was doing some interesting clinical trials, including a stem-cell trial. ", "But he also said that Ted should not feel pressured to go to Emory—he could also get him into the Mayo Clinic in Jacksonville or into some other ALS centers.", "\n\nTed decided on Emory.", "\n\nIt would prove to be a fateful choice.", "\n\nA few weeks later, Ted found himself sitting on an examining table at the Emory University ALS clinic. ", "Emory is a teaching hospital, so when Dr. Glass walked in he was with a group of medical students. ", "They began examining Ted.", "\n\n\"I'm in an episode of _House_ ,\" Ted thought.", "\n\nAfter the exam was over, Dr. Glass asked, \"So what did Dr. Williams tell you?\"", "\n\n\"He said he was pretty sure I had ALS,\" Ted replied.", "\n\nDr. Glass's demeanor changed. ", "He put his hand on Ted's knee.", "\n\n\"I'm sorry to tell you this, but you do have ALS. ", "You need to know that there's nothing you did to get it and nothing you could have done to avoid getting it. ", "And I have to apologize too, because my career has been devoted to finding a cure, but right now I don't have a cure for you. ", "It's 100 percent fatal.\"", "\n\nHe told Ted that 80 percent of people with ALS die within five years of diagnosis.", "\n\nUp until that moment, Ted had been holding on to hope. ", "But now his world shattered. ", "Here he was in the doctor's office and, instead of discussing treatment options, Dr. Glass was explaining that he needed a will and to get his affairs in order.", "\n\nTed had received a death sentence.", "\n\nFollowing his diagnosis, Ted went home. ", "One of his friends lent him and Michelle his weekend home in the mountains so they could get away and be alone together. ", "Sitting on the front porch, they finally broke down. ", "Ted told her he was sorry—for letting her down and letting their kids down. ", "Nonsense, she told him, her eyes welling with tears, he had nothing to be sorry about. ", "He and Michelle cried in each other's arms, as all the bottled-up emotions finally came pouring out.", "\n\nIt was one of the hardest nights of Ted's life.", "\n\n\"But the next day, the sun rose,\" Ted says, \"and so did I.\"\n\nOver breakfast, he told Michelle he loved her and that the night before had been cathartic. \"", "We needed that,\" he said, \"But I don't want to do that every day. ", "Look, this disease is going to take me. ", "But right now, I'm still alive. ", "I don't want to be mourned while I'm alive.\"", "\n\nTed also decided that he was not going down without a fight. ", "He began to study ALS. ", "What he found was not encouraging. ", "ALS is a cruel disease. ", "It causes the motor neurons inside your spinal cord to selectively die. ", "A motor neuron sends wires out to the muscles with signals instructing them to move. ", "When the motor neurons die, the wires that go out to the muscles degenerate or die. ", "When the wires die, the signals stop. ", "When the signals stop, the muscles begin to atrophy and die. ", "And when the muscles that control swallowing and breathing die, you die.", "\n\nThe one part of the body not affected in most cases is cognition—which means that patients are aware of everything that is happening to them every step of the way.", "\n\nIt is a horrific way to go.", "\n\nTed's condition began to rapidly deteriorate. ", "A man who loved to wrestle on the floor with his children now could barely make it up the stairs to kiss them good night. ", "He could walk only short distances with the help of a cane. ", "Simple tasks, like getting the mail, became unbearable chores.", "\n\nAs his symptoms grew worse, Ted had to quit his job as the district manager at a shredding company.", "\n\nEventually, his hands became so weak that he could not even open a Ziploc bag.", "\n\nTed Harada was dying.", "\n\nON OCTOBER 20, 2012, two years after his diagnosis, Ted bent over and tied the laces on his running shoes. ", "He stood up, without the help of a cane, and walked confidently to the starting line to begin Atlanta's two-and-a-half mile \"Walk to Defeat ALS.\"", "\n\nHe completed the full course without any difficulty whatsoever. ", "His left leg kept pace with his right. ", "He had no shortness of breath.", "\n\nNot only was Ted walking again; he was back in the family pool playing Marco Polo with his kids. ", "At night, he bounded up the stairs to tuck them into bed. ", "He was biking, hiking, and walking the dog just like he used to. ", "His lungs felt strong and his grip had returned.", "\n\nHe could go most days without thinking he had ALS.", "\n\nHis transformation was nothing short of miraculous. ", "No one in recorded history had ever gotten better after a diagnosis of ALS.", "\n\n_No one_.", "\n\nBut Ted Harada was getting better.", "\n\nLike Lazarus of the Bible, who rose from the dead, Ted had experienced a modern-day resurrection.", "\n\nWhen Dr. Williams and Dr. Glass first diagnosed Ted, they were clear that there was no cure for ALS. ", "But that was not good enough for Ted. ", "If he was going to die, so be it—but he was going to fight this disease until it stole his very last breath.", "\n\nAs he began to research emerging treatments, he found that his doctors were right. ", "Every drug being tried was failing. ", "Nothing slowed the advance of the disease. ", "And certainly nothing reversed it.", "\n\nThat was about to change.", "\n\nNo one can call an ALS diagnosis a blessing, but Ted Harada was blessed to have been diagnosed at the right place, at the right time, by the right doctors. ", "Ted lived near Atlanta, which just happens to be home to one of the nation's leading centers for ALS research. ", "And his diagnosis came just as an Emory-led team of medical researchers was about to shock the world with perhaps the biggest breakthrough ever in the treatment of ALS.", "\n\nSurgeons at Emory were getting ready to try an unprecedented new procedure in which they would inject stem cells into the diseased areas of the spinal cord, where the pools of motor neurons affected by ALS are located. ", "The hope was that the inserted cells would repair and replace the damaged and diseased cells and thus slow or stop or perhaps even reverse the degeneration of the motor neurons.", "\n\nThe surgery—which had been pioneered by Dr. Nick Boulis of Emory University and a Bethesda, Maryland, pharmaceutical firm called Neuralstem—was revolutionary. ", "Doctors were not simply injecting the cells into the spinal cavity or the spinal fluid. ", "They planned to open up the spinal cord itself and transplant the cells directly into the gray matter of the spinal cord—beyond the blood-brain barrier.", "\n\nIntraspinal surgery like this had never been tried before. ", "It was incredibly risky. ", "One mistake, even the slightest movement, could cause irreparable damage to the spinal nerves. ", "The patient could be instantly paralyzed, or worse.", "\n\nThe experimental surgery was being performed only at Emory, which happened to be just forty-five minutes from Ted Harada's home.", "\n\nWhen Ted learned about the surgery, he told Dr. Glass and his team, \"I want to do this trial.\" ", "It had been in the back of his head ever since Dr. Williams had mentioned it in passing the day he was first diagnosed.", "\n\nBut it turned out getting into the trial was not so easy. ", "The researchers at Emory told Ted that they were not recruiting for the trial at that moment. ", "Perhaps he might want to look at other options? \"", "No,\" Ted told them. ", "He wanted to wait to be in the stem-cell trial. ", "He asked them to tell him as soon as they began recruiting again.", "\n\nEvery week he emailed Crystal Kelly, one of the clinical research coordinators, reminding her that he wanted to be considered. ", "Every week the answer was the same: We're not recruiting yet.", "\n\nFinally, after a month of persistent nagging, they told Ted that they were recruiting again and he should come in for a screening to see if he qualified.", "\n\nThe day Ted arrived at Emory, there was a TV crew from Fox 5 news there to film another patient who was undergoing the experimental surgery that day.", "\n\nTed took it as a sign.", "\n\nWhen Ted was finally accepted into the trial, Dr. Glass and his team tried to temper his hopes. ", "They explained that the procedure was in phase I safety trials. ", "The objective was not to help Ted, but to show that the procedure itself would not kill him.", "\n\nTed told them he understood. ", "He had made peace with his diagnosis.", "\n\n\"If this is what the cutting edge is, then you need people to move the ball. ", "You need people to man the spaceships. ", "Let me be that person,\" he said.", "\n\nWhen he was accepted into the trial, his parents and his in-laws were elated. ", "It was the first sign of hope they had had since learning of his terminal diagnosis. ", "Ted had to explain to them that the surgery was only to help others.", "\n\nYes, they said, but it _could_ help you.", "\n\n\"No,\" he insisted, \"it can't. ", "They told me it's not going to help me.\"", "\n\nBut in the back of his mind, he held the smallest bit of hope. ", "He looked at it like buying a lottery ticket. \"", "You don't win when you buy a lottery ticket,\" Ted thought, \"but you know that saying 'You can't win if you don't buy a ticket'? ", "Well, this was my ticket.\"", "\n\nDr. Glass and his colleagues were blunt about the danger he faced. ", "The surgery had been tried only a few times before. ", "It could paralyze him. ", "It could kill him. ", "Ted signed a fifteen-page consent form acknowledging he understood all the risks. ", "Emory then videotaped him and Michelle, explaining to them on camera that this was a safety study that was designed not to benefit him, but for the benefit of future patients down the line.", "\n\nAt one point Ted turned to Dr. Glass and said, \"Look, I get it. ", "But I feel like I have a moral obligation for those people who come after me to do what I can.\"", "\n\nDr. Glass stopped him cold.", "\n\n\"You have no obligation to do this, Ted,\" he said.", "\n\n\"Look, I get the legalese,\" Ted told him. \"", "I am not suggesting that you are telling me I have an obligation. ", "I am telling you morally I feel like I have a duty to do this for my fellow man.\"", "\n\nIf he could not save himself, Ted figured, perhaps he could help save others.", "\n\nAnd who knows, he thought, miracles happen.", "\n\nThe day before his surgery, Ted went to Mass at his parish church, Saint James in McDonough, Georgia, to pray for that miracle. ", "He received the last rites of the church—communion, confession, and the anointing of the sick.", "\n\nTed's surgery took place on Ash Wednesday, the day in the Catholic calendar when the priest places ashes on the foreheads of the faithful and tells them, \"You are dust and to dust you shall return.\" ", "He arrived at the hospital at 6:00 a.m., and changed into his surgical gown.", "\n\nHe felt completely at peace.", "\n\nDr. Glass checked the stem cells, which had arrived by FedEx that morning. ", "At least 80 percent had to have survived for the surgery to go forward. ", "The results were good. ", "There were enough living cells to proceed.", "\n\nHe came into Ted's room.", "\n\n\"Are you ready?\" ", "he asked.", "\n\n\"Yeah, let's do it!' ", "Ted replied.", "\n\n\"Is he always this calm?\" ", "Dr. Glass asked Michelle.", "\n\nTed hugged his wife and said what could very well have been his last words to her: \"Hey, I'm in love with you. ", "I have always been in love with you. ", "You're my best friend.\"", "\n\nThe words seemed so final, so he quickly added: \"I'll see you in six hours.\"", "\n\nWith that, the nurses rolled Ted down the hallway to the surgical suite. ", "His neurosurgeon, Dr. Nick Boulis, carefully opened a two-centimeter section of Ted's lumbar region—the lower spinal cord—while Dr. Glass drew the stem cells into a flexible tube specially designed to insert them without damaging spinal nerves.", "\n\nThe first injection went exactly as planned. ", "They moved on to the second. ", "Then the third, until one million cells had been implanted in Ted's spinal cord. ", "Then they closed Ted up, sent him to recovery, and came out to tell Michelle the good news.", "\n\nThe surgery had gone exactly as planned.", "\n\nTwo weeks later, Ted was back at home recuperating, sitting in his favorite green recliner, when he noticed something. ", "Before the surgery, his left leg had a deadness, a heaviness to it. ", "But now, suddenly, the deadness, the heaviness, was missing.", "\n\n\"Maybe it's just because of the medication,\" he thought.", "\n\nSo he called Michelle over and asked her to push on his leg to see if he could break her strength.", "\n\nThis was not Michelle's favorite thing to do. ", "Before the surgery Ted would have Michelle test his strength at home so he could see how far the disease was progressing. ", "Each time, Ted's resistance had gotten weaker until, eventually, he could not resist even the slightest pressure from Michelle. ", "It broke her heart to watch his decline.", "\n\nMichelle sighed, and put her hand on his leg.", "\n\nTed lifted his leg with ease.", "\n\nThey looked at each other in disbelief.", "\n\n\"Maybe I didn't try hard enough,\" Michelle said.", "\n\nBefore the surgery, she never had to try at all. ", "She would put a few fingers on his leg and was able push it down without any effort at all.", "\n\n\"Press harder,\" Ted told her.", "\n\nShe did.", "\n\nHe lifted his leg.", "\n\n\"Use both hands this time,\" Ted said.", "\n\nShe pressed down hard with both hands.", "\n\nHe lifted his leg.", "\n\nThe debilitating weakness was gone.", "\n\nTears started streaming down Michelle's cheeks.", "\n\n\"That's not supposed to happen!\" ", "she said, sobbing.", "\n\nShe kept saying it over and over again. \"", "That's not supposed to happen . . . ", "That's not supposed to happen . . . ", "That's not supposed to happen.\"", "\n\n\"I know,\" Ted told her. \"", "But it did!\"", "\n\nNow they were both crying.", "\n\nTed had seen joy in Michelle's eyes before—the day they were married, the day each of their kids was born. ", "Now he saw that same joy in her eyes again.", "\n\nTed picked up the phone and called Emory. ", "He reached Crystal, one of the clinical research coordinators.", "\n\n\"Crystal, tell me the truth—is anyone getting better?\" ", "he asked.", "\n\n\"Not that we can measure,\" she told him.", "\n\n\"Well, I am getting better,\" Ted told her.", "\n\nCrystal told him that the surgery was a very intense procedure, and that often the more intense the procedure, the more intense the placebo effect is.", "\n\n\"Crystal, hear me out here. ", "You know me. ", "I'm not crazy. ", "I'm a pretty rational guy. ", "I know what a placebo effect is. ", "This is not placebo effect.\"", "\n\nShe laughed, and told him that he was scheduled for a follow-up next week and that they would test him then. \"", "In the meantime, whatever you are experiencing—just enjoy it while it lasts. ", "See you Monday!\"", "\n\n\"She thinks I'm crazy,\" Ted thought as he hung up the phone.", "\n\nTed went to bed that night worried that he would wake up the next day and whatever he was feeling would suddenly be gone. ", "So every morning, Ted had Michelle test him. ", "Not only was the feeling not gone but he kept getting stronger with each passing day.", "\n\nWhen he arrived at Emory for his postsurgical exam, the nurses told him that since he was so insistent that he was getting better, they would go ahead and do some tests that weren't scheduled to be done yet—just to see.", "\n\n\"Okay! ", "Good!\" ", "Ted said.", "\n\nHe smiled sportively at Michelle.", "\n\nThe first test they did was the hand dynamometer—to test his grip strength.", "\n\nTo Ted's chagrin, there was no change in his hand strength from before the surgery.", "\n\nThey checked his arms as well. ", "There was no change to his upper body at all.", "\n\nTed's heart sank a little. ", "He didn't have a hand dynamometer at home and he and Michelle had not tested his upper body. ", "For a moment, he began to doubt.", "\n\n\"Who am I kidding?\" ", "he thought. \"", "Michelle and I aren't doctors. ", "We probably did the tests wrong.\"", "\n\nThen they moved to his legs. ", "The nurse pressed down on his left leg and Ted broke her strength with ease.", "\n\nShe looked up at him in surprise.", "\n\n\"What the . . .\"", "\n\nShe called over the other nurse to try it—with the same result.", "\n\n\"They were looking on at me like 'What is going on?'\" ", "Ted recalls.", "\n\nHe started laughing. \"", "I told you!\"", "\n\nAt that moment, Dr. Glass walked in.", "\n\n\"How's the patient?\" ", "he asked.", "\n\n_\"Really_ good,\" the nurses said.", "\n\n\"Come on, doc. ", "You've gotta check it out. ", "It's real!\" ", "Ted told him.", "\n\nDr. Glass smiled and went over to test Ted's leg. ", "When Ted easily broke his strength, he stepped back and stared for a moment.", "\n\nHe tried again. ", "Same result.", "\n\nDr. Glass sat down in stunned disbelief. ", "He kept running fingers through his hair, bewilderment in his eyes, Ted recalls.", "\n\n\"Were you trying that all the time before the surgery?\" ", "he finally asked Ted, grasping for a logical explanation.", "\n\nTed assured him he was.", "\n\n\"Get me all the paperwork on Harada right now. ", "Everything we have on him,\" Dr. Glass told the nurses. ", "Dr. Glass looked over the paperwork, which showed the steep decline in Ted's strength prior to the surgery. ", "It checked out. ", "Ted really was regaining his strength.", "\n\n\"I don't know what to say, I'm speechless,\" Glass told him.", "\n\nAfter he recorded the results, showing Ted's miraculous turnaround, he held the chart in his hands for a moment.", "\n\n\"What do I do with this?\" ", "he asked.", "\n\nHe was holding the first medical documentation in history that showed a patient with ALS getting better.", "\n\nAfter pausing for a moment, he signed the paperwork.", "\n\nThen he looked at Ted.", "\n\n\"I need you to keep this to yourself right now. ", "Don't talk about this. ", "Don't tell anyone else.\"", "\n\nTed promised.", "\n\nBack at home, Ted continued to feel better with each passing day. ", "When he came back to Emory a few weeks later for his next appointment, they did all the strength tests again.", "\n\nBefore the surgery, Ted's hand strength had been steadily deteriorating every month. ", "The last test before the procedure showed, on a scale of zero to 100, that his left hand was in the mid-30s and his right hand was in the mid-50s. ", "Two weeks earlier, while doctors had found improvement in his legs, Ted's hands were exactly the same as before the surgery.", "\n\nThis time, when they gave Ted the hand dynamometer, he squeezed it and . . . ", "both his hands were at 100.", "\n\nThe advance of ALS in his hands had been completely reversed.", "\n\nThe results were so unprecedented that Dr. Glass decided to go back to the beginning, and reconfirm that Ted even had ALS. ", "In thirty years, Dr. Glass had never had a misdiagnosis. ", "But he wanted to make sure. ", "So he ran all the original diagnostic tests and every test came back the same way.", "\n\nTed had ALS.", "\n\n\"If you don't have ALS, then what you have has never been identified in the world,\" Dr. Glass told him.", "\n\nTed also went back to see Dr. Williams, his original neurologist at Peachtree.", "\n\n\"A little birdy told me you are feeling better, so let's check,\" Dr. Williams told him.", "\n\nHe conducted all the same tests that they had done at Emory—with the same miraculous results.", "\n\nTed says he had never seen a doctor drop so many expletives. ", "With every muscle Dr. Williams pushed came a new F-word: \"Holy f—! . . . ", "What the f—!\"", "\n\nHe finally stopped and gave Ted a big hug. ", "He was just amazed.", "\n\nDr. Williams also reconfirmed Ted's original diagnosis. \"", "He told me the same thing: 'Ted, there is no doubt you have ALS. ", "There is not a doubt in my mind.'\"", "\n\nDr. Glass started calling Ted at home to check in on him.", "\n\n\"I go to sleep thinking about you. ", "I wake up thinking about you,\" he confessed.", "\n\nTed smiled. ", "Under any other circumstance, that would be an awkward thing to hear from your doctor.", "\n\n\"I always thought if I found one person, they would give me the answers I was looking for,\" Dr. Glass told him. \"", "But all you have given me is more questions.\"", "\n\nTed's quantum leaps of improvement lasted for about ten months. ", "Then he started to get weaker again—though more gradually than before. ", "He was like a train that had rolled up a hill and now had started slowly rolling back down again.", "\n\nSince Ted's response to the first surgery was so unprecedented, Dr. Glass and his team decided to see how he would respond a second time. ", "They asked Ted to be one of three of the original fifteen patients to undergo a second round of surgery.", "\n\nOn August 22, 2012, Ted went through the procedure again. ", "This time doctors opened up the cervical area of his spinal cord—the upper area that controls respiration—and injected another 500,000 stem cells.", "\n\nAnd this time, just like the first time, Ted's strength returned. ", "The procedure was working.", "\n\nA few months after the second surgery, Ted stood before participants at the ALS walk and shared his story.", "\n\n\"I think to myself: what would Lou Gehrig think today?\" ", "Ted told the crowd. \"", "Because I'm going to walk today. . . . ", "I'm going to walk two and a half miles. . . . ", "So I apologize if it's a little clichéd, but I truly today can understand the words Lou Gehrig spoke so many years ago when he said, 'Today, I feel like the luckiest man on the face of the earth.'\"", "\n\nTed credits both his doctors and his maker for his turnaround. \"", "Saint John Paul II said faith and science go hand in hand because God is the author of them both,\" he says. \"", "And there's no doubt that science made this happen, but I feel like faith had a part in it as well.\"", "\n\nBut if faith and science are helping him, there is one powerful force now standing in his way: the federal government.", "\n\nIn phase I of the clinical trials, Ted received just 1.5 million stem cells over the course of two surgeries. ", "Doctors had wanted to use more cells, but the US Food and Drug Administration (FDA), which was supervising the trials, would not let them.", "\n\nThe agency forced doctors to cut the number of cells by three-quarters.", "\n\nMoreover, following the success of the phase I trial, the FDA allowed doctors to dramatically increase the number of stem cells injected in phase II. ", "Instead of 100,000 cells per injection, each patient received forty injections with 400,000 cells _per injection_. ", "That's about 16 million cells in a single procedure—more than ten times as many as Ted received over the course of two surgeries.", "\n\nIf 1.5 million cells reversed Ted's ALS symptoms, imagine what 16 million cells might do for him.", "\n\nBut Ted won't find out anytime soon. ", "He is not allowed to undergo the procedure again. ", "He no longer qualifies for the study, because the date of his diagnosis is too distant and patients from the phase I trial cannot participate in phase II. ", "And Ted cannot undergo the surgery outside the study, because the treatment has not yet been approved by the FDA.", "\n\nFour years later, the procedure is still undergoing clinical trials.", "\n\n\"If I have shown twice that the surgery is safe and effective, why should I ever have to ask the FDA for permission to do it?\" ", "he asks. \"", "Why should there ever be a risk they could say no to me? ", "If I have a doctor and a drug company willing to provide this to me, and I obviously have informed consent, why should I ever be in a position where I have to go hat in hand to the FDA asking for their permission for something that has been shown to work for me twice? ", "Why should my life rest in their hands?\"", "\n\nThose are good questions. ", "And here is another.", "\n\nTed Harada is one of just thirty-two Americans who have been allowed to try this cutting-edge therapy. ", "Many of the others have also responded well to the treatment, which has either slowed the progression of the disease or allowed them to maintain, for several years, the same level of functionality they had before the surgery.", "\n\nBut in the four years since the clinical trial began, twenty-four thousand people in the United States have died from ALS.", "\n\n_Twenty-four thousand._", "\n\n\"Every ninety minutes someone is diagnosed with ALS,\" Ted says, \"and every ninety minutes someone dies from ALS.\"", "\n\nThe total number of Americans with ALS never changes, despite the fact that there are five thousand to seven thousand new diagnoses each year—because they all die. ", "No one ever recovers from ALS.", "\n\nBut Ted Harada did recover.", "\n\nSo why should only thirty-two Americans with ALS have a chance to try to save their lives? ", "How many other fathers like Ted Harada are there out there? ", "And what about the millions of Americans with other terminal illnesses? ", "Why are so many people dying when promising treatments exist?", "\n\nWhat about _their_ right to try?", "\n\nWHEN TED HARADA WAS preparing to take his miraculous two-and-a-half mile \"Walk to Defeat ALS\" in the fall of 2012, terminal illnesses were the furthest thing from my mind.", "\n\nI had just adopted my first daughter out of the foster care system and had opened a second crib to foster another newborn. ", "The organization I lead, the Goldwater Institute, was busy spearheading a campaign called \"Save Our Secret Ballot\" (S.O.S.)—passing amendments to state constitutions across the country to protect the right of workers to vote by secret ballot in elections determining if a union will represent their workforce. ", "In Washington, federal legislation—the Secret Ballot Protection Act—was stalled on Capitol Hill. ", "If the federal government would not do its job and protect the right to a secret ballot, we decided, states had both the authority and the responsibility to step in and do it themselves. ", "And today, the constitutional amendment the Goldwater Institute developed has been adopted in eight states—and we have successfully defended it in federal court.", "\n\nUnbeknownst to me, this success had caught the attention of a group of oncologists from Cancer Treatment Centers of America (CTCA), one of the nation's leading networks of cancer-treatment hospitals and outpatient clinics. ", "In September 2012 they called the Goldwater Institute and said they wanted to meet with us to discuss what they said was a national medical emergency.", "\n\nThen-CEO Steve Bonner told us the story of how CTCA got started.", "\n\n\"We were founded and are still owned by a guy named Richard Stephenson,\" Bonner explained. \"", "He's an Indiana-born and-bred kid who then came to Northwestern, got a law degree, and started merchant banking, and had no real interest in health care.\"", "\n\nBut then something happened that would change the course of Stephenson's life—and the course of cancer treatment for tens of thousands of Americans. ", "His mother, Mary Brown Stephenson, came down with a very serious form of bladder cancer. ", "She tried all the known and approved therapies at the time, but none of them worked. ", "So Stephenson began searching for alternative treatments.", "\n\n\"He was drawn to try to be helpful as a son would and looked all over the world for therapies that might be helpful to her,\" Bonner said. \"", "He found a number of promising things around the world and brought them back to her bedside—and was blocked there by the FDA and by the AMA and by the insurance companies. ", "And she died never having had a chance to avail herself of innovative therapies.\"", "\n\nRichard Stephenson's mother was denied the right to try to save her own life.", "\n\nThe therapies, Bonner says, \"may not have helped her but why shouldn't she have had an opportunity to try some of these things?\"", "\n\nThe experience inspired Stephenson to found CTCA. \"", "He wanted to create an organization that is focused truly on the patient and that everything flows from that,\" Bonner explained.", "\n\nNow, decades later, cancer patients still face the same dilemma that Mary Brown Stephenson faced. ", "They are being denied access to innovative treatments that could potentially save their lives. ", "It turns out there are currently more than twenty thousand FDA trials for cancer medicines and treatments in phase II and phase III—which means they have all passed basic safety tests and many had shown efficacy in patients. ", "But unless the drugs are already approved for another indication, it is unlawful for oncologists to use those medicines and treatments outside of those carefully controlled clinical trials, because they are not yet fully FDA approved.", "\n\nToday, about 40 percent of cancer patients attempt to enroll in clinical trials, but only about 3 percent end up participating. ", "That means the vast majority do not make the cut, whether because they fail to meet the strict criteria or a trial is thousands of miles from their home. ", "Many of those denied access are the sickest patients—often precisely because they are too sick to be useful for study.", "\n\nWorse still, the FDA takes as long as fifteen years to bring a new medicine to market. ", "Americans are now waiting 60 percent longer for the FDA to approve life-saving medical devices—such as stents and valves—than we did ten years ago.", "\n\nThe FDA does have a \"compassionate use\" policy, which is supposed to provide access to investigational treatments for terminal patients on a case-by-case basis, and the FDA believes the system works. ", "In a 2014 radio interview, then–FDA commissioner Dr. Margaret Hamburg said, \"At the FDA we are very, very concerned about patients that are suffering and their lives are at stake from devastating diseases for which they may not have an approved therapy as an option. ", "And they have a very real need to turn to experimental treatment options. ", "We have a long history of supporting access to experimental treatments for patients under those conditions. ", "And we have a very good track record of approving or allowing requests for compassionate or expanded access to proceed. . . . ", "In these instances where an individual does not qualify for a clinical trial, where there is no approved drug as a treatment for their disease and when they may need to turn to an experimental treatment option outside of the clinical trial mechanism.", "\n\n\"I actually do not believe that we are the barrier in these instances. . . . ", "In fact, in many cases I actually think that FDA engagement, working with the families, working with the patient's physician, and working with the companies, have helped make expanded access actually available.\"", "\n\nNo doubt FDA officials are concerned about the suffering of these patients. ", "Like Dr. Hamburg, many of them are physicians who have dedicated their careers to curing diseases and saving lives. ", "Their hearts are in the right place. ", "But as we will see in the pages ahead, the system is broken.", "\n\nIn 2012, the year CTCA came to the Goldwater Institute, there were just 940 requests for experimental drugs approved in the entire country under the FDA's compassionate use program. ", "According to the American Cancer Society, that same year about 1,638,910 Americans were diagnosed with and about 577,190 died from cancer alone. ", "Millions more are diagnosed each year with other terminal diseases. ", "Clearly, the system is failing to help the vast majority of Americans who are fighting to save their lives.", "\n\nThe FDA is a federal agency, so fixing this problem should be Congress's responsibility. ", "But gridlock in Washington is blocking a solution. ", "Since 2008 multiple bills have been introduced in Congress with bipartisan support to expand access for terminal patients to drugs stuck in the FDA pipeline, but most have gone nowhere.", "\n\nSeeing the inaction on Capitol Hill, CTCA had come to us for help. ", "They wanted to know if there was anything the states could do to help those dying from terminal diseases to get access to innovative treatments that could save their lives.", "\n\nBonner recalls, \"I just asked the question: I wonder if there's any way to empower patients using the state authority and to give them access to care that they're otherwise not going to have access to, where they're dealing with truly a life-threatening form of the disease. ", "If you have to go through double-blinded studies at the FDA, you know you're talking about years and people with late-stage cancer don't have years. ", "So is there a possible exception we could carve out here for cancer patients or [others] at late stage disease?\"", "\n\nAs I listened to Bonner and his colleagues, I immediately thought of my uncle Kenny. ", "He died when I was about four years old from Hodgkin's lymphoma—a form of cancer for which there are now multiple treatments with very high cure rates. ", "He was my father's only brother, and I distinctly remember my dad saying, when I was growing up, that Uncle Kenny had died just months before a new treatment was approved. ", "At that moment it hit me: if Kenny had been allowed to try that treatment earlier, my father might still have his brother, and my cousins might still have their father.", "\n\nThe idea that the federal government was standing in the way of people fighting for their lives was infuriating. ", "It's one thing for people to die because science has not come up with a treatment for their illness yet. ", "It's quite another for someone to die when a promising treatment _exists_ , but a patient can't get access to it because of governmental obstacles.", "\n\nAnd if Washington would not fix the problem, then it was our job to step in.", "\n\nThe US Constitution provides a floor for freedom, not a ceiling. ", "We can use state constitutions and powers reserved to the states to defend and expand our freedoms far above the federal baseline.", "\n\nWhile the US Constitution protects the rights to free speech, religious liberty, and private property, many states expressly protect those freedoms to a stronger degree. ", "Nearly every state constitution protects free speech more robustly than federal courts do under the First Amendment, protecting more types of speech and imposing a stronger burden on government to justify its censorship.", "\n\nIn _Federalist_ number 51, James Madison wrote that a system of competing federal and state governments, each with explicit protections of individual liberties, would provide a \"double security\" for the rights of the people. ", "In _Federalist_ number 28, Alexander Hamilton declared, \"If [the people's] rights are invaded by either [government], they can make use of the other as the instrument of redress.\"", "\n\nThe Founders understood that the rival of power is power, and the only power sufficient to rival Washington is the collective body of our fifty states. ", "That is why they and their successors didn't give us just one Constitution—they gave us fifty-one.", "\n\nI am a Goldwater conservative and a firm believer in federalism, the constitutional authority and responsibility of the states to check and balance Washington's overreach. ", "In recent years, activists on the left have gone to the states to pass initiatives on everything from medical-marijuana legalization to the right to assisted suicide. ", "If states have the authority to give their citizens access to marijuana and drugs to end their lives, certainly they have the authority to allow cancer patients access to investigational medicines to save their lives.", "\n\nIf you have the Right to Die, you have the Right to Try. ", "And you don't have to wait for Washington to secure it.", "\n\nWe enthusiastically agreed to take on the project. ", "In the months that followed, we came up with a proposal that would expand access to investigational medicines and prevail in court if challenged.", "\n\nI met Dick Stephenson over lunch and explained our plan of action. ", "Our draft law would protect a person's fundamental right to try to save his own life by expanding access to promising new drugs that await the FDA's green light if:\n\n• the patient has a terminal diagnosis and has exhausted all conventional treatment options;\n\n• the patient's doctor has advised that the use of an investigational treatment is the best medical option to extend or save the patient's life;\n\n• the treatment has successfully completed basic safety testing and is part of the FDA's ongoing evaluation and approval process;\n\n• the patient has provided \"informed consent\" acknowledging the potential risks associated with the use of the drug; and\n\n• the company developing the medication is willing to make it available to the patient.", "\n\nWe assembled an unprecedented coalition of conservatives, liberals, and everyone in between to fight for the lives of terminal patients. ", "And in the months that followed, Right to Try legislation has passed with overwhelming bipartisan majorities almost everywhere it has been brought up.", "\n\nWe knew from the beginning that Right to Try laws would be popular, but the speed with which they have taken off has been eye-opening.", "\n\nWhen I began writing this book in the fall of 2014, Right to Try laws had been approved in five states—Colorado, Missouri, Louisiana, Michigan, and Arizona. ", "Today, as we go to press, the number has grown to twenty-four. ", "In those state legislatures, there have collectively been 3,045 votes in favor of Right to Try and just 26 votes against. ", "To put that in perspective, if those were the vote totals in an election, Right to Try would have won by a margin of 99 to 1 percent.", "\n\nThe only place in the world you'll find results more lopsided than that is in North Korea.", "\n\nIn Colorado, Missouri, Louisiana, Arkansas, Indiana, Mississippi, Oklahoma, Virginia, Tennessee, Texas, Nevada, North Carolina, Oregon, and Alabama, Right to Try passed without _a single dissenting vote_ in either house. ", "In Arizona, where the legislature referred it to the voters as a ballot initiative, it got 1,111,850 votes and was approved by an overwhelming 78.5 to 21.5 percent margin.", "\n\nFatal diseases do not distinguish between Republicans and Democrats. ", "Right to Try has been signed into law by both Democratic governors (Colorado's John Hickenlooper, Missouri's Jay Nixon, Montana's Steve Bullock, Minnesota's Mark Dayton, Oregon's Kate Brown, and Virginia's Terry McAuliffe) and Republican governors (Arkansas's Asa Hutchinson, Illinois's Bruce Rauner, Indiana's Mike Pence, Michigan's Rick Snyder, Louisiana's Bobby Jindal, Mississippi's Phil Bryant, Oklahoma's Mary Fallin, South Dakota's Dennis Daugaard, Utah's Gary Herbert, Wyoming's Matt Mead, North Carolina's Pat McCrory, North Dakota's Jack Dalrymple, Tennesee's Bill Haslam, Nevada's Brian Sandoval, Alabama's Robert Bentley, Florida's Rick Scott, and Texas's Greg Abbott).", "\n\nWe anticipate that by the end of 2015 about half the states in the Union will have Right to Try laws on the books—and the other half is soon to follow.", "\n\nThis book tells the story of how this movement to save lives took off, and how a relatively small grassroots organization is uniting people across the political spectrum in a fight for human dignity. ", "In the pages that follow, we will meet courageous Americans who beat illnesses no one thought could be defeated. ", "We will meet moms and dads who won the fight to get their children access to cutting-edge cures and those who were denied life-saving treatments by their own government. ", "Sometimes these miracles and tragedies have taken place within the same the family.", "\n\nWe will meet incredible healers—doctors and medical researchers who are pioneering revolutionary cures and treatments for diseases that were once thought incurable. ", "We will go inside the federal bureaucracy that is stopping millions of our fellow citizens from getting access to those lifesaving treatments. ", "And we will meet some of the courageous leaders in states across this country who are fighting to give their fellow Americans the chance to save their lives.", "\n\nThis book is a story of medical miracles, but it is also a story of political miracles. ", "Our country's politicians often seem to enjoy fighting and finger pointing more than problem solving. ", "Yet in the midst of this age of pettiness and division, the Right to Try movement has united Americans of all political persuasions, and has shown that our country can still put politics aside to serve the common good.", "\n\nIt seems we cannot agree on much these days. ", "But when it comes to fighting terminal illness, we can still agree on this much:\n\nEveryone deserves the Right to Try.", "\n\n# 1.", "\n\nSophie's Choice\n\n_How the FDA Let a Mother Save One Son . . . ", "and Left Her Other Son to Die_\n\nImagine the joy of watching your dying son experience a miraculous recovery thanks to an experimental medicine.", "\n\nThen imagine the horror of watching your other son slowly die from the exact same disease—because the federal government prevented him from receiving the same life-saving treatment as his brother.", "\n\nThat is the nightmare that my friend Jenn McNary has lived for the past three years.", "\n\nJenn was a senior in high school when she had her first child, Austin. ", "Three years later, Max came along. ", "Jenn was a single mom, living in Vermont, struggling to support her family. ", "She ran a child-care facility during the day and was studying child development at night school. ", "Life was hard, but she and her young family were getting by. ", "Both her boys seemed to be typical, healthy, happy kids.", "\n\nThen, one day, Jenn began to notice that Austin was not keeping up with his friends.", "\n\n\"I was learning about all these age-appropriate developmental skills,\" she says, \"like picking up a ball, standing on one foot, the ability to alternate legs going up stairs.\"", "\n\nAustin was not meeting the developmental marks.", "\n\nIn the day care she ran, when all the other kids were going to the park, Austin was the only one who cried and refused to walk. ", "He began to stumble and fall a lot and seemed to get concussions on a monthly basis. ", "In his first-birthday picture, Jenn recalls, he had a huge bruise on his head from falling into a wall. ", "By the age of three he had broken his arm from falling.", "\n\nJenn also noticed that Austin didn't seem to get up from the floor like the other kids. ", "He would lift up his hips with his hands on the floor and then use his hands to crawl up his legs until he got to a standing position. ", "He had unusually thick, muscular calves. ", "And he crawled up stairs instead of walking like most kids his age.", "\n\nSomething was wrong.", "\n\nIt took her eight months to convince Austin's pediatrician that there was a problem, but finally the doctor agreed to have Austin tested.", "\n\nOne day, while Jenn was at work, the doctor called her and asked her to come in to the office. ", "Jenn had a day care full of kids and could not get away.", "\n\n\"Can't you just tell me?\" ", "she said.", "\n\nSo the doctor told her over the phone that Austin had Duchenne muscular dystrophy.", "\n\n\"I don't even know what that is,\" Jenn said. \"", "Is that like the Jerry's Kids thing?\"", "\n\n\"Exactly,\" the doctor said.", "\n\nShe explained to Jenn that Duchenne was a disorder that leads to muscle degeneration and eventually death. ", "It turned out Austin's bulging calves were not muscular at all. ", "The muscle was breaking down and being replaced by calcium deposits that made his legs thick and hard. ", "She explained to Jenn that there are actually forty-three different types of muscular dystrophy. ", "Some affect children, but the majority of them affect adults. ", "There are only a handful that are fatal.", "\n\nAustin had one of the fatal ones.", "\n\nJenn asked the doctor what the treatment plan for Austin would be. \"", "Does he need chemotherapy or something? ", "Will he lose his hair?\"", "\n\n\"There is no treatment,\" the doctor told her flatly.", "\n\nJenn was bewildered. ", "After a long pause, she asked, \"So what do I need to do?\"", "\n\n\"You really don't need to do anything,\" the doctor told her. \"", "There are no options. ", "The disease is progressive and fatal 100 percent of the time.\"", "\n\nJenn was incredulous. ", "There had to be _something_ she could do. ", "This was America, after all. ", "Certainly in this day and age, we have treatments for everything.", "\n\nShe took Austin to a specialist to get a second opinion. ", "He told her the same thing as her pediatrician. ", "There was no treatment, no cure.", "\n\n\"Frankly, it's a shame you know this young,\" he said. \"", "There is no benefit to you knowing this early.\"", "\n\n\"Do we need to do any more testing?\" ", "Jenn asked.", "\n\n\"No,\" the doctor told her.", "\n\n\"What about steroids? ", "I read about steroid use.\"", "\n\nThe doctor got angry with her.", "\n\n\"Why do you want to do that to your kid? ", "It only prolongs the inevitable.\"", "\n\nThe _inevitable_. ", "The word hung in the air.", "\n\n\"So _what_ do I do?\" ", "Jenn demanded. ", "She wasn't just going to sit back and watch her son die.", "\n\n\"Well,\" the doctor told her, \"when Austin is losing the ability to walk, come back and we will get him a wheelchair ordered, okay?\"", "\n\nJenn couldn't believe it. ", "She was supposed to do nothing and pretend she didn't know Austin was sick until her son lost the ability to walk? ", "That was the plan?", "\n\n\"No, not okay,\" Jenn told him, as she stormed out of the doctor's office.", "\n\nJenn immediately began researching Austin's disease. ", "She had no Internet access at home, so she went to the public library and started reading everything on Duchenne she could find. ", "When she discovered that the disease was genetic, Jenn had her three-month-old, Max, tested—and found out, to her horror, that he also had Duchenne.", "\n\n\"I had this newborn baby who was going to die,\" she recalls. \"", "I was the mother of two dying children.\"", "\n\nJenn became active in the Duchenne community, connecting with doctors, researchers, and other parents at conferences and online forums. ", "And as her boys grew, and the disease progressed, she kept looking for a cure. ", "She told herself, \"By the time they are two and five years old there will be a cure.\" ", "When there wasn't a cure then, she told herself, \"By the time they are five and eight years old, there will be a cure.\" ", "But by the time Austin turned nine and a half, she says, \"I stopped thinking there was going to be a cure.\" ", "Jenn pulled out of Duchenne advocacy and decided to just love her children while she still had them.", "\n\nAustin began declining rapidly. ", "But then, just as Austin turned ten years old, hope appeared on the horizon. ", "Jenn heard about a new type of investigational therapy that appeared to be working overseas. ", "There were two companies in London working on something called exon skipping—a treatment that coaxes cells to \"skip\" over the faulty sections of genetic code that causes Duchenne.", "\n\nThe underlying cause of Duchenne is an error in the gene that produces a protein called dystrophin that is needed to support muscle strength. ", "Without dystrophin, ordinary physical exertion leads to muscle breakdown. ", "As muscle fiber degenerates, children lose their ability to move—and eventually they lose the ability to breathe.", "\n\nBoth Austin and Max were unable to produce this critical protein, because they were missing a section of the dystrophin gene called exon 51.", "\n\nScientists in Europe were conducting clinical trials on a therapy for Austin's and Max's specific gene mutation, which affects about 13 percent of Duchenne sufferers. ", "The scientists believed they had found a way to coax cells to skip the broken section of the gene that Austin and Max were missing. ", "If they could do that, they might be able to restore the gene's ability to produce the vital protein.", "\n\nHow does exon skipping work? ", "To understand this better, think of the genetic code for a protein as a sentence. ", "According to Margaret Wahl of the Muscular Dystrophy Association, \"Cells have to read the genetic 'sentence' in units of three 'letters' each\" in order to produce the protein.", "\n\nThe gene sentence in healthy kids would read like this:\n\n_The mad cat ate the fat rat and the big hat._", "\n\nBut kids with Duchenne have a deletion which messes up the three-letter sequence (known as the reading frame) and makes the sentence unreadable. ", "These are called \"nonsense mutations\" because they turn the sentence into nonsense and make the genetic code incomprehensible.", "\n\nFor example, imagine that in Austin and Max the letters _fa_ in \"fat rat\" are missing. ", "That makes the sentence look as follows:\n\n_The mad cat ate the tra tan dth ebi gha t._\n\nThe cells can't read the sentence beyond the error point. ", "And if they can't read the sentence, they can't get the instructions they need in order to produce the protein.", "\n\nIn exon skipping, scientists had found a way to convince the cells to skip the broken exon, or sentence fragment:\n\n_The mad cat ate the [tra tan dth e] big hat._", "\n\nwhich restores the \"reading frame\" and produces a shorter but readable sentence:\n\n_The mad cat ate the big hat._", "\n\nThe gene is still mutated, but now the shorter readable sentence can produce a shorter but still functional dystrophin protein again.", "\n\nIf this new drug worked, it would transform Austin's and Max's deadly Duchenne muscular dystrophy into a much milder form of muscular dystrophy called Becker's. ", "Their condition would become chronic instead of fatal.", "\n\nExon skipping was just the ray of hope Jenn had been looking for. ", "As soon as she heard about it, she hopped on a plane and flew to London, where the CEOs of the two companies that were developing the exon-skipping drug were scheduled to attend a Duchenne conference.", "\n\nShe found them in a corner chatting and went right up to them.", "\n\n\"I said, 'All right, guys, my kids need this drug, which of you is going to be in the US first?\"", "\n\nThe two men told Jenn that they would probably be in North America about the same time, but she'd need to go to Canada to get the drug.", "\n\n\"I said, 'Okay, Canada it is.' ", "And I made sure I sent both companies my kids' genetic reports.\"", "\n\nWhile she was in London, Jenn also began talking to some of the parents who were participating in the clinical trial.", "\n\n\"All the results were great,\" she says. \"", "The parents were very happy.\"", "\n\nBut one mom told her a tragic story: Her son had broken his back during the trial for one of the drugs. ", "Because he could not walk, he was disqualified. ", "Researchers measured how well the drug was working by comparing the patients' ability to walk before and after receiving it. ", "That meant only kids who were ambulatory could participate in the trial.", "\n\n\"She was devastated,\" Jenn recalls, \"because she was certain that the drug would have done something for her son.\"", "\n\nJenn's heart broke for the mom, but the news also terrified her. ", "Austin was still ambulatory, but just barely. ", "If he lost his ability to walk, he would not qualify for the study—just like the boy with the broken back. ", "His window to enter a clinical trial was quickly closing.", "\n\nThen, suddenly, the window slammed shut. ", "Corporate politics and a patent fight brought the London clinical trial to a halt. ", "Jenn flew home knowing she would not get access to the promising drug she believed would save her boys. ", "She was devastated.", "\n\n\"Years went by, and I really sort of lost hope again,\" Jenn says. \"", "I went gray.\"", "\n\nWithin two years, Austin, then twelve, lost his ability to walk. ", "He was now confined to a motorized wheelchair. ", "The process of watching him lose his mobility was absolutely heartbreaking for Jenn.", "\n\n\"At the end stages of walking, they take maybe two or three steps and then the crumple and fall to the ground,\" she says. \"", "And there is this really echoing thud that shakes the whole house, because it is dead weight. ", "They walk and then they are on the floor. ", "And they can't at that point get back up. ", "So they fall to the floor and they are stuck there. ", "And you go and lift them up.\"", "\n\nWhen Austin finally decided it was time to get his power chair, Jenn says, \"It was sort of a relief. ", "He gained a lot of speed! ", "When you aren't able to walk, and then you get this power chair that goes five miles an hour, it is pretty enlightening and freeing.\"", "\n\nMeanwhile her other son, Max, was now nine years old. ", "He was declining and starting to use a wheelchair occasionally as well. ", "Jenn could see that he would soon lose his mobility, just like his older brother. ", "It was only a matter of time. ", "His window to a cure was closing too.", "\n\nThen something happened that would change their lives.", "\n\nOne day in 2011 Jenn was on her computer checking Facebook when she saw a message from a friend in the Duchenne online community named Mindy Leffler. ", "Mindy's son Aidan had been diagnosed with Duchenne in 2006 after he broke his leg playing on a slide. ", "He had the same missing exon as Max and Austin.", "\n\nMindy posted on Facebook that she was flying Aidan from their home in Bellevue, Washington, to Nationwide Children's Hospital in Columbus, Ohio.", "\n\n\"Fingers crossed!\" ", "Mindy wrote.", "\n\nJenn messaged her:\n\n\"Fingers crossed for what?\"", "\n\nMindy wrote back that she was taking Aidan to be tested for admission into a clinical trial for an investigational drug called eteplirsen that was being developed by Sarepta Therapeutics. ", "It was the same exon-skipping technology that Jenn learned about a few years earlier in London, targeting the precise genetic abnormality that Max and Austin suffered from.", "\n\nThe drug had finally made it to America!", "\n\nBut there was a catch. ", "Just like in London, only ambulatory, or walking, patients qualified for the trial.", "\n\nThat meant it was too late for Austin. ", "Only Max had a shot at getting in.", "\n\nJenn was determined to get the drug for Max before he lost his ability to walk. \"", "I looked up all my old contacts and started calling,\" Jenn says. ", "She began lobbying the hospital furiously, asking them to take a look at Max. ", "She was told \"no\" over and over again. ", "But she refused to take \"no\" for an answer. ", "She knew this could be Max's only chance.", "\n\n\"I was harassing them,\" she says now, looking back. \"", "And they actually said, 'Jenn, you are harassing us. ", "We aren't even enrolling yet. ", "We are just looking at kids.' ", "And I said, great, I want you to look at Max.\" ", "But they would not look at him.", "\n\nOne day she reached the principal investigator for the trial, Dr. Jerry Mendell. \"", "What do I have to do to get you to look at Max? ", "He's perfect. ", "You need him,\" she said.", "\n\nHer persistence finally paid off. \"", "I guess you can bring him here and we will take a look at him,\" Dr. Mendell told her.", "\n\nIt was the first ray of hope she had since the London trials were canceled.", "\n\nJenn immediately got on a plane with Max and her newborn daughter (Jenn now has two other children, both of whom are healthy) and flew to the hospital in Ohio, where Max was examined. ", "He took a test that measured how far he could walk for six minutes. ", "If Max could not walk far enough, he would not be admitted into the trial. ", "If he walked too far, he would also not be admitted into the trial. ", "The investigators were looking for patients who would naturally stop walking during the course of the study—so they could see if they the drug slowed, stopped, or even reversed the progression of the disease.", "\n\nSoon after returning home, Jenn got a phone call. ", "Max had failed the walk test. ", "He had walked too far to qualify for the trial. ", "It was a terrible irony: to qualify, he would need to deteriorate further, but by then, it would be too late.", "\n\nMax would not get the drug.", "\n\nJenn cried for two days straight. ", "This had been Max's only hope. ", "The rejection was as good as a death sentence.", "\n\nThen, a month after being rejected, Jenn got another call from the hospital. ", "Two participants had been disqualified, and Max could retest. ", "This time, Max passed.", "\n\nMax became patient twelve of twelve, the last child admitted into the trial.", "\n\nIt broke Jenn's heart that Max had to get in this way, and she vowed to herself that if this drug worked for Max, she would make it her mission to fight to get eteplirsen to everyone who needed it.", "\n\nBut first, she had to save her son.", "\n\nJenn began flying to Columbus from her home in Vermont once a week so that Max could receive infusions of the new drug. ", "She used a wheelchair for Max during the trip, even though he was still walking. ", "She was not going to let him fall and break something and get kicked out of the trial like the boy in London.", "\n\nJenn was quite a sight walking through the airport. \"", "I have a newborn strapped to the front of me, a car seat strapped to the back of me, pushing a wheelchair and pulling a suitcase,\" Jenn says. \"", "Every Tuesday morning we left. ", "Every Wednesday he had an infusion. ", "Every Thursday we flew back to Connecticut and then drove to Vermont. ", "That was our week for about a year and a half.\"", "\n\nMax was enrolled in what is called a \"double-blind placebo controlled trial,\" which meant that some kids in the trial were getting the drug while others were not, so that doctors could compare the outcomes. \"", "I didn't know if he was on the drugs, on high dose, low dose, or nothing,\" Jenn says. ", "She could very well have been making the arduous weekly hike from Vermont every week for an infusion of useless saline solution.", "\n\nBut about sixteen weeks after the infusions began, Jenn started noticing changes in Max. \"", "The kid stopped wanting to use his wheelchair,\" she says. ", "A few weeks later, he was asking to play outside—something he had not done in years. ", "Then Max started regaining his fine motor skills. ", "He was able to open containers again—a skill he had lost as his disease had progressed.", "\n\nAfter about a year, he abandoned the wheelchair completely and hasn't used it since.", "\n\n\"Last summer he played soccer with his school soccer team,\" Jenn says. \"", "This summer he is learning how to pedal a bicycle. ", "He is able to go to the fair and walk all day long. ", "He is able to walk through the airport. ", "We no longer use handicap access because he just doesn't need it.\"", "\n\nMax was getting better.", "\n\nBut Jenn's joy at seeing Max recover was bittersweet. ", "At the very same time she was watching one beloved son recover, she was watching as her other beloved son continued to deteriorate.", "\n\n\"Austin is no longer able to transfer himself,\" Jenn says, her voice choking back tears. \"", "That was something he could do [when Max joined the trial]—get into his own bed, open doors, pick things up. ", "He was nonambulatory, but he was a really independent nonambulatory kid. ", "He was able to dress himself in his wheelchair, roll over on his own, pull up his own blankets.\"", "\n\nNow, at age sixteen, he could do none of those things. ", "Every day, every week, every month that went by without the drug, Austin was losing ground.", "\n\n\"Pretty soon he will lose the ability to feed himself,\" Jenn says.", "\n\nYet amid this tragedy, something beautiful happened. ", "As Max improved while Austin declined, the younger brother became the older one's caregiver. ", "The boys shared a room, and Max would wake up in the middle of the night to reposition Austin in his bed or get him water. ", "He would help Austin dress, pack his backpack, and get ready for school. ", "If Austin needed to go to the bathroom, Max would help him transfer from his wheelchair to the toilet.", "\n\nAustin didn't get the drug, but he got a brother who could help take care of him.", "\n\nIt has been heartbreaking for Jenn to see one of her sons improve while the other declines with each passing day. ", "It has been even more difficult for the boys.", "\n\n\"Austin is very angry right now,\" Jenn says, \"because he is not on the drug and he knows the drug works. ", "He is angry because he is not fighting against science anymore. ", "It is not that a treatment doesn't exist. ", "It's just that he doesn't have access.\"", "\n\nJenn says Austin \"doesn't understand why the grown-ups in his world can't figure this out and make things happen faster for him.\"", "\n\nJenn can't understand it either.", "\n\n\"It is one thing if your child is dying from an untreatable disease, but to have your child dying from a treatable disease is freaking devastating,\" she says. \"", "I never thought it would be the government I would be working against.\"", "\n\nJenn worries about her family, and how Max will take it if he survives but Austin doesn't. \"", "How is that going to affect Max?\" ", "Jenn asks. \"", "I mean, the guilt. ", "There was only enough drug for twelve kids; there was not enough for thirteen.", "\n\n\"Having a child that is dying is the most painful thing in the world. ", "The only thing that is more painful is having a child that is dying and having a drug that could help him, and not being able to have access to it. ", "It's a crime.\"", "\n\nJenn looks at her boys and sighs.", "\n\n\"I could have the first child in history to survive Duchenne and the last child to die from it, living in the same house.\"", "\n\nBY THE SUMMER OF 2012 Jenn had had enough of watching one son get better while the other slowly declined. ", "She decided she was going to get the drug for Austin.", "\n\nAnd she was going to do it the only way she knew how—by cornering the CEO of the drug company.", "\n\nShe found out that the chief executive of Sarepta, Chris Garabedian, would be attending the annual conference of the Parent Project for Muscular Dystrophy in June 2012 in Fort Lauderdale. ", "So she booked a plane ticket for Florida.", "\n\nGarabedian was a different kind of CEO from those she had met in London. ", "He had come to tiny Sarepta (then called AVI Biopharma) from two giants of the biotech field: Gilead Sciences and Celgene. ", "Gilead was a pioneer in the field of antiviral medicine, developing some of the most widely used anti-AIDS drugs, and Celgene was one of the leading developers of drug therapies for cancer. ", "The two companies were like the Apple and Google of biotech. ", "Landing one of their top managers as CEO was a major coup for the small, struggling company.", "\n\nBy the time Garabedian took over in 2011, the firm was in trouble. ", "It had spent thirty years and $250 million on research and development and didn't have a drug anywhere near FDA approval. ", "Moreover, the firm had alienated the Duchenne community. ", "Upon his arrival, Garabedian made it his first priority to get to know the community and explain to them that the company was headed in a new direction. ", "He was going to move forward in a very progressive, accelerated way and do everything in his power to get the drug to their children as fast as possible.", "\n\nBut when he arrived in Fort Lauderdale in June 2012, his prospects for doing so looked dim. ", "Sarepta was struggling to stay afloat. ", "The company's stock was down 30 percent. ", "He was running out of cash. ", "Garabedian couldn't find any investors to give him the money he needed to keep Sarepta in the black.", "\n\nHe didn't know if Sarepta was going to survive.", "\n\nWorse, he didn't know if he even had a product. ", "Eteplirsen had completed a phase I trial, which proved that the drug was safe. ", "But the clinical signal—the actual improvement in function of the patients—from that initial trial was not strong. ", "Garabedian was betting everything he had on the tiny, twelve-patient phase II trial that Max was in.", "\n\nEven putting that trial together had been a struggle. ", "When he first took over the company, Garabedian told the BioBeat blog, he had called up his head of manufacturing and asked how much of the drug they had in stock.", "\n\n\"Not much,\" the department head told him.", "\n\n\"How much is not much?\" ", "Garabedian asked.", "\n\n\"We have enough to treat eight patients for about twenty-four weeks,\" he said.", "\n\nThat was not good.", "\n\n\"How long will it take to get more drug?\" ", "Garabedian asked nervously.", "\n\n\"Nine months to a year,\" came the reply.", "\n\nWith a limited supply of drug and no capacity to make more quickly, Garabedian took what he had and came up with the best small trial he could design. ", "The study would enroll twelve patients. ", "Eight would get the drug, while four more would be placed in a placebo control group.", "\n\nTo put this in perspective, his nearest competitor, Prosensa and its pharmaceutical partner, GlaxoSmithKline, were conducting a 180-patient study for its drug, which was targeting a different flaw in the exons. ", "It was just the kind of large, double-blind randomized trial the FDA favored.", "\n\nA large trial like that was out of reach for Garabedian. ", "His little twelve-patient study would have to do. ", "If the data showed his drug worked, he could raise money to scale up production, move the four patients in the placebo group onto the drug, and keep the study going.", "\n\nIf not, Sarepta could be finished.", "\n\nWhen Garabedian flew to Fort Lauderdale, it was early in the study and he had no idea if his drug was working . . . ", "until, that is, Jenn McNary cornered him.", "\n\n\"I was approached by a mom I had never met or heard of at the time, Jenn McNary,\" Garabedian explained in an interview with _Boston Business Journal_. \"", "She approached me in the summer of 2012, before the company even had its 36-week data that was the first signal of a clinical efficacy. ", "And she told me, 'Your drug is working. ", "My son is in your trial.'\"", "\n\nJenn recalls the moment. \"", "I didn't know him, but I waved him over. ", "I said, 'You're the CEO of Sarepta, right? ", "Great, my son is getting better and your drug works.' ", "And he looks at me and goes, 'We don't have the data to back that up yet.' ", "I said, 'Oh, I have the data. ", "He lives with me. ", "It works.'\"", "\n\nJenn told Garabedian how Max had gone from using a wheelchair half the time to playing in the yard with his siblings. ", "She also told him about Austin, who did not qualify for the trial because he was already wheelchair bound, and how desperately he needed the drug.", "\n\nGarabedian was moved by Austin's plight, but he explained that he literally didn't have any drug to give him. ", "Sarepta was barely able to churn out enough to keep Max going in the trial. ", "He didn't have any cash, didn't have any drugs, and didn't have any manufacturing capacity. ", "The company was on its final breath. ", "He was rolling the dice on Max's trial. ", "They needed data showing a separation between the placebo-delayed group and the early treatment group in the trial, or there would be no more drug, period.", "\n\nGarabedian later told reporters that his conversation with Jenn was the first evidence he had that his drug was working. \"", "She saw what [the company] didn't see, and the rest of the marketplace and DMD community didn't see, because she had a boy in our study.\"", "\n\nA month after speaking with Jenn, in July 2012, Garabedian finally got some desperately needed good news. ", "The thirty-six-week analysis of Max's trial showed the clinical signal he had been hoping for. ", "Four boys on the highest dose of eteplirsen saw their walking ability decline by just 8.7 meters, compared with a decline of 78 meters in walking ability for boys who were not on the drug.", "\n\nEteplirsen had dramatically slowed their decline. ", "When Sarepta announced the interim results, its stock went up 150 percent.", "\n\nThen, three months later, the forty-eight-week data came out, and the news was even better. ", "The clinical outcomes were unprecedented. ", "Boys on the drug were able to walk an average of 21 meters _farther_ than at the start of the study, and 89 meters farther than those on placebo.", "\n\nMoreover, muscle biopsies showed that levels of dystrophin—the protein they had been missing to repair their muscles—in the boys on the drug were increasing significantly. ", "Two boys, a set of twins, had not been able to benefit from the treatment. ", "But all the other boys were doing phenomenally well.", "\n\nDr. Mendell, the principal investigator, hailed the results, saying the data \"represent a significant milestone and a defining moment of progress and hope for patients with DMD and their families.\" ", "Eteplirsen, he said, \"has demonstrated unparalleled effects on enabling dystrophin production and slowing the progression of the disease.\"", "\n\nEveryone from the placebo-delayed group was now getting the drug. ", "The moms started tweeting, posting videos, spreading the word:\n\nEteplirsen was working.", "\n\nJenn recalls, \"The day the forty-eight-week data came out, I called him and said, 'Great, now you know it works. ", "So what are you gonna do? ", "I have this other kid who is still dying. ", "You have to help.\"", "\n\nBut he could not help. ", "Unlike pharmaceutical giants like GlaxoSmithKline, he did not have the money to scale up production. ", "The only way he could raise enough cash to do so was if the FDA gave Sarepta a green light for accelerated approval of the drug. ", "Then the stock would go up, and Garabedian could raise money in anticipation of the drug's being approved, produce the drug, and have it ready to sell immediately on approval.", "\n\nAs word spread on social media of eteplirsen's success, Sarepta was inundated with requests like Jenn's. ", "So Garabedian issued an open letter to the Duchenne community explaining the company's predicament:\n\nWe know that drug development is a painfully drawn-out process for those who are waiting and we take seriously our responsibility to act as a true partner of the DMD community as we move forward together. ", "We are currently producing eteplirsen at a scale that is sufficient to meet the needs of the 12 patients in this study. . . . ", "At the present time, we do not have excess drug supply to make eteplirsen available outside of a clinical trial setting on a compassionate use basis.", "\n\n\"We can only imagine how difficult this is to hear, but unfortunately we have no other options available to us right now,\" he continued. ", "The only way to get the drug to people who needed it, Garabedian explained, was to \"advance this therapy through the regulatory process and, ultimately, secure approval for all DMD patients who would benefit.\"", "\n\nWhen she read Garabedian's letter, Jenn was heartbroken. ", "But she also realized Sarepta was not holding out on her. ", "It could not afford to produce the drug on a wider scale until the company knew that there was a pathway for approval. ", "And the only agency that could clear that pathway was the Food and Drug Administration. ", "The FDA had the authority to get the drug to her son or withhold it. ", "The FDA held the power of life and death. ", "So Jenn decided that is where she would focus her energy from here on out. ", "Instead of targeting the company, Jenn would target the FDA and focus on convincing it to accelerate the approval of eteplirsen.", "\n\nFortunately, Congress had recently passed a new law that could help her do just that. ", "On July 9, 2012—the same month Sarepta announced its thirty-six-week findings—President Barack Obama signed the Food and Drug Administration Safety and Innovation Act (FDASIA). ", "The law created a new designation at the FDA for \"breakthrough therapies\" and encouraged the agency to speed the review of new drugs for fatal diseases by measuring a \"surrogate\" outcome (such as how much dystrophin Duchenne boys are producing) instead of a \"clinical\" outcome (how far they can walk).", "\n\nIf a drug meets a surrogate outcome—or \"end point\" in the FDA's terminology—it strongly suggests that eventually the clinical outcome of improving how patients feel, function, or survive will also be met. ", "For example, the lack of dystrophin is the cause of Duchenne. ", "So if a drug helps Duchenne kids start producing dystrophin, it is likely that they will eventually meet the clinical outcome of walking farther. ", "In clinical trials, the surrogate outcome is usually reached before the clinical one. ", "You can measure how much dystrophin the body is producing long before the protein starts to have a measurable impact on muscle function—and thus progress in a six-minute walk test.", "\n\nThe new law encouraged the agency to approve breakthrough drugs on the basis of the surrogate outcome, so patients can get access to the drug faster. ", "Then the agency can require additional studies after approval to confirm that the clinical outcome had been achieved as well.", "\n\nSarepta would be one of the first companies to seek accelerated approval for a breakthrough therapy under the new law. ", "Congress had just sent clear instructions to the FDA: accelerate approval of treatments for rare diseases. ", "Now Garabedian's company was going to ask the FDA to live up to Congress's mandate and approve eteplirsen on the surrogate goal of dystrophin production.", "\n\nGarabedian knew this would not be easy. ", "FDA officials were ambivalent about accelerated approval to begin with. ", "The neurological division of the FDA, which had the final say over his drug, had not granted accelerated approval to any drug since 2004. ", "It was not clear how the division would respond to the new directive from Congress. ", "The law had _authorized_ but did not _require_ accelerated approval based on surrogate markers for breakthrough drugs.", "\n\nHe and his company were entering uncharted territory.", "\n\n\"We were testing the intent of [the law],\" Garabedian says, and when you're \"one of the first to try to apply legislation like FDASIA, it's tough. ", "It's tough on all parties to be the first. ", "And you're trying to run through that wall. ", "And you're going to get hurt. ", "But once you crack through that wall, and allow others to follow, if it's done the right way and it's an appropriate application, it's for the benefit of all.\"", "\n\nThere was another important change under the new law: Congress had created a new role for patients and disease advocacy groups.", "\n\n\"One of the aspects of FDASIA was to encourage the FDA to open its doors and meet more often with patients groups because the legislation wanted it to be considered as part of the drug approval process,\" Garabedian says.", "\n\nThat meant FDA officials had to meet with Jenn McNary.", "\n\nSo not only did Sarepta's case become the first test of a company seeking accelerated approval for a rare disease under the new law; it was also the first test of the patient community engaging the FDA since FDASIA was passed.", "\n\nIf Jenn was going to take on the federal government, she could not do it alone. ", "She needed reinforcements.", "\n\nAnd her son Max was about to help her find them.", "\n\nJUST BEFORE MAX BEGAN his clinical trial, he and Austin had been invited to attend a special weeklong overnight camp for kids, teens, and adults with muscular dystrophy. ", "Camp Promise was a program of the Jett Foundation, a small charity started by a Boston-area nurse named Christine McSherry and named for her son Jett.", "\n\n\"When I had my son he appeared perfectly normal and healthy,\" Christine says. \"", "The first couple of years were very uneventful. ", "He was growing. ", "He had beautiful blue eyes and big eyelashes and blond hair. ", "He was a spitting image of my husband and it was like falling in love with my husband all over again.\"", "\n\nChristine's house was always in a state of barely controlled chaos. ", "Jett was the third of five children, and his two little brothers were a whirlwind of hyperactivity.", "\n\n\"You would leave the room and come back and all the furniture would be rearranged or upside down,\" Christine says. \"", "And Jett would just be sitting there like 'I don't know what happened.' ", "So I really thought Jett was just a mellow kid and the others were not.\"", "\n\nThere were no signs of trouble. ", "Jett walked on time, crawled on time; he could run, play sports, and ride a bike. \"", "There was really nothing significant to set us off—other than he had trouble getting up off the floor and his calves were a little enlarged,\" Christine says.", "\n\nWhen Jett turned five, Christine took him to the pediatrician's office for his annual well check. ", "That day, she says, \"my world changed.\"", "\n\nThe pediatrician became concerned watching Jett get up off the floor in his office. ", "Just like Austin, Jett put his hands on his knees and used them to crawl up his legs to a standing position.", "\n\n\"Oh dear, we have a problem,\" the doctor told Christine.", "\n\nThe pediatrician sent Christine to a neurologist, who drew Jett's blood. ", "When the results came in, Jett's CPK level was off the charts. ", "In muscular dystrophy, the muscles in the body break down and release the CPK enzyme, which is the signal that the muscles are dying. ", "Christine is a registered nurse, and when she saw the results, she says, \"I thought immediately there must be a mistake because you can't have a CPK level that high—even in a heart attack.\"", "\n\nUnless, that is, you have Duchenne muscular dystrophy.", "\n\nShe watched Jett jumping on and off the examining table as she tried to take in the crushing news: Jett was dying.", "\n\n\"The doctor told me there wasn't a drug or a treatment that I could give him,\" she says. \"", "I was a nurse for a long time. ", "I was very accustomed to finding the solution and giving it to the patient, and was shocked to find out that there was no solution whatsoever.\"", "\n\nChristine was told that Jett would not be likely to make it past the age of fifteen.", "\n\nThat weekend, Christine and her husband told their family and friends they were going skiing. \"", "But in fact we put the cars in the garage, we drew the blinds in the house, and we shut off all the lights, and we sat in the bed for an entire weekend, and just mourned. ", "The kids sat in bed with us and we all ate Cheerios and watched cartoons on TV in mom and dad's bed for an entire weekend. ", "The kids slept there and everything. ", "We all just slept together and mourned.\"", "\n\nWhen Monday arrived, Christine's husband decided to go to work. \"", "I've got to do something productive,\" he told her. ", "She told him she understood.", "\n\nLater that morning, when the babysitter arrived, Christine took Jett, put him in the car and headed to Cape Cod.", "\n\n\"I never understood, even when I was a nurse, how much pain people were in to want to kill themselves,\" she says. \"", "There were many suicide attempts that came into the hospital where I worked. ", "I would take care of those patients, but I could never understand what could cause so much hurt to make them want to kill themselves. ", "They would say that the pain was just too bad. ", "How could they be in that much pain? ", "That Monday morning I understood exactly what those patients were talking about.\"", "\n\nShe drove to the Sagamore Bridge that connects Cape Cod with the mainland of Massachusetts across the Cape Cod Canal. ", "Christine remembered driving across the bridge as a little girl and seeing the big blue sign at either end that read \"Desperate? ", "Call the Samaritans.\"", "\n\n\"All I could think is that I just had to end my life, Jett's life, because I couldn't let the other four children go through watching their brother die. ", "And I certainly couldn't have their father, who I love so much, witness the same thing. ", "There must be something better.\"", "\n\nShe just sat there in the car, staring at the bridge.", "\n\nJett looked at her.", "\n\n\"What are we doing here, Mom?\" ", "he asked.", "\n\n\"I'm not really sure,\" Christine told him.", "\n\n\"Well, let's take a walk, Mom,\" Jett said.", "\n\nSo Christine parked the car and together they walked down to the causeway, sat down, and stared out at the water.", "\n\nIt was a cold February morning, so she and Jett were all alone. ", "As she sat there, she imagined what it would be like for her girls to hear that mom was not coming back, that their little brother was not coming back.", "\n\n\"And for some reason, I just had the revelation that maybe somehow we could survive this,\" Christine says. \"", "Maybe I could do something to help my family survive it even if Jett did not survive.\"", "\n\nPerhaps, she thought, she could turn the pain she was feeling into something productive—something that could help Jett, help her family, and help others.", "\n\nChristine and Jett got back into her car and came home. ", "And slowly, her despair turned into determination.", "\n\n\"I wasn't going to let him die like they told me he would,\" Christine says. \"", "Being able to throw a ball, being able to ride a bike, being able to walk, being able to go to the prom, being able to become a man, to have a career, have children. ", "There had to be something that we could do.\"", "\n\nSo she started the Jett Foundation. \"", "We picked the logo of the fighter plane because we were determined that we were going to fight this.\"", "\n\nOver the next fifteen years, the foundation grew—and so did Jett. ", "His disease progressed more slowly than Christine had anticipated.", "\n\n\"He was able to play a lot of sports,\" she says. \"", "He played baseball, he played soccer, he swam, he participated on a ski team. ", "We tried to give him everything that we thought that he could potentially do. ", "Because eventually, you know, all you have left when they go is memories. ", "So we wanted to create as many memories for him as possible.\"", "\n\nAs Jett got older, so did his awareness of the seriousness of his condition. ", "One day, he was alone on the computer and decided to look up his disease. \"", "He typed in 'Duchenne' and it said 'fatal before the age of 19,'\" Christine says. \"", "And we walked into his room, and he was throwing things around and just going crazy.\" ", "Christine tried to comfort him. ", "She told him it would be all right. ", "She had a plan, she was working hard to save his life, it wasn't going to end that way for him.", "\n\nJett screamed at her: \"What makes me so special? ", "What makes me so special? ", "What makes you think that that can happen?\"", "\n\nFrom that moment, Christine gave up everything in her life except fighting for Jett—no more dinners, birthday parties, baseball games, visiting her parents. \"", "I was 125 percent in,\" she says. \"", "I just gave up years and years and years of being a mommy.\"", "\n\nLike Jenn McNary, she kept waiting for a cure that never seemed to come. \"", "I had in my mind the entire time all these years that a treatment would happen just in the nick of time.\"", "\n\nAs Jett progressed in his disease, she watched him losing his independence. ", "And through her work in the Jett Foundation, she saw other kids doing the same.", "\n\n\"As a nurse my instinct has always been to try to help other people,\" she says. ", "So Christine started reaching out to local sports teams and organizing events for Duchenne kids. ", "The Boston Bruins invited the kids on the ice in their power chairs for a skate. ", "The New England Patriots hosted them for a special Duchenne day at the Patriots training camp.", "\n\nOne day, Christine noticed that the Muscular Dystrophy Association camp stopped at age seventeen—and she thought about all the Duchenne kids she knew who had beaten the odds and made it to nineteen or twenty. ", "They didn't qualify for camp anymore. ", "Christine decided to start a camp of her own that would be open to kids and adults of all ages. ", "And in 2009, Camp Promise was born.", "\n\n\"There was this family in Vermont who I knew of through Facebook,\" Christine says. ", "They would come to some of her events. ", "And they came to the first year of Camp Promise.", "\n\nChristine remembers keeping a special eye on Max that week.", "\n\n\"I watched him specifically because he was in that transition age where you go from being ambulatory to not ambulatory,\" Christine recalls. \"", "And it can be very difficult because kids will often fall. ", "And when kids with Duchenne fall, they spontaneously collapse. ", "It's not like they trip over anything, or there's a sign of weakness when they fall. ", "They just all of the sudden fall for no reason. ", "Their legs go out from under them. ", "It's scary as anything. ", "A lot of kids end up breaking their bones, because they can't even brace themselves for the fall because they don't know it's coming.\"", "\n\nThe last thing she wanted was for any of the kids to fall and get seriously injured at her first camp, so she watched Max like a hawk.", "\n\n\"I was probably a little bit more cautious with him than most kids,\" she says, \"so I had a very good idea of what his skill set was and what he could do and what he couldn't do.\"", "\n\nThe following year, Max did not come to Camp Promise, but he did come to Patriots Day training camp.", "\n\nChristine recalls what happened next. \"", "We gathered everybody down in the parking lot and then we started walking down toward the practice field. ", "And as we were approaching the practice field, I noticed Max actually ran past me. ", "I couldn't understand it. ", "I was like, 'All right, wait a minute, is this the same kid?'\"", "\n\nShe grabbed her phone and looked up some pictures from camp the previous year just to make certain she had the right kid.", "\n\n\"Sure enough it was him,\" she says.", "\n\nChristine spent the rest of the day watching Max. \"", "Max was doing some things that you wouldn't expect a child who had previously spent more than half their time in some sort of a mobility device to be doing. ", "He was goofing off with his little sister and his little brother and jumping on and off a little wall and climbing on the wall.\"", "\n\nShe remembers Jenn McNary getting a little bit irritated with Max, telling him, \"Would you stop it? ", "Would you just sit down?\" ", "Christine kept thinking, \"Don't make him sit down! ", "Don't make him sit down! ", "He's moving! ", "This is amazing!\"", "\n\nShe didn't say anything to Jenn, but when she got home she went back on Facebook and looked at Jenn's profile. ", "She saw what Jenn had posted about the clinical trial Max was in, how he was getting better, and how she could not get the drug for Austin. ", "She was reaching out to the online Duchenne community for help.", "\n\nSo Christine sent Jenn an email. \"", "I told her I agree there's a change in Max and I know that because I saw him at camp last year. ", "And I said, listen, I'll help you because I believe that Jett would also be amenable to that exon and let's team up and see what we can do together.\"", "\n\nJenn had been running into brick walls in the wider Duchenne community. ", "She wanted to get _all_ the Duchenne organizations behind eteplirsen. ", "So she approached the Muscular Dystrophy Association, the Parent Project Muscular Dystrophy (at whose conference she had first met Chris Garabedian), and other leading Duchenne groups, and asked for their help in a campaign to get eteplirsen approved.", "\n\nThey all turned her away.", "\n\n\"I was told by leaders from major Duchenne organizations that I was not going to be useful. ", "That I am undereducated. ", "I am not a nurse. ", "I am not anything. ", "I never went to college,\" Jenn says. \"", "I was told several times: you are just a mom of two kids, you don't belong in the halls of Congress. ", "You don't belong on TV talking about this. ", "You don't belong at the FDA trying to make a point. ", "Leave that to the experts.\"", "\n\nChristine says, \"She was doing her best to reach out to every organization and they were doing their best to dissuade her. ", "She finally just realized that these people are not doing what's best for Austin. ", "So we started working together.\"", "\n\nThey worked remotely at first, Jenn from Vermont and Christine from Boston.", "\n\n\"We reached out to everyone, everywhere we could, and kind of got a master's degree in FDA relations, policy, everything that you can imagine so that we could be effective,\" Christine says.", "\n\nThen, in the spring of 2013, Jenn's life shattered. ", "She had gotten married after Max and Austin were born, but now her husband told her he wanted a divorce. ", "He left her all alone with four children—two of them with a fatal illness—and no income.", "\n\nJenn called Christine in a panic. \"", "She's like 'I can't do this. ", "I can't do this alone. ", "I don't have any money. ", "I don't know what to do. ", "I don't have a job. ", "I can't get a job. ", "I can't take Max to his infusion.'\"", "\n\nChristine knew that if Jenn could not take Max to his infusion, Max would lose all the incredible progress he had made. ", "Worse still, the study would be compromised, and the chances of the FDA approving the drug would be set back. ", "There were only twelve kids in the trial, so losing one—especially one in whom the drug was working—would have been catastrophic.", "\n\nSo Christine swung into action. \"", "I said pack everything that you can pack and I will be there in like a week and I will move you to my town,\" Christine says.", "\n\nWhere would she live? ", "Jenn asked. ", "She had never lived anywhere but Vermont.", "\n\nChristine told her, \"I don't know. ", "I'll figure it out. ", "Don't worry about it. ", "I'm going to be there with a truck in a week. ", "You've got a week to pack up.\"", "\n\nChristine found Jenn an apartment in her hometown and helped her get the boys signed up for school. \"", "I knew, one, I could give her a job; two, eventually we'd get the infusions transferred down to the Boston area so it would be closer; three, she would be safe and she would have housing; and four, her kids would go into the school system where Jett had already been and they understood Duchenne. ", "So there wasn't going to be a problem.\"", "\n\nJenn went to work full-time at the Jett Foundation as an advocate for Duchenne families. ", "That gave Jenn a way to support her family and keep Max in the trial. ", "Even more important, it also meant she was no longer just a lone single mom confronting CEOs at conferences or fighting the federal government on her own. ", "Now she was part of a team.", "\n\nNow she had reinforcements.", "\n\nSuddenly, Jenn was meeting with senators and congressmen, testifying before the FDA, and meeting with its top leaders—all the things the Duchenne community had told her it was not her place to do. ", "And Jenn blossomed in her new role.", "\n\n\"She found her voice,\" Christine says.", "\n\nJenn began to apply the same tenacity that got Max into that clinical trial to helping Austin and other Duchenne kids get the same life-saving treatments. ", "Her goals expanded. ", "Not only would she get Austin the drug; she was going to make the FDA approve the drug so that every kid like Austin could get it as well.", "\n\nShe and Christine began recruiting more Duchenne moms into their growing campaign.", "\n\nFirst, they brought Mindy Leffler, Jenn's Facebook friend who had told her about the Sarepta trial, into the fold. ", "It turned out that Mindy's son, Aidan, had been rejected for the Sarepta trial—not for being too sick, but for being too _healthy_.", "\n\nJenn says, \"They were choosing children that walked less than four hundred meters in a six-minute walk test because they were trying to choose children that naturally would stop walking during the course of a trial.\" ", "The irony was surreal: Austin did not qualify because he could not walk at all; Aidan did not qualify because he could walk _too far_.", "\n\nAfter Aidan was turned down, Mindy and her husband, Mitch, scrambled to join the trial for the competing drug being developed by Prosensa. ", "For forty-eight weeks, they took Aidan back and forth between Bellevue and Vancouver, British Columbia, where the trial was being held. ", "When he didn't have the same side effects as the other kids, Mindy figured out that Aidan was probably on the placebo—which meant she was likely going back and forth to Canada every week for an infusion of saline solution. ", "And when all the boys in the placebo group were finally put on the drug, Mindy didn't see any meaningful progress in Aidan's condition.", "\n\nThen, without warning, the study was shut down. \"", "No one called us,\" Mindy told _Businessweek_ at the time. \"", "We learned the trial was over from a GSK [GlaxoSmithKline] investor conference call. . . . ", "There's no safety net. ", "You just crash.\"", "\n\nMindy realized her best hope for Aidan was to get him eteplirsen. ", "So she teamed up with Christine and Jenn and the other Duchenne moms to fight for FDA approval. \"", "I want Aidan on that drug and I want it to happen before he's in a wheelchair or worse,\" she said.", "\n\nThe moms quickly found Tracy Seckler, whose son Charley had been diagnosed with Duchenne and who had started her own foundation—Charley's Fund—that had raised millions for Duchenne research. ", "Then came Marissa Penrod, whose youngest son, Joseph, had been diagnosed with Duchenne. ", "Neither Charley nor Joseph could benefit directly from eteplirsen, since both were missing a different exon from the one Austin, Max, and Jett were missing. ", "But Tracy and Marissa knew that Sarepta's technology would work on other exons as well. ", "Once the FDA approved eteplirsen, it would help clear the way to approval for Sarepta's follow-on therapies.", "\n\nTogether, this growing army of Duchenne moms launched a campaign they called the \"Race to Yes\" to press the FDA to approve eteplirsen.", "\n\nThey chose the Duchenne community's hourglass as their symbol, because time was what they were up against.", "\n\nWhile the moms mobilized their growing forces, eteplirsen continued showing progress in clinical trials. ", "But instead of fast-tracking the drug for speedy approval, the FDA played \"Lucy with the football.\"", "\n\nAfter the forty-eight-week results came out in October 2012, Jenn had launched a petition on Change.org demanding accelerated approval of the drug. ", "By February 2013 her petition had collected more than 170,000 signatures.", "\n\nA month later, Sarepta made its first formal presentation to the FDA. ", "Chris Garabedian, Sarepta's then-CEO, said, \"We could have been told, 'No chance, go back and do a large placebo-controlled study, come back and talk to us in a few years.'\" ", "Instead, the response was encouraging.", "\n\nOn April 15, 2013, Sarepta announced, \"The FDA has requested that Sarepta provide additional information from the existing Eteplirsen dataset to inform a decision on the acceptability of this dataset for a New Drug Application (NDA) filing under . . . ", "Accelerated Approval.\"", "\n\nThis announcement was good news, but it—and the ones that followed—became a source of tension between the company and the FDA. ", "As part of his commitment to transparency with his investors and the Duchenne community, Garabedian decided to make all the company's interactions with the FDA public. ", "Every time Sarepta executives interacted with the FDA, the company would put out a press release detailing the outcome of the meeting, including any guidance the agency gave it or data the FDA requested.", "\n\nInvestors appreciated the unprecedented transparency because the company's stock was tied almost exclusively to whether or not the FDA was supportive of accelerated approval. ", "The Duchenne community appreciated the transparency because, as Christine put it, \"it gave us the fuel that we needed to go back to the FDA and argue their point.\" ", "When the agency would raise objections—for example, questioning whether dystrophin is important—the Duchenne moms would enlist scientists and provide data proving that dystrophin was in fact important.", "\n\nThe only party that didn't like the transparency was the FDA. ", "Christine says, \"The agency did not like us knowing all the communications between the company and them. ", "They did not like the fact that the company was able to highlight some of their ignorance around personalized medicine and Duchenne in general. ", "They did not like the fact that the advocates—we were now called 'the advocates'—knew more about the drug and about the data than they did. ", "Because that's what we were doing 24/7. ", "We were eating it for breakfast, basically. ", "And the agency and the neurology division were looking at other drugs other than just eteplirsen.\"", "\n\nAs Sarepta engaged with the FDA, the Duchenne moms launched a full-court lobbying press. ", "They held congressional briefings, organized letters from members of Congress to the FDA, and had seven conversations in six months with Dr. Janet Woodcock, the director of the FDA's Center for Drug Evaluation and Research. ", "In fact, the moms were getting more time with the FDA hierarchy to discuss eteplirsen than the company was.", "\n\nAt first, their efforts seemed to pay off. ", "On July 24, 2013, Sarepta announced that the FDA had provided the company with official guidance indicating that it would be open to a new drug application (NDA) for eteplirsen later in the year.", "\n\n\"We are encouraged by the feedback from the FDA and believe that data from our ongoing clinical study . . . ", "will be sufficient for an NDA filing,\" Garabedian declared in a press statement.", "\n\nThe Duchenne moms were elated. ", "It looked like the drug was finally moving forward toward accelerated approval.", "\n\nIn October, both Christine McSherry and Dr. Janet Woodcock were honored at a gala hosted by the EveryLife Foundation—Christine for her advocacy and Dr. Woodcock for her work advancing faster drug-approval pathways. ", "Jenn and Christine brought their kids to the gala. ", "It was the first time Dr. Woodcock got to meet Max, Austin, and Jett. ", "They posed together for pictures. ", "Everyone was smiling. ", "The system appeared to be working.", "\n\nThe smiles did not last long, however. ", "A month after the gala, the FDA pulled the football away. _", "Businessweek_ reported that FDA \"evaluators . . . ", "told Sarepta not to bother applying for approval.\" ", "The decision was based, in part, on the failure of its competitor's clinical trial. ", "Sarepta tried to explain how its drug was different from the competitor's and to show why the data from its studies was compelling, but the evaluators would not budge. ", "They said that an application for accelerated approval would be \"premature.\"", "\n\nThe moms felt betrayed. ", "They had been meeting with Dr. Woodcock and senior FDA officials for months and were getting nothing but encouraging signals. ", "The setback came as a complete surprise. ", "They felt they had been lied to.", "\n\nNot ones to back down, they ramped up the pressure on the FDA. ", "Christine recalls some of the tactics they employed.", "\n\n\"There was the day when Jenn published Janet Woodcock's phone number on Facebook and told everybody to call on a Monday morning at 9:00 a.m. and literally shut down the phone system at the FDA,\" she says. \"", "We got an email from Janet's assistant that said, 'We got the message. ", "Could you guys please tell people to stop calling my line?' ", "Then there was another time when we asked everybody to email the agency and I believe we shut down their server for a couple of hours.\"", "\n\nThey also took advantage of a system President Obama had established allowing citizens to start online petitions on the White House website. ", "Any petition that got 100,000 signatures within thirty days would get an official response from the White House. ", "So in February the moms launched a White House petition urging the FDA to \"say yes\" to a cure for Duchenne.", "\n\nBy the end of March, they had gathered 106,782 signatures, enough to force an official response.", "\n\nAt the same time that they launched their White House petition, the moms brought seven of the world's Duchenne experts to Washington to meet with FDA officials. ", "They came from Perth, London, and Toronto, and included the Harvard professor who discovered dystrophin in 1987.", "\n\n\"If the government officials won't listen to us, we reasoned, surely they would listen to the experts,\" Tracy Seckler explained in an op-ed for the _Huffington Post_. \"", "All in attendance . . . ", "agreed that Eteplirsen is producing the missing protein. ", "All agreed that producing dystrophin is more than 'reasonably likely' to lead to clinical benefit. ", "All agreed that we are in fact already seeing clinical benefit in the 12 boys exposed to treatment.\"", "\n\nOnce again, it seemed that the petition and the meetings had an impact. ", "In April 2014 the FDA reversed itself and once again invited Sarepta to submit an NDA later that year.", "\n\nSoon after the announcement, Dr. Woodcock issued the official response to the Duchenne moms' White House petition—and, not surprisingly, she touted the FDA's decision:\n\nWe share your sense of urgency to make safe and effective drugs available for patients with Duchenne muscular dystrophy as soon as possible. ", "That's why we're actively engaged with a number of drug companies focused on developing new drugs for Duchenne muscular dystrophy, including Sarepta Therapeutics, the company developing eteplirsen. . . . ", "Sarepta Therapeutics has publicly announced its intention to file a New Drug Application for eteplirsen by the end of 2014 as well as plans to initiate several additional clinical studies with eteplirsen later this year. ", "As mentioned above, we are willing to explore the use of all potential pathways for the approval of drugs for Duchenne muscular dystrophy (including accelerated approval) as appropriate.", "\n\nThe moms had not even mentioned eteplirsen in their petition, yet Woodcock cited the drug by name. ", "They were thrilled that eteplirsen was back on track for accelerated approval.", "\n\nAlas, their victory was short-lived. ", "A few months later, the FDA pulled the football back once again—withdrawing the guidance inviting an NDA and demanding even more data.", "\n\nThe agency told Sarepta that it could apply in mid-2015.", "\n\nChristine says, \"The agency was getting so upset that the company kept releasing the information about their meetings and how they kept asking for additional data, additional data, additional data that they actually became somewhat vindictive. ", "It seemed like the more we pushed, the more things they asked for, so we backed off a little bit.\"", "\n\nWhen the moms complained about the delay, they were told it was just six months.", "\n\n\"What does that mean?\" ", "Tracy Seckler, Charley's mom, said during a Google chat organized by the Jett Foundation following the decision.", "\n\nIt's not just six months, it's six _more_ months added onto the delays we've already endured. [", "And] once the New Drug Application is filed, the review process, if it's expedited takes _another_ six months. ", "And [then] we already know it takes six months for Eteplirsen to start producing dystrophin. ", "So from today it's going to be another year-and-a-half before all eligible children can start benefitting from Eteplirsen. ", "That's another year-and-a-half on top of the year-and-a-half we have already spent fighting.", "\n\nThe only analogy I can think of that comes close to this is the _Titanic_. ", "Our children are on the _Titanic_ and we know it's going down with 100 percent certainty. ", "There's a lifeboat and a team of engineers has reviewed the lifeboat and said it's reliable. ", "We need to get the kids into these lifeboats instead of questioning every single bit of minutia about the way the lifeboat was developed. ", "Because while we're asking those questions, the kids on the _Titanic_ are going down. ", "Let's work together to get more lifeboats in the water and to get every kid a chance to keep them afloat; better and stronger lifeboats will come along but what good will it do if we leave our kids on the _Titanic_ while we're waiting for them?", "\n\nMarissa Penrod, Joseph's mom, said, \"The FDA is failing our children. ", "Every passing second, every day, every minute, ever hour, children with Duchenne are losing muscle. ", "My ultimate fear is that my little boy will lose the ability to hug me. ", "He walked across the room to me over the weekend and about five feet before he got to me his legs just gave out without warning. ", "He buckled and went to the ground.\"", "\n\nHer message to the FDA? \"", "Our children can no longer be your science experiment. ", "The children are not here to serve science. ", "The science should always serve the children.\"", "\n\nYet nearly three years after Sarepta first demonstrated that eteplirsen was safe and helping Duchenne kids, the FDA still had not invited Sarepta to apply for approval of the drug.", "\n\nHow many kids were being hurt by the FDA's delays? ", "There are about fifteen thousand to twenty thousand boys in the United States with Duchenne, and eteplirsen can help about 13 percent of them. ", "That is about 1,950 to 2,600 boys who desperately need this drug.", "\n\nBut that is only scratching the surface. ", "Sarepta estimates that its broader portfolio of exon-skipping compounds—all based on the same technology as eteplirsen—could help about 80 percent of those boys. ", "That's twelve thousand to sixteen thousand kids in the United States alone—and tens of thousands more across the globe who could benefit.", "\n\nBut today, Jenn says, \"There are only twelve children in the world receiving that medicine. ", "The rest of the children are wasting away and dying.\"", "\n\nThat, she says, is unacceptable. \"", "Kids die from this disease every day. ", "I know at least two personally who have died [since Max's clinical trial began] who needed this drug. ", "Five children with Duchenne died last week that I know of. ", "Of course, there are more that we don't know personally. ", "This is not hypothetical. ", "This is children dying every day.\"", "\n\nJenn continues to fight for those kids, and her own, but the fight has taken its toll.", "\n\n\"This has not been an easy road,\" she says. \"", "It caused a divorce in my life. ", "It brings me away from my family. ", "But I think that it was very important to speak up. ", "I very, very strongly believe that if I had never said to the public, 'Hey this drug exists! ", "It's working and we deserve access!' ", "nobody would know about it.\"", "\n\nWhile she is confident she will ultimately prevail, she is also aware that success may come too late for her son.", "\n\n\"This may not make a change for Austin. ", "He may be too far gone by the time he does get on the drug,\" Jenn says. \"", "But hopefully, I will save some kids who are just being diagnosed right now. ", "And they may never have to experience the symptoms of this disease.\"", "\n\nUnfortunately, Jenn, Christine, Mindy, Tracy, and Marissa were not alone in their struggle with the federal government. ", "Halfway across America, in Phoenix, Arizona, an eleven-year-old boy was about to launch an epic battle to save his own life—a battle that would ultimately help him save the lives of countless others.", "\n\n# 2.", "\n\nFive Thousand Miles for a Cure\n\n_How One American Family Moved Overseas to Save Their Dying Son_\n\nHow far would you go to get a drug that could save your child's life? ", "Halfway across the world? ", "Unfortunately, that is exactly what the government is forcing some families with dying children to do.", "\n\nLike many young kids, Diego Morris is a sports fanatic. ", "He has a Phoenix Suns blanket on his bed and Larry Fitzgerald's Arizona Cardinals jersey on the wall of his room. ", "A dual-sport athlete, he loved playing both soccer and Little League baseball.", "\n\nOne morning, when he was eleven, Diego woke up with intense pain in his left knee. ", "At first his parents, Paulina and Jason, figured it was a sports injury. ", "They gave him some Advil and an ice pack and waited to see if it got better.", "\n\nWhen the pain didn't go away, they decided to take him to the pediatrician to have it checked out just in case.", "\n\n\"I have to tell you, it didn't faze me,\" says Diego's father, Jason. \"", "Of course his knee is bothering him. ", "He's a tough kid, he plays aggressively.\"", "\n\nPaulina brought Diego to the doctor's office. ", "When the pediatrician touched his knee, Diego yelped in pain. ", "She had known Diego all his life and had never seen him respond this way. ", "So she sent him to an orthopedic surgeon, who took an X-ray.", "\n\nIt wasn't a sports injury.", "\n\n\"The orthopedic surgeon turned to me after looking at the X-ray, and he was white as a ghost,\" Paulina says. \"", "He said, 'I think this is serious.'\"", "\n\nPaulina gave Diego her iPad and told him to go play in the lobby while she and the doctor talked. ", "When he left, the doctor closed the door to the examining room. ", "He sat Paulina down and told her that, while he'd have to take an MRI to confirm it, the X-ray indicated Diego had osteosarcoma—a rare bone cancer.", "\n\nCancer? ", "Paulina thought. ", "A few minutes ago she was worried he might have twisted his knee on the soccer field. ", "Now he was facing a life-threatening diagnosis.", "\n\nShe immediately called Jason, who was picking Diego's brother Mateo up from school, and told him to come to the doctor's office at once.", "\n\n\"I was driving home with Mateo when Paulina called and she was in tears and I could hear it in her voice immediately, she was scared to death,\" he says. ", "He rushed over to join her.", "\n\nPaulina says that the doctor \"ran us down to the MRI in his building and they took a scan, and sure enough we knew by that night that it was likely osteosarcoma.\"", "\n\nFortunately, the scan showed they had spotted the cancer early, before it had spread.", "\n\nWhen they got home, Paulina and Jason tried to maintain a semblance of normalcy. ", "They had a family dinner and put the kids to bed. ", "But as soon as the kids were asleep, they called their close friends, Chris and Irene, and asked them to come over immediately. \"", "He's a radiation oncologist and she's a pediatrician,\" Paulina says. ", "They had two girls the same ages as Diego and Mateo and had known the boys all their lives. ", "They came over that night, and took a look at the scans on the computer. ", "After examining the images, they confirmed the bad news: it was almost certainly osteosarcoma.", "\n\nThey could not be certain of the diagnosis until Diego underwent what is called a core-needle biopsy. ", "A doctor takes a long, hollow needle, inserts it into the tumor, and uses it to extract a core of the tissue to test whether it is cancerous.", "\n\nChris said they needed to choose carefully which doctor did the procedure because, he told Paulina, \"if somebody does a needle biopsy and they don't do it properly, the cancer can spread.\" ", "Chris's partner in his medical practice had survived childhood cancer and was treated at St. Jude Children's Research Hospital in Memphis, Tennessee—the cancer center founded by the late entertainer Danny Thomas. ", "It is one of the best pediatric cancer hospitals in the country. ", "He arranged for Diego to go to St. Jude for the test and by Monday the Morris family was on a plane to Memphis.", "\n\nWhen they walked through the doors of St. Jude, Diego was terrified. ", "Everywhere he looked he saw kids with cancer. \"", "We love going back there now,\" Jason says, \"but when you're uninitiated and you arrive on a campus like this, it's like being on a planet full of cancerous children all of whom are going through some form of treatment. ", "They have no hair, they're in wheelchairs, they're being pulled around in little red wagons, they all have intravenous drips going, and it's terrifying.\"", "\n\n\"I hadn't been diagnosed yet,\" Diego says. \"", "Being there and seeing all the other kids who had cancer . . . ", "everyone around me was a patient with cancer. ", "So that makes it very, very scary.\"", "\n\nThey stayed at St. Jude for ten days. ", "Doctors opened up Diego's knee and took what's called a frozen section—removing some of the tumor and examining it right there on the operating table. ", "After seeing thousands of tumors, they could tell with a high level of certainty whether it was osteosarcoma.", "\n\nDiego had been told that if the doctors believed it was cancer, they would immediately place a port in his chest while he was still under anesthesia so he would have his chemotherapy administered without having to use a needle.", "\n\nWhen he woke up, the first thing he did was look at his mom and dad and ask:\n\n\"Did they put the port in?\"", "\n\n\"Yes,\" his parents said.", "\n\n\"So I've got cancer?\" ", "Diego cried out.", "\n\nJason nearly breaks down recalling the moment. \"", "It's a string of horrible memories that I try not to think about, and as I'm telling you I'm shaking,\" he says.", "\n\nA few days later the lab results came in and confirmed the diagnosis.", "\n\nPaulina and Jason had to make some quick decisions. ", "Diego needed ten weeks of chemotherapy to reduce the size of the tumor before he underwent resection surgery to remove it, and then limb-salvage surgery to see if doctors could save his leg. ", "Before 1970 the only way to treat osteosarcoma had been amputation of the affected limb, but today doctors can save the limb in most cases so long as the cancer remains localized.", "\n\nThe doctors at St. Jude encouraged the Morrises to stay in Memphis for both the chemotherapy and the surgeries. ", "But they also told Jason and Paulina that the presurgery chemotherapy was standard for every child who has osteosarcoma, which meant they could also get it back in Phoenix. \"", "We could go to the hospital basically less than a mile from us and he would receive the same treatment and he'd be able to be around his friends and he'd be able to sleep in his own bed at night,\" Jason says.", "\n\nPaulina and Jason decided as a family to bring Diego back to Phoenix for the chemo. ", "The whole experience had been overwhelming for the eleven-year-old. ", "In less than a week, he had gone from playing soccer with his friends to a hospital bed in a children's cancer ward fourteen hundred miles from home. ", "He was scared, he was homesick, and he missed his new puppy, Mojo.", "\n\n\"We wanted to be in our home, we wanted to have Diego in his bed as much as possible,\" Paulina says. \"", "We knew the strength of being at home and having your support system around you.\"", "\n\nLittle did they know they would soon have to leave that support system behind and uproot their family in order to save their son.", "\n\nAfter finishing his chemotherapy at Phoenix Children's Hospital, Diego boarded the flight back to Memphis for his surgery at St. Jude. ", "He now looked like the children who had terrified him on his first visit to the hospital.", "\n\n\"He had lost all his hair; he was walking on crutches,\" Jason says.", "\n\nDuring the flight, Jason noticed that the man in the seat near Diego was chatting him up. ", "Toward the end of the flight, the man came up to Jason and introduced himself.", "\n\n\"Hi, I talked to your son. ", "I understand you're going to St. Jude. ", "It's an amazing place, you couldn't be taking him to a better place. ", "If it's all right with you, I live in Memphis, I'd like to stop by and keep in touch.\" ", "The man said his name was Joe and Jason gave him his business card. ", "That was just the type of kindness they had encountered in Memphis. ", "It felt like the entire city had embraced the children of St. Jude.", "\n\nJason said, \"I'm touched, thank you very much.\" ", "He thought nothing of it.", "\n\nThe next day, Jason's secretary called. \"", "There's a guy named Joe Theismann who called and wants your mobile number,\" she told him. ", "The man on the plane was the former Washington Redskins quarterback and Super Bowl champion. ", "He was on the board of St. Jude and came to visit Diego and took the family to lunch. ", "For a sports fanatic like Diego, it was one bright moment of happiness in an otherwise devastating time.", "\n\nSoon, Diego went into surgery. ", "Doctors were able to remove all of the tumor and save his leg. ", "But when the procedure was over, the Morrises got some bad news. ", "The chemotherapy Diego underwent before surgery had not been as effective as his doctors had hoped. ", "Ideally, presurgery chemotherapy kills 90 percent or more of the cancer. ", "In Diego's case, it had reduced the tumor by only 50 percent.", "\n\nThat meant the risk that Diego's cancer could return and spread was high.", "\n\nWhen osteosarcoma comes back, it does not usually return at the site of the original tumor. ", "It comes back in the lungs. ", "And once osteosarcoma reaches the lungs, it is highly resistant to chemotherapy. ", "Diego's cancer had already resisted the initial cycle of chemotherapy, so there was a significant risk that even the most extensive chemotherapy alone would not prevent the cancer from returning.", "\n\nOsteosarcoma has a 70 to 85 percent mortality rate once it has spread.", "\n\nThere had to be something more they could do, Paulina thought.", "\n\nBack home, the Morrises' friends Chris and Irene had been researching osteosarcoma treatments and one day they called Paulina and Jason with some exciting news. ", "They had found a drug that might be able to help Diego.", "\n\n\"You need to see these studies about this drug, mifamurtide, that is showing some promising results with kids just like Diego,\" they said.", "\n\nMifamurtide (also known as MEPACT or MPT) is a biological therapy that stimulates the immune system to attack cancer. ", "The drug activates large white blood cells called macrophages (which is Greek for \"big eaters\") and gets them to hunt down, engulf, and devour cancer cells.", "\n\nTo work, mifamurtide has to be given at the same time as postsurgical chemotherapy. ", "The two treatments work in tandem. ", "According to a description of the drug from MD Anderson Cancer Center in Houston, where it was discovered, \"The chemotherapy acts like a bomb sent in to destroy the tumor, while MEPACT acts as a special forces unit sent in to clean out any remaining pockets of microscopic disease.\"", "\n\nThe drug was pioneered at MD Anderson by a doctor named Eugenie Kleinerman. ", "She began studying mifamurtide in 1982 as a young researcher at the National Cancer Institute (NCI) after attending a lecture by a colleague, Dr. Josh Fidler, at a national cancer conference. ", "She sat in the audience, mesmerized, as Dr. Fidler described how he had used mifamurtide to eradicate melanoma cancer in the lungs of lab mice.", "\n\n\"What Dr. Fidler did was create a Trojan horse,\" Dr. Kleinerman says. \"", "One of the jobs of a macrophage is to get rid of old red cells. ", "When a red cell becomes old, the macrophage says, 'Oh, old red cells, need to get rid of it.'\"", "\n\nDr. Fidler had fooled the macrophages into thinking that cancer cells were old red cells. ", "He got them to attack the melanoma cells without harming healthy tissue.", "\n\nIf mifamurtide worked against melanoma, Dr. Kleinerman thought, maybe it would work for osteosarcoma as well.", "\n\nSo she reached out to Dr. Fidler and together they decided to find out. ", "They did a series of laboratory studies that showed, first, that human macrophages responded the same way as mouse macrophages (selectively killing tumor cells and not normal cells) and, second, that mifamurtide stimulated human immune cells to react against osteosarcoma cells just as it did against melanoma.", "\n\nThe results were exciting, and armed with this preclinical evidence, they approached the National Cancer Institute about conducting clinical trials in humans. ", "But, Dr. Kleinerman says, the institute was focused on other therapies and was not interested in supporting their work.", "\n\nIn 1984 Dr. Fidler was recruited away by MD Anderson Cancer Center. ", "He asked Dr. Kleinerman to come with him. ", "MD Anderson was ready to support their research.", "\n\nIn 1986 they conducted a phase I clinical trial of mifamurtide in humans, which determined the safety and optimal dose of the drug.", "\n\nThen in 1988 they conducted a phase II trial of the drug in children with osteosarcoma, which showed improved survival in patients who had not responded to chemotherapy.", "\n\nFinally in 1993 the drug was ready for a large phase III, multicenter clinical trial. ", "So Dr. Kleinerman joined forces with Dr. Paul Meyers at Memorial Sloan Kettering Cancer Center in New York to conduct a massive phase III trial. ", "They recruited about seven hundred newly diagnosed osteosarcoma patients. ", "It was, Dr. Meyers says, \"the largest trial of osteosarcoma ever conducted in the world.\"", "\n\nBut in the midst of the trial, the drug company that owned mifamurtide, Ciba Geigy (now Novartis), stopped manufacturing the drug. \"", "They decided this is an orphan disease, this is an expensive drug to make, we really don't care about it,\" Dr. Kleinerman says. ", "Fortunately, another company, Jenner Biotherapies, picked mifamurtide up, allowing it to complete the trial. ", "But then Jenner went out of business—leaving the orphan drug an orphan itself.", "\n\nWithout a sponsor to cover the costs, the results were never fully analyzed. ", "In 2005 Drs. ", "Kleinerman and Meyers published a paper describing the data they had collected up to 2003 and said the results were inconclusive. \"", "The addition of MTP to chemotherapy might improve [event-free survival], but additional clinical and laboratory investigation will be necessary,\" they wrote.", "\n\nMifamurtide, it seemed, had hit a dead end.", "\n\nA few years later Dr. Meyers got a call out of the blue from Bonnie Mills, the vice president of clinical operations at a company called IDM Pharma. ", "IDM had bought the bankrupt drugmaker, and she had been asked to look through the portfolio of drugs it had acquired to see if there were any with untapped potential.", "\n\nShe had some exciting news: mifamurtide worked.", "\n\nDr. Meyers recalls, \"She said, 'Did you know that your drug actually statistically significantly improved survival among the patients who got it?' ", "And I said, 'What are you talking about?'\"", "\n\nThey had never looked at the survival rates.", "\n\nDr. Meyers explains that when you do a clinical trial, before you start, you first develop a detailed plan for how you will analyze the results. ", "The plan for the mifamurtide study called for them to take the first look at survival data once they had observed half of the expected patient deaths. \"", "In other words, if you predict there will be 100 deaths and you've seen 49 deaths, you're not supposed to look at the survival data. ", "If you've seen 62 deaths you're allowed to look at the survival data,\" Dr. Meyers says.", "\n\nThey had never reached the number of deaths required to trigger an analysis of survival data. \"", "The reason we hadn't seen half of the expected deaths was there were fewer deaths than expected,\" Dr. Meyers says. \"", "Why were there fewer deaths than expected? ", "Because the drug was _actually working_.\"", "\n\nThe company decided to go back and track down patients in the trial and confirm how many had survived. ", "The results were astounding. ", "What they found, according to MD Anderson, was that \"MEPACT, when given in conjunction with combination chemotherapy, resulted in a 30% reduction in the mortality rate at eight years after diagnosis, compared to the patients who received chemotherapy alone.\"", "\n\nIt was the biggest breakthrough in the treatment of osteosarcoma in more than two decades.", "\n\n\"At that point,\" Dr. Meyers says, \"the company said we need to go to the FDA and show them these data and ask for approval for this drug. ", "This is an exciting drug, the first drug to punch the needle in this disease for over twenty years.\"", "\n\nThe FDA did not share their enthusiasm.", "\n\n\"We went to the FDA and we had _extraordinarily_ hostile reception,\" Dr. Meyers says. \"", "I mean a really nasty, angry, 'Get out of my face, what the hell are you doing here' reception.\"", "\n\nWhy did the FDA react with such hostility to news of a historic breakthrough in the treatment of a rare, but deadly cancer? \"", "I can only speculate,\" Dr. Meyers says. \"", "I can tell you that the usual course of action in developing a drug is—before you ever initiate the clinical trial that you want to submit for approval—you go to the FDA and you ask them to review your clinical trial. ", "And [they] say, 'Yes, we agree that your trial design is appropriate, your sample size appropriate, your end points are appropriate, we like the way you've designed this trial.' ", "That never happened because when we began the clinical trial no one had the faintest idea that we would ever be seeking approval for this drug.\"", "\n\nIn other words, the agency was unhappy because it had not been consulted before the trial began.", "\n\nThe FDA also pointed to the article Drs. ", "Kleinerman and Meyers had published, citing their own words back to them declaring that the results of the trial were inconclusive. \"", "We said, 'But we have new data! ", "Look at our new data!'\" ", "Dr. Meyers says. \"", "And they said, 'Go away and don't come back.'\"", "\n\nBut the company did come back. ", "It insisted that mifamurtide get a formal hearing before the Oncology Drugs Advisory Committee.", "\n\n\"It was as if we had slapped them in the face,\" Dr. Meyers says. \"", "What are you doing here? ", "We told you not to come back.\"", "\n\nThe hearing took place on May 9, 2007. ", "The FDA made a very negative presentation before the committee. \"", "The review team and Division Director find that the Applicant, IDM, has failed to demonstrate that their product . . . ", "provides substantial evidence of efficacy,\" the FDA declared, adding, \"FDA finds that there is not sufficient evidence of a survival advantage for the addition of MTP-PE to the standard chemotherapeutic regimen.\" ", "Dr. Meyers later learned that the FDA had used the old data as the basis of its presentation—not the new data that showed increased survival rates.", "\n\nDr. Kleinerman testified that the FDA was wrong. \"", "This is the first time that we have seen a five-year survival rate approaching 80 percent for patients with nonmetastatic disease, the first improvement in the treatment of osteosarcoma in over twenty years,\" she told the committee. \"", "If we assume that about 600 children will be diagnosed with osteosarcoma each year, we estimate the use of MTP will save an additional 50 children per year in the United States or 500 children in 10 years. . . . ", "If it is not approved at this time, we will have failed our patients. ", "For every year that MTP's use is delayed, fifty potential avoidable deaths will occur from osteosarcoma. ", "Our patients must have access to this agent,\" she declared.", "\n\nDrs. ", "Kleinerman and Meyers brought in patients who had been cured by mifamurtide to testify. ", "The Sarcoma Foundation of America came to lobby for approval of the drug.", "\n\nYet despite their best efforts, the drug was rejected.", "\n\n\"I was extremely depressed,\" Dr. Kleinerman says.", "\n\nA few months later, she got a call from IDM. ", "It still believed in mifamurtide and had decided to bring it before the European Medicines Agency (EMA), the European equivalent of the FDA. ", "IDM asked her and Dr. Meyers to help them guide mifamurtide though the approval process in Europe. ", "They agreed.", "\n\nThe process in Europe was completely different. \"", "Each country has two representatives and you walk in the room and it looks like the United Nations,\" Dr. Kleinerman says. \"", "They're sitting around and viewing computers. ", "So [unlike the FDA] they're viewing the primary data\"—including the new survival data the FDA had ignored.", "\n\nThe FDA had given them just a few hours to make their case. ", "By contrast, the European agency put them through three hearings. \"", "They sent a team of auditors to sites around the United States which had participated in a clinical trial including my hospital,\" Dr. Meyers says. \"", "I had four auditors in my hospital for five days. ", "They were looking at the patients' charts to be sure that the data we wrote down and submitted to the data management center was accurate.\"", "\n\nBased on its careful review of the new information and its field investigation of the clinical trial, the EMA determined that mifamurtide was safe and effective. ", "It approved it in 2009 for use in all twenty-seven EU member states as well as Iceland, Liechtenstein, and Norway.", "\n\nIn 2011, after a careful three-year review, mifamurtide was also approved by Britain's National Institute for Health and Care Excellence (NICE), the agency that determines which drugs will be paid for by the government in the United Kingdom. ", "NICE chief executive Sir Andrew Dillon pointed out that while only 150 new cases of osteosarcoma are diagnosed in the United Kingdom each year, \"for the small number of patients who benefit from Mifamurtide, the health benefits continue over the rest of their lives, effectively being a cure.\"", "\n\nIn 2012 mifamurtide received the prestigious Prix Galien Award, the gold medal for pharmaceutical research and development in the United Kingdom. ", "At a gala in London, Professor Sir Michael Rawlins, president of the Royal Society of Medicine, declared, \"Apart from its novel mechanism of action—and clear evidence of its clinical effectiveness—the jury were also extremely impressed that such an advance in the management of osteosarcoma represents the first significant change in outcomes in ten to twenty years of managing this disease.\"", "\n\nThe more Paulina and Jason Morris learned about mifamurtide, the more excited they became. ", "An award-winning drug that could reduce their son's risk of dying by 30 percent, and has been declared a \"cure\" by the British government?", "\n\nMifamurtide seemed perfect for Diego.", "\n\nThe problem was, the drug was still not available in America.", "\n\nAfter the EMA approved mifamurtide, a Japanese pharmaceutical company, Takeda, acquired IDM Pharma, and the rights to mifamurtide. ", "Takeda tried to bring the drug back to the FDA for approval. ", "Now that the EMA had endorsed mifamurtide, surely its American counterpart would have to acknowledge the possibility that it had made a mistake and take another look.", "\n\n\"They tried to go to the FDA and [asked them] to re-review the data,\" Dr. Kleinerman says. \"", "And they refused to re-review the data. ", "They're insisting on another trial.\" ", "The trial the FDA demanded would require approximately nine hundred patients. ", "There are only about eight hundred new cases of osteosarcoma a year to begin with, so finding nine hundred patients to participate in a _second_ large trial for a disease this rare would be next to impossible. ", "The cost was prohibitive. \"", "What the FDA is requiring would cost them $160 million and they just cannot justify that outlay of resources for an orphan disease,\" Dr. Kleinerman says.", "\n\nWhile mifamurtide languishes in a bureaucratic quagmire here in the United States, more and more countries across the world have approved it for use. \"", "It is standard of care in the UK, Spain, Portugal, and Italy,\" Dr. Kleinerman says. \"", "Israel, everyone is getting it. ", "Korea did another study and they duplicated our findings that there was superior overall survival in patients that got mifamurtide. ", "This summer I'm going to Kazakhstan. ", "It's being launched in Thailand, it's being launched in Colombia, Mexico, Venezuela.\"", "\n\nDr. Meyers is traveling the world as well. \"", "I'm leaving for Argentina on Wednesday to talk to the Argentinean oncologists about the drug. ", "I'm going to Finland in two weeks to talk about the drug.\" ", "Dr. Meyers does not make a penny from mifamurtide. ", "He does it, he says, because \"I believe that the drug works. ", "I believe the drug should be available for every child with osteosarcoma. ", "It's not available in the United States and it doesn't look as if it will ever be available in the United States.", "\n\n\"My strategy is simple,\" he says. \"", "I plan to get this drug approved in 194 of the 195 countries on earth. ", "At some point the cure rate for osteosarcoma in those countries will exceed the cure rate for the US and people will start to ask questions about why.\"", "\n\nOver the years, Dr. Kleinerman has kept up with several of the clinical trial patients she treated in the United States. \"", "In my phase II study, I had one young man whose pediatric oncologist sent him home to die. ", "He was in high school. ", "He's now an orthopedic oncologist at the University of Pittsburgh,\" she says. ", "Another patient was a young Vietnamese girl whose mother brought her to MD Anderson to be treated. \"", "I was at her wedding ten years ago. ", "I was at her wedding. ", "These are kids that are cured.", "\n\n\"So the tragedy is, US children showed it was effective. ", "It was developed in the United States. ", "A lot of my preclinical work was supported by National Institutes of Health grants. ", "We can no longer get it in this country,\" she says.", "\n\nWhat does she think of the FDA approval process? \"", "I think it is broken,\" Dr. Kleinerman says. \"", "My experience with the FDA is [like] a saying in my house about men. ", "What are the three things men can never say? '", "I was wrong.' '", "I'm sorry.' ", "And 'I'm lost.' ", "So I think the FDA cannot say: Perhaps we didn't judge this correctly. ", "Let's take another look. ", "Perhaps we were wrong.\"", "\n\nShe does not fault the FDA alone. \"", "I also fault my pediatric oncology colleagues, because I think if we would get together and were more vocal and put pressure on the FDA—but everybody is afraid, you know. ", "Well, if I make them mad then my hospital president won't be happy, and I won't get my tenure renewal, or I won't get promoted, the FDA will not put my trial in—you can create a hundred scenarios.\"", "\n\nMifamurtide, she says, is \"a drug that has a great safety profile with over 25 years of data. . . . ", "It is adding benefit in terms of survival with good quality of life. ", "I would think you would bend over backward to see how you could get this available for patients in this country.\"", "\n\nBut it is not available for patients in this country—and that meant Diego Morris would have to go abroad to get the drug he needed to save his life.", "\n\nPAULINA AND JASON COULD not believe they were unable to get the drug Diego desperately needed—a safe and effective drug in use across the world—here in America. ", "And because he needed to start immediately, at the same time he underwent postsurgery chemotherapy, they had only a brief window to gain access to this life-saving medication.", "\n\n\"We tried everything,\" Paulina says. \"", "We talked to the drug manufacturer. ", "We talked to our political representatives' offices. ", "We talked to the FDA. ", "We tried every avenue we could think of to get the drug here. ", "Because, like our initial decision of having chemotherapy in Phoenix, we knew the value of being in your own home and having your loved ones around you.\"", "\n\nThey looked into clinical trials, Jason says, \"but all the trials had finished and the FDA had denied approval.\" ", "They looked into the FDA's \"compassionate use\" program, but that was a dead end. ", "The FDA had stopped compassionate use of mifamurtide in 2012. ", "So they started looking abroad.", "\n\n\"We contacted the drug company and said, 'Is there anything else going on? ", "Are you testing this somewhere else in the world?'\" ", "Jason says. \"", "And they said, 'No we're not testing it somewhere else in the world, because it's being used elsewhere in the world.'\" ", "That was when they learned about all the countries where mifamurtide was available.", "\n\nThey kept looking for a way to get it here at home. ", "One option was to get the drug abroad and import it themselves—just like the AIDS activists in the movie _Dallas Buyers Club_. ", "The rep from the drug manufacturer explained it was legal in Mexico and being used routinely by patients. ", "She offered to explore which border city would be closest to them. \"", "They would meet us at the border and we could import it ourselves,\" Jason says.", "\n\nAt first it seemed like the perfect solution, but the more Jason and Paulina thought about it, the more problems they saw. \"", "This drug has to be kept refrigerated and I was worried: how do we do that?\" ", "Jason says. \"", "Secondly, if it was confiscated, what if they didn't refrigerate it? ", "Would I ever get it back? ", "It's about a quarter of a million dollars worth of drugs. ", "So that would be money thrown away if we didn't have the drugs. ", "And then, the last part is I'd need to find somebody to administer it and I wouldn't want to put any of my medical friends at risk and ask them to do that because that's asking them to put their career on the line. ", "So, although it was tempting, that didn't seem like a solution for us.\"", "\n\nThey quickly came to a stark realization. ", "If they were going to get the drug for Diego, they would have to move to a foreign country.", "\n\nBut where? ", "Jason and Paulina began reaching out to every hospital and clinic across the world they could find that treated patients with mifamurtide. \"", "I called some doctors in Israel and some doctors in Germany and Italy and London,\" Jason says. ", "The good news was, every clinic they contacted said Diego was welcome.", "\n\nThey weighed the different options. \"", "Israel was appealing, but there are no direct flights between Israel and Arizona. ", "And in addition to worrying about my son's health, I would be worried about the political reality in the Middle East,\" he said.", "\n\nAnother possibility was Mexico. ", "Irene, their pediatrician friend who had helped diagnose Diego, was born outside Mexico City. ", "She quickly found a hospital there that was treating children with mifamurtide. ", "So Irene, Paulina, and Jason got on a plane to Mexico to investigate.", "\n\n\"The three of us flew there; my husband and I and this doctor,\" Paulina says. \"", "She interpreted medical Spanish. ", "And the doctors there told us how promising this drug was and they showed us scans, and they showed us basically the drug at work on the children they were using it on. ", "It almost looked like Pac-Man. ", "You could see their own bodies going to work on [the cancer].\"", "\n\nThey also spoke to Dr. Meyers at Memorial Sloan Kettering—the doctor who had run the mifamurtide studies with Dr. Kleinerman. ", "Jason asked what he would do if it was his son or grandson.", "\n\n\"I would go,\" Dr. Meyers told Jason, \"I would get it.\"", "\n\nThat is what they decided too.", "\n\n\"We were down to the wire,\" Jason says. ", "It was either London or Mexico City. ", "Mexico seemed to make the most sense. ", "Jason would have to commute between his job in Phoenix and wherever Diego went for treatment, and Mexico City was closest to their home in Arizona. ", "But Paulina said, \"There was also the issue of interpreting medical conversations and that can be very difficult.\" ", "And, Jason adds, \"I was worried about them living in Mexico City.\"", "\n\nJason had family in England and there was a well-regarded clinic in London that was willing to provide the treatment. ", "It would be much farther from home and a much more challenging commute. ", "But they had a support network there and shared a common language with the doctors who would be treating Diego.", "\n\nThey decided to move to London.", "\n\n\"Thank God we were able to make that decision to make that move,\" Paulina says. \"", "So many people can't.\"", "\n\nThe Morrises stayed with Jason's first cousin Jack and his wife, Susan. ", "They were just planning to stay there a few days, until they found an apartment near the hospital. ", "But soon their cousins told them to stop looking and stay with them for the full nine months.", "\n\n\"What will happen to your younger son and when you're in the emergency room or in the hospital?\" ", "Jack and Susan asked. \"", "How can you possibly handle this when Jason's going to be back in Phoenix quite a bit? ", "Stay with us and let us take care of you.\"", "\n\n\"So again, we were blessed,\" Paulina says. \"", "We had a loving family to stay with. ", "And it was still difficult. ", "It was still terrible to be in another country and be away from our home and my husband, Diego's father, at the worst time of your life.\"", "\n\nDiego underwent twenty-one rounds of debilitating chemotherapy. \"", "The oncologist had told us this is going to get rough and you're going to be afraid that you're killing him with this chemotherapy, because it's going to ravage his body,\" Paulina says. \"", "And it sure did. ", "He didn't have an ounce of hair on him. ", "If you ever meet Diego you'll laugh because he's the hairiest kid! [", "His skin] was translucent. ", "By the last chemotherapy, the skin was coming off of his hands. ", "It was really frightening.\"", "\n\nPaulina and Jason had their doubts plenty of times throughout the chemo. ", "Jason says, \"The doctor summed it up well when she said, 'This would kill an adult. ", "Children's cells divide faster and they are a little bit more resilient and so we can do this to a child but we couldn't do this to an adult because it would kill them. ", "Their body couldn't take it.'\"", "\n\nAt the same time as Diego underwent chemo, he received forty-eight doses of mifamurtide, getting the immune therapy intravenously twice a week for three months, and then once a week for another six months. ", "His body was a war zone, with the chemo \"bomb\" going off and the mifamurtide \"special forces\" hunting down the microscopic cancer cells.", "\n\nAll the time that Diego was undergoing the harrowing treatment, Jason commuted back and forth between London and Phoenix every ten to fourteen days.", "\n\n\"He was ridiculously tired,\" Paulina says, \"as you can imagine because you can't get your body reset.\"", "\n\nWhenever Diego was out of the hospital, Jason would try to plan fun things for the family to do together to keep his son's spirits up. ", "One night, he got tickets to a show called _STOMP_ , in which performers use sticks, garbage cans, and garbage lids as drums. \"", "It was the loudest show,\" Paulina recalls, \"and we were laughing because Jason was asleep throughout the show.\"", "\n\nBut the hardest part for Jason was not the exhaustion. ", "It was being five thousand miles away during Diego's many scary emergency room trips.", "\n\nTheir oncologist had warned them that Diego would probably find himself back at the hospital often between treatments. \"", "Your immunities are so low, and it's so dangerous at that point, because your platelets are almost zero and your ability to fight anything is so low that it's a scary time,\" Paulina says. \"", "There were some emergency room visits that were pretty awful that I don't even like to think about. ", "And my husband had to hear about them long distance and that's very difficult for a parent.\"", "\n\nOnce Diego woke up in the middle of the night with an uncontrollable nosebleed. \"", "At that point his body couldn't stop the bloody nose. ", "So our cousin Jack got a bucket and his wife got towels. ", "And my younger son was freaking out seeing all the blood. ", "He had been really strong through it all, but at that point he latched on to me saying, 'Please don't go.'\"", "\n\nDiego was terrified. \"", "I was having to tell him, 'It's okay, this is normal, we're going to get you to the hospital.' ", "Jason wasn't there and our cousin was speeding trying to get to the hospital because it was faster that way than trying to wait for an ambulance.\"", "\n\nPaulina had called ahead to the hospital, so the nurses and doctors were there waiting and went straight to work on Diego. \"", "They were all trying to stop the bleeding and giving him a transfusion and doing as much as possible. ", "But we were scared. ", "We were scared. ", "I remember telling a nurse that I was doing a lot of praying that night. ", "And she said, 'We all were.'\"", "\n\nJason says that leaving London—knowing he would not be there for his family at those terrible moments—was almost unbearable. \"", "It was excruciating getting on that plane,\" he says. \"", "It was the most painful ten hours that I would go through. ", "It was truly miserable. ", "I'd have to gear myself up to get on the plane and then I would spend a lot of time on that plane just lost in time and wishing I didn't have to come back [to Phoenix].\"", "\n\nEven after moving to London, the Morris family never stopped trying to get mifamurtide back home. \"", "We never gave up,\" Paulina says. \"", "We thought there must be a way to get this drug in the United States. ", "It's America, right? ", "We should be able to get things that are showing promise and that are being approved everywhere else in the world.\"", "\n\nShe recalls how the doctors, nurses, and patients they met at the clinic were stunned that these Americans had to come to London for treatment. \"", "I can't tell you how many times we heard, 'We cannot believe you're Americans getting care in London. ", "We thought you have everything in terms of medicine and access to everything you can get there,'\" Paulina says.", "\n\nShe thought to herself, \"You're right, we should be able to get this in the United States.\"", "\n\nLittle did she know that her young son was about to enter the political arena, and help lead the fight to do just that.", "\n\nWHEN HIS TREATMENT WAS complete, Diego and his family returned to Phoenix. ", "They felt like they were coming home from war. ", "No more rushing to the emergency room in the dark of night. ", "No more ten-hour commutes for Jason or juggling plane and treatment schedules. ", "No more watching chemotherapy ravage their son, as a battle took place inside his body to kill the cancer before it killed him.", "\n\nOnce the chemotherapy stopped, Diego's hair came back thicker than ever and he shot up several inches seemingly overnight. \"", "He started to grow immediately because children don't grow when they're on chemotherapy, because it's stopping the cells from dividing, it's killing everything,\" Jason says.", "\n\nBecause of the massive dose of chemotherapy Diego received, he needs to get regular tests of his heart and his hearing. \"", "All of the medical staff are amazed at how little impact the amount of chemo he had had on his body,\" Jason says. \"", "His hearing's great, his heart is wonderful, all of the things that they're most concerned with. ", "So we're blessed.\"", "\n\nWhen she heard about Diego's recovery, Dr. Kleinerman—the MD Anderson doctor who discovered mifamurtide and tried to get it approved here in America—was elated. \"", "It makes all the tough years of frustration I went through with this drug, that's what makes it all worthwhile. ", "All the gray hairs on my head and the broken pieces of glass I've thrown.\"", "\n\nJason and Paulina never forgot how many other people there were who did not have access to drugs like mifamurtide. ", "They were on the lookout for an opportunity to do something to help others. ", "Jason recalled the conversation he had with Dr. Meyers, at Memorial Sloan Kettering, who encouraged them to go to London to get mifamurtide. ", "Jason was so grateful for his guidance and kindness that he asked Dr. Meyers if there was anything they could do to thank him. \"", "He said, 'I don't need anything. ", "But if you can spread the word and help people get access to this drug that would be great.'\"", "\n\nThey found that opportunity in 2014 when the Right to Try initiative came to their home state of Arizona.", "\n\nI had heard about Diego from my Goldwater Institute colleague, Victor Riches, who told me the amazing story of an Arizona boy who nearly died from cancer and whose family had to move to England to find a cure. ", "We knew we needed to reach out to the Morris family and see if they would be interested in helping the Right to Try effort.", "\n\nThe entire family came to our offices for a briefing, and we walked them through the proposed law and how it could help other kids like Diego. ", "Diego said \"yes\" immediately, but we asked him to take his time and talk it over with his parents. ", "After a few days of careful consideration, we got a call from the Morrises: Diego enthusiastically agreed to become the honorary chairman of the Right to Try initiative in Arizona.", "\n\nThe state legislature had referred the Right to Try act to the voters as a ballot measure in the November 2014 election. ", "Diego became the face of Arizona's Right to Try campaign, giving speeches, doing radio and television interviews, writing letters to the editor, and even cutting a television campaign ad for Prop 303. ", "He movingly spoke at the Goldwater Institute's headquarters, sharing his story and making the case for the Right to Try. ", "When he was finished, there wasn't a dry eye in the house.", "\n\nDiego could have been doing anything else at that point. ", "He had been through a harrowing ordeal. ", "He had gotten the treatment he needed. ", "He was finally back home and no one would have blamed him if all he wanted to do was just go to school, spend time with friends, get back on the ball field, and try resuming a normal teenage life. ", "But he wanted to help others. ", "He had been through the vale and now he was going back to bring others through as well. ", "I was inspired by his courage. ", "And so were his mom and dad.", "\n\n\"It was so healthy,\" Paulina says of Diego's decision to get involved with Right to Try. \"", "We watched him become comfortable with telling his story and knowing that there's no shame and there's no need to hide from this—to be actually proud of your strength and what you've overcome and what you've managed to do.", "\n\n\"We were constantly dropping things to work on the campaign,\" Paulina continues. \"", "And he loved it. ", "He _loved_ it. ", "He loved being able to do something positive, to take something that was so negative, so debilitating, such a nightmare, and turn it into something positive.\"", "\n\nHis efforts paid off. ", "On November 4, 2014, the people of Arizona approved Right to Try by a margin of 78.5 to 21.5 percent. ", "The victory was overwhelming. ", "Thanks in large part to Diego's tireless campaigning, 1,111,850 people pulled the lever in favor.", "\n\nDiego and his family celebrated on election night and did interviews with the local media. \"", "Two years ago, I had cancer, and my family and I had to go to another country to get an experimental drug that could have possibly saved my life. ", "And luckily I'm here today,\" Diego told KJZZ news. ", "Now that Prop 303 was law in Arizona, he said, \"it will give people the opportunity to not have to go through what we had to go through.\"", "\n\nThanks to Diego, that was true in the state of Arizona. ", "But in much of the rest of the country, Americans still did not have the Right to Try. ", "And this lack of access to cutting-edge medicines is driving many people with terminal illnesses abroad in the search for cures.", "\n\nWhile few Americans have heard of Diego Morris, there was someone almost everyone is familiar with who was forced to travel abroad for treatment.", "\n\nIn fact, you may very well have one of his products in your pocket right now.", "\n\n# 3.", "\n\nWhat Steve Jobs Saw\n\n_How the FDA Stops American Doctors from Using a Proven Cancer Treatment_\n\nWhen Paulina Morris first got her son Diego's diagnosis, she sent him into the lobby to play on her iPad while she talked to his doctor—the start of a long journey that would take her family halfway across the world to cure Diego's cancer.", "\n\nWhat Paulina did not know at the time was that the man who invented that iPad had taken a similar journey.", "\n\nFor the past two decades, the most respected American doctors in the field of carcinoid and neuroendocrine cancer have been sending their patients to clinics in Rotterdam, the Netherlands; Bad Berka, Germany; and Basel, Switzerland.", "\n\nThey have had to, because the most effective treatment is still not available here in America.", "\n\nIN 2004 STEVE JOBS, the founder and CEO of Apple, was diagnosed with a rare cancer in his pancreas called neuroendocrine carcinoma, or NET cancer. ", "According to the Center for Carcinoid and Neuroendocrine Tumors at the Mount Sinai School of Medicine in New York, \"About 12,000 cases are diagnosed each year in the United States, and it has been estimated that there are 102,000 people in the country with this slowly progressing malignancy.\"", "\n\nJobs was extremely secretive about his diagnosis and course of treatment, so many of the details are not known to this day. ", "According to news reports, he at first decided against surgery, seeking to treat his cancer with a special diet. ", "Then, according to his biographer Walter Isaacson, Jobs underwent cancer drug therapy that \"had grueling side effects. ", "His skin started drying out and cracking.\"", "\n\nFinally, Isaacson writes, \"in his quest for alternative approaches, he flew to Basel, Switzerland, to try an experimental hormone-delivered radiotherapy . . . ", "developed in Rotterdam known as Peptide Receptor Radionuclide Therapy\"—or PRRT for short.", "\n\nIt's a complicated name, but the concept behind it is actually quite simple.", "\n\nThe cells in NET cancer tumors have a receptor on the surface which binds to a hormone (or peptide) in the body called somatostatin. ", "In the 1980s researchers developed a laboratory-made version of this peptide called octreotide. ", "When it is injected into the bloodstream, it travels through the body, finds the cancer cells, and attaches itself to them. ", "It is used principally for diagnostic purposes (as part of what is called an OctreoScan that helps doctors locate tumors in the body) though it is also used as a treatment because the peptide has some cell-inhibiting impact.", "\n\nIn PRRT, the therapy Steve Jobs underwent, doctors turn that diagnostic tool into a highly effective cancer killer by adding a small amount of radioactive material to the peptide before injecting it into the bloodstream. ", "This turns the peptide into a radiopeptide, which not only finds and attaches itself to the cancer cells but then delivers a high dose of radiation directly to the tumors, destroying them.", "\n\nAccording to Dr. Richard Warner, director of Mount Sinai's NET cancer center, \"The receptor is like a magnet and this [radiopeptide] is like a piece of iron filing. ", "And so this radioactive pharmaceutical agent is injected into the bloodstream . . . ", "and anywhere that a neuroendocrine tumor having the receptors is located . . . ", "it attracts this material and . . . ", "it gives internal radiation to the tumor.\"", "\n\nThe beauty of PRRT, he says, is that it can find and kill tumors that are so tiny that doctors cannot find them on a scan. ", "Any NET cancer cell—however small or well hidden in the body it may be—will attract the radiopeptide like a magnet and thus irradiate itself.", "\n\nPRRT not only hunts down hidden tumors; it also allows doctors to treat tumors that are inoperable because they are embedded in vital organs. ", "It is extremely safe, Dr. Warner says, because \"the range of the radioactive rays that it emits is very short, so it doesn't irradiate adjacent structures. ", "But it does irradiate the tumors to which it's attracted and thereby wounds or kills them by radiation.\" ", "The radioactive material is flushed out of the patient's system in a few days.", "\n\nPRRT is not a cure. ", "The tumors eventually come back, and when they do the process must be repeated. ", "But with multiple treatments, PRRT can beat back NET cancers and add not just weeks or months, but many years to the lives of patients.", "\n\nIt is unknown what impact the treatment had on Jobs, who died in October 2011. ", "But studies show that PRRT has extended the lives of many thousands of other cancer patients. ", "Indeed, it is far more effective at killing NET cancers than chemotherapy.", "\n\nA 2010 study in Rotterdam found that chemotherapy slowed the progression of NET cancers by less than eighteen months. ", "By contrast, when patients received PRRT using the two most common radioactive agents—Y-90 and Lu-177—they beat back the cancer far longer. ", "In PRRT using Y-90, the treatment slowed their cancer progression for thirty months—a year longer than chemotherapy. ", "Lu-177 was even more effective. ", "It slowed cancer progression for forty months—almost two full years longer than chemotherapy.", "\n\nTwo more years is a lot of time—and some patients can turn that into decades by repeating the treatment. ", "Not only does it buy dying patients more time than chemotherapy; it gives them a much better quality of life. ", "Chemotherapy often has debilitating side effects, because the treatment indiscriminately damages both healthy and cancerous tissues. ", "But according to the Society of Nuclear Medicine and Molecular Imaging, \"Radiopeptides are highly selective in their ability to damage neuroendocrine tumor cells, while limiting radiation exposure to healthy tissue. ", "As a result, PRRT typically has milder side effects compared with chemotherapy.\"", "\n\nPRRT is safer, has fewer side effects, and is more effective than chemotherapy—which is why, over the past two decades, it has become the standard of care in Europe. ", "Dr. Tom O'Dorisio, a professor of medicine at the University of Iowa and one of the leading NET cancer specialists in America, says that when PRRT was first introduced \"all of Europe went bananas with it. ", "Since 1996, every country has had this treatment.\"", "\n\nEvery country, that is, except the United States.", "\n\nTo this day—despite its widespread use, high success rate, and strong safety profile—PRRT is still not approved for use in the United States. ", "Dr. O'Dorisio and his wife, Dr. Sue O'Dorisio, work as a team at their University of Iowa clinic, treating patients and conducting cancer research. ", "He says, \"We, for the first time, just got permission about two days ago from the FDA to do the trial, which is the very same treatment that they've been doing since 1996 in Europe.\"", "\n\nThe FDA has actually approved _half_ of the treatment. ", "Octreotide—the peptide that finds and attaches itself to cancer cells—has been approved by the FDA since the 1980s.", "\n\nBut the FDA does not allow doctors in America to attach the radioactive materials to the peptide that actually destroy the cancer.", "\n\nThis is like giving our military permission to use drones to track down terrorists—just as long as they don't attach a warhead with a bomb that will actually kill them.", "\n\nIf that were not bad enough, the story gets even worse. ", "While the FDA forces American doctors to use the antiquated OctreoScan pioneered in the 1980s—which cannot find many smaller tumors—doctors in Europe are using an advanced high-resolution gallium scan, which is far more effective. ", "The gallium scan uses a radiological material called gallium-68, which is—you guessed it—not approved by the FDA.", "\n\nDr. Warner says the gallium scan is \"ten times more sensitive\" than the FDA-approved OctreoScan. ", "Dr. O'Dorisio says the old scan \"sensitivity-wise is kind of like looking through my cataracts,\" whereas the gallium scan is like looking \"through a very precise magnifying glass.\" ", "The gallium scan, which has been used in Europe for many years, has just been permitted on a clinical trial basis in a few other locations in the United States. ", "One of those is Mount Sinai, Dr. Warner's hospital. ", "But, he says, \"We're not allowed to charge for it and we're having problems funding it, because we have to pay for every patient. . . . ", "It costs us about $3,800 for each scan that we do. ", "We're going to run out of money pretty soon.\"", "\n\nSo most Americans with NET cancers cannot get the most accurate scan to find their tumors, or the most effective treatment to kill those tumors.", "\n\nSo what do these Americans do to save their lives?", "\n\nLike Diego Morris and Steve Jobs, many go to Europe.", "\n\nDr. Tom O'Dorisio says he has personally sent almost 490 patients to the University of Basel Hospital in Switzerland. ", "He says that most of his patients don't have the same resources as Steve Jobs and can't afford to go abroad.", "\n\nHere's my dilemma, and this is a monster dilemma, and that is that people of means can go. ", "But people who have the same degree of disease, they have glass eyes stare back at you [when you tell them how much it costs]. ", "There's no way they can afford to go for $12,000 per treatment let alone cost for travel. . . . ", "And not just one treatment. ", "They're nine weeks apart and they are anywhere from two to three initially and then three more down the road. ", "So you're talking about an enormous amount of money. ", "And that's the part that's been so ethically tough for me.", "\n\nIn a small number of cases, he is able to convince insurers to cover at least part of the cost. ", "But most patients have to pay for the treatment out of pocket.", "\n\nHis wife, Dr. Sue, says the dilemma is hardest when the patients are children. \"", "Not everybody, and particularly parents, have the resources [to travel abroad]. ", "Usually, with a child, one of them has to quit their job to be able to take care of the child who's sick. ", "And then for both of them to be able to quit their job and take the child over there, that's—I mean it's heroic but not everybody can do it.\"", "\n\nAt the other end of the spectrum, Dr. Tom says, are the older patients who are retired and on fixed incomes. \"", "The other bad, tragic thing is many of these patients come due at an age when they're in Medicare. ", "And absolutely Medicare will not pay.\"", "\n\nDr. Warner has faced the same dilemma. \"", "I've had literally dozens of patients that I've sent to Europe. . . . ", "And they require four treatments at roughly six-week intervals. ", "So you can figure out what it costs. ", "And of course, being out of the country, it's not covered by anybody's insurance.", "\n\n\"I have a patient waiting to go right now who's trying to get contributions from her friends and other people to cover her treatment . . . ", "she doesn't have the money,\" he says. \"", "I can think of one fellow who unfortunately died because he couldn't afford it.\"", "\n\nWhat is it like to tell patients their only hope of survival is to get a treatment abroad that they cannot afford and is not covered by insurance?", "\n\n\"It's intolerable,\" Dr. Warner says. \"", "It really disturbs me and I hate to be in a position where I have to explain that or tell that to people. ", "It makes me feel impotent.\"", "\n\nSo why is this treatment still not available in America? \"", "The FDA wouldn't accept the data from Europe and required everything to be done all over again here like rediscovering the wheel,\" Dr. Warner says. \"", "It's been accepted in just about every major country in Europe where it's being widely used. ", "Those of us who are involved and have had patients that were treated know that it's a good treatment and that it does work in 82 percent of the cases, which is a very good statistic.\"", "\n\nThe man who receives many of the patients referred from America is Dr. Damian Wild, the director of nuclear medicine at the University Hospital of Basel in Switzerland. ", "He says his hospital does about fifty treatments a year for Americans. ", "Asked if the treatment should be available to them at home, he does not hesitate: \"Of course it should be, yes.", "\n\n\"We treat American patients; that's not a problem. ", "We like to treat them,\" he adds. \"", "But of course for many Americans it's a hassle. ", "It's a relatively long trip to Europe and not all of those patients are in very well shape. ", "And so traveling is a hassle for most of those patients.\"", "\n\nOne patient who learned this firsthand was Lindsey Miller. ", "Before she passed away in May of 2014, she documented her experiences fighting NET cancer on a blog she called _I Am a Liver_. ", "Here is how she described her trip in May 2013 to get treated at a hospital in Germany:\n\nMany many many months ago when I imagined that day far, far in the future that I would (probably) have to travel overseas to seek the famed PRRT treatment for my cancer, I imagined that it would be (secretly) exciting to go to Europe for treatment. ", "That I would get treatment one day and be out eating pretzels and drinking beer the next. ", "I imagined that I would beg my parents to take me to Paris or Prague or Berlin or Amsterdam beforehand, you know, while we were in the area. ", "I imagined I would be wearing heels—isn't that what fabulous European women wear?", "\n\nNow that the day is today, I am not not excited. ", "I had imagined I would be feeling much better before I left. ", "I have been laying low in my living room for weeks and now i'm supposed to be ready to hop on a plane to fly halfway across the world? ", "I'm not sure i'm up for this; but I have to be, because my tumors are growing and doing crazy things (like causing my legs to swell up) and I need to do something to take care of them. ", "Contrary to my imagination, I will be in the hospital in Germany all week, not eating pretzels or drinking beer. ", "The forecast says rain. ", "I don't have the energy for much sight-seeing. ", "I can't fit into any of my shoes. ", "My suitcase doesn't have room for heels next to all my stretchy pants, compression stockings, prescription bottles, and lung drainage bottles.", "\n\nIn truth, I will be happy when the ordeal is over.", "\n\nIt is shameful that her government put her through such an ordeal.", "\n\nShe also wrote movingly for the _Huffington Post_ about her struggle to raise money for her treatments. ", "She conducted three successful fund-raising campaigns at a medical crowdfunding site called Give Forward.com that raised about $23,000—enough to put a dent in her medical expenses, but not to cover them.", "\n\n\"The cost is unfathomable,\" she wrote. \"", "Steve Jobs is rumored to have tried the same treatment at another site in Basel, Switzerland. ", "Presumably, he had no trouble affording it.\"", "\n\nAnd what about the Americans who cannot find the money to go to Europe?", "\n\n\"There's no other FDA-approved treatment,\" Dr. Tom O'Dorisio says. \"", "Chemotherapy bounces off of these tumors because they're so slow. ", "They're so slow that chemo doesn't work. ", "So all we have is octreotide and people become resistant to the octreotide over time. ", "I turn it upside down. ", "I have tricks that I've learned along the way [to help keep the cancer at bay], but it doesn't hold them. ", "And then people die.\"", "\n\nSince there are no other options that can improve survival, Americans often have to spend their life savings to go abroad. ", "That's what happened to Kenneth Jolley, a sixty-four-year-old Vietnam veteran living in Allen, Oklahoma. ", "According to the _Daily Oklahoman_ , Jolley was diagnosed in 2011 with stage-four neuroendocrine carcinoid cancer, which had spread to his liver, lung, and chest. ", "His doctors at the Oklahoma City Veterans Administration Medical Center told him there was little he could do but \"wait and watch.\"", "\n\nJolley says, \"I was classified as Stage 4 and the VA absolutely had no treatment for it. ", "In fact they told me to go home and get my affairs in order.\"", "\n\nThe Department of Veterans Affairs (VA) offered to pay for palliative care.", "\n\nThat didn't suit this military veteran. \"", "I am not a quitter—I battle,\" he said. \"", "And I will give up when they put me six feet under.\"", "\n\nSo he got a second opinion at Vanderbilt University Medical Center in Nashville, where a doctor told him that the best course of treatment was PRRT—but that he would have to travel to Germany to get it. ", "The VA refused to pay for treatment in Europe and so did his insurers. ", "So he was forced to use his retirement savings and borrow money to cover the costs. \"", "Mortgaged everything to the hilt,\" he says. ", "He traveled to Bad Berka, Germany, three times, at a cost of over $50,000.", "\n\nThe trips were grueling. \"", "When you're looking at an eleven-hour flight three days after you've been treated and this makes you extremely nauseated, you are so miserable by the time you get back here in the States. ", "Every trip, even with medical papers, you spend anywhere from an hour and a half to three hours in Customs trying to get through because you're radioactive.\"", "\n\nAnd after three courses of therapy he could not get in America, Jolley underwent a gallium scan as part of a clinical trial at the National Cancer Institute—which revealed the treatment worked. ", "His existing tumors had shrunk by 42 percent.", "\n\nWhen he returned to Oklahoma, he found a clinic in Houston that was conducting a clinical trial of PRRT that was authorized by the FDA. ", "Surely the VA would pay for that, he thought. ", "Wrong. ", "The VA refused, even though at $45,000 the treatment cost less than six months of the palliative care the VA had agreed to cover. ", "His private insurer also refused to pay for the treatment because it is investigational. ", "So he had to pay for it with loans from family and friends and donations he's been able to scrounge up.", "\n\n\"I managed to pay for the first one,\" he told the _Daily Oklahoman_. \"", "I have no idea how I'm going to pay for the second, but the Lord will provide a way.\"", "\n\nWhen his six-year-old granddaughter, Emerson, heard that Papa Ken was struggling to pay for his medicine, she told her mom: \"Well, if I save my allowance for two months, I will give it to him, and then he will have enough money to get better.\" ", "She saved up forty dollars for her beloved Papa Ken's treatment.", "\n\nEventually, after years of fighting, he finally got the VA to relent and pay for his treatment in Houston. \"", "I had exhausted all my funds,\" he says. \"", "I'm still paying the balance on my treatments in Europe.\"", "\n\nStill, even though he's broke, he says he's lucky. \"", "So many people don't have even the resources I have, and they can't just jump on a plane and go to Europe. ", "It's hard to take. ", "As a veteran, it was hard to swallow.", "\n\n\"If [it weren't for] this treatment, I would not be here today,\" he says.", "\n\nIs this any way for America to treat a veteran fighting a terminal cancer diagnosis?", "\n\nThe clinical trial Ken Jolley joined was run by Dr. Ebrahim Delpassand, the head of the Excel Diagnostics & Nuclear Oncology Center in Houston, the first research facility in the United States to receive authorization to initiate this much-needed therapy.", "\n\nJolley was lucky he could get into the trial when he did. \"", "FDA has just come to me and said that you need to stop this,\" Dr. Delpassand says. \"", "FDA is allowing us to continue treatment for the previously enrolled patients, but we cannot enroll any new patients at this point. ", "And this is a major disappointment to our patients, to their family members, because really there's no other option here until the drug is commercially available.\"", "\n\nWhy did the FDA shut down his trial? ", "Dr. Delpassand says, \"They said that this therapy has a lot of side effects and it does not. [", "They said] it doesn't have a meaningful clinical response which, again, that's another really wrong conclusion. ", "The reason that they say this is they don't consider a 'stable disease' as response in these progressive patients. ", "I mean these were patients that the physicians they were giving them three months, six months to live. . . . ", "And now our drug is making them stable for two years, thirty months, [and] FDA doesn't look at it as a response.\"", "\n\nDr. Delpassand says that \"this drug has been in use in Europe for a long time, [but] what was lacking was a randomized trial actually, which is considered the gold standard in the scientific way in looking at the effectiveness of this drug.\" ", "He says that a European company called Advanced Accelerator Applications is now conducting such a trial in Europe and the United States. ", "The trial began recruiting patients in 2012 and completed enrollment in February 2015.", "\n\nDelpassand says that it will be at least two years before the trial is completed. ", "In other words, by the time the treatment is finally approved in America— _if_ it is finally approved in America—it will be two decades after it first went into widespread use in Europe.", "\n\nMeanwhile, European doctors are already developing the next generation of PRRT treatments. ", "Dr. Tom O'Dorisio says that researchers at the University Hospital in Basel, Switzerland, have developed a new technique he compared to a \"broken key.\"", "\n\nDr. Wild, the director of nuclear medicine in Basel, who helped pioneer the new technique, explains that he and his colleagues have found a way to \"bend the key of the synthetic hormone so that now it jams longer in the lock. ", "Furthermore more keys can jam in the lock. ", "And so apparently now that a higher number of keys stay longer in the membrane of the tumor cell, it's apparently better than the currently used key that carries the radiopeptide. ", "This results in a several times higher accumulation of radioactivity on the tumor cell.\"", "\n\n\"It is a big breakthrough,\" Dr. O'Dorisio says. ", "But that breakthrough is not coming to America anytime soon. ", "In Europe, he says, \"they are putting other treatments on top of the ones we don't have\" while here in America \"we're still flopping around like fish trying to get\" the old treatment.", "\n\nSo what is the solution?", "\n\nDr. Delpassand thinks he knows. ", "He points to the Right to Try laws. ", "He says,\n\nThe Right to Try Act essentially says that that is the decision between patient and their physician for the investigational drug. ", "Of course the drug should have had phase I trial showing the basic safety of the drug. ", "But after that, it is between physician and the patient. ", "And patients with terminal diseases, which cancer is considered a terminal disease, they can request investigational drugs and their physicians can provide it to them.", "\n\nGoing through the FDA process, one, is extremely expensive and two, is extremely lengthy. ", "And here there are many patients that they don't have that kind of timing in their life. ", "They need the medication much earlier. ", "So something like having the Right to Try Act I think helps in those situations.", "\n\nIf that law passes [in Texas] we don't need FDA's blessing on this. ", "We can go ahead and treat the patients.", "\n\nA few weeks after he said that, the Texas legislature passed and Governor Greg Abbot signed Right to Try into law in Texas. ", "At this writing, Dr. Delpassand is working with lawyers and Texas officials to clear the way to providing the treatments under the new law.", "\n\nAnother doctor who is preparing to treat patients permitted by Right to Try is Dr. Eugene Woltering, professor of surgery and neuroscience and director of surgical research at Louisiana State University Health Sciences Center/Ochsner in Kenner, Louisiana. ", "On May 30, 2014, Louisiana governor Bobby Jindal signed Right to Try into law. \"", "This is . . . ", "about individual freedom and liberty,\" Jindal said. \"", "If individuals facing terrible diseases want to try something, why should the government stop them from doing that?\"", "\n\nWill Woltering use the new law to offer PRRT at Ochsner Medical Center? \"", "Oh, absolutely. ", "Yeah, we're doing the Right to Try,\" he says. \"", "I mean we are just ready to flip the on switch and start treating people,\" he says.", "\n\nAs soon as the law passed, he says, \"I sat down with the Attorney General's Office through my connections at LSU, where I'm a professor. ", "Met with the chancellor, met with the dean. ", "Everybody was really excited. ", "The Ochsner system and the LSU system has agreed with me, and the Attorney General's Office has agreed with me.\"", "\n\nAll that is left, he says, \"is to get the local bureaucrats who have to sign off on nuclear pharmacy regulations at the hospital level.", "\n\n\"The minute we get the sign-off we'll be on top of this like white on rice,\" he says.", "\n\nHe simply needs to put the radiological agent onto the FDA-approved peptide, octreotide—to effectively attach the warhead onto the drone.", "\n\nDoing that is easy, he says, \"because it requires so little drug. ", "You're hooking the blimp to a grain of rice. ", "The radioactivity is the big kahuna and the amount of peptide that it takes to do a therapeutic dose is micrograms. . . . ", "So for $25,000 worth of drug you can make enough drug to treat a hundred people.\"", "\n\nHe expects to be up and running this year.", "\n\n\"I'm a huge advocate\" of Right to Try laws, he says. \"", "I mean I think that this ought to be the wave of the future. ", "People who have no other options need to be given options.\"", "\n\nHe says he tried working with the FDA to allow PRRT at his clinic.", "\n\n\"We have people who are dying who maybe have a year to live at the max, having failed all conventional therapies,\" he says. \"", "And so we go to the FDA and we say we would like to treat somebody with PRRT. ", "And their argument is, 'Yeah, but five years from now they could develop renal failure.' ", "And I'm going, 'These people would be happy to go to their own funeral five years from now rather than a year from now.' ", "And they go, 'No, that's not the way it works.'\"", "\n\nThe way it works now in Louisiana is that patients with a year to live will finally have the Right to Try.", "\n\nDr. Woltering's message to the FDA? \"", "Quit regulating and micromanaging every little piece of information that we have. ", "Be working with the docs who are trying to take care of patients, not working against them.\"", "\n\nDrs. ", "Tom and Sue O'Dorisio also support Right to Try laws. \"", "That's the system that's in place in Europe, which is why Europe is ahead of us,\" Dr. Sue says. \"", "Any physician in Europe is allowed to treat a patient on a personal basis if they think it's clinically indicated.\"", "\n\nDr. Tom agrees. \"", "We try to play by the rules,\" he says, \"but this is a new rule. ", "I think it's very exciting. ", "I think if there was a Right to Try, you know . . . ", "I'd be not ambivalent but say it could be very valuable if it was carried forward in a systematic way.\"", "\n\nThe fact that Americans with deadly cancers have to travel abroad to get treatments that should be available right here at home is appalling. ", "Right to Try will soon help these patients get access to these treatments without having to cross an ocean. ", "It puts the decision back where it belongs—between doctor and patient.", "\n\nRight to Try it is only part of the solution. ", "Dr. Woltering can move forward so quickly because, with PRRT, he does not have to convince a drug company to provide the product. ", "But today, FDA rules discourage drug manufacturers from providing investigational drugs to dying patients even under its own compassionate use program.", "\n\nWe need a system that encourages drug companies to rescue dying patients. ", "We need a system that moves quickly to approve safe treatments. ", "And we need a system that can help patients _now_. ", "It's time for the powers that be to take a lesson from Steve Jobs and the folks at Apple:\n\n\"Think Different.\"", "\n\n# 4.", "\n\nMaking Medical Miracles\n\n_The Cutting-Edge Cancer Killers You Can't Get Yet_\n\nWhile Americans must travel abroad for proven cancer treatments blocked by the FDA, doctors here in North America are pioneering the next generation of cancer treatments, with cures and therapies that were once unimaginable.", "\n\nBut most Americans can't get access to these treatments either—unless they are among the 3 percent of cancer patients who qualify for and are able to participate in a clinical trial. ", "For the rest, they must wait for years, sometimes a decade or more, for the government to approve these revolutionary therapies. ", "That is time most people with a terminal diagnosis don't have.", "\n\nSpeeding access to these treatments is why Cancer Treatment Centers of America came to the Goldwater Institute in the first place—and the reason we launched the Right to Try.", "\n\nON A CLEAR MORNING in June 2013 Stacy Erholtz woke up with a mission: this was the day that she was going to finally kill Evan.", "\n\nMake no mistake, Evan had it coming. ", "He had put a hole in Stacy's head the size of a golf ball. ", "And he was getting more aggressive with each passing day. ", "If Stacy didn't kill him now, he was going to kill her for sure. ", "Time was running out.", "\n\nStacy had a plan. ", "She was going to kill Evan by exposing him to a deadly virus. ", "The virus would overwhelm Evan's internal defenses, and then begin replicating itself inside him, until his cells began to explode and he died.", "\n\nSound horrible? ", "Don't be alarmed. ", "Stacy is no serial killer. ", "She is a fifty-year-old mom from Pequot Lakes, Minnesota, who is fighting multiple myeloma—a deadly blood cancer that attacks bone marrow.", "\n\n\"Evan\" is her brain tumor.", "\n\nEvan grew under her forehead and pressed so hard on her skull that he finally broke through the bone, leaving a large lump exposed. ", "Stacy's kids gave him the name.", "\n\nThey wanted Evan dead too.", "\n\nEvan was not alone. ", "Stacy had tumors growing on her collarbone, on her sternum, and up and down her spine. \"", "On the scans, I lit up like a Christmas tree,\" she says. ", "She had been fighting this disease for ten years, but no matter what treatments she tried, her cancer kept coming back with a vengeance. ", "She was dying and running out of options.", "\n\n\"For the longest time, my local doctors couldn't figure out what was wrong with me,\" she said in an interview on the Mayo Clinic website. ", "When Stacy first went to her physician complaining of chronic fatigue and neck pain, she received a prescription for Celebrex, an anti-inflammatory drug. ", "It had no effect. ", "Her symptoms got worse. ", "She experienced random vomiting and threw her back out. ", "Her tongue became swollen and she got sores in her mouth. ", "She developed bumps and bruising around her eyelids, lost fifty pounds, and twice underwent surgery for carpal tunnel syndrome. ", "She was constantly exhausted. ", "She grew so tired she had to crawl up the stairs to get to her bedroom. ", "One day, she slipped on the ice and cracked her spine.", "\n\nFinally, she went to an internist, who referred her to an oncologist. ", "He did multiple tests, including a bone-marrow biopsy, and finally gave her the correct diagnosis: multiple myeloma.", "\n\nBy that point, Stacy was too sick to be devastated. ", "She just wanted to know what was wrong and find a course of treatment. ", "She had two bone-marrow transplants, which did not work. ", "Finally, she was sent to the Mayo Clinic in Rochester, Minnesota, where Dr. Stephen Russell, took over her treatment.", "\n\n\"She was just forty-nine when she came to the clinic with relapsing myeloma about nine months after her most recent bone-marrow transplant,\" Dr. Russell says. \"", "She had a large sort of egg-sized tumor growing out of her left forehead. ", "We did a CT scan and found that she had four other tumors in her body as well as that one that were all very hot on the CT scan. ", "We also put a needle in her bone marrow . . . ", "and we found that that was diffusely infiltrated by myeloma cells.\"", "\n\nAt Mayo, Stacy underwent all the standard government-approved treatments. ", "She had her first stem-cell transplant. ", "At first it appeared to work, but then the cancer came back. ", "She tried a variety of novel antimyeloma drugs. ", "The effect was the same—temporary improvement, after which her cancer always returned.", "\n\nOne day when Stacy was watching the news she saw her physician, Dr. Russell, discussing exciting new research he was doing using the measles virus to combat multiple myeloma. ", "The idea was to administer a version of the measles vaccine that most Americans get as children, except the virus is given in much higher doses and is genetically engineered to kill cancer cells.", "\n\nThe virus would enter the bloodstream, bind itself to cancer tumors, and use them as hosts—turning them into machines to replicate itself and eventually destroying the tumors. ", "Any remaining cancer cells in the bloodstream would now have the measles vaccine's genetic imprint, which would trick the body into thinking that they are measles virus. \"", "Then the immune system can come in and mop up the residue,\" Dr. Russell explained.", "\n\nStacy listened transfixed. ", "She was convinced that this was the treatment that would save her. \"", "From that point forward,\" Stacy says, \"I pestered him at every appointment.\"", "\n\nThe use of viruses to fight cancer was nothing new. ", "Doctors have long used viruses against cancer by injecting them directly into individual tumors to shrink and destroy them.", "\n\nBut what Dr. Russell was doing was different. ", "In this revolutionary treatment, the virus would be injected not into the tumor, but into the patient's _bloodstream_. ", "Once infused, it would conduct a search-and-destroy mission—hunting down and killing cancer that had spread throughout the body.", "\n\nThis had never been tried before. ", "If it worked, it would be the first time in medical history that viral therapy had been successfully deployed against distributed, metastasized cancer in a human being.", "\n\nDr. Russell chose the measles virus because, he says, it is extremely safe. ", "Billions of doses have been given to children over the course of many decades.", "\n\n\"We were very concerned about safety and we wanted the virus that we worked with to be one that was absolutely not going to cause risks to the human population or to the treated patient,\" he says. ", "Measles was the obvious choice because \"natural measles infection in America is associated with 0.01 percent mortality and we know that most of the population is immune to measles virus.\" ", "There was no chance of unleashing the Andromeda strain.", "\n\nAnother advantage, he says, is that the measles virus is capable of infecting blood cells—which makes it perfectly suited for treating blood cancers like multiple myeloma. ", "Moreover, while most Americans are inoculated against measles as children, patients with multiple myeloma have compromised immune systems and tend lose their measles immunity—which means they have no protection against the measles virus.", "\n\nViruses are particularly effective cancer killers because a virus is about a thousand times smaller than a cell, Dr. Russell says, so it can bind itself to the cell, take over the cell, and then turn into a factory for the production of new viruses.", "\n\n\"We call viruses 'pirates of the cell,'\" he explains.", "\n\nViruses are also easy to transform. ", "First, doctors can adapt the virus to kill cancer by training it and evolving it in a culture. ", "Second, they can manipulate its genetic code—removing genes that attack healthy tissue and inserting genes that attack cancer.", "\n\nThe genome of the measles virus, Dr. Russell says, has only six genes, so \"we can go in and we can change the genes at will and then re-create a virus with altered genes.\"", "\n\nTo treat multiple myeloma, Dr. Russell and his team trained the virus in cultures to attack multiple myeloma cells. ", "Then they stitched a new gene into the measles virus that would allow them to follow its fate once it was released into the body.", "\n\n\"One of the scary things about giving a virus as a therapy is that you give it and it's going to grow in the patient and it's going to move around the body,\" he says. \"", "And our hope is that the virus just specifically attacks tumor wherever it is in the body. ", "But how do we actually keep tabs on that? ", "We can't give the patient a virus and then come and biopsy every tissue every five minutes.\"", "\n\nSo to keep tabs on the virus, Dr. Russell added a genetic tracer to it. \"", "We can give a virus that has a kind of 'snitch' in it, that allows us to see where it's up to and do an imaging study and see where in the body is this infection now taking place.\"", "\n\nThe \"snitch\" he added to the measles virus also made it a more effective cancer killer. \"", "The gene that we put in . . . ", "causes radioactive iodine to concentrate in the virus infected cells, which enhances the ability of the virus to kill the cells,\" he says. \"", "So it's a way of delivering radioactivity to the site of tumor growth. ", "We call that radio viral therapy. ", "We add the radioactive iodine to the viral therapy and basically increase the potency. ", "The two together are better than either alone.\"", "\n\nIf his theory was right, the measles virus would kill the cancer in two stages.", "\n\n\"The first we call the oncolytic phase when the virus is just killing the tumor cells directly by infecting them,\" Dr. Russell says. \"", "The cancer cell becomes a slave to the virus when it's infected, and just makes numerous copies of viruses to the expense of everything else. ", "So it stops taking care of itself and it therefore dies.\"", "\n\nThe second is called the immune phase. ", "Cancer cells that survive the initial attack by the virus are then targeted by the immune system. ", "The virus essentially paints a target on the cancer cells, which makes the immune system think they are a measles infection and go after them and kill them.", "\n\n\"So [the cancer] dies either because the virus kills it or because the immune system recognizes there's a problem and kills it,\" Dr. Russell says. \"", "It's really a timing question of whether the immune system will kill the cell before the virus kills it.\"", "\n\nRadio viral therapy seemed perfect for Stacy. ", "But when she first applied for the clinical trial, she was rejected. ", "Dr. Russell explained to Stacy that she did not qualify because she had not exhausted all the existing FDA-approved treatments.", "\n\n\"You have to be the biggest loser first,\" she says. \"", "I needed to fail every type of treatment available before I could qualify for the study.\"", "\n\nSo she had another stem-cell transplant and tried the remaining available myeloma drugs. ", "It took about eighteen months, but by May 2013 she had undergone every possible treatment. ", "Nothing had worked. ", "So she was finally admitted into the trial.", "\n\nThose delays may have actually saved her life.", "\n\nWhen the FDA allowed Dr. Russell to begin his first human trials, the agency required that he start at extremely low doses of measles vaccine. \"", "They then insist that you design the trial such that you start from a guaranteed safe dose,\" he says.", "\n\nThe FDA, in its wisdom, determined that a safe dose was one million infectious units—a dose Dr. Russell knew would not be enough to beat back the cancer.", "\n\n\"We knew from our mouse studies that we'd have to give a minimum of a thousand times that dose to have a hope of seeing anything in terms of efficacy,\" he says.", "\n\nWhat that meant was that the patients who volunteered for the early stages of the trial hoping for a cure stood no chance of clinical benefit until the FDA allowed Russell to get to that top dose.", "\n\n\"I just think that it's fundamentally wrong,\" Dr. Russell says. \"", "I think if somebody has reached the end of their viable options, and wants to try something experimental, they don't want to try a homeopathic dose. ", "They are prepared to take a risk. ", "But the rules imposed by FDA say, 'Well, tough, you can't do that.'\"", "\n\nHe adds, \"I'm not criticizing the guys at FDA, okay? ", "I suppose what I'm criticizing is the policy under which they labor. ", "What they're told is safety first. ", "And so they're not given the option of looking at the balance between the risk and the benefit, and the ethical considerations behind whether a patient should be given an opportunity.\"", "\n\nAs a doctor treating patients, he says, \"I struggle with that. ", "I certainly know if I had terminal cancer, and I wanted to try a virus, I definitely wouldn't want to try if I was getting a dose that wasn't going to work.\"", "\n\nBy the time Stacy was allowed to join the trial, the FDA had approved a dose containing one hundred billion infectious units. ", "That was enough measles vaccine to inoculate ten million people—and, more important, enough virus to have a chance at being effective against her cancer.", "\n\nOn June 5, 2013, Stacy arrived at Saint Mary's Hospital in Rochester, Minnesota, for what was supposed to be a thirty-minute viral infusion. ", "She was about to become only the second person in the world to receive such a massive dose.", "\n\nDr. Russell inserted a needle into her forearm and the virus began to slowly drip down into her veins. ", "At first she was fine, but five minutes into the treatment, Stacy developed a terrible headache.", "\n\n\"We had to stop it,\" Dr. Russell says. \"", "It was the worst headache she'd ever had.\" ", "They treated her headache and asked if she wanted to call off the treatment, but Stacy insisted on going forward. \"", "After it settled she said, 'Right, I want to do this,'\" Dr. Russell says. ", "So they resumed the infusion.", "\n\nIt took an hour to get all of the measles virus into her system. \"", "She was fine for a couple of hours,\" Dr. Russell says, \"and then she started rigoring. ", "Her temperature went up very high. ", "It was about 104, 105.\"", "\n\nHer immune system was kicking in, responding to the measles invasion. ", "She passed out from the pain.", "\n\nThe next morning, Stacy opened her eyes and looked around her hospital room.", "\n\nShe felt perfectly fine.", "\n\nSo good, in fact, that she was able to check out of the hospital that day and walk across the street to her hotel. ", "One day of feeling awful and the next she was better. ", "That had never happened with any of the other treatments. ", "They had all either required long hospital stays or sapped her energy for extended periods.", "\n\nBut would the treatment work?", "\n\nA day and a half after her infusion, Stacy told Dr. Russell that Evan had started to soften and had begun shrinking. ", "And within a few weeks, Evan was gone.", "\n\nAfter six weeks, a scan showed no sign of disease anywhere in her body. ", "None at all.", "\n\nAll the other tumors were gone.", "\n\n\"There was no evidence of any cancer that we could detect,\" Dr. Russell says. ", "Stacy was in full remission.", "\n\nThey had made medical history. ", "It was the first time that a patient with cancer spread throughout the body had gone into complete remission through intravenous viral therapy.", "\n\nUnfortunately, the other patient in the trial didn't have the same lasting results. ", "The virus shrank the cancer, but it came back after nine months.", "\n\n\"I think if we had been able to give a bigger dose, we might have gotten a better outcome in the second patient,\" Dr. Russell said.", "\n\nThe lesson is that \"number one, you need a really big dose and, number two, the patient needs not to have an antibody to the virus.\" ", "He is now studying ways to break down the body's immune system before treatment in hopes that the treatment can be harnessed for people who do have measles immunity.", "\n\nLike the ax murderer in a bad horror movie, nine months after Stacy's treatment, Evan made one final attempt to return.", "\n\nWhen Evan reappeared, Dr. Russell ran all the diagnostic tests and scans and, he says, \"We couldn't see any evidence of cancer elsewhere.\" ", "It was just Evan. ", "So Dr. Russell finished him off with a dose of radiation therapy. ", "He has not returned since and Stacy has no other signs of cancer.", "\n\nEvan was dead. ", "And Stacy was alive.", "\n\n\"I saw her back a couple weeks ago,\" Dr. Russell says. \"", "She's now twenty-one months out from the viral therapy and she remains in complete remission. ", "And you know, she just is on top of the world. ", "She says this is the best therapy she's ever had because all other myeloma therapy, she's kind of had to stay on long term and they've really impacted her quality of life in a negative way. ", "Whereas with this, she's been off all therapy and she just kind of feels like she got her life back.\"", "\n\nDr. Russell says Stacy is now focused on helping other patients achieve the same remission she has.", "\n\n\"She keeps on pestering me, saying, 'When are you going to actually achieve the same thing in another patient?'\" ", "he says. \"", "And we haven't yet done that. ", "But that's our obsession now . . . [", "to] turn this into a reproducible reliable outcome for patients who are treated with the virus.\"", "\n\nSince word of Stacy's recovery spread, Dr. Russell has been inundated with requests by patients seeking the same treatment.", "\n\nHe has given the treatment to a number of patients outside the clinical trial on a compassionate use basis. \"", "Because this whole thing is owned by Mayo Clinic and there isn't a company at the moment in control of it, then it's sort of a Mayo Clinic decision. ", "And so we have our mantra—the needs of the patient come first.\"", "\n\nHe says, unfortunately, for most of the patients the treatment did not work.", "\n\n\"Those individuals have been people with very high disease burden and it hasn't been the answer that they were looking for,\" he says.", "\n\nHowever, the process of attempting to save these late-stage patients through compassionate use taught him some critical lessons. \"", "What we think at the moment is that probably it's going to be very important the amount of myeloma that the patient has in their body and the stage of the disease,\" he says. \"", "Because we did try to treat people who had very, very advanced myeloma—who had so much disease in their body that they probably had not long at all to live. ", "And we found that the virus was not able to impact the myeloma in the same way that it had in Stacy.\"", "\n\nHe says that Stacy had less than a quarter of a pound of tumor in her body at the time she underwent treatment. ", "The patients he subsequently tried to treat on a compassionate basis had between two and six pounds of tumor in their bodies.", "\n\n\"That clearly is biting off more than we can chew,\" he says.", "\n\nHe used the information he gained from these patients under compassionate use to improve his clinical trial. \"", "We're looking at people who are more like Stacy was at the time she was treated to find out whether that's the sweet spot. ", "We don't think it was a fluke, because we've had other patients who've had quite a significant reduction in their myeloma burden—but just not to the same extent as Stacy.\"", "\n\nDr. Russell believes in providing dying patients access to experimental treatments outside of clinical trials. \"", "If I see a patient who's out of options who wants to try something then my perspective is, well who am I to block that? ", "And if I'm in a position to help them get compassionate use then I would like to do so.\"", "\n\nHowever, he says, current FDA rules can make it difficult to justify taking the risk of providing experimental medicines on compassionate grounds.", "\n\n\"If a patient receiving an experimental therapy dies and the experimental therapy is somehow implicated in causing the death, it can derail the development of a drug,\" he says. \"", "And so the entire group of patients that could benefit may either not benefit, or the benefit may be greatly delayed, because the pathway to approval is compromised.\"", "\n\nHe continues, \"[In a] hypothetical situation where somebody's going to die next week, and you kind of do the Hail Mary and you give them the experimental therapy, and they die next week, then you have to be able to hand-on-heart say the drug had no part to play in this patient's death. ", "And you can't do that. ", "The drug may have been implicated and then FDA are all over you because they want to make sure that no one is exposed to unnecessary risk.", "\n\n\"So I see both sides of it,\" he says. ", "If he were a manufacturer, he might not be so eager to support compassionate use, \"but you know, as a physician with a patient I'm more focused on the needs of the patient who I'm seeing.\"", "\n\nDr. Russell knows what it is like to see someone you love denied access to an experimental treatment, because he lost a cousin to cancer who could not get access to an investigational drug he was working on.", "\n\nA few years after he moved from the United Kingdom to Minnesota to take his current post at the Mayo Clinic, Dr. Russell says, \"I had a cousin who was in his early fifties with a young child, he had myeloma. ", "He'd had all available therapies and he was relapsing and looked like he'd probably die soon.\"", "\n\nAt the time, doctors at the Mayo Clinic were developing a myeloma drug called Velcade that he believed could help his cousin.", "\n\n\"I knew that Velcade was a good drug and we were using it in clinical trials. ", "So I tried to get him compassionate use and they wouldn't do it. ", "And I was just—as far as I was concerned the system was completely wrong and stupid for disallowing that. ", "And I still would maintain that, because I think there was enough evidence on the safety efficacy profile of Velcade to justify it.", "\n\n\"I was very upset,\" he says. \"", "It seemed like the people developing the drugs just had no real interest in sob stories, and were more concerned about the pathway to market and the profits. ", "So I totally agree with [compassionate use] up to a point. ", "But I can see how you do have to weigh it, depending on what stage of development the drug's at and depending on what the data available is.\"", "\n\nMeanwhile, Stacy Erholtz has made the transition from cancer patient to patient advocate.", "\n\n\"This could potentially be the cure to cancer,\" she recently told _Medical Daily_. \"", "If we can start treating cancer with measles, let's do it and remove all barriers in the process.", "\n\n\"I want people to join me in remission right now.\"", "\n\nDr. Russell believes this treatment could become a \"single shot cure for cancer.\" ", "He and his colleagues at the Mayo Clinic are now testing the effectiveness of the measles virus against ovarian, brain, head, and neck cancers, as well as against mesothelioma, a cancer that attacks the tissue lining the lungs, stomach, heart, and other organs.", "\n\nDoctors may soon be able to harness other viruses to kill cancer as well. ", "Dr. Russell points to research being done at Duke University using polio virus to treat glioblastoma, a deadly brain cancer.", "\n\n\"Polio is a virus that naturally damages the spinal cord, so it has a propensity to destroy nervous tissue,\" Dr. Russell says. \"", "But what was done in this case was the virus was engineered to remove a critical component, and replace it with the identical component taken from a common cold virus. ", "And the result was this engineered polio virus that can't any longer damage the brain or the central nervous system, but can still damage tumors that are located at that site.", "\n\n\"It's early stage, it's phase I,\" he says, \"but they have had some remarkable outcomes in a small number of patients whose tumors have shrunk—quite dramatically actually—following the injection of the virus into the tumor.\"", "\n\nThe treatment was recently featured on CBS's _60 Minutes_ , where a correspondent, Scott Pelley, interviewed the first person ever treated with polio virus—a twenty-year-old nursing student named Stephanie Lipscomb.", "\n\nWhen Stephanie came to the hospital complaining of headaches in 2011, doctors took a scan and found a brain tumor the size of a tennis ball. ", "Subsequent tests confirmed she had glioblastoma. ", "She underwent surgery, in which doctors removed 98 percent of the tumor, followed by radiation and chemotherapy.", "\n\nBut a year later, her cancer was back with a vengeance. ", "She was out of treatment options—except for one that had never been tried on a human being before. ", "Doctors told her about the new polio treatment. ", "They would take a needle and inject the polio virus into her brain, directly into the tumor.", "\n\nWhen her mother heard that they wanted to inject polio into her daughter's brain, she wanted to walk out of the hospital. ", "Stephanie was scared, but she decided to give it a try.", "\n\n\"I had nothing to lose, honestly,\" she told CBS.", "\n\nSo she underwent the procedure. ", "At first, scans showed the tumor had grown after the treatment. ", "Glioblastoma tumors are aggressive, doubling in size every two to three weeks, and Stephanie's appeared to be growing. ", "Doctors thought the treatment wasn't working.", "\n\nBut it turned out that this was part of the immune reaction. ", "As Scott Pelley reports, \"Five months after her infusion, an MRI showed that the tumor hadn't been growing at all. . . . ", "Stephanie's immune system had awakened to the cancer and gone to war.\"", "\n\nThe tumor began to shrink. ", "And after twenty-one months, it was completely gone. ", "Today, Dr. Annick Desjardins, the physician overseeing her treatment, says, \"She is cancer free.\"", "\n\nWhen they upped the dose in a subsequent patient, it caused an immune reaction that was too strong. ", "The patient pulled out of the trial and later died. ", "But now doctors believe they have determined the optimal dose. ", "Of the twenty-two patients in the phase I trial, half have shown significant improvement and four are in remission.", "\n\nNow Duke researchers are testing the polio vaccine against other cancers in a petri dish. \"", "We have done this for lung cancers, breast cancers, colorectal cancers, prostate cancers, pancreatic cancers, liver cancers, renal cancers,\" said Dr. Matthias Gromeier, the Duke molecular biologist who's been working on this treatment for a quarter century.", "\n\nDr. Henry Friedman, the deputy director of Duke's brain tumor center, said, \"This, to me, is the most promising therapy I've seen in my career, period.\"", "\n\nIn Oregon doctors at the Providence Cancer Center are working on another potentially revolutionary glioblastoma treatment—this one using not a deadly virus but a deadly bacteria called _Listeria_. _", "Listeria_ attacks the brain and central nervous system. ", "Researchers believe that by adding cancer-specific proteins to _Listeria_ , they can teach the immune system to think that cancer cells are a dangerous bacterial infection and attack them.", "\n\n\"By putting the two together, the bacteria and the tumor, we teach the immune cells that this target is bad and needs to be destroyed,\" Dr. Marka Crittenden, the principal investigator, said in an article on the hospital website. \"", "This is an appealing area for immunotherapy because if we can get the immune system involved in controlling this tumor, we may be able to eliminate those other areas where microscopic residual tumor remains.\"", "\n\nThe study is only in phase I trials. ", "But even if it proves safe, it will take years to make it broadly available to cancer patients. ", "Dr. Keith Bahjat, the director of the immune monitoring lab at Providence, says, \"These studies take a significant amount of time and significant amounts of money. ", "If money were unlimited, which it is not, we could see this push through clinical studies, and if the results are positive, have an application submitted to the FDA as an approved drug in five to six years' time.\"", "\n\nIn Ohio, the _Minneapolis Star Tribune_ reports, doctors at the James Cancer Hospital and Solove Research Institute are working on a vaccine \"to treat pancreatic cancer using Reolysin, a proprietary variant of the virus that causes the common cold.\" ", "The principal investigator, Dr. Tanios Bekaii-Saab, told the paper \"he expects one of these virus 'platforms' is likely to become standard treatment for a cancer such as myeloma or pancreatic cancer within three to four years.\"", "\n\nIn the United Kingdom researchers have developed a vaccine to treat melanoma using the herpes simplex virus. \"", "The virus was obtained from the cold sore of a patient who worked at the company,\" Dr. Russell of the Mayo Clinic says. \"", "It was grown on cultured cells. ", "It was engineered by removing a couple of the viral genes that make it capable of causing damage. . . . ", "And an additional gene was added in to enhance its ability to stimulate the immune system.\"", "\n\nThe British researchers used it on patients who, Dr. Russell says, \"had melanoma that had spread all over their skin. ", "And what they would do with the virus is just inject one site repeatedly every two weeks with virus. ", "And what happened in proportion to the patients was that the melanoma everywhere resolved. ", "And so it was a local injection of the virus. ", "It spread locally; it didn't spread via the bloodstream to other sites, so there was destruction of the melanoma cells at the injection site and then there was this dramatic immune activation and immune mediated destruction of the melanoma at other sites.\"", "\n\nThe vaccine recently completed a phase III trial with about 430 patients, and it had a \"durable response\"—meaning the tumor goes away and does not return—in about 16 percent of melanoma patients, compared with 2 percent in a control group. ", "The drug, called T-VEC, was bought by Amgen, which is seeking FDA approval for it.", "\n\nPerhaps one of the most amazing developments in viral therapy is taking place at Children's Hospital in Philadelphia, where doctors are harnessing the power of one of the worst killers in the history of viruses—HIV, the virus that causes AIDS—to cure leukemia.", "\n\nIn this revolutionary treatment, doctors don't inject the virus into a tumor or even infuse a genetically altered virus into the bloodstream.", "\n\nThey genetically engineer the patient's _own blood_ to kill cancer.", "\n\nIn cancers such as acute lymphoblastic leukemia (ALL), certain cells in the blood called B-cells become cancerous. ", "Normally, T-cells—special white blood cells that are the predators in the body's immune system—would hunt down the cancer and kill it. ", "But in ALL, the B-cells have developed a cloaking mechanism that allows them to fly under the radar of the killer T-cells.", "\n\nIn T-cell immunotherapy, doctors draw blood from the patients and separate out T-cells. ", "They then use a disabled form of the HIV virus (which knows how to infect T-cells) to insert a special gene that reprograms the T-cells to recognize and attack the cancerous B-cells. ", "The genetically altered T-cells are then infused back into the patient's body, where they go to war with the cancer.", "\n\n\"The virus has been engineered so that it can't cause disease anymore,\" says Dr. Carl June, the oncologist at the University of Pennsylvania who pioneered the technique. \"", "But it still retains the ability to reprogram the immune system so that it will now attack cancer cells. ", "We call those modified immune cells 'serial killer' cells. ", "Each infused cell can kill more than a thousand different tumor cells.\"", "\n\nIn April 2012 a seven-year-old girl named Emily Whitehead became the first child ever to undergo T-cell immunotherapy treatment. ", "Two years earlier, when Emily was just five years old, she was diagnosed with ALL. ", "About 90 percent of children under fifteen respond to a special combination of chemotherapy drugs first pioneered in the 1960s by Dr. Emil Freireich, a professor at MD Anderson Cancer Center. ", "But Emily was among the minority of patients in whom it did not work. ", "She underwent two rounds of chemotherapy, but relapsed each time.", "\n\n\"We spent two years in the hospital,\" says Tom Whitehead, Emily's father.", "\n\nShe was running out of options, and the Whiteheads began looking into experimental therapies. ", "They reached out to Children's Hospital, where doctors told them about a phase I trial for the new T-cell therapy. ", "Doctors explained why they were hopeful for the treatment, and that it had already worked in several adults. ", "But they also told the Whiteheads that a phase I trial was intended not to cure the patient, but rather to determine the safety and optimal dose of the drug.", "\n\nAt first the Whiteheads were not sure. \"", "My wife's in research at Penn State so she looked into it, and she just said we're not ready to just try a trial to find out what dose will work for future patients, we need something that will help Emily,\" Tom says.", "\n\nBut then Emily started declining rapidly. ", "Doctors said her major organs could fail within days. ", "With their beloved daughter slipping away, they decided to try the experimental therapy.", "\n\nDoctors removed Emily's blood, reengineered her T-cells, and then infused them back into her body. ", "The adults who had undergone the procedure had experienced mild flu-like symptoms, but Emily became violently ill. ", "She developed chills and then a raging fever that spiked to 105. ", "Her blood pressure plummeted, her lungs flooded, and she was rushed to the pediatric intensive care unit, where she ended up on a ventilator.", "\n\n\"At one point they told me that there's a one in a thousand chance Emily would survive the night,\" Tom says, \"and that was pretty tough to hear.\"", "\n\nWith Emily at death's door, her doctors figured out that the level of an immune protein called IL-6 had become elevated as a result of the T-cells growing in her body. ", "Then Dr. June hit on an idea: his daughter was taking a medication for juvenile rheumatoid arthritis that is known to turn off production of that same protein. ", "He gave it to Emily. ", "It worked. ", "Emily stabilized. ", "Her fever broke, and her T-cells went to work fighting the cancer.", "\n\nA week later, on her birthday, she woke up. ", "And twenty-eight days after her treatment, doctors conducted a bone-marrow examination to look for cancer. ", "They could not find any. ", "None. ", "Zero. ", "They could not believe it. ", "Doctors tried the test again and came up with the same result. ", "Her cancer was completely gone.", "\n\n\"It was like the calm after the storm,\" Dr. June says. \"", "The clouds went away and she woke up and there was no leukemia. ", "When that child survived, it was of course an amazing event.\"", "\n\nAs of May 10, 2015, she's been in remission for three years. ", "The genetically altered T-cells are still in her body, protecting her against a recurrence of the cancer.", "\n\nSince Emily underwent her treatment, _Forbes_ reports, thirty people (twenty-five other children and five adults) have undergone the same treatment. ", "Of those, twenty-seven have had a full remission.", "\n\nT-cell immunotherapy is being backed by the pharmaceutical giant Novartis. ", "It is a risky investment that breaks the traditional mold of \"blockbuster\" drugs that can be mass-produced for multiple patients. ", "The vaccine is unlike other cancer treatments—even cutting-edge viral therapies—because the company cannot mass-produce it. ", "Each dose must be custom-made using the patient's own blood. ", "It is truly personalized medicine.", "\n\nNovartis CEO Joseph Jimenez told _Forbes_ , \"I've told the team that resources are not an issue. ", "Speed is the issue. ", "I want to hear what it takes to run this Phase III trial and get this to market. ", "You're talking about patients who are about to die. ", "The pain of having to turn patients away is such that we are going as fast as we can and not letting resources get in the way.\"", "\n\nNovartis is to be commended for investing in this technology. ", "But Jimenez's statement raises a question: if resources are not an issue, why does Novartis have to turn patients away? ", "It is one thing for a tiny biotech like Sarepta—which literally has no cash to produce a drug outside of clinical trials—to say that it cannot provide its drug under compassionate use.", "\n\nBut why can't a company like Novartis provide it?", "\n\nI asked Novartis how many patients had been turned away. ", "A Novartis spokesman, Scott Young, did not give a specific answer, but said, \"Decisions regarding treatment have been based on strictly defined eligibility criteria agreed with the FDA.\"", "\n\nThe fact is, for Emily Whitehead, Stephanie Lipscomb, and Stacy Erholtz, the experimental treatment came just in time. ", "But for many other desperately ill Americans, the chance to save their lives never comes. ", "The American Cancer Society estimates that about 1,450 Americans will die of acute lymphoblastic leukemia, the cancer Emily beat, in 2015. ", "Another thirteen thousand will die of glioblastoma, the cancer that afflicted Stephanie, while some eleven thousand will die of multiple myeloma, the cancer that nearly killed Stacy.", "\n\nThese dying Americans don't have access to promising new therapies. ", "And while there is no guarantee such therapies would save them, most dying patients are not looking for a guarantee—they just want a fighting chance. ", "And at the current pace of drug approvals—even under the FDA's painfully slow accelerated approval process—most of these treatments will not be available to patients for many years.", "\n\nOne person who says that this needs to change is Dr. Freireich, the doctor who discovered the standard treatment for Emily's cancer—childhood ALL—five decades ago. ", "He believes patients with terminal diagnoses should not have to wait for the government to approve next-generation treatments. \"", "The FDA is preventing . . . ", "physicians from making decisions about treatment, patients making decisions about their own healthcare. ", "It's doing everything that we as a country believe is wrong. ", "Fundamentally wrong,\" he says. \"", "When a patient has a terminal illness and is not eligible to participate in a drug-testing program that is FDA-approved, they should have access to that drug if their physician and they want to take that risk.\"", "\n\nAnother person who agrees is Dr. John Bell, an award-winning scientist at the Center for Innovative Cancer Research at Ottawa Hospital Research Institute in Canada. ", "Dr. Bell is considered one of the pioneers of modern oncolytic viral therapy. ", "He was the first scientist to show that vaccinia viruses, used in smallpox vaccine, could be delivered intravenously to infect and kill cancer tumors without harming normal tissue in patients.", "\n\nHe is also a big advocate for expanding access to experimental therapies.", "\n\n\"I think it's absolutely critical,\" he says. \"", "If we have therapies that work, there's no reason not to treat people with those.\"", "\n\nLike most doctors who are working on the cutting edge of cancer research, Dr. Bell gets inundated with requests from desperate patients. \"", "I get phone calls every day,\" he says, \"and I have to say, 'Sorry, I can't offer you anything.'", "\n\n\"There's a huge need in society for the solution to this problem,\" he says. \"", "I think there should be more access to these experimental therapeutics. ", "So we need to expand access to these and allow us to give more experimentation in combinations to people who really want to have a shot at it, rather than just have palliative care that's really only going to potentially maybe reduce pain—maybe not—and maybe actually just make their life more unpleasant.\"", "\n\nHe says viral therapies are safe. ", "The fact is, we give people viruses all the time, without FDA testing. ", "When kids go to get a flu vaccine, they're getting flu virus. ", "And when kids get measles vaccine, they're getting measles virus. ", "So we inject viruses into people every day. \"", "That's why we're not worried about safety because we have a tremendous safety profile from the last two hundred years of vaccinations.\"", "\n\nNot only are viral therapies safe; they are far milder on cancer patients than most approved treatments. \"", "These therapies are much more benign then chemo and radiation therapy by a long stretch and that's good,\" he says. \"", "So even if they were only as effective as chemotherapy, the fact that they're much less toxic is a good thing.", "\n\n\"I don't want to say chemotherapy is horrible,\" he adds. \"", "We actually have some studies showing that some kinds of chemotherapy in combination with viruses actually do much better.\" ", "But, he says, \"Our current chemo and radiation therapies are not curing people with metastatic disease, which is a lot of people. ", "So since we're not curing them anyhow, why not give them the option [to try investigational treatments]?\"", "\n\nNo treatment is without risk, he says, but \"lots of people die every day from chemotherapy. ", "So let's just get over ourselves here and say this isn't working, we're paying a lot of money for it, we're putting people in the hospital with these treatments; we should really start to try to move forward faster.", "\n\n\"I think it's unethical in my opinion—it's unethical to withhold these treatments if there's a potential there. ", "It's unethical to treat people with things we know are not going to cure them and that could make them very, very sick,\" he says.", "\n\nThere is no guarantee that patients will have the same miraculous response as Stacy Erholtz, Emily Whitehead, and Stephanie Lipscomb. ", "But, Dr. Bell says, \"a 16 percent [chance] is better than zero, and maybe 1 percent is better than zero and maybe a small percentage is better if you have a therapy that doesn't basically debilitate you.\"", "\n\nOne of the criticisms of Right to Try is that it will drive patients into the arms of charlatans. ", "But Dr. Bell says that it is the lack of access to promising therapies with real science behind them that is driving people to quacks.", "\n\n\"In cancer there's a lot of really bad people who exploit people's desperation. ", "There's a guy in Ottawa who calls himself 'Dr. Hope' who basically gets people to give him money and he promises them good outcomes with really no good basis in science or therapies that make any sense at all.\"", "\n\nHe says of the FDA, \"In fairness, they're trying to keep people from being exploited.\" ", "But he adds that \"the problem is they're actually not [protecting people]. ", "We over-engineer our regulatory system to try to keep [bad] people from benefitting. ", "And we don't stop them. ", "They still carry on. ", "And it just makes it harder for people like myself, who are willing to do science the right way, to get going forward. ", "It's just bizarre, and it's also bad for the patients.\"", "\n\nTom Whitehead, Emily's father, agrees. ", "Before Emily got access to an experimental treatment, when it seemed they were out of options, Tom says they thought about traveling abroad. \"", "I can tell you that was a consideration of ours. ", "There were different times when we thought it's possible we might have to go overseas. ", "Because doctors would tell us, 'Hey, there's this thing in Germany . . . ", "that's not approved here yet.'", "\n\n\"I've seen families that went to Mexico, where they told them they'll heat their body up to a certain temperature and different things. ", "When you're desperate, you're going to try something if you can't get anything here, I guarantee it.", "\n\n\"As a parent,\" he says, \"you would do anything to save your child.\"", "\n\nDr. Bell supports Right to Try laws. \"", "It's a great idea,\" he says. \"", "Our societies are too paternalistic. ", "We think we know better than the patient, what they really want.", "\n\n\"Society wants this and I don't know why we're sort of stuck in this quagmire.\"", "\n\nHe believes we are at the cusp of unprecedented breakthroughs in cancer treatment. \"", "I've been doing this for a long time, about thirty years in this field, and I've never seen the developments like we've seen in the last five years,\" he says.", "\n\n# 5.", "\n\nInside Man\n\n_How One Biotech CEO Came to Champion Right to Try_\n\nWhen the Goldwater Institute first launched Right to Try, it was immediately embraced by doctors, patients, and legislators across the country. ", "But at first, no one in the pharmaceutical or biotechnology industries stepped forward to openly support the idea . . . ", "until, that is, one courageous CEO of a cutting-edge biotech firm came out publicly and declared: Yes, dying Americans do have the Right to Try.", "\n\n\"THAT'S MY SON'S BRAIN tumor.\"", "\n\nRichard Garr points to a shelf in his office. ", "Among the books, awards, mementos, and scientific models sits a large misshapen piece of plastic. ", "He picks it up and holds it in his hand.", "\n\nIt is the size of a grapefruit.", "\n\n\"They make a mold of it with computers,\" Garr says. \"", "He had a tumor when he was very small, when he was four years old.\"", "\n\nTwenty-three years ago, Garr's son Matthew began complaining about disabling pain in his neck. ", "The pain came and went, and doctors never thought it was anything serious. ", "Then one day, during a routine eye exam, his optician looked into the back of Matthew's eyes and saw signs of enormous pressure. ", "He said it probably was nothing, but suggested that Matthew should have an MRI done.", "\n\n\"We sort of knew immediately it wasn't 'nothing,'\" Garr says. ", "And indeed, the MRI showed a massive tumor in Matthew's brain.", "\n\nWithin a week, he was on the operating table at National Children's Medical Center in Washington. ", "The surgery took eighteen hours. ", "The tumor had wrapped itself around Matthew's brain stem, and removing it was incredibly complicated. ", "Thankfully, Dr. Dennis Johnson, one of the leading neurosurgeons in the country, was able to perform the surgery.", "\n\n\"We were fortunate that Dr. Johnson was available,\" Garr says. \"", "There are very few guys even in that elite universe who could do what he did, get it all out without killing him. ", "We are more blessed than you can imagine.\"", "\n\nAfter Matthew's surgery, he lay in a coma for several weeks. ", "When he finally recovered and was able to return to school, he had to start kindergarten a year late.", "\n\nThat delay would end up saving Ted Harada's life . . . ", "and change the course of medical history.", "\n\nWhen Matthew finally began classes at the McLean School in Potomac, Maryland, he became best friends with a classmate named Arthur Johe. ", "The two boys spent a lot of time together outside school, and Richard Garr became friends with Arthur's dad, Karl. ", "When Richard told Karl about Matthew's surgery, Karl's response shocked him:\n\n\"Well, someday we'll be able to fix that.\"", "\n\nKarl Johe, it turned out, was a scientist at the National Institutes of Health (NIH). ", "And not just any scientist. ", "Johe had discovered neural stem cells, which can grow to become brain or spinal cord cells. ", "The two men bonded over their shared interest in brain science.", "\n\nGarr, who was then a successful real estate attorney, was looking for something he could do to help his son and others like him. \"", "Every parent of every child who faces a life-threatening illness looks for a way to help,\" Garr says. \"", "Usually you end up helping to raise money for charity, or getting involved with the brain tumor society or something like that. ", "And Lisa, my wife, and I, we did all those things.\"", "\n\nBut Garr felt a growing passion to do more.", "\n\nMeanwhile, Johe was feeling a growing frustration with the NIH and the politics of obtaining research grants. ", "So in 1997 the two men decided to go into business together.", "\n\n\"We ended up starting a company, which is very unusual in the life sciences,\" Garr says. \"", "You see it in high tech—two guys in a garage. ", "You don't see that in biology. ", "But we did it.\"", "\n\nSoon Neuralstem was born. ", "And at this writing, eighteen years later, Garr is among the longest-serving CEOs in the stem-cell industry.", "\n\nAs we have seen at the start of this book, their work in the ensuing decades produced a modern-day medical miracle, when Ted Harada became the first person in recorded medical history to see his ALS symptoms reversed. \"", "Our goal,\" Garr says, \"is to try and turn ALS into a chronic manageable disease as opposed to a fatal disease.\"", "\n\nBut Neuralstem's technology has applications far beyond treatment of ALS. ", "The company is also targeting a host of other major central nervous system conditions.", "\n\n\"We are also treating ischemic stroke, actually in China; those are direct injections in the brain,\" Garr says. \"", "And we have two spinal cord injury trials. ", "One that started in UC San Diego which is for chronic spinal cord injury . . . ", "where there is no sensory or motor function below the injury. ", "Then we're setting up an acute spinal cord injury trial in Seoul, which is right after the accident.\"", "\n\nAnother area in which neural stem cells show promise is as a platform for treating depression, a deadly disease that leads to tens of thousands of suicides a year in the United States. ", "In the late 1990s, Neuralstem won a contract to work on the Pentagon's \"War Fighter of the Future\" project. \"[", "They] came to us and said, 'We'd like you to put your cells in dishes and screen against them to find a new class of drugs that will cognitively enhance the soldiers,'\" Garr says.", "\n\nThe drug they developed, which is now in clinical trials, is a small molecule pill that may stimulate the brain's capacity to generate new neurons. ", "If it works, it has the potential to treat central nervous system conditions such as major depressive disorder (MDD), traumatic brain injury, cognitive deficit and schizophrenia, and post-traumatic stress disorder (PTSD).", "\n\nGarr explains how it works: \"So inside your head you're pretty much hardwired. ", "But there's an area of your brain called the hippocampus, which is sort of like your processing center where all your thinking and a lot of your emotions are seated.", "\n\n\"And your hippocampus actually has a little bit of a reservoir of neural stem cells—not the hardwired, fully adaptive neurons and nuclei, but their precursor cells,\" Garr says. \"", "And through life they sort of replenish the hippocampus with new synaptic contacts. ", "You have more of them when you are young, and fewer of them when you're old, and so maybe that's why it's easier to learn a language and things . . . ", "when you're young.", "\n\n\"Well, we can grow those precursor cells in dishes,\" Garr says. \"", "That's what our technology is. ", "It's growing stem cells.\"", "\n\nNeuralstem just completed a phase Ib trial of the pill. ", "According to Garr, \"We released the data last summer. ", "The top guy in the field at Harvard did our trial, released the data, and it showed that in fact we reduced depression and the cognitive deficit in the depressed patients in a clinically meaningful way. ", "Statistically significant and clinically meaningful. ", "And so we're going into a phase II now to treat depression and we expect to start a trial to treat the cognitive deficit in schizophrenia.\"", "\n\nAsked by an interviewer recently if the pill could one day reverse some of the effects of aging, Dr. Johe said, \"Yes, there's no question that degeneration of the hippocampus and other parts of the brain is part of the aging process. ", "As we now take many different food supplements to counter or slow that aging process, I see this as a potential 'vitamin for the brain' to slow down or counter that aging process in our mental capacity.\"", "\n\nOne of the most dreaded neurological diseases affecting aging Americans is Alzheimer's. ", "At the University of Michigan, Dr. Eva Feldman—the doctor who pioneered the neural-stem-cell treatment that reversed Ted Harada's ALS symptoms—is now developing stem-cell surgery that might one day reverse the symptoms of Alzheimer's.", "\n\nThe _Detroit News_ reports that Dr. Feldman recently completed preclinical trials that showed that neural stem cells had a remarkable impact on mice engineered with the gene that causes Alzheimer's. ", "In the study, Dr. Feldman injected one group of mice with neural stem cells into their hippocampus, while a second group was injected with saline solution. ", "She then evaluated the two groups by giving them memory tests.", "\n\n\"Those animals [who got the neural stem cells] retained their ability to think, as a mouse does, to recognize objects so they looked just like an animal that doesn't have Alzheimer's disease,\" she told the paper. \"", "It's really remarkable.\"", "\n\n\"When you work in science, you do as many experiments that don't work as that do,\" Dr. Feldman said. \"", "When you get something that works so beautifully (like this experiment), you can quickly see its translational potential. ", "I am looking at a mouse but someday I could be looking at a man. ", "As a clinician scientist, those are the moments you live for.\"", "\n\nShe's still a long way away from human testing. ", "But the results hold great promise for a fatal disease that is estimated to affect as many as five million Americans age sixty-five and older.", "\n\nI first learned about Garr and Neuralstem during the fight to pass Arizona's Right to Try law. ", "One day I was scanning stories about Right to Try when a blog post Garr wrote on Neuralstem's company website caught my eye.", "\n\n\"The 'Right to Try' bill is making its way through the (now infamous) Arizona State Legislature,\" Garr wrote. \"", "The Arizona State Legislature is the incubator of some of the worst laws in the history of bad laws, embodying obviously hateful and penal opposition to all manner of group.\"", "\n\nOh boy, I thought, here we go.", "\n\nBut then came the surprise twist:\n\n\"I suspect that this bill may resonate broadly both in and outside of Arizona,\" he wrote.", "\n\nHuh? ", "I checked his bio again. ", "This was coming from the CEO of a biotech company?", "\n\nQuoting the reggae legend Bob Marley (\"Every man gotta right to decide his own destiny\") Garr continued:\n\nThe basic premise of the Bill is that patients with fatal and incurable diseases should be able to choose for themselves whether or not to try an experimental drug. ", "The Bill's authors state that they should not be constrained by the FDA's approval process. . . .", "\n\nThe Bill was drafted by the libertarian leaning Goldwater Institute, and is based on the premise that the FDA's approval process denies citizens the right to choose their own medical path. ", "The Bill stipulates that it only applies to fatal diseases, and only to medicines that have passed a FDA Phase I safety trial, and further to medicines that are currently in (at least) a FDA Phase II trial; so there is some effort to restrict the scope of this program to drugs that have had a good level of FDA scrutiny. ", "There must still be a licensed medical doctor involved to prescribe the investigational drug; and the law states that companies cannot be forced to provide the drug if they so choose. ", "Finally, there is language that looks to allow for companies to charge for these treatments. ", "The provision is vague but seems to reference cost reimbursement language.", "\n\nAt Neuralstem we are keeping a sharp eye on this legislation. ", "As we move into the final stretch of transplantations for our Phase II therapy for ALS . . . ", "we are keenly aware of all of the patients who cannot be included in the trial; both because of the small number of patients in the trial, and also because of the exclusive nature of inclusion/exclusion criteria the trial is built around. ", "And as we begin to design the next trial, a trial which we hope will lead to approval by the FDA, we are thinking more and more about ways to broaden access to our cells.", "\n\nWe support the intent of this bill. ", "One does not have to be a fire breathing libertarian to wish that cutting edge technology could get to its intended recipients sooner and with less red tape. . . . ", "Right to Try is a good idea with lots of flaws; but a good idea nonetheless, and an idea worth supporting and pursuing.", "\n\nI immediately picked up the phone and called him.", "\n\nHe seemed surprised to hear from me. \"", "My personal politics are 180 degrees from Goldwater,\" he said. \"", "I'm your typical knee-jerk Democrat, born and raised in Washington, lifelong liberal.\"", "\n\nWe began discussing Right to Try. ", "He told me that \"from the land of the worst ideas ever, this is not such a bad idea. ", "It has flaws, but there are ways this could really help the ALS community in particular.\" ", "I candidly asked him why he was so willing to support the Right to Try when most CEOs were taking the \"don't rock the boat\" approach, not wanting to get crosswise with the FDA. ", "He said that even if his company's ALS treatment proved successful, by the time it reached the market, all his patients outside the few in the clinical trials would be dead. ", "Garr would spend hours at night emailing and talking with patients desperate to get into his ongoing trials, and he was powerless to help. ", "He wanted to get those patients, and other terminal patients, faster access to promising new treatments.", "\n\nSo I asked him to work with me and help us fix the flaws. ", "He agreed.", "\n\nWeeks later, Garr and I published an article in _USA Today_ asking the FDA and legislators to support the Right to Try. ", "Today Garr speaks out for Right to Try at biotech industry meetings and conferences on rare diseases.", "\n\nWhen he started making the case for Right to Try, he says, \"The industry push-back shocked me.", "\n\n\"They would say all these terrible things like, 'Well, who's going to pay for it? ", "How are you going to control the proper consent to the patients? ", "How do you know they're not being scammed?' ", "And my answer was: Well, yeah, those are all real questions. ", "And by the way it's going to pass anyway, and they're going to get dumped in your lap. ", "So rather than fight it and say this is a horrible idea and wring your hands, you should get inside and get behind it and make sure that it addresses all these questions. ", "They're all legitimate questions.\"", "\n\nHe says he is slowly making progress.", "\n\n\"They're coming around to the point where they'll actually talk to me,\" he says.", "\n\nHe is sympathetic to the concerns the critics raise. \"", "My view is that there are real issues that have to be resolved. ", "Who is going to pay for this? ", "Are the insurance companies going to reimburse for this? ", "If they don't, does this mean only rich people are going to be able to access Right to Try?\"", "\n\nBut, he says, \"there are people in our industry who spend all day, every day, figuring out who pays for what and why. ", "So this isn't peace in the Middle East, right? ", "These are tough questions, but there are people who do that all the time. ", "You may not like their answers, but don't tell me there's no way to get to that answer, right?\"", "\n\nHe says his approach is to tell his colleagues, \"Let me explain why you should support it—not why I'm right and you're wrong—why _you_ should support it. ", "What we're telling industry is, look, you're going to be under pressure to provide this anyway. ", "You don't want to be on TV and some woman holding her child saying, 'They wouldn't give me the emergency drugs, my child's going to die.'\"", "\n\nIt is better for industry to support Right to Try and help solve the very real challenges, he says, than to be standing outside opposing it while a large, grassroots political movement demanding access grows across the country.", "\n\nHe says the logistics can be solved. ", "As evidence, he points out that \"nobody had any problem getting around all the issues with Ebola.\"", "\n\nIn July 2014, when the American medical missionary Dr. Kent Brantly was caring for Ebola patients in Liberia and contracted the deadly disease, he was given an experimental antiviral drug called ZMapp, which was produced by the San Diego–based Mapp Biopharmaceutical. ", "It had undergone no human clinical trials or safety tests before it was given to Dr. Brantly. ", "Indeed, it had never been tried on human beings before. ", "When the Ebola outbreak happened, the _New York Times_ reported, Mapp had just been \"gearing up to start the larger animal toxicity studies typically needed before testing it in humans, with an eye on doing the first human safety studies in healthy volunteers\" in 2015.", "\n\nIn all, at least six people are known to have received ZMapp, according to the World Health Organization. ", "Two have recovered, three have shown improvement, and one has died.", "\n\nAccording to the _Washington Post_ , the FDA allowed the makers of ZMapp and two other experimental Ebola drugs \"permission to use the unapproved medications on humans, even though their safety and effectiveness against Ebola has not been proven.\" ", "Indeed, the Obama administration has asked Congress for $58 million to ramp up production and testing of ZMapp and to speed the development of two other experimental treatments.", "\n\nThe assistant general director of the World Health Organization, Marie-Paule Kieny, praised the FDA for its willingness to clear safety and bureaucratic hurdles so quickly, calling the speed of action \"absolutely unprecedented.", "\n\n\"We have to change the sense that there is no hope,\" she said.", "\n\nFor Jenn McNary—the mom we met in chapter 1 whose son can't get access to a promising Duchenne drug—watching the FDA clear bureaucratic red tape to allow dying patients to try untested, experimental treatments was bittersweet.", "\n\n\"I read about Ebola and how drug companies are able to just sort of take this drug wherever because it is an emergency,\" she says. \"", "Duchenne is also an emergency. ", "Kids die from this disease every day. ", "It is the most common lethal genetic disorder in children.\"", "\n\nHow could the FDA throw out the rule book to permit the use of a treatment for Ebola that has not been proved safe or effective, while at the same time denying Jenn's son, Austin, access to a drug that has been shown to be safe and effective in his own brother? ", "How can the FDA permit the use of an Ebola drug that has never even been tested on a human being while denying cancer patients access to medicines that have passed phase I, phase II, and sometimes phase III FDA testing?", "\n\nGarr says the answer is simple: Ebola is contagious.", "\n\n\"Duchenne disease is not contagious. ", "ALS is not contagious. ", "Cancer is not contagious. ", "So society has answered that question. ", "We're willing to waive all these issues if it's contagious and it can affect me. ", "We're not willing to waive all these issues without a big fight if it's not. ", "I mean, that's where I see it sitting right now.\"", "\n\nWhen Ebola arrived in America, Garr says, \"nobody hesitated two seconds. ", "All these other questions went out the window with Ebola immediately. ", "Pull everybody off of everything, we'll figure out how you get paid later . . . ", "give it to them, give it to them, give it to them.", "\n\n\"In my mind, the Ebola situation should have just evaporated any arguments, all the other arguments that people had against [Right to Try],\" he says.", "\n\nWhile there are legitimate issues that need to be resolved when it comes to implementing Right to Try, many objections raised by critics are based on a misunderstanding of what the law does and does not do. ", "For example, there is a perception that Right to Try laws cut the FDA out of the picture. ", "One of the nation's leading cancer specialists actually said in an interview for this book, \"Right to Try is 'I'm dying of cancer, there's this new drug that's been given to seven dogs, three chimpanzees, and one human being, and I'm saying I demand that drug today.'\"", "\n\nThat is not what Right to Try is.", "\n\nQuite the opposite, as Garr explained in a recent blog post: \"The FDA is an indispensable party in this process. ", "Indeed the [Right to Try] bill relies heavily on their expertise and diligence. ", "That is why the bill only applies to fatal diseases, and only to drugs or therapies that have passed an FDA-approved safety trial, and are still actively being developed under the FDA umbrella in further trials.", "\n\n\"The FDA is not the enemy,\" Garr says.", "\n\nThe problem is that the existing emergency structures from the FDA are not adequate to meet the rising demand for access to emerging drugs. ", "That's because compassionate use is designed for small numbers of people who are seeking access to later-stage AIDS and cancer drugs for which there have been big trials but the drug is still a few years away from approval. ", "It is not designed for broad access by large numbers of patients to early-stage innovative technology that is showing promise in small trials and could make a difference for patients with an unmet need.", "\n\nThe Right to Try movement is demanding that kind of access to investigational drugs on a much broader scale—and the current system is not designed to accommodate that demand.", "\n\nGarr points out that Right to Try presents different challenges to small and large companies. ", "Many small companies can't afford to accommodate compassionate use requests. \"", "If you're Glaxo or Merck, it doesn't cost you anything to manufacture a thousand pills,\" Garr says. \"", "But most of these innovative drugs are coming out of . . . ", "small biotechs.\"", "\n\nHe is right. ", "As we saw earlier in the case of Sarepta and its Duchenne drug, eteplirsen, small companies don't always have the resources to produce enough drugs or to cover their costs for patients to get compassionate use.", "\n\nHe says the challenge for the big pharmaceutical companies—those who _can_ afford it—is that they are afraid that providing access to experimental treatments, even under the existing FDA-approved compassionate use system, will put their investments at risk.", "\n\n\"The way the FDA works is if you put your drug in somebody—whether it's approved or not—and something bad happens, you have to tell the FDA,\" Garr says. \"", "If that person dies, the FDA could stop their trial.\"", "\n\nFor a major new drug, that could cost the company millions and delay getting the drug to market.", "\n\n\"So that's where big pharma, that's the real push-back you get from the people who can afford to do this,\" he says.", "\n\nTo make Right to Try work on a large scale, companies need some guarantee that if they offer an experimental treatment to someone who does not meet the criteria of a clinical trial—because the patient has complications or is in a late stage and at high risk of dying—the FDA is not going to stop their trial if that high-risk patient dies.", "\n\nBy contrast, he says, \"if you can protect them against the negative [of] having it affect their clinical trials, if you can protect them, then there's nothing but upside for them to treat these higher-risk patients, because if something goes wrong they're not going to lose their clinical trial, they're not going to get liability, but the payoff is somebody with a late stage or something is cured, the publicity and everything that comes with it is dramatic.\"", "\n\nOthers have raised concerns that Right to Try laws will push terminal patients into the arms of quacks with unproven treatments who prey on the desperation of dying Americans. ", "But Ted Harada—the ALS survivor whose symptoms were reversed thanks to Garr and Johe's technology—says the opposite is true.", "\n\n\"The FDA is pushing us to the snake-oil salesmen,\" Ted says. \"", "Because someone dying is going to try anything— _anything_. ", "People don't want to die without hope. ", "The FDA pushes them into trying riskier things.\"", "\n\nToday, the world outside the United States is filled with nefarious characters taking advantage of the sick and dying, promising cures for everything from brain tumors to Alzheimer's. ", "People are holding bake sales and fund-raisers to send their children to Colombia, Mexico, and other countries for false cures.", "\n\nA few years ago, the _Wall Street Journal_ reported: \"Some patients with fatal Lou Gehrig's disease, frustrated by the slow pace of clinical drug trials or unable to qualify, are trying to brew their own version of an experimental compound at home and testing it on themselves.\"", "\n\nSuch actions show how desperate the ALS community is, Ted says.", "\n\nRight to Try laws actually direct people away from false cures like these by giving them access to treatments at home that have real science behind them. ", "Before a drug can even begin a phase I trial and be put into a human being, a company must spend millions of dollars and show the FDA reams of data from laboratory testing and animal studies. ", "So once a drug completes phase I trials, it has tens of millions of research dollars behind it. ", "Those that complete phase II trials and move into phase III have even more scientific data behind them and an even better chance of eventual success. ", "These treatments are not guaranteed to work. ", "But unlike quack treatments that patients will find abroad, they have a real _chance_ of working.", "\n\nThis is why critics are wrong when they say Right to Try gives patients false hope. ", "Terminal patients who have exhausted all the FDA-approved treatments have _no hope_. ", "Right to Try does not promise them a cure; it offers them a _chance_. ", "It gives terminal patients real hope by granting access to promising investigational treatments. ", "Denying them that hope—telling them to go home and die when there is still a chance, even a remote chance, to save their lives—is flat-out cruel.", "\n\nThere are solutions to all the challenges we face, Garr says, but we are not going to find those solutions without the forcing mechanism of Right to Try laws. \"", "Right to Try provides a scaffold where you could build the structure to answer all these questions,\" Garr says. \"", "And they're not going to get answered hypothetically. ", "The insurance companies are not going to say, 'Okay, we'll reimburse for this' until it's put to them.", "\n\n\"So yes, all of these things have to be addressed,\" Garr says. \"", "But again, informed consent, reimbursement, all these things are addressed by this industry all day every day for really tough questions.\"", "\n\nGarr's point is that none of these are arguments against the Right to Try. ", "They are challenges to overcome in _implementing_ the Right to Try. ", "We need to solve them. ", "But we cannot allow them to become excuses for inaction.", "\n\nI believe that most Americans understand this, and that this is why the Right to Try movement is sweeping the country.", "\n\n# 6.", "\n\nWe Are the 99 Percent\n\n_How Right to Try Has Taken America by Storm_\n\nThe first Right to Try law passed in May 2014. ", "In a little over a year since then, Right to Try has passed in twenty-four states and counting.", "\n\nThat is a legislative land-speed record.", "\n\nAnd it is only a matter of time before it is the law of the land in all fifty states.", "\n\nWhy has Right to Try taken the country by storm? ", "Simple: almost everywhere it has passed, courageous Americans fighting terminal illnesses have stepped forward to fight for it. ", "These patients and their families have testified before state legislatures, lobbied their elected leaders, and shared their stories with the media—asking their fellow citizens to stand with them in the fight to save their lives.", "\n\nThese stories have captured the imaginations of legislators of both parties and inspired millions to rally around the terminally ill. ", "Some of their stories have had happy endings. ", "Others have ended tragically. ", "In others, the final chapters are still being written.", "\n\nThese Americans moved hearts—and votes—in support of the principle that every American has a fundamental right to try to save his or her own life.", "\n\nLet's meet some of the heroes of the Right to Try movement—starting with one who is just five years old.", "\n\n**INDIANA**\n\nLike most little boys his age, Jordan McLinn wanted to be a fireman.", "\n\nUnlike most little boys his age, Jordan actually got his wish—and then rallied his fellow firefighters to pass a new Indiana law that will help save lives.", "\n\nOn January 17, 2013, when Jordan was three, a routine visit to the pediatrician turned into a nightmare: he was diagnosed with muscular dystrophy.", "\n\nBut doctors did not know which kind of muscular dystrophy he had—Becker, a chronic but survivable form of the disease; or Duchenne, which is fatal. ", "So they told Jordan's mom, Laura, to bring him to the lab on Monday to leave the blood sample that would confirm which kind it was.", "\n\n\"They said it would take three weeks to get that test back,\" Laura says. \"", "I remember that I fasted [from] all food for almost the full three weeks and prayed so hard that it would not come back as Duchenne. ", "It was the hardest three weeks of my life. ", "It was like we were in mourning but trying to create hope at the same time.\"", "\n\nThree weeks later the news finally came: Jordan had Duchenne.", "\n\n\"I will never forget the day I got the call,\" she says. \"", "We pretty much felt like our world had come to an end.\" ", "Like other Duchenne moms we have met, Laura was told that there was nothing she could do to help her son.", "\n\nShe was devastated.", "\n\nOne morning after his diagnosis, Laura was making breakfast for her family and watching the _Today_ show when she saw a story that riveted her. ", "The reporter told the story of Jenn McNary and her struggle to save her sons, Max and Austin.", "\n\n\"Each day brings Jenn McNary another dose of hope and heartache as she watches one son get healthier while the other becomes sicker,\" the _Today_ show correspondent said.", "\n\nThe correspondent interviewed Dr. Jerry Mendell, the principal investigator in Max's clinical trial. ", "He explained how eteplirsen allowed children with Duchenne to \"skip\" a broken exon in their genetic code and start producing dystrophin—the protein their muscles need to avoid breaking down and maintain their function.", "\n\n\"Everything I can tell indicates that this is a winner,\" Mendell told the _Today_ show \"It's a game changer.\"", "\n\nLaura was mesmerized. ", "Could this be the cure for Jordan?", "\n\nShe immediately Googled Dr. Mendell. \"", "I didn't really even know anything about exon skipping but I sent him an email and told him about Jordan. ", "I asked him if Jordan could benefit from exon skipping and would he be willing to see Jordan,\" Laura says. \"", "He emailed me back in the middle of the night, which was awesome, and told me that Jordan could be a candidate for skipping exon 53 and that that drug was coming up through the pipeline. ", "He invited Jordan to come and be his patient.\"", "\n\nIt was the first good news Laura had gotten in months.", "\n\nShe took Jordan to Columbus to see Dr. Mendell. \"", "We've had this hope that Jordan would get into the clinical trial for skipping exon 53 because they keep saying it's coming up, coming up. ", "Well, when I talked to Sarepta a month or two ago, I called them and they said they are still on track with starting a clinical trial this summer, but you have to be seven to get in it, and Jordan will be six in May.\"\n\nJust like Mindy Leffler's son, Aidan, Jordan was too healthy to be admitted into the study.", "\n\n\"Obviously we were heartbroken because we'd had so much hope that he would make it into this trial,\" Laura says.", "\n\nWhile she kept working to save Jordan's life, Laura also focused on helping Jordan make the most of the life he had left. ", "He was obsessed with becoming a fireman, so Laura hit on an idea she thought would bring joy to Jordan and help raise awareness for Duchenne.", "\n\nShe would try to get Jordan a \"job\" helping out at the local fire station.", "\n\n\"I put together a little résumé for my son to get a job as a firefighter,\" Laura says. \"", "It's got a cute little picture of him in some fire gear.\"", "\n\nThe résumé read:\n\nJordan Joseph Nelson McLinn, Age 5\n\nDate of Birth 5/15/09\n\nObjective: To obtain a job at the fire station helping the firefighters.", "\n\nQualifications: I am strong. ", "I love God. ", "I love helping people. ", "I am super smart.", "\n\nChallenges: I have Duchenne Muscular Dystrophy. ", "Science says within 3 to 7 years I will be in a wheelchair and within 15 years I will most likely be living in heaven because all my muscles will be deteriorated. ", "We don't really believe that though.", "\n\nSkills: Taking Care of Dogs, Cleaning, Building Things, Playing with Cars & Trucks, Dancing, Cooking, Making People Smile.", "\n\nAt the bottom, Laura added:\n\nJordan says he wants to be a firefighter when he grows up. ", "He was given a fatal diagnosis of DMD last year. ", "It would be awesome if there is anything he can do maybe once a week for a short time to help out at the fire station. ", "We are pretty flexible with days/times. ", "He is an awesome little boy, happy and full of life! ", "Please let me know if I can bring him in for an, \"interview.\" ", "Thank you for your consideration.", "\n\nLaura crossed her fingers, and sent the résumé to Ernest Malone, chief of the Indianapolis Fire Department.", "\n\nAfterward, just for fun, she posted Jordan's résumé on her Facebook page with a message that said, \"Hey, wish us luck.\"", "\n\nIt went viral.", "\n\n\"The next thing I know, within hours Jordan was getting job offers from New York City, Las Vegas, Alabama, Michigan,\" she says.", "\n\nFirefighters from all over the country were reaching out to help the little boy.", "\n\nRight before Christmas, Jordan had two job \"interviews.\" ", "One was with the firehouse at Bargersville, a small town south of Indianapolis, and another with IFD Station 13 in downtown Indianapolis.", "\n\nOn Christmas Eve, Jordan came to Ladder 13, and had a tour of the firehouse. ", "He got to climb into the driver's seat of the ambulance and fire trucks, turn on the lights and sirens, and even take a slide down the fire pole. ", "The fire department chaplain gave him a copy of the firefighters' Bible.", "\n\nThen Jordan sat down for his interview with Captain Tim Robinson. ", "He was the first candidate Captain Robinson had ever interviewed who had arrived clutching a big brown teddy bear.", "\n\n\"Do you think you could get up every morning and help us clean the firehouse?\" ", "Captain Robinson asked him.", "\n\n\"Yeah,\" Jordan said. ", "He asked if maybe they could call to wake him up.", "\n\n\"We can do that,\" Captain Robinson said.", "\n\n\"I think it went well,\" the captain told Jordan's mom when the interview was done, as she wiped back tears from watching her son so happy.", "\n\nOn Christmas, Santa delivered some good news.", "\n\n\"He wakes up on Christmas morning and had two letters in his stocking with job offers,\" Laura says. ", "One was from Bargersville, the other from the Indianapolis Fire Department.", "\n\nThe letter from the IFD read:\n\n___Dear Jordan McLinn,_\n\n_Congratulations! ", "You have been selected to be an honorary Firefighter for the Indianapolis Fire Department. ", "At this time you are being given a Conditional Offer of Employment by the IFD. ", "This offer is contingent on your successful completion of the following requirements:_\n\n_1. ", "Always be fire safe. ", "Know two ways out of every room and have a family meeting place._", "\n\n_2. ", "Always use your best crayons when coloring a fire truck picture!_", "\n\n_3. ", "Always keep your bedroom clean with your fire boots ready for action!_", "\n\n_4. ", "Make sure the fire hydrant near your house is clear of leaves and snow._", "\n\n_5. ", "Get plenty of rest at night so you are always ready for action._", "\n\n_The start date of the next full Recruit Class is dependent upon the various remaining testing components, in conjunction with approval by the Public Employees Retirement Fund (PERF) of the state of Indiana. ", "In the meantime, you are to report at 10:30 am for pre-recruit class training on Thursday, January 8, 2015 at IFD Station 13 located at 429 W Ohio St. Indianapolis, IN. ", "Please ask for Captain Tim Robinson when you arrive._", "\n\n_Sincerely,_\n\n_Ernest Malone, Chief of Fire,_\n\n_Indianapolis Fire Department_\n\nLaura filmed Jordan opening the letter.", "\n\n\"I got hired!\" ", "he shouted, \"Thank you, Chief Malone!\"", "\n\nJordan accepted both job offers and did work days with both firehouses. ", "He traded in his plastic toy fire helmet for a real one with a big \"13\" on the front, and a real fireman's jacket with \"McLINN\" on the back. ", "He even got his own locker stall in the firehouse next to those of all the other firemen where he could hang his gear.", "\n\nHis story got tons of media attention. ", "Local TV news crews came to cover his interviews and first day on the job. ", "And as word spread, more and more firehouses began reaching out to Jordan.", "\n\n\"Firefighters all over the country have just embraced our family and every day it's like there's something new,\" Laura says. ", "Helmets, patches, T-shirts, and toy trucks started arriving from firehouses coast to coast—Texas, Illinois, Minnesota, Washington State, Alabama, Nevada, and New Jersey, among others—along with invitations to visit.", "\n\nAnd in Indianapolis, Laura says, \"The whole fire department has basically just embraced our family. ", "We go and eat lunch all the time and Jordan does little trainings and it's just awesome. ", "Like we're just a part of the firefighter family now, and not just one station. ", "It's awesome for Jordan. ", "It's awesome for our whole family.\"", "\n\nIf it ended there, it would be a nice, heartwarming story—firefighters embrace dying boy and make his dream come true.", "\n\nBut the story didn't end there.", "\n\n\"This, to me, is where the story gets _really_ good,\" Laura says.", "\n\nOne day, Tom Hanify, the president of the Professional Firefighters Union of Indiana, called Laura and said, \"Hey, I would like to take you and Jordan on a tour at the statehouse and Jordan can help me do some lobbying for the firefighters.\"", "\n\nIt seemed like a great opportunity to learn a little about how government works. ", "So Jordan and Laura spent a day at the state capitol with Hanify and Mike Whited of the firefighters union.", "\n\n\"They taught us how to lobby,\" she says. \"", "They showed us the statehouse. ", "We had lunch with our senator. ", "We met lots of senators and representatives and Jordan walked around in his fire gear. ", "He was actually helping Tom lobby for protecting the pension for the firefighters, something for a training academy, and then also to get a Dalmatian in every firehouse. ", "So that was kind of like just a little fun thing. ", "And the whole day was really just meant to be for fun.\"", "\n\nA couple of weeks later, however, one of Laura's neighbors called and said, \"Hey, did you see the front page of the _Indianapolis Star_? ", "Have you ever heard of Right to Try?\"", "\n\nThere was a big story about how the Indiana legislature was considering a bill to make investigational medicines not yet approved by the FDA available to patients in Indiana with terminal illnesses.", "\n\nLaura started making calls and found out that the Indiana House Health Committee was holding a hearing that very day. ", "So she and Jordan decided to put their new lobbying skills to work.", "\n\n\"Within a matter of hours, I put together these lobbying sheets, just like Tom Hanify taught us, with Jordan's story on it,\" she says. \"", "And within hours Jordan and I were standing before the House Health Committee and we were actually testifying about Right to Try and how it might benefit him. ", "Literally within hours I get all this stuff together and we go to the statehouse and they let us testify.\"", "\n\nAll the news stations that had covered Jordan's interview with the fire department learned what he was doing and started covering Jordan's lobbying campaign.", "\n\n\"We passed out our little papers to everyone that we saw in the statehouse and all the media was there and there are several news stations here that have been following Jordan since the whole Christmas thing and so they did coverage of it. ", "And so the health committee unanimously decided to move it forward.\"", "\n\nA week later, Jordan was up in the balcony of the House chamber and got to witness the vote when the House unanimously approved Right to Try.", "\n\n\"Everybody in the room voted yes and it was very emotional,\" Laura says.", "\n\nJordan's work was not over. ", "Now the bill went to the Senate. \"", "We go and we get our sheets together and we start contacting senators and then we actually went and testified before the Senate Health Committee,\" Laura says.", "\n\nOn March 4, 2015, Jordan walked into the Senate hearing room.", "\n\n\"From the instant Jordan McLinn walked into the Statehouse committee room Wednesday, the 5-year-old made it his own,\" the news channel Fox 59 reported that day. ", "Dressed in his fire gear, he walked behind the dais and introduced himself to the senators, shaking hands with each one, before joining his mom at the witness table.", "\n\nMy Goldwater colleague Kurt Altman was there to testify as well. ", "Kurt recalls, \"In the middle of my testimony, Jordan walks right up to me at the table and starts to tap on the microphone while I'm answering the senators' questions. ", "I kind of chuckled and put my arm around him, and he sat on my lap for the rest of my testimony.\"", "\n\nWhen Jordan's turn to speak came, his mom asked him: \"Do you want to say something?\"", "\n\nThe bright-eyed boy leaned into the microphone with a big smile, and offered three simple words:\n\n\"Please say yes.\"", "\n\nThey did.", "\n\nThe vote in committee was unanimous and the vote in the full Senate was as well.", "\n\nIndiana governor Mike Pence invited Jordan to be there when he signed the bill into law. ", "Jordan stood right next to the governor, dressed up in his fire gear, and handed him the pens as he added his signature to the bill.", "\n\n\"I've signed this today with a prayer that the right to try will be a pathway toward healing for Hoosiers for generations to come,\" Pence declared.", "\n\n\"All the firefighters from the Ladder 13, which is his fire station downtown, they actually surprised us and they all showed up in their dress uniforms,\" Laura says. \"", "So we were all in there together. ", "Tom Hanify was there from the firefighters union, all the firefighters, and Jordan and our family.\"", "\n\nLaura knows Right to Try won't help Jordan in the immediate term. \"", "Right to Try doesn't work unless a drug has made it through the first phase of the FDA. ", "Technically his drug hasn't made it through that first phase, so Right to Try doesn't really apply to Jordan yet,\" she says. \"", "But we're trying to be proactive and we're trying to raise money to pay for the drug\" when it becomes available.", "\n\nLaura has gotten to know Jenn McNary. \"", "Jenn's kids, they are leading the way, which is awesome for all these boys,\" she says.", "\n\n\"I knew from the first day that we started this that Jordan might not benefit from Right to Try, but, my God, there're so many people that can, and how incredible is it for him to be a part of maybe saving other people's lives.\"", "\n\nThat's why Jordan wanted to be a firefighter—to help others.", "\n\nAfter Jordan was first diagnosed, Laura had prayed fervently for a miracle. ", "Now she is convinced her prayers are being answered.", "\n\n\"I believe God gives us miracles in many different ways,\" she says. \"", "Sometimes it can be an instant healing. ", "Sometimes he gives scientists knowledge to create treatments. ", "And sometimes miracles aren't physical in nature at all. ", "I see Jordan's destiny coming into play every day in a new way as we go through this process. ", "He is helping people and giving people hope at just five years old.", "\n\n\"Obviously we hope and pray that something, anything comes through for Jordan,\" Laura says.", "\n\nBut, she adds, \"My dream is for my son to change the world. ", "And that's what Right to Try I think is going to do for Jordan.\"", "\n\n\"He's going to be able to say, 'I saved a life.'\"", "\n\nBecause _that_ is what firemen do.", "\n\n******COLORADO**\n\nIn Colorado—the first state to pass Right to Try—it was the story of a forty-one-year-old dad with cancer that inspired the Right to Try movement.", "\n\nIn March 2010 Nick Auden went to the doctor and had a cancerous mole removed. ", "He thought the worst was over. ", "But in September 2011 he came home and told his wife, Amy, that he had found a lump under his arm. ", "After going back to the doctor for tests, he learned the devastating news: he had a stage four melanoma that had spread throughout his whole body. ", "He was told he would probably die in less than a year.", "\n\nAt the time, Amy was pregnant with their third child.", "\n\nNick beat those odds, and two years later he was still alive, still fighting his cancer. ", "But the tide of the struggle was turning against him. ", "His tumors were growing, the radiation and cancer drugs he was taking had stopped working, and time was running out.", "\n\nThen one day, his oncologist told him about an emerging treatment called anti-PD-1 immunotherapy. ", "The reason the body's immune system does not attack certain cancers is that the cancer cells have a cloaking mechanism called PD-1, which helps them hide. ", "Scientists had developed anti-PD-1 drugs that stripped away the cloaking mechanism, exposing the cancer to the immune system, which then attacks it.", "\n\nThe anti-PD-1 drugs were being developed by Bristol-Myers Squibb and Merck. ", "Nick immediately tried to get into a clinical trial. ", "Unfortunately, his tumors had spread to his brain. ", "He was told that to qualify for a trial, he had to have no brain tumors or at least ones that were no longer growing. ", "So Nick and his oncologist worked to stop the growth of his brain tumors so he could qualify for the trial.", "\n\nBy July 2013 they had succeeded. ", "Scans showed his brain tumors had stopped growing. ", "Nick was admitted into the Merck clinical trial.", "\n\nBut then disaster struck. ", "Within a few hours of learning that he was admitted, Nick was rushed to the emergency room with a bowel obstruction—a common occurrence for patients with certain advanced cancers. ", "Tests showed he had a perforated intestine. ", "Doctors stabilized him, but the new medical complication disqualified him from the trial again. ", "He would not get the drug he needed to save his life after all.", "\n\nIn the weeks that followed, Amy could not sleep. ", "Lying awake at 3:00 a.m. one night, she decided she was not going to sit back and watch her husband die. ", "They were going to do something. ", "They were going to fight. ", "They were going to get the companies to provide the PD-1 drug under compassionate use.", "\n\nThey petitioned both companies and both turned them down. ", "So Amy launched a website called SaveLockysDad.com. ", "It included a moving video featuring Nick's seven-year-old son, Lachlan \"Locky\" Auden.", "\n\n\"I love my dad,\" Locky says, with an adorable gap-toothed grin. \"", "My dad is so strong that he can get better. ", "I want my dad to get the PD-1 drug because then I can do all the things I like to do with him all the time.\"", "\n\nAmy looks at the camera and says, \"When we were told two weeks ago that this is the end of the road, I can't accept that. ", "Waiting for FDA approval is not going to work either. ", "We can't wait. ", "We need this drug now. ", "And we want you to help us. ", "We want Merck and Bristol-Myers Squibb to help us.\"", "\n\nShe asked viewers to sign her Change.org petition.", "\n\nOver 524,000 people did.", "\n\nBut the drug companies did not budge. ", "They assured Nick and Amy they were working as fast as possible to get the drug approved. ", "But time was running short. ", "In October Auden told ABC News, \"Not everyone has as short a window as I. Why can't they supply me now rather than me missing by a couple of months? ", "Imagine Amy explaining that to the kids.\"", "\n\nHe died a month later, on November 22, 2013.", "\n\nAfter his death the family issued a statement:\n\nWith saddened hearts, we must convey to Nick's hundreds and thousands of supporters that Nick Auden passed away Friday morning with Amy by his side. . . .", "\n\nThis mission is not over. ", "Nick and Amy's fight and your support of them—and in the end, Nick's death—beams a spotlight on a glaring need for change in compassionate access practices for life-saving drugs in late-stage investigational trials.", "\n\nMore on this when the time is right.", "\n\nThe time was right the following year, when the Colorado legislature became the first in the country to consider Right to Try legislation. ", "We had specifically chosen Colorado to be first because it was a state with a Democratic governor and a Democratic legislature. ", "We wanted to make clear from the outset that notwithstanding Goldwater's reputation as a conservative organization, this was a nonpartisan effort.", "\n\nThe bill was cosponsored by Democratic representative Joann Ginal and Republican representative Janak Joshi, two legislators who are generally on opposite sides of most issues. ", "Representative Joshi is an Indian-born physician, who came to America with nothing more than a suitcase and a hundred dollars, and built a successful medical practice in Colorado Springs. ", "Representative Ginal is bioscientist who had worked in the biological and medical fields for more than twenty years, sometimes as a medical liaison for pharmaceutical companies. ", "So both legislators had a professional knowledge of the issues involved, and their opinions carried weight with their colleagues. ", "Their partnership also sent a signal that this effort transcended the usual party lines. (", "At one point, Representative Ginal told Kurt Altman, \"I never thought I'd be partnering up with the Goldwater Institute!\")", "\n\nWhen the bill came up for a hearing, several groups came out in opposition, including local hospice organizations, whose representatives testified that the bill would hurt patient care (they argued that if you're trying to actively save your life, you wouldn't be eligible for hospice care that you might need). ", "Kaiser Permanente also sent representatives to testify that the law was unnecessary because the FDA already ran an expanded access program, which worked just fine.", "\n\nSo, we encouraged the patients to speak for themselves. ", "One such patient was Lorraine McCartin, who traveled to Colorado all the way from Boston. ", "Lorraine had been diagnosed with stage four breast cancer and had run out of FDA-approved treatment options, when her doctor found an expanded access program for an experimental drug called T-DM1 at Boston's Dana-Farber Cancer Institute. ", "But just before her treatments were about to begin, the program at Dana-Farber shut down. ", "The only way she could get access to the drug was through a clinical trial in Fairfax, Virginia, 465 miles away. ", "She was usually too sick to fly, so her family drove her, every three weeks, back and forth, between Boston and Virginia so she could get the drug—which ended up saving her life. ", "But she had to make the grueling trip over sixteen times, logging about fifteen thousand miles, before the FDA finally allowed her to get the drug in Boston.", "\n\nLorraine was still undergoing treatment when Colorado held its hearings, but she insisted on flying out to testify. ", "The hearing was supposed to start at 2:00 p.m., but another controversial bill was on the agenda before it, and the hearing on that bill dragged on late into the night. ", "Kurt Altman, who was there to testify, was worried about Lorraine and tried to convince her to go back to the hotel. ", "She told him, \"There is no way that I'm going back. ", "I'm here for this reason, I'm going to testify.\" ", "And around midnight, she did, explaining to the committee how the current FDA system was failing patients like her. ", "Her strength was inspiring and left legislators in tears.", "\n\nNick Auden's widow, Amy, also lobbied for passage. ", "She told the _Denver Post_ she believed Merck and Bristol-Myers Squibb did not give Nick the drugs he needed to save his life because they were concerned that if he died while on the drug outside the clinical trial, they would have had to report it to the FDA.", "\n\n\"We needed hope but didn't receive it through our battle. ", "I want others to have opportunities to gain access to medication that can potentially be helpful,\" she said. ", "Right to Try, she said, \"gives patients more of a chance to get the medicines they need, to possibly cure an illness. ", "For the patients, for their families, it offers some hope.\"", "\n\nInspired by stories like Amy and Nick Auden's, and the testimony of survivors like Lorraine, legislators passed the bill unanimously.", "\n\nGovernor John Hickenlooper became the first governor in the nation to sign Right to Try into law. \"", "Patients should be able to try a treatment even though it hasn't been approved if it's an attempt to save their life,\" Hickenlooper said.", "\n\nWhen the nation's first Right to Try law was finally enacted, the _Coloradan_ reported that \"Nick Auden didn't live to see the legislation, but the case of the Denver melanoma patient who died while seeking access to an experimental drug helped inspire a first-of-its-kind law in Colorado.\"", "\n\nThe new Colorado law was nothing short of a political miracle: a bill crafted by an organization named after Senator Barry Goldwater passed without a single dissenting vote by a Democratic-controlled legislature, and was signed by a Democratic governor. ", "The signal to Washington should have been crystal clear: at a time when Republicans and Democrats can agree on almost nothing, we are unanimous when it comes to the Right to Try.", "\n\nAnd Colorado would be the first of many states where that unanimity would become apparent.", "\n\n**MISSOURI**\n\nAs a medical doctor and a representative in the Missouri state legislature, Jim Neely understood firsthand just how important it is to provide patients with quicker access to potentially life-saving treatments. ", "In 2013 his stepdaughter, Kristina, was pregnant with her fifth child when she began experiencing excruciating pains. ", "An ultrasound revealed that she had a tumor, which was soon diagnosed as stage four colon cancer. ", "The cancer had spread to her liver.", "\n\nHer pregnancy made her ineligible for enrollment in any clinical trials, and liver failure from her rapidly progressing disease left her with even fewer treatment options.", "\n\nKristina's plight inspired her stepfather, Jim, to introduce Right to Try legislation that would clear the roadblocks preventing terminal patients from trying to save their own lives.", "\n\nOn February 26, 2014, Jim testified before a Missouri House committee. ", "He choked up as he shared Kristina's story. ", "But, he said, \"this is about more than just one patient, it's about guaranteeing the rights of those who are most in need. ", "This legislation offers a beacon of hope for terminal patients who have nowhere else to turn. ", "It's true that we don't know if some of these investigational drugs will work, but we do know they are better than the alternative of simply waiting to die with no hope for a cure.\"", "\n\nNeely read aloud from a 2002 _Wall Street Journal_ essay by Edie Bacon, a Massachusetts mother who had been diagnosed with a rare and deadly form of cancer called metastatic soft tissue sarcoma. ", "Bacon wrote about her failed effort to get access to an emerging drug called ET-743, owned by Johnson & Johnson. ", "The closest clinical trial was in San Antonio, she wrote, and she was too sick to travel once a week to Texas. ", "So she had asked Johnson & Johnson to give her the drug under compassionate use. ", "The company turned down her request.", "\n\n\"Why?\" ", "she wrote. \"", "FDA rules.\"", "\n\nAccording to Bacon,\n\nAny outside use of the drug that cannot be monitored directly by the doctors in charge of the test could \"taint\" the whole test, if the patient were to experience an unpredicted symptom. ", "The FDA could require more tests, costing Johnson & Johnson millions more in testing costs and delays and hurting its reputation with the FDA.", "\n\nIf you're me, you wonder what the FDA is thinking. ", "I'm dying here; I'm a citizen and a taxpayer. ", "Why must Johnson & Johnson be paralyzed by the prospect of getting in trouble with the government if it gives its drug to dying people? ", "The government wants proof of efficacy before it will allow me to take this drug outside of an approved trial. ", "But the \"proof\" is years away and I need the drug now. ", "It's safe. ", "It might work. ", "Johnson & Johnson would let me have it if they could do so without the threat of a government hassle. ", "But they're so caught up in the FDA web that the life of an individual patient has no importance whatsoever.", "\n\nWithout ET 743, I'm a dead woman walking. ", "Five kids are going to wonder why they're left without a mother. ", "Won't somebody help me get this drug?", "\n\nBacon died three years later. ", "She never got the drug. ", "It is available for use in Europe under the name Yondelis (trabectedin), but it is still not approved here in America. ", "In 2015— _thirteen years_ after Bacon made her public appeal—the FDA granted Yondelis priority review. ", "The priority review came too late for the Massachusetts mom.", "\n\n\"I can substitute my daughter for that woman,\" Neely told the committee, as he put down his copy of the article. \"", "People fighting for their lives shouldn't have to battle red tape. ", "People have a right to determine their future, not the FDA.\"", "\n\nKristina joined her stepfather's campaign for the Right to Try. ", "She was too sick to testify, but she invited PBS _NewsHour_ to her home and shared her story. ", "FDA bureaucrats, she said, are \"not sitting there counseling me on these medications and what I should do, what I shouldn't do. ", "How to take care of myself to keep myself healthy. ", "And my doctor is. ", "And if my doctor thinks this medication would help me in some way, then that's up to my doctor. ", "That shouldn't be up to somebody that has no involvement in my care.\"", "\n\nKristina's public appeal, Jim Neely's touching testimony, and Edie Bacon's tragic story inspired a unanimous vote in both chambers of the Missouri legislature in favor of Right to Try. ", "And on July 14, 2014, Democratic governor Jay Nixon signed it into law. \"", "We want to do what we can if people want to get the most up-to-date treatments, to have as few as limitations at the state level to that,\" Nixon said.", "\n\nKristina passed away in April 2015. ", "But thanks to her incredible efforts, and those of her stepfather, other Missourians will now have the Right to Try.", "\n\n**ILLINOIS**\n\n\"I am a person who is living with HIV,\" Illinois state representative Greg Harris says.", "\n\n\"I tested positive early in the epidemic back in the '80s. ", "I'm of a generation where most of the people who are gay men of my age, a lot died back then just because there were no choices available.\"", "\n\nHe recalls that painful period with deep sadness. \"", "There wasn't even AZT at that time,\" he says. \"", "Then every once in a while you would hear from a friend or from your doctor, 'Hey, they finally invented a new medicine that might be able to save your life and it's in the testing phase and you might be able to get access to it in a clinical trial.'\"", "\n\nHe managed to get into a trial, but he knew many people who didn't.", "\n\n\"Clinical trials are very strictly designed,\" he says. \"", "I came to learn that there are all kinds of factors that limit your access to it, whether it's your age, any coexisting illnesses, or previous health conditions. ", "There are all these restrictions that you couldn't always get into a clinical trial. ", "But it was the only way you could get access to a drug that could be the only thing that would save your life.\"", "\n\nThe Oscar-nominated movie _Dallas Buyers Club_ told the story of how an AIDS patient diagnosed in the mid-1980s smuggled unapproved drugs into Texas while facing opposition from the FDA. ", "In response to AIDS patients' demands for access to investigational drugs, the FDA began its first formal expanded access—or compassionate use—programs in 1987 to allow limited access to patients outside the clinical-trial setting.", "\n\n\"To this day I cannot watch a movie like that because it just brings up too much emotion for me,\" Harris says. \"", "I did live it and it's just too distressing for me to have to go back and relive those days, to be really honest—of wondering every day if you were going to survive or if you were going to get some opportunistic infection that would be the end of you.\"", "\n\nHarris says that the FDA's compassionate use program, which emerged from the AIDS crisis, is insufficient to meet the needs of Americans fighting terminal illnesses.", "\n\n\"The FDA process is too lengthy and cumbersome for many to complete,\" he says, \"and only a small fraction of those who want access are able to get it. ", "The application alone can take physicians a hundred hours to fill out.\"", "\n\nSo when Republican state senator Mike Connelly approached him about sponsoring Right to Try legislation in the Illinois House, Harris jumped at the opportunity.", "\n\n\"Having seen so many people die in front of my eyes from . . . ", "just with this one disease, not to mention the people with cancer and MS and other conditions who have struggled knowing that there was something out there that they could not have access to, it was just a perfect opportunity to work on it.\"", "\n\nConnelly and Harris made an unlikely pair: a socially conservative Republican and a gay liberal Democrat with HIV. ", "Kurt Altman flew out to Chicago to represent the Goldwater Institute at the press conference at which Connelly and Harris announced they were introducing Right to Try. ", "He says, \"Reporters asked me afterward, 'How did you do this? ", "These guys have never been on the same side of any issue, ever.' ", "I told them, 'It's not a Republican or Democratic issue. ", "They're both human beings and this is important to human beings.'\" ", "Connelly says his alliance with Harris makes sense, because accessing life-saving treatments is an issue that crosses all ideological lines.", "\n\n\"This is the first bill I've ever encountered that is both pro-life _and_ pro-choice,\" Connelly says. \"", "It gives people the freedom to choose to fight for their life.\"", "\n\nConnelly says that he never saw such unanimity as when he approached his colleagues on the Senate floor and asked for their support. \"", "Everybody has had a family friend or neighbor who's gone through some form of terminal illness, and they've seen them fight with everything they have to live.\"", "\n\nThat includes him. ", "Connelly says his brother-in-law was diagnosed with a glioblastoma around 2006 and was given just a few years to live. \"", "I remember like it was yesterday him sitting up in his hospital bed at Northwestern Memorial Hospital on his computer. ", "And he's already looking at experimental treatments. ", "This is the first day he was diagnosed!", "\n\n\"So he's already thinking, 'Okay, I'm not taking this terminal diagnosis as a final answer. ", "I'm going to do what I have to do.' ", "And that's a natural human reaction. ", "Which is, 'Wait, I'm going to do something myself, I'm going to fight for myself, and I'm going to fight to get better.'\"", "\n\nKurt testified before both the House and the Senate health committees. ", "In the House, he said, Harris had wrapped up the votes before the hearing even began. \"", "He had talked to everybody. ", "The respect that he commands in that Illinois legislature is pretty cool to see. ", "Literally, the hearing took like four minutes, because he had it all done [in advance]. ", "Everybody votes unanimously—we're done.\"", "\n\nIn the Senate, the hearing took longer but also went smoothly. ", "Kurt was taking questions from the chairman of the committee. \"", "He's this old guy,\" Kurt recalls. \"", "Been in the legislature forever and he looks at me and goes, 'Mr. Altman, I have one more question. \"", "Goldwater,\" is that Barry Goldwater?' ", "I said, 'Mr. Chairman, it is, the institute is named after Senator Barry Goldwater.' ", "He goes, 'Do you have one of them bumper stickers that says \"AuH2O,\" you know, for \"Goldwater\"?' ", "I said, 'Mr. Chairman, in fact I do have one of those bumper stickers.' ", "He goes, 'You know what my bumper sticker said?' ", "I said, 'No, Mr. Chairman, I do not.' ", "He goes, 'Mine said, \"LBJ4USA.\" ", "I said, 'Well, Mr. Chairman, it certainly appears there were a lot more of those bumper stickers then there were of the ones I have.' ", "He's says, 'Yes indeed there were!'\"", "\n\nThe Senate committee passed Right to Try unanimously as well. ", "And thanks to Connelly and Harris's leadership, Right to Try was then approved in the Illinois House by a vote of 114 to 1 and in the Illinois Senate by a vote of 55 to 0.", "\n\nAsked about his hopes for the new law, Harris says, \"I hope this shows that in Illinois, Republicans and Democrats, social liberals and social conservatives, can reach across the aisle to solve problems for suffering families. ", "These families are desperate to cut through red-tape to access possible cures for their loved ones when all other treatments have failed.", "\n\n\"Right to Try is a huge leap forward to help connect our state's most terminal patients with some of the nation's best medical resources, including here in Chicago, and give them the gift of life.\"", "\n\n**TEXAS**\n\nIn 2007 Andrea Sloan was diagnosed with ovarian cancer. ", "A beloved Austin lobbyist who quit her job as a corporate lawyer to run a nonprofit that provides free legal services to victims of domestic violence, she underwent two rounds of chemotherapy, five surgeries, and a stem-cell transplant. ", "Nothing worked. ", "The cancer kept coming back.", "\n\nBy 2013 Sloan's oncologist at MD Anderson Cancer Center, Dr. Charles Levenback, told her that her only hope of survival was an experimental drug called BMN-673. ", "The drug, made by the California drug manufacturer BioMarin, inhibits DNA repair in cancer cells and is particularly effective in patients who had a genetic mutation called BRCA—which made it perfect for Sloan.", "\n\nThe drug was not yet approved by the FDA and Sloan did not qualify for a clinical trial. ", "So she and Dr. Levenback tried to get it for her on a compassionate use basis. ", "But BioMarin refused to even look at her medical records or engage her in a dialogue.", "\n\nIt just said \"no.\"", "\n\nSloan launched a campaign to convince the company to change its mind, and her many friends in the world of Texas politics rallied around her. ", "They formed what they called \"Andi's Army\"—a grassroots movement to win access to the drug she needed to save her life. ", "They started a Change.org petition that got 234,837 supporters. ", "Eighty-two Texas state lawmakers petitioned the company on her behalf. ", "Sloan even made a video with a direct plea to BioMarin's CEO, Jean-Jacques Bienaimé.", "\n\nBut the company was unmoved.", "\n\nFinally, when it became clear BioMarin would not budge, Sloan and her supporters approached another drug company that was developing a similar drug. ", "The company agreed to give Sloan the drug, but asked to do so anonymously.", "\n\n\"It would have been better a few months ago,\" Dr. Levenback told the _Huffington Post_ , expressing frustration with BioMarin's refusal to share its version of the drug. \"", "The point is it's cancer. ", "If you don't do anything, it gets worse.\"", "\n\nOnce the company agreed to provide the drug, Sloan faced another delay when she had to seek FDA approval to take it. ", "Dr. Levenback had to spend over one hundred hours on Andrea's application. ", "Then, says Andrea's best friend, Michelle Wittenberg, a lobbyist, it took nearly a month to get FDA approval for an expanded access petition, during which time her health deteriorated. \"", "We waited twenty-four days for the FDA to give their approval,\" she says. \"", "It took them twenty-four days to process an application. ", "That's really problematic because I saw her every day and she did deteriorate on a daily basis during that twenty-four-day period.", "\n\n\"She would say, 'Michelle, what's going on? ", "What's the delay? ", "The drug company's agreed to give it, why is it taking so long? ", "The FDA said they didn't have a problem, why is it taking so long? ", "What do we do?'\"", "\n\nWhen the FDA finally cleared the way for Sloan to get the drug, a miracle happened. ", "The drug actually worked—scans showed it was beating back the cancer. \"", "She had scans that were done in her body in July that had black spots, i.e., cancer that showed up prevalently,\" Wittenberg says. \"", "And then she had scans on December 16 after taking the drug for two and a half months. ", "We got the results of those scans on December 18 and her parents were there, I was there, Andrea was there, her medical team was there—Dr. Levenback in the lead and another gentleman who's one of the heads of the Moonshot program for ovarian cancer at MD Anderson. ", "And I've never in my life seen a more giddy group of physicians. ", "It was a turnaround. ", "They put the scans up against each other and, oh, it was unbelievable. ", "It's like, where are the black spots? ", "They're gone. ", "We got the scan, it was _glorious_ , _amazing_ , _amazing_ improvement. ", "She was weak, but everything was on the upward trajectory and just was amazing.\"", "\n\nThen, a few days after getting the scans, Sloan suffered a setback when she came down with pneumonia. \"", "And thirteen days later, she was dead,\" Wittenberg says. \"", "Her system wasn't strong enough to fight it off.\" ", "She died on New Year's Day 2014—just two weeks after learning that the drug was beating back the cancer.", "\n\nThe terrible injustice was that, based on her response to the drug, if she had gotten access sooner, it might well have saved her life. \"", "It wasn't just the disease, it was the delay that killed her,\" Wittenberg says. \"", "The delay in getting that drug, that was working, killed her. ", "Three months' waiting is too long. ", "Two months' waiting was too long. ", "The extra month tacked on because of the FDA process, too long. ", "And that should be unconscionable to anybody.", "\n\n\"I will say this about the FDA, they wanted to help Andrea,\" Wittenberg says. ", "But she cannot understand the reason for the twenty-four-day delay. \"", "You look at their website and it says they can process an emergency application in a day. ", "Well, this was an emergency. ", "How come it took almost a month? ", "When somebody's life is on the line, your bureaucratic process helped contribute to the cost of a life. ", "That would weigh on me.\"", "\n\nAndi had died, but Andi's Army didn't disband. ", "Quite the opposite: her friends kept the movement alive, and deployed it to fight a new fight—to pass the Right to Try law in Texas.", "\n\nWittenberg was doing some research on compassionate use reform when she came across the Goldwater Institute's website and read about Right to Try. \"", "I looked online and sent a blind email to someone at the Goldwater Institute,\" she says. ", "She connected with Victor Riches and Kurt Altman, who walked her through the law and how it was handled in other states. \"", "I was kind of a hard sell,\" she says. ", "This was her best friend's legacy and she wanted to do right by Andrea. ", "But once she became convinced that Right to Try was the right thing to do, she rallied Andi's Army behind it and swung into action.", "\n\n\"There were two state legislators who are about my age and Andrea's age, forty-four years old—their names are Ken King and Kyle Kacal,\" Wittenberg says. \"", "Their mothers had both died of ovarian cancer within the past year. ", "And we were all good friends and they knew Andrea and watched what she went through too.\" ", "Wittenberg told them about Right to Try, and they became the principal sponsors of what became known as the \"Andrea Sloan Right to Try Act.\"", "\n\n\"We hit our 150 members in the Texas house, and over 100 signed on as coauthors, which is not common,\" Wittenberg says. \"", "The senate bill had over twenty authors, and there are only thirty-one Texas senators.\"", "\n\nVictor Riches remembers Wittenberg as a legislative force of nature. \"", "I went out there to meet with the legislators and she literally set up meetings with thirty legislators over about a forty-eight-hour period. ", "She was very passionate about it.\"", "\n\n\"She asked us to Texas probably four or five times,\" Kurt Altman recalls. \"", "Texas's statehouse is just huge and it's very confusing with all these different levels. ", "I was lost all the time. ", "And Michelle would always be fifteen yards in front of me, and I would lose her in the crowd she'd be so fast. ", "She was on a mission, and she would be marching and literally I would be sweating every day because I'd have to chase her through the statehouse.\"", "\n\nIn meetings, Kurt recalls, \"she would start to talk about Andrea Sloan somehow and at least once or twice a day she would start to tear up and it would just kill me and she'd look at me and go, 'Stop, stop, I told you I wasn't going to do this.' ", "We'd always be in front of a senator or somebody who knew her, and he would say, 'Now, Michelle, it's all right.' ", "She'd wipe her tear away and say, 'We're good, you just make sure that we get this through, this is important.' ", "She was very inspirational. ", "She's such a go-getter, and there was no way if I was ever tired that I'd be able to stop when I was with her.\"", "\n\nThe Texas legislature meets only every other year, for a very short session, so the window of opportunity to move the legislation was short. ", "Wittenberg was not going to wait two years to try again—she was determined to pass the law immediately.", "\n\nWittenberg testified before the Texas Senate Committee on Health and Human Services, as did Sloan's physician, Dr. Levenback, and Sloan's parents. ", "Andrea's mother, Karen Sloan, spoke movingly of her daughter's fight to save her life and of the FDA's unconscionable delays. \"", "Twenty-four days is a lifetime for people who are terminally ill,\" she told the committee.", "\n\nTheir efforts paid off. ", "On May 22, 2015, the Texas state senate unanimously passed the Andrea Sloan Right to Try Act, and the Texas assembly soon approved it unanimously as well.", "\n\nAt the bill-signing ceremony, Sloan's oncologist, Dr. Levenback, took Wittenberg aside and asked if there was any way he could get a formal copy of the new law. \"", "He said, 'I'd like to get a copy of the bill and a picture of Andrea and have it framed, and I want to put it out in the waiting room.' ", "He said, 'People should know what she did. ", "I want our patients to know.'\"", "\n\nShe got him a copy, and the Right to Try law now occupies a place of honor on the wall outside his office at MD Anderson Cancer Center.", "\n\n\"The spread of these laws shows the level of public dissatisfaction with this part of the medical economy,\" Dr. Levenback told the _Houston Chronicle_. \"", "It just seems fundamentally not right to put so much time and money into drug development, to brag about this great health care system that produces such great medical innovations, and then for it to prove so difficult for deserving patients to get new drugs.", "\n\n\"We deserve better,\" he said.", "\n\nThanks to Andrea Sloan and the soldiers in Andi's Army, deserving patients in Texas will now have the chance to get better.", "\n\nThey now have the Right to Try.", "\n\n**VIRGINIA**\n\nWhen a Virginia boy named Josh Hardy was just nine months old, he was diagnosed with kidney cancer. ", "The tumor on his left kidney was the size of a softball, and the one on the right was the size of a walnut.", "\n\nHe underwent ten rounds of chemotherapy, six days of radiation, and surgery to remove the tumors. ", "He beat the cancer, but it came back three times as he grew—returning in his thymus, lung, and bone marrow. ", "Each time he beat it back, but the treatments took a toll on his system.", "\n\nIn January 2014 doctors told his parents, Todd and Aimee Hardy, that Josh had developed a bone-marrow disorder that often follows intensive cancer treatments. ", "He needed a bone-marrow transplant. ", "So they took him to St. Jude Children's Research Hospital in Memphis for the surgery.", "\n\nAfter undergoing the transplant, Josh experienced heart failure; he had to be put on a ventilator and was in a coma for sixteen days. ", "His doctors had to give Josh special drugs to suppress his immune system so that his body would not reject the new bone marrow. ", "While his immune system was compromised, Josh developed a life-threatening adenovirus infection that spread throughout his body. ", "Doctors tried an FDA-approved antiviral drug, cidofovir, but it caused complications with his kidneys and had to be stopped.", "\n\nJosh was dying.", "\n\nJosh's doctors at St. Jude said the only hope for Josh was an antiviral drug called brincidofovir. ", "The drug was being developed by a North Carolina company called Chimerix. ", "They believed it would work for Josh because they had participated in some of the clinical trials, and had seen brincidofovir clear up adenovirus in children in two weeks.", "\n\n\"Our doctor said they had done an adenovirus study at St. Jude's, and in every child that had been a part of that study they had suppressed the adenovirus,\" Aimee Hardy says. \"", "So he's like, 'I really want this medicine for him.'\"", "\n\nBut there was a problem: Josh did not qualify for a clinical trial, because the drug was being tested only in adults at that point. ", "They would have to ask the company to provide the drug on a compassionate use basis.", "\n\nOn February 12 Josh's doctors at St. Jude called Chimerix and asked for permission to use the drug. ", "The company said no. ", "It had once had a compassionate use program but had discontinued it, deciding to focus instead on accelerating FDA approval.", "\n\nChimerix would not provide the drug.", "\n\nJosh's parents were stunned.", "\n\nAfter consulting with his doctors, they decided to try again. ", "His doctors composed an email explaining Josh's circumstance, why they believed the drug would save him, and the case for giving Josh access to the drug. ", "An executive wrote back by email saying that Chimerix was not \"in a position to provide drug for this and other subjects in similar circumstances due to a limited inventory and our limited resources.\"", "\n\n\"The company kept saying no, no, no,\" Aimee says.", "\n\nThey had hit a dead end.", "\n\nWith Josh barely hanging on to life, his parents had little to lose. ", "So they decided to make their fight public. ", "They launched a Facebook and Twitter campaign with the hashtag #savejosh and asked people to tweet, email, and call the company. ", "The campaign went viral. ", "Thousands of strangers rallied around Josh and the fight to save his life.", "\n\n\"We were just brainstorming, like, who do we know that might have some influence with the company or something? ", "And then we thought, we don't know anybody,\" Aimee says. \"", "We put it out on Facebook and it turns out we know a lot of people. ", "It was just an amazing thing to find out how many people really support us.\"", "\n\nWhen one of Josh's cousins, Regina Breedlove, launched a Change .org petition, it got nearly twenty thousand signatures in a matter of days. ", "The Washington Redskins quarterback Robert Griffin III urged his 1.3 million Twitter followers to join the crusade to #savejosh. ", "People flooded the company with calls and emails demanding that it give the drug to Josh. ", "They simply could not believe that the company would let a boy die of an illness that was entirely curable.", "\n\nSoon, national news organizations picked up Josh's story. ", "On March 11, 2014, CNN ran a spot titled \"Company Denies Drug to Dying Child.\" ", "The network reported:\n\nIn an intensive care unit in Memphis, a virus ravages the body of a 7-year-old who's in heart and kidney failure. ", "He vomits blood several times an hour as his family gathers in vigil.", "\n\nIn a cabinet in Durham, North Carolina, there's a drug that could likely help Josh Hardy, but the drug company won't give it to him. ", "They're adamant that spending the time to help Josh and others like him will slow down their efforts to get this drug on the market. . . .", "\n\nWhen asked how he will feel if Josh dies—and he's in critical condition, so sadly that could happen soon—the president of the company that makes the drug doesn't hesitate to answer.", "\n\n\"Horrible,\" said Kenneth Moch [the company's CEO]. ", "He would feel horrible and heartbroken.", "\n\nBut still, he said there's no way he's going to change his mind. ", "There's no way he's going to give Josh this drug.", "\n\nThe Hardys kept up the pressure. ", "Fox News and other networks aired the company's phone number and email address on screen, prompting thousands of calls and messages.", "\n\nAs pressure mounted, the company protested that it had only fifty employees and could not afford to provide the drug to everyone who wanted it on a compassionate basis. ", "But that excuse evaporated when it emerged that Chimerix had received $72 million in federal funds.", "\n\nThen, a private charity, the Max Cure Foundation, stepped forward and offered to cover the costs of Josh's treatment. \"", "I spoke to Mr. Moch yesterday by phone,\" Richard Plotkin, the vice chair of Max Cure, told Peter Johnson Jr., Fox News' chief medical correspondent. \"", "I told him that we had the $50,000 that I thought he was claiming he needed to supply the drug. ", "He then told me it isn't about money. ", "He told me it's all about ethics.\" ", "Plotkin said he asked Moch what he would do if it were his child or grandchild. ", "Moch, he said, hung up on him.", "\n\nWhen Fox News emailed a member of Chimerix's board of directors, Tim Wollaeger, and asked whether the board would give the drug to Josh, he answered, \"Don't you people realize there is an FDA? ", "We have done what we can. ", "Say a prayer for Josh.\"", "\n\nIn fact, thousands of Americans _were_ praying for Josh—and tweeting, and emailing, and calling, and writing, and demanding that Chimerix do the right thing.", "\n\nEventually those prayers were answered. ", "After days of public shaming, Chimerix finally relented. ", "It opened a special twenty-person clinical trial for children and agreed to admit Josh as the first patient.", "\n\nHis mom, Aimee, posted the news on Facebook: \"Glory to GOD! ", "They are releasing the drug for Josh!!!!!\"", "\n\nWithin days of receiving the drug, Josh began to make a remarkable recovery. ", "The level of adenovirus in his blood dropped from 250,000 copies per millimeter to 367 copies per millimeter. ", "On March 31, the family celebrated Josh's eighth birthday—a milestone that seemed unreachable just a few days earlier.", "\n\nIn April Moch stepped down as CEO of Chimerix.", "\n\nIn July, after six and a half months at St. Jude, Josh finally went home. ", "He was not yet able to go to school or spend a lot of time in public places, because of the danger of contracting another virus. ", "But he got tutoring at home, and he was able to play video games with his siblings and ride his bike on the street in front of their house.", "\n\nWhen a local news channel visited the Hardy family after Josh's return, Aimee talked about her dreams for Josh. \"", "I want him to play baseball and slide home after he hits a great hit, and go to school, go on family vacations and dive in the ocean waves. ", "The whole nine yards.\"", "\n\nJosh had slightly different dreams. ", "He wanted to go to Chuck E. Cheese and a Washington Wizards game. ", "A year later, he got his wish when the Wizards invited him to sit courtside for their game against his other favorite team, the Memphis Grizzlies—from the hometown of the doctors who saved him at St. Jude Children's Research Hospital.", "\n\nAs Josh got better, Aimee started hearing from other patients who had received the drug as a result of their campaign.", "\n\n\"Afterward I had a little seventeen-year-old girl message me on Facebook and she had had a liver transplant and she had developed the adenovirus,\" Aimee says. \"", "When we got ours she was able to get it as well. ", "And she said that she thanked her doctor for getting it and he said, 'Don't thank me. ", "Thank Josh Hardy's family, because they're the reason that you have access to it. ", "You would have never gotten it otherwise.' ", "And that was kind of neat to know that that helped another family. ", "And apparently it's helped about seventy other families.\"", "\n\nIndeed, instead of limiting the new trial to twenty patients, Chimerix made it open-ended. ", "And that decision not only helped save dozens of other lives but led Chimerix to seek additional FDA approval for the drug in the pediatric indication Josh presented.", "\n\nAimee and Todd wanted to help make sure other kids did not have to face the same struggles to get life-saving treatments that Josh did. ", "That opportunity soon presented itself.", "\n\nJosh's parents grew up in Virginia's Richmond County with Todd Ransone, whose wife, Margaret, just happened to be a member of the Virginia House of Delegates.", "\n\n\"I actually grew up playing with Margaret's husband,\" Aimee says. \"", "They were neighbors of family members and they knew us very closely, and so she was impacted emotionally\" by Josh's plight.", "\n\n\"I had a son the exact same age,\" Ransone says. \"", "I vowed to that mom I'm going to do everything that I can to research this and see what we can do.\" ", "She did some research and saw that Colorado had recently passed a Right to Try bill. ", "So she teamed up with state senator Bryce Reeves—whose son plays lacrosse with Josh's brother—to introduce the Right to Try Act in the Virginia General Assembly.", "\n\nJosh became the public face of the fight to pass Right to Try in Virginia. ", "Aimee testified before the health committees in the Virginia House and Senate, lobbied legislators, and held press conferences as the bill wound its way through the legislature.", "\n\nStanding in the briefing room of the capitol, she shared the story of her family's fight to save Josh. \"", "That's what was also really maddening to me—that he could survive cancer four times, and have a simple virus take him down.\" ", "she said. \"", "Having to leave their bedside while they are in the ICU to fight for a drug is just—it's just it shouldn't happen.\"", "\n\n\"You need to not have to go on national TV or beg people to call the company for you or do all these things,\" she said. \"", "Everyone should just have the right to try.\"", "\n\nAimee was joined in her campaign for the Right to Try by Frank Burroughs, a Virginian who had faced a similar situation fourteen years earlier when his college-age daughter Abigail developed head and neck cancer.", "\n\n\"She had run out of FDA-approved options in her battle to save her life and we were trying to get the drug Erbitux for her,\" he says. ", "Abigail did not qualify for clinical trials. ", "The company had studies for colon cancer under way at the time, but Abigail's cancer was in her head and neck. \"", "She had the right cancer cells in the wrong part of her body so that ruled out any chance at a clinical trial.\"", "\n\nThe company, ImClone, refused to provide the drug on a compassionate use basis. ", "So, just like the Hardys, Frank Burroughs and his daughter launched a campaign to get it to change its mind. ", "This was in 2001, before the age of social media, so there was no Twitter or Facebook or Change.org petition to rally supporters to their cause. ", "But Frank got stories in the _Washington Post_ and the local ABC News affiliate.", "\n\nSadly, it wasn't enough.", "\n\n\"We weren't able to get the drug,\" Frank says. \"", "She died on Saturday, June 9, 2001.\"", "\n\nAbout ten hours after she died, amid his unspeakable grief, Frank Burroughs had an epiphany.", "\n\n\"The thought just flashed into my head,\" he says. \"", "Why should I quit now? ", "There are other people as precious as Abigail.\"", "\n\nEleven days after Abigail's death, Frank testified before the Virginia House Government Reform Committee. ", "He told the legislators:\n\nMy only child, dear, sweet, loving, talented and compassionate Abigail, died at 2:30 p.m. two Saturdays ago, June 9th. ", "The loss of my beautiful compassionate child has left a hole in my life. . . .", "\n\nAbigail was an Echols honor student at the University of Virginia. ", "Abigail cleaned toilets and changed beds in men's homeless shelters. ", "Abigail worked in a poor neighborhood in Syracuse, NY, fixing up houses and running a free day camp for inner city children. ", "Abigail started a major tutoring program for middle school children who were having learning problems. . . . ", "The world has lost a brilliant young woman who would have done great things.", "\n\nI am here today because the issue of the wider use of compassionate use of drugs is a very important issue, because it touches tens of thousands of lives. ", "Compassionate Abigail wants us to keep this issue alive, although we could not keep Abigail alive. . . .", "\n\nAbigail is now in the arms of God. . . . ", "With the strength of Abigail's memory, beautiful memory . . . ", "I will keep this issue alive so others may have a chance to live, a chance that Abigail, compassionate Abigail, did not have.", "\n\nWith that, the Abigail Alliance for Better Access to Developmental Drugs was born.", "\n\nBurroughs has spent the last fourteen years fighting to save the lives of children like Abigail, and he has turned the Abigail Alliance into a force to be reckoned with. ", "He has pushed for the accelerated approval of a number of cancer drugs. ", "He sued the FDA demanding access to experimental drugs on constitutional grounds. ", "He worked with members of Congress to introduce the Compassionate Access Act of 2005, a bill he says \"never went anywhere.\" ", "But he did succeed in lobbying for reforms in the Food and Drug Administration Safety and Innovation Act (FDASIA Act) in 2012 to create the new \"breakthrough therapy\" designation that allows faster approval of novel drugs treating unmet needs. ", "He works every day with patients to guide them through the FDA's bureaucracy when they seek compassionate use.", "\n\nAnd today he's fighting for Right to Try laws.", "\n\n\"Meeting Frank Burroughs, I mean I was heartbroken to hear his story,\" Aimee says. \"", "I just can't imagine to have that drug out there and then just a couple of years later it's available.\"", "\n\nThey teamed up to lobby Virginia legislators. ", "Frank joined Aimee Hardy at the capitol building in Richmond to urge them to pass Right to Try.", "\n\n\"The Virginia 'Right to Try' bill is an important part of paving the way for much needed and very doable change at the FDA that will save lives,\" he said. \"", "In Virginia and other states that have passed 'Right to Try' laws there is broad public support for this change.\"", "\n\nMargaret Ransone, the bill's sponsor, was a force to be reckoned with. ", "Kurt Altman recalls her lobbying tactics: \"She literally marched me to fifteen or twenty different offices. ", "She'd walk in and say, 'Can we get ten minutes of your time?' ", "She'd lay it out for whoever it was. ", "She'd introduce me, I'd answer all their questions. ", "And then she'd look them right in the eye and say, 'So I need to know right now, are you with me? ", "Are you with me?' ", "And they were funny. ", "They all were taken aback. ", "Most of these meetings end up with, 'Okay, well, I appreciate the information,' and then you leave. ", "We would not leave an office until she got an answer from whomever we talked to. '", "Are you with me? ", "I need to know if you're with me. ", "Did I tell you why I did this? ", "Because my friend is the mother of Josh Hardy. ", "Josh would have died. ", "I just need to know, where are you? ", "'Cause I need to know what else I have to do. ", "Are you with me?' ", "They'd say, 'Margaret I think this is a great idea. ", "Yeah, Margaret, I'm with ya. ", "I'm with ya.' ", "It must have happened twenty times.\"", "\n\nBetween Aimee Hardy's and Frank Burroughs's heartrending stories, and Delegate Ransone's relentless lobbying, Virginia legislators got the message.", "\n\nIn January 2015 the Virginia House voted 99 to 0 in favor of Right to Try, and the Senate approved it 39 to 0 the following month.", "\n\nIn March Democratic governor Terry MacAuliffe signed it into law.", "\n\nWhen Right to Try passed, Aimee Hardy was elated. \"", "We are super excited that hopefully families won't have to experience what we went through,\" she told reporters.", "\n\nShe simply does not understand people who oppose the Right to Try.", "\n\n\"When you're on that last train out and there's a little glimmer of hope and you're being told you can't even try it, you should be able to have the right to try,\" she says. ", "When she hears pharmaceutical executives like Ken Moch say that giving the drug to Josh could make it harder to save future Joshes, \"I'm like, well, what's wrong with saving Josh right now?\" ", "she says.", "\n\nAimee acknowledged that Right to Try did not solve all the problems related to reforming compassionate use but she said, \"It's a step in the right direction.\"", "\n\n\"The whole system needs to be reformed. ", "And this is a great start.\"", "\n\nFrank Burroughs agrees.", "\n\n\"What is so huge about the Right to Try legislation in Virginia and the other states where it's passed is that it paves the way for changes at the national level,\" Burroughs says. \"", "People have said this Right to Try law is not going to do much,\" he says. \"", "And I always say, well that's just not true—absolutely not true. ", "What's happening is it's elevating this issue further. ", "We've seen a pattern here. [", "It has passed in] every state [where] it's been introduced. [", "It's] batting a thousand. ", "What this clearly shows is that the vast majority of the public is behind this. ", "So that's what's huge about this bill. ", "And that message is being heard at the FDA and the message is being heard on Capitol Hill.", "\n\n\"The last time I checked, this is a democracy,\" he says.", "\n\nIN OTHER STATES, THE story was the same.", "\n\nIn Utah, seven-year-old Bertrand Might, a boy with a rare genetic disease called NGLY1, was the face of the local Right to Try movement. ", "Bertrand joined Governor Bob Herbert as he signed Right to Try into law. \"", "Thanks for helping out, buddy, you got legislation passed,\" Herbert told him.", "\n\nIn Michigan, Terry Kalley championed Right to Try along with his wife, Arlene, who is in her fourth year battling stage four breast cancer. \"", "Of course there are risks,\" Terry Kalley told lawmakers, \"but by far the greatest risk to my wife and her fellow terminally ill patients is not to have access to these drugs. ", "Without access, her risk of death increases to 100 percent.\" ", "Lawmakers responded by passing the Right to Try by a margin of 109 to 0 in Michigan's House and 31 to 2 in its Senate, and Governor Rick Snyder signed it into law.", "\n\nIn Minnesota, Republican state Representative Nick Zerwas championed Right to Try. ", "Zerwas was born with a three-chambered heart and survived thanks only to experimental surgery that removed the right side of his heart and replaced it with a cow's pericardium. \"", "That was my right to try,\" the thirty-four-year-old Republican from Elk River told the floor. \"", "We gave it a shot and we got it right.\" ", "He introduced Right to Try legislation, which passed the Minnesota House 123 to 0 and was signed into law by Democratic governor Mark Dayton.", "\n\nIn Alabama, a ten-year-old boy named Gabe Griffin with Duchenne muscular dystrophy inspired legislators to pass Right to Try. ", "On June 3, 2015, Governor Robert Bentley signed Alabama's Senate Bill 357, the Gabe's Right to Try Act. \"", "Gabe Griffin is a special child who has worked hard to advocate for this legislation,\" Governor Bentley said. \"", "As a physician, I believe it is extremely important to give terminally ill patients the option to consider experimental treatments. ", "Gabe's story has touched many lives. ", "I appreciate the Alabama Legislature passing this bill and giving Gabe and other children like him hope for the future.\"", "\n\nIn North Dakota, it was three brothers—Lane, Tanner, and Ty Kulsrud—who suffer from a rare metabolic disorder called PKAN that is leaving deadly iron deposits in their brains. ", "They were joined in supporting the law by the president of the State Bar Association of North Dakota. ", "During the legislative hearings in Bismarck, my colleague Craig Handzlik was preparing to testify when the president was testifying in favor of Right to Try. \"", "He's saying North Dakotans need this, especially the rural folks who would not have access to clinical trials and would have to travel long distances,\" Craig recalls. \"", "He seems fairly knowledgeable about Right to Try and he finishes his testimony, thanks the committee, and turns around from the podium, looks at me, and says, in front of the whole galley, 'Goldwater Institute, huh? ", "You guys are suing me, asshole.'\"", "\n\nCraig had to call back to the office to ask: Why are were suing the state bar association? ", "We had just filed a suit against them for misusing mandatory dues for political lobbying purposes (we prevailed). ", "It just goes to show, Craig says, that \"Right to Try originated with the Goldwater Institute, but it is so widely supported that even folks we are suing will stand up and testify to support it.\"", "\n\nIn Mississippi, a woman with ALS named Janet Champion and her husband, Sid, spoke out in favor of Right to Try. ", "And, of course, in Arizona it was Diego Morris, the boy we met in chapter 2 who moved to London to get the medicine to cure his osteosarcoma, who led the charge for Right to Try.", "\n\nPowered by these and other stories of hope and heartbreak, the Right to Try movement is sweeping the nation. ", "Here are the results so far:\n\nArkansas: 96–0 in the House and 33–0 in the Senate.", "\n\nColorado: 65–0 in the House and 35–0 in the Senate.", "\n\nIndiana: 92–0 in the House and 50–0 in the Senate.", "\n\nLouisiana: 96–0 in the House and 37–0 in the Senate.", "\n\nMichigan: 109–0 in the House and 31–2 in the Senate.", "\n\nMississippi: 118–0 in the House and 50–0 in the Senate.", "\n\nMissouri: 143–0 in the House and 26–0 in the Senate.", "\n\nMontana: 93–7 in the House and 50–0 in the Senate.", "\n\nOklahoma: 96–0 in the House and 44–0 in the Senate.", "\n\nSouth Dakota: 61–1 in the House and 32–0 in the Senate.", "\n\nUtah: 69–3 in the House and 26–0 in the Senate.", "\n\nWyoming: 58–1 in the House and 28–1 in the Senate.", "\n\nNorth Dakota: 91–0 in the House and 42–5 in the Senate.", "\n\nMinnesota: 123–0 in the House and 60–4 in the Senate.", "\n\nFlorida: 113–0 in the House and 39–1 in the Senate.", "\n\nIllinois: 114–1 in the House and 55–0 in the Senate.", "\n\nTexas: 134–0 in the House and 31–0 in the Senate.", "\n\nVirginia: 99–0 in the house and 39–0 in the Senate.", "\n\nAlabama: 97–0 in the House and 29–0 in the Senate.", "\n\nNevada: 41–0 in the House and 20–0 in the Senate.", "\n\nTennessee: 95–0 in the House and 31–0 in the Senate.", "\n\nNorth Carolina:118–0 in the House and 47–0 in the Senate.", "\n\nOregon: 60–0 in the House and 29–0 in the Senate.", "\n\nAnd that's not counting Arizona, where over one million people voted for Right to Try at the ballot box, a pro vote of more than 75 percent.", "\n\nPut it all together, and in 24 states there have been 3,045 votes in favor or Right to Try and a grand total of 26 votes against. ", "This means Right to Try has been approved in the states where it has come up by a margin of 99 to 1 percent. ", "That's about as close to unanimity as you will ever achieve in a democracy.", "\n\nAnd more states are at bat. ", "Right to Try laws have been introduced in Alaska, California, Connecticut, Delaware, Georgia, Hawaii, Kansas, Kentucky, Maine, Massachusetts, New Hampshire, New Jersey, New York, Pennsylvania, Rhode Island, West Virginia, and Wisconsin. ", "In many of these states, the law has already been approved in committee and is awaiting floor action.", "\n\nThe critics of Right to Try say legislators are uninformed and are being manipulated by heartbreaking stories. ", "My colleague Victor Riches, who spearheaded the first days of Right to Try, sees it differently. \"", "This is the kind of issue that comes around maybe once in a lifetime, when you have an issue that really strikes a chord across the country. ", "And once we got it going, it really started moving like wildfire. ", "And it wasn't a Republican issue, wasn't a Democrat issue, it was literally just a human being issue.\"", "\n\nHere is a thought for the critics: when you are losing a debate 99 to 1, maybe it's time for some introspection.", "\n\nThere is a reason Americans are instinctively siding with Jordan McLinn, Nick Auden, Andrea Sloan, Josh Hardy, Abigail Burroughs, and all the other patients who are demanding their Right to Try. ", "Most of us have lost a loved one to a terminal illness or know someone who has. ", "As Americans, we believe in fairness. ", "We believe in opportunity. ", "We believe in compassion. ", "We all want the chance to save our lives if we need it.", "\n\nThe patients, legislators, and voters of these states have a message for the government:\n\nWe are the 99 percent.", "\n\nWe demand change, and we will get it.", "\n\nBecause Frank Burroughs is right: this _is_ still a democracy.", "\n\n# 7.", "\n\nCompassionate Use\n\n_The Mythical Unicorn_\n\nThe FDA often cites its compassionate use program as the reason why Right to Try laws are unnecessary. ", "Richard Klein, the director of the FDA's patient liaison program, says, \"The agency has a pathway. ", "It seems to work quite well, and I'm not sure what the state Right to Try bills really add to that.\"", "\n\nExcept that it doesn't work so well. ", "Just ask the hundreds of thousands of Americans who are stymied each year in their efforts to get the drugs they need to save their lives.", "\n\nThe FDA's indifference helps explain why the Right to Try movement has taken off in just a year. ", "The agency has buried its head in the sand. ", "Its expanded access system is badly broken. ", "Not only has the FDA created obstacles for patients and doctors seeking access to new treatments, but the agency has also created a system that discourages drug companies from offering innovative treatments on a compassionate basis.", "\n\nRight to Try laws are a critical part of the solution. ", "But if we are going to make innovative medicines available to all who need them, we also need to change the FDA—by removing obstacles to compassionate use and creating new incentives for manufacturers to do the right thing and help dying Americans who are fighting for their lives.", "\n\nAmericans like Mikaela Knapp.", "\n\nLATE ONE NIGHT, WHILE his wife, Mikaela, lay dying from kidney cancer in her Northern California hospital bed, Keith Knapp opened his email to find a cryptic message that seemed like something out of a spy novel.", "\n\n\"Keith and Mikaela,\" the message began, \"I created this email account to share some information with you. ", "It isn't secret information, but my employers might not appreciate me disseminating it. ", "My wife thought it best to be an anonymous helper right now.\"", "\n\nThe nameless writer had seen Keith and Mikaela on _Good Morning America_ making a public plea for access to an experimental drug that was her last hope—anti-PD-1 immunotherapy, the same treatment Nick Auden tried and failed to gain access to.", "\n\nThe drug was being developed by three pharmaceutical companies—Merck, Bristol-Myers Squibb, and Genentech—but still had not received final FDA approval.", "\n\nMikaela had spent six months being treated by doctors at the University of California–San Francisco Medical Center and had tried every approved drug or treatment. ", "She underwent gamma knife radiation treatment for the cancer that had spread to her brain, and both whole brain and spinal radiation treatment. ", "Nothing worked. ", "The cancer had spread to her lungs, making it difficult for her to breathe.", "\n\nMikaela tried to get into clinical trials for all of the three anti-PD-1 drugs, but she did not qualify. ", "For one thing, she had the wrong kind of cancer—kidney cancer, not melanoma, which was the focus of the trials. ", "Second, her cancer had spread to her brain, and this disqualified her as a study subject. ", "Like most cancer patients in America, she did not qualify for a clinical trial.", "\n\n\"This drug that we wanted, for some reason they don't want people with brain mass,\" Keith says. \"", "They want a very standardized sample, they want people who have very localized spreads at worst. ", "So when you start getting people with brain mass and different kind of peculiar circumstances, it can skew their results—which is weird to me because then once the drug is approved it gets used on those people all the same, so it's kind of a strange way to do things.\"", "\n\nEventually Mikaela and Keith went to an oncologist at Stanford University Medical Center for a second opinion. ", "She told them that since Mikaela had run out of approved treatment options and could not get into a clinical trial, she could seek compassionate use of the anti-PD-1 drug under the FDA's expanded access program.", "\n\nTo qualify, Keith says, \"you need a doctor willing to administer [the drug] and then the drug company willing to provide the drug.\"", "\n\nThey had the doctor. ", "Now they needed a drug company.", "\n\n\"The Stanford doctor said she'd be willing to supervise the treatment,\" Keith says. \"", "So we asked Merck and Bristol-Myers Squibb and Genentech if they would provide their version of the drug.\"", "\n\nBristol-Myers Squibb said its drug was still too early in the development process. ", "Genentech said it did not have enough of the drug to supply it outside clinical trials. ", "Merck was the closest to bringing its version of the drug to market, so Keith and Mikaela focused their efforts on Merck.", "\n\nWhen they told Mikaela's original doctor at UC–San Francisco they were seeking compassionate use, Keith says, \"he seemed kind of frustrated that we found out about it. ", "What was really frustrating was that they had the drug right there in the hospital where she was being treated where he worked. ", "His direct colleagues were running clinical trials of the drug we wanted.\"", "\n\nThe drug she needed was right there, but Mikaela could not get access to it.", "\n\nOne night, Mikaela was rushed to the emergency room. ", "Keith looked at his high school sweetheart lying there in the ICU, tubes and wires attached to her body. ", "They had been married just two years and already he was losing her. ", "She was running out of time.", "\n\nHe asked Mikaela what she wanted to do. ", "He would have understood if she decided to stop and just make the most of the time they had left.", "\n\nBut Mikaela said she wanted to fight.", "\n\nKeith had read about the case of Josh Hardy, the young Virginia boy who survived cancer but needed an experimental drug to fight a life-threatening infection. ", "After being repeatedly turned down, Josh's parents launched a social media campaign to convince the manufacturer to give him the drug. ", "It worked. ", "Josh got the drug and got better.", "\n\nInspired by Josh's success, Keith contacted some of Mikaela's friends and former colleagues from her days working in public relations and asked them for help.", "\n\n\"They were able to get us up on some Bay Area blogs and it kind of just took off from there,\" he says.", "\n\nMikaela's friends started a Facebook page with the title \"We Got This\" and a Twitter account with a hashtag #WeGotThis. \"", "Help Mikaela live beyond 25,\" they pleaded. ", "They also started an online petition at Change.org with a message from Keith: \"We fully understand the risks with experimental medicine, but we have nothing to lose and much to gain.\" ", "To his astonishment, the petition quickly gathered nearly half a million supporters.", "\n\nA GiveForward.com fund-raising page raised $19,000 to help Mikaela get the genetic testing she needed to prove the drug could help her. ", "They recorded a YouTube video of Mikaela from her hospital bed making an impassioned plea for access.", "\n\nThe campaign was heartbreaking for Keith. ", "Every time he left Mikaela's bedside for a TV interview or a meeting, he knew it could be the last time he saw her alive. ", "But she wanted to fight, so fight he did.", "\n\nWithin a few short weeks, their story was all over the news. ", "Keith was approached by Frank Burroughs of the Abigail Alliance, who gave him advice on his efforts to convince one of the drug companies to give Mikaela the drug and told him that the Abigail Alliance could help them guide it through the FDA approval process if the drug company agreed.", "\n\nSoon, Keith and Mikaela were on _Good Morning America_.", "\n\n\"Mikaela's always been my rock. ", "You know, she's in a lot of pain. ", "She's facing death at age 25. ", "She's just such a fighter,\" Keith told correspondent Jim Avila.", "\n\n\"We just need someone to say that they are going to provide us the drug.\"", "\n\nLittle did he know his public appeal had touched the heart of someone on the inside.", "\n\nShortly after his _GMA_ appearance, Keith got the anonymous email. \"", "I am a proponent of compassionate use of investigational drugs and your story drew my extreme interest for a specific reason—I am a Merck employee who works on the anti-PD-1 antibody every day,\" the source wrote him from a secret email account. \"", "I have seen the amazing clinical results from our melanoma trials, and I am well aware of the multiple cancer types that could be treated with our drug.\"", "\n\nMerck could help them if it chose to, the anonymous informant told Keith. \"", "Merck should have plenty of their drug to spare for one person—as an employee, I've followed the dramatic scaling up of production for this antibody over the last year plus.\"", "\n\nBut he explained the reason why they were facing such resistance. \"", "As you have experienced already, this is going to be a difficult drug to get companies to allow compassionate use. ", "The anti-PD-1 drugs hold the promise of billions of dollars a year in revenue. ", "Merck, Bristol-Myers, and Genentech are all going to be very hesitant to allow the drug to be used outside of the controlled and predictable clinical trials. ", "If this drug were to cause complications while being used with Mikaela, the companies would be worried about that association with their drug.\"", "\n\nIf Mikaela died while she was on the drug, he explained, the company was afraid the FDA could halt the trial and force it to prove that the disease, and not the drug, was responsible for her death. ", "That could lead to delays in drug approval that could cost it a fortune.", "\n\nThere was no incentive for the company to help Mikaela—and every incentive for it not to help her.", "\n\nThe source gave Keith advice on how to build pressure on the company, revealing the little-known location of the Merck lab where researchers were working on the drug Mikaela needed.", "\n\n\"The address is 901 S. California Avenue, Palo Alto, CA 94304,\" he wrote. \"", "There is a big Merck sign right out front—a decent backdrop for a rally.\"", "\n\nKeith said he needed help figuring out whom to contact at Merck to make his plea. \"", "It was pretty much a black box for us,\" he said. ", "So the source gave Keith the direct numbers of top Merck executives.", "\n\n\"I want to wish you two the best from the bottom of my heart,\" he wrote. \"", "I wish we could have been faster in our work so you wouldn't be having to go through this additional struggle. ", "Let me know if you need any additional help. ", "Don't give up and enjoy every moment together.\"", "\n\nKeith and his anonymous source began exchanging emails. ", "And they eventually met up at a Starbucks near Merck's Palo Alto lab to strategize.", "\n\n\"He was just kind of telling me about how critical this drug was to Merck, how this is the best hope they've had since the '80s, and really their entire business is dependent on this drug working out,\" Keith says.", "\n\n\"They had been saying that they couldn't give her the drug because they didn't know the dosing schedule and they didn't know the risks with her situation,\" Keith says.", "\n\nHis source told him that this wasn't true.", "\n\n\"It was just like a pure business thing,\" Keith says. \"", "There was no way they were going to risk this drug taking longer to get to market. ", "He was saying that sometimes these drugs, to push it all the way through it can cost like a billion dollars. ", "And so any small percentage increase in that is a pretty large sum. ", "And then you add in the fact that the really promising drugs, you're kind of racing each other to get approved first.\"", "\n\nKeith never learned his new friend's name, but sadly, in the end, his secret source was right. ", "Merck turned down Keith and Mikaela's requests.", "\n\nShe died on April 24, 2014.", "\n\n_Less than five months later_ , on September 4, 2014, the FDA approved the drug she had been seeking—a huge financial boon for Merck. \"", "I think we are watching a revolutionary change in cancer therapy,\" Merck's head of research and development, Roger Perlmutter, declared. \"", "Certainly the most important advance in my lifetime and maybe the most important advance since the introduction of radiotherapy.\"", "\n\nThe government's stamp of approval came just a few months too late for Mikaela Knapp.", "\n\nUnfortunately, she is not alone. ", "Countless others have lost their struggle to gain access to life-saving drugs because drug companies had no incentive to provide the drugs they needed outside of clinical trials.", "\n\nOne of the most famous cases was that of Kianna Karnes.", "\n\nKianna was a forty-one-year-old mother of four children when she was diagnosed in 2002 with kidney cancer. ", "She was treated with interleukin-2, the only medication approved by the FDA at the time to treat her disease. ", "The drug nearly killed her. ", "When that treatment failed, her father, John Rowe, began researching investigational medications.", "\n\nRowe himself was a cancer survivor, whose life had been saved because he was able to obtain a cutting-edge cancer drug, Gleevec, in a clinical trial. ", "As a result, he had experience with the clinical trial process and how to get access to emerging medicines.", "\n\nAfter doing some digging, he learned that both Bayer and Pfizer were conducting clinical trials for new investigational medications to treat kidney cancer—BAY 43-9006 at Bayer and SU11248 at Pfizer. ", "But his hopes were soon dashed. ", "Kianna was ineligible for the clinical trials because her cancer—like Mikaela Knapp's—had spread to her brain. ", "Although surgeons had removed her brain tumors, she was still disqualified from joining the clinical trials.", "\n\nSo her father decided to try to get the drugs for his daughter under the FDA's expanded access program. ", "Working with Frank Burroughs of the Abigail Alliance, he contacted Pfizer and Bayer to ask for the drug on a compassionate use basis. ", "He got nowhere.", "\n\nRowe had worked for US congressman Dan Burton, who was then the chairman of the powerful House Government Reform Committee. ", "As Kianna's condition deteriorated, he finally asked Congressman Burton for help. ", "Soon, the _Wall Street Journal_ took up Kianna's cause, publishing an editorial drawing attention to her plight. ", "He told the _Journal_ , \"If the only alternative is death, then for God's sake let 'em have the drug.\" ", "The _Journal_ asked, \"Who could disagree?\" ", "and called on Congress to pass a \"Kianna's Law\" mandating access to experimental medicines for dying patients.", "\n\nThe public shaming and political pressure worked. ", "The editorial appeared on March 24, 2005. ", "That morning, the FDA told Congressman Burton's office it would approve compassionate use for Kianna. ", "That afternoon, both companies contacted Kianna's doctor offering to make the drug available.", "\n\nBut sadly, it was too, little too late. ", "Kianna died that same night at 9:41 p.m.\n\n_Less than a year later_ , both drugs were approved by the FDA. ", "Speaking after his daughter's death, Rowe said, \"I don't know that either of these drugs would have saved Kianna's life, but wouldn't it be nice to give her a chance?\"", "\n\nKianna actually had a better chance than most patients at receiving expanded access. ", "As her father explained to the _New Yorker_ , \"Here is a case where her old man understood clinical trials. ", "I knew about compassionate use; I had a friendship with a powerful member of Congress; I've got the _Wall Street Journal_ behind me. ", "But I still couldn't save her life.", "\n\n\"Now, what about the thousands of people out there who don't have these kinds of resources available to them?\" ", "he asked.", "\n\nWhat about their right to try?", "\n\nONE EXCHANGE DURING A hearing on Right to Try in the Colorado legislature highlights why compassionate use isn't sufficient and why we need the Right to Try.", "\n\nJosh Gordon, a senior research specialist with Kaiser Permanente, was testifying against Right to Try, explaining that the law was not needed.", "\n\n\"There is already a process in place for that through the FDA,\" Gordon told the committee. \"", "It has a variety of names—compassionate use, single patient use, expanded access,\" he said, adding, \"At Kaiser, we do have a pathway. ", "We use the FDA's IND pathway to get access to drugs before they are approved for certain patients.\"", "\n\nSo, he was asked, how many patients got compassionate use at Kaiser Permanente?", "\n\n\"We typically do about four to eight single patient use requests per year,\" Gordon testified.", "\n\nFour to eight? ", "Millions of Americans are dying of terminal illnesses and Kaiser Permanente makes only four to eight compassionate use requests every year?", "\n\n\"I agree with the concept of streamlining that process,\" Gordon told the committee.", "\n\nLittle wonder Right to Try passed unanimously in Colorado.", "\n\nThe compassionate use process needs more than just streamlining: it needs a dramatic overhaul. ", "The FDA boasts that it approves more than 99 percent of all compassionate use requests. ", "That sounds good, but let's take a closer look at the data.", "\n\n• In 2014 the FDA received 1,882 requests for expanded access and allowed 1,873 (or 99.5 percent) to proceed.", "\n\n• In 2013 the agency received 977 requests, and approved 974 (99.7 percent approved).", "\n\n• In 2012 the number of requests was 940 and the number approved was 936 (99.6 percent approved).", "\n\n• In 2011 there were 1,200 requests and 1,199 approvals (99.9 percent approved).", "\n\n• In 2010 there were 1,030 requests and 1,014 approvals (98.4 percent approved).", "\n\nThat is an average of twelve hundred requests each year.", "\n\nSo what stands out about those numbers? ", "The FDA points to the high approval rates. ", "But what is really striking is the infinitesimally small number of requests.", "\n\nAccording to the American Cancer Society, in 2015 about 1,658,370 Americans will be diagnosed with cancer and 589,430 will die of it. ", "That is about 1,615 people dying of cancer _every single day_. ", "Yet the FDA receives only twelve hundred requests for compassionate use of investigational drugs in _an entire year_?", "\n\nThe FDA objects that some of those requests are for multiple patients. ", "And, it says, some people die while pursuing standard treatments, while still others may decide that, after running out of approved options, they want to stop fighting and enjoy whatever time they have left with loved ones.", "\n\nFair enough.", "\n\nSo how many cancer patients want access to emerging medicines but can't get them? ", "According to the Center for Information and Study on Clinical Research Participation (CISCRP), 40 percent of all cancer patients attempt to join a clinical trial. ", "But only 3 percent of adult cancer patients actually succeed in getting into a trial.", "\n\nWhy is that? ", "As Dr. Emil Freireich, the MD Anderson Cancer Center doctor who pioneered the cure for childhood acute lymphoblastic leukemia, explains in the _British Medical Journal_ , \"most cancer patients cannot participate in phase II trials because they are either ineligible or they are unable to fulfill the financial and social requirements for participating in such trials, such as staying in the centers conducting these trials, sometimes for many weeks or months.\" ", "Moreover, Dr. Freireich says, in many cases trials \"are designed to give the highest probability of a positive outcome. ", "Thus, they have patient eligibility requirements which assure that only the healthiest patients at the earliest point in their disease are entered. ", "These decisions are not based on any reasonable evidence that patients who are ineligible would not benefit, but are strictly designed to fulfil the regulatory requirements established by bodies such as the Federal [Food and] Drug Administration (FDA) and the regulatory components of industry and academia that govern these clinical trials.\"", "\n\nAnd the problem is getting worse. ", "According to the Tufts Center for the Study of Drug Development, the total number of eligibility criteria for clinical trials has nearly doubled over the past decade, making it harder and harder for patients to qualify.", "\n\nIf 40 percent of cancer patients try to get into trials and only 3 percent succeed, that means most fail to get access to emerging treatments through clinical trials. ", "Since there will be about 1,658,370 new cancer diagnoses in 2015, that means there are hundreds of thousands of cancer patients who want experimental medicines but cannot get them. ", "And that is not counting all the hundreds of thousands of other Americans who will be diagnosed with other terminal illnesses this year.", "\n\nAnd yet the FDA considers twelve hundred compassionate use requests each year a system that \"seems to work quite well\"?", "\n\nWhen so many Americans are fighting terminal illnesses and fewer than 1 percent are getting access to investigational drugs, the system isn't working well. ", "It is broken. ", "Either patients don't know that they can apply for investigational treatments through compassionate use, or the barriers to applying are so overwhelming that patients and doctors cannot overcome them, or they don't bother to try.", "\n\nIn all likelihood, the answer is all of the above. ", "Keith and Mikaela Knapp's first doctor did not even tell them compassionate use was an option. ", "It was only because they were lucky enough to find another doctor who told them about compassionate use (and was willing to fill out a hundred hours of paperwork) that they learned they could pursue an experimental treatment.", "\n\nMany doctors simply can't spend the time it takes to get access to emerging drugs, especially when it means taking weeks off from treating other patients. ", "One doctor at a leading cancer hospital told me that he had never once applied for compassionate use for a patient. \"", "It's just too daunting,\" he said.", "\n\nFor many doctors, a patient getting compassionate access is like the mythical unicorn—a creature that legends say exists, but one no one has actually ever seen. ", "Earlier, we met Andrea Sloan—the Texas lawyer who died after a long battle trying to get access to an experimental drug. ", "Her oncologist at MD Anderson Cancer Center, Dr. Charles Levenback, told CBS News, \"I cannot recall in my practice in the last 10 years a patient who got compassionate use of a drug.\"", "\n\nThink about that: when compassionate use is so rare that a leading cancer specialist at one of the nation's leading cancer research hospitals has never seen it happen in the last ten years, there is clearly something deeply wrong with the system.", "\n\nAs his MD Anderson colleague Dr. Freireich explains, \"It is tragic that regulatory bodies have created a circumstance where people have to live in an aura of hopelessness even though they have the will, the resources, and the ability to expose themselves to the risk of participating in investigational studies and to enjoy the potential for benefit. ", "The solution is legislation or judicial action to permit expanded access to experimental treatments for patients with limited life expectancy.", "\n\n\"Patients with advanced cancer and limited life expectancy should have the same privilege as all individuals in a free society—that is, to decide their own benefit [to] risk ratio,\" he says.", "\n\nThe vast majority of doctors agree. ", "In 2015 SERMO, a social network for medical doctors, asked 2,182 physicians, \"Should compassionate use be allowed for unproven drugs or therapies?\" ", "An overwhelming 93 percent of the doctors said yes, while only 7 percent were opposed.", "\n\nPolls also show that doctors see the FDA as an obstacle to their ability to get cutting-edge treatments for their patients. ", "For many years the Competitive Enterprise Institute has polled medical specialists about their attitudes toward the FDA—orthopedic surgeons (2007), oncologists (2002), emergency room doctors (1999), neurologists and neurosurgeons (1998), and cardiologists (1996). ", "And over the years, the institute has found the same consistent results: by wide margins, these specialty doctors—those most likely to treat terminally ill patients—believe that (1) the FDA takes too long to approve drugs, (2) the FDA hinders their ability to treat patients, and (3) patients should have much broader access to investigational drugs and medical devices that have not yet been approved by the FDA.", "\n\n• When asked, \"Would you say the FDA's approval process has hurt your ability to treat your patients with the best possible care?\" ", "80 percent of neurologists and neurosurgeons said yes, as did 78 percent of orthopedic surgeons, 77 percent of oncologists, 71 percent of cardiologists, and 58 percent of emergency room doctors.", "\n\n• When asked, \"Do you agree or disagree with the following statement: the FDA is too slow in approving new drugs and medical devices?\" ", "76 percent of orthopedic surgeons agreed, along with 67 percent of neurologists and neurosurgeons, 65 percent of cardiologists, 64 percent of emergency room doctors, and 61 percent of oncologists.", "\n\n• When asked whether they would support a \"proposal to change FDA law so that unapproved drugs or medical devices could be made available to physicians as long as they carried a warning label about their unapproved status,\" 73 percent of neurologists and neurosurgeons said they would, as did 70 percent of orthopedic surgeons, 69 percent of emergency room doctors, and 68 percent of oncologists.", "\n\nIn other words, the vast majority of doctors believe that people who are fighting for their lives have a right to try investigational treatments. ", "Yet it is not happening—at least not on a scale that remotely meets the needs of patients and the desires of their treating physicians.", "\n\nSo who is to blame for this sad state of affairs?", "\n\nThe drug companies blame the FDA.", "\n\nThey believe that if their emerging drugs are taken by the sickest patients, like Mikaela, who have exhausted their standard treatments, these patients will have a higher incidence of mortality and their drugs will appear less promising. ", "These \"less promising\" results could cause the FDA to require years more testing and cost millions of dollars—a risk that companies don't want to take.", "\n\nIn 2010 the Biotechnology Industry Organization issued a white paper outlining the \"dilemma\" its member companies face when they receive compassionate use requests. ", "When patients ask for compassionate access, they wrote, \"biotech companies must balance those interests with their responsibility to move products through the regulatory process to receive marketing approval; a process that could be delayed or put at risk by providing access to the product outside of a clinical trial.\"", "\n\nThey listed two principal risks companies face from FDA regulators.", "\n\nFirst, they cited the risk that compassionate access could cause the FDA to delay approval of their new drugs:\n\nSince the company will be providing an unapproved product to a patient outside the scope of a clinical trial . . . ", "should an adverse event occur with a patient in the early access program, the company puts its broader clinical testing program at risk since the FDA may require the company to initiate new clinical trials or expand existing trials as part of its investigation of the event. ", "This could delay or even prevent the approval of the product. ", "Consequently, a larger patient population may be denied a potentially beneficial product.", "\n\nIn some circumstances, therefore, by allowing early access, the company risks market approval of the product. ", "Thus, the question often confronting companies is whether to put an entire project at risk—and therefore jeopardize availability of a drug for a larger patient population—in order to provide early access to a product for an individual or small group of patients.", "\n\nSecond, the Biotech Industry Organization says, if compassionate use becomes widespread, it will be harder to recruit patients for the large, randomized placebo trials that the FDA requires (in which some patients receive the drug while others get sugar water):\n\nIf patients knew they could access a treatment outside the clinical trial process, it would reduce their incentive to enroll in a trial especially since they may receive a placebo and therefore not be treated for their illness. ", "Therefore, if early access programs become extremely common, the clinical trials system could break down, delaying or ending some product development programs.", "\n\nMore recently, two Merck executives—Michael Rosenblatt and Bruce Kuhlik—wrote in the May 2015 issue of _JAMA: The_ _Journal of the American Medical Association_ that expanded access programs (EAPs)\n\npose real risks: conduct of an EAP may jeopardize enrollment or retention of patients in ongoing clinical trials of a drug that determine safety and efficacy and ultimately gain regulatory approval. . . . ", "Because many patients requesting early access are extremely ill and are outside the profile of patients eligible to participate in clinical trials, serious adverse events, including death, occur. ", "If such an event occurs in an EAP, it might not be possible to determine if it is drug-related. ", "As a result, a promising therapy might be delayed, or even abandoned before sufficient clinical trial data can be generated.", "\n\nAsked about these concerns, Dr. Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research, insisted that the FDA is not a deterrent to compassionate use. \"", "We serve the people that take medicine: the patients, the people who need medicine. ", "That's the reason we're here and that's what we do, that's our mission,\" she said in an interview. \"", "We serve them by trying to get drugs that are reasonably well studied on the market as expeditiously as possible, evaluating those drugs while they're on the market to make sure that nothing untoward happens. ", "And also we do believe and do run a lot of access programs obviously because we think people should have the ability to take an investigational drug if they don't have other alternatives. ", "That's what we think.", "\n\n\"There are a lot of problems with this, so we acknowledge those,\" she says. ", "But she adds, \"We don't usually stand in the way of access. ", "It's up to the companies whether or not they provide these programs and at what level. ", "And they can publicize them and make them widely available, or they can only respond to calls, or they can refuse to have an access program.\"", "\n\nWhat does she make of industry's concern that granting compassionate access could cause the FDA to delay drug approvals?", "\n\n\"Well, they certainly say that,\" Dr. Woodcock says. \"", "We've heard that hundreds of times. ", "We know of only one instance where we took some action based on what we observed—and that was pretty recent actually—in an access program. ", "So we don't think [that is a legitimate reason].\"", "\n\nShe says she understands that companies fear the FDA. \"", "Well, we hold sort of the power of whether they're going to be successful with their development program or not. ", "People are afraid of the IRS too. ", "Regulators are not popular. ", "It's not our 'job' really,\" she says. \"", "There's a huge amount of risk in drug development because there's so many failures. ", "They want to be conservative, but we don't think that's a very valid excuse.\"", "\n\nShe says that the drug companies, not the FDA, are the main obstacle to expanding access to emerging drugs. \"", "We don't, as I said, stand between patients who are dying getting access to investigational drugs. ", "But I get that the companies don't always want to run access programs.\"", "\n\nIf it is not fear of jeopardizing FDA approval or clinical trials, then what is the reason?", "\n\n\"I think there are a lot of reasons that companies don't want to give drugs out,\" she says. \"", "It's a very expensive thing to run an access program.\"", "\n\nIs it FDA's responsibility to help patients get access to experimental treatments?", "\n\n\"To the extent we are capable of,\" Dr. Woodcock says. ", "She says the FDA has a twenty-four-hour call line for emergency requests. \"", "Our doctors and our other personnel are often arranging access.\" ", "And she says the agency is working on establishing a clearinghouse that will provide \"one-stop shopping\" for doctors seeking approval for access requests. \"", "We have talked to [members of Congress] and we had a meeting with some patient advocates a few months ago . . . ", "and talked about could the companies post their policies, number one; and then could there be established some kind of clearinghouse so there would be one-stop shopping. . . . ", "Somebody to call if you wanted access to an experimental drug and then hopefully they could work those things out.\"", "\n\nBut, she says, there is only so much the FDA can do.", "\n\n\"We do not make or develop the drugs. ", "We don't own the drugs,\" she says. \"", "We can't extract drugs out of the hands of companies and give them to people.\"", "\n\nSo here is where it stands: The drug companies blame the FDA. ", "The FDA blames the drug companies. ", "Meanwhile, patients are dying—and no one is doing much of anything to help patients access promising drugs and treatments.", "\n\nSo what is the solution?", "\n\nFirst, we need to create grassroots pressure for change. ", "That is what the Right to Try movement is doing. ", "Today, the FDA touts its expanded access program as a reason why Right to Try is unnecessary. ", "But back in the 1980s, when AIDS activists chained themselves to the gates of the FDA demanding expanded access, the FDA said _that program_ was unnecessary too—often using virtually the same language it uses against Right to Try.", "\n\nIn February 1988 FDA commissioner Frank Young declared, \"We've been working very rapidly in getting new drugs into people,\" adding that the \"FDA is not the bottleneck\" and \"the real hang-up is the science.\" ", "At the FDA, he said, \"We feel it's important that people have access to drugs as soon as possible.\" ", "To do that, FDA spokesman Don McClaren said, \"We have to balance [dying patients' concerns] with the legal requirement that the drugs we license are safe and effective.\"", "\n\nIf that sounds familiar, it's because FDA officials are singing the same tune today. \"", "I don't think we are a barrier to access for patients,\" FDA commissioner Margaret Hamburg declared in 2014, but \"at the end of the day we have to be guided by science in everything we do. ", "It has to be our compass.\" ", "She added that \"we adapt and improve models and timetables to help patients get earlier access to promising new drugs,\" but said that \"we must balance the eagerness to find ways to get promising treatments to patients as quickly as possible . . . ", "with the need to provide assurance that the benefits of these treatments outweigh the risks.\"", "\n\nThe officials are still deploying the same, worn-out arguments thirty years later.", "\n\nIn 1980 AIDS activists rejected the FDA's claim that everything was fine, and demanded fundamental reform. \"[", "The advocacy group] ACT UP's fundamental contention was that, with a new epidemic disease such as AIDS, testing experimental new therapies is itself a form of health care and that access to health care must be everyone's right,\" wrote Douglas Crimp, an activist. ", "Not only did activists protest; they exercised their Right to Try by organizing networks of underground pharmacies, or \"buyers clubs,\" that distributed unapproved drugs, often imported from overseas, to dying members of the AIDS community.", "\n\nThese were acts of civil disobedience, and they put lifesaving drugs in the hands of the dying. ", "They shamed the FDA into changing its policies, saved lives, and gave birth to our compassionate use system.", "\n\nToday, as we have seen, that system is not meeting the needs of dying patients, who are still not getting access to the drugs they need. ", "So the Right to Try movement is picking up the mantle and continuing the fight for change.", "\n\nInstead of using underground pharmacies, the Right to Try movement is using state law to expand access to emerging drugs. ", "Instead of chaining ourselves to the gates of the FDA, we are harnessing the power of millions of Americans to get our message to Washington: Compassionate use is broken, and Americans with terminal illnesses don't have time to wait.", "\n\nThe Right to Try movement is using state constitutions exactly as our Founding Fathers intended—as \"instrument[s] of redress\" (Alexander Hamilton, _Federalist_ number 28). ", "We are using the states to reclaim our fundamental rights and pressure the federal government to change course.", "\n\nAnd that pressure is starting to work.", "\n\nFor years doctors have been complaining about the FDA's application forms for compassionate access, which even by the agency's admission take over a hundred hours to fill out. ", "It is daunting even for doctors from major research hospitals, who are used to filling out mountains of paperwork for clinical trials. ", "But for a local community doctor seeking compassionate access for a single patient, getting FDA approval is like climbing Mount Kilimanjaro. ", "One hundred hours is two and a half weeks of working full-time doing nothing but filling out government paperwork. ", "Few doctors can afford that kind of time. ", "As a result, few seek compassionate use of investigational medicines for their patients—one reason why the FDA receives so few applications.", "\n\nIn May 2014 FDA commissioner Margaret Hamburg appeared on NPR's _Diane Rehm Show_ , where she said that \"in numerous cases we have proceeded within 24 hours or overnight. ", "We move these applications as expeditiously as possible.\" ", "And she expressed shock that other guests had suggested the application process for compassionate use was too complicated. \"", "I was surprised . . . ", "to hear about how cumbersome the process is and how it takes weeks or months at the FDA,\" she said. \"", "I'm looking at the form now. ", "It's three pages long. ", "A lot of it is checking off boxes.\"", "\n\nBut on February 4, 2015—nine months after Commissioner Hamburg claimed getting compassionate use was a simple as \"checking off boxes\"—the FDA suddenly did an about-face.", "\n\nWriting on the FDA's blog, associate commissioner Dr. Peter Lurie declared, \"We heard concerns from patients and physicians that the process for gaining access to investigational drugs was too difficult, and pulled together a team to find a way to make that process simpler.\"", "\n\nAfter reviewing the forms, Dr. Lurie wrote, FDA officials concluded that \"the existing application form was too complex: it called for 26 separate types of information and seven attachments. ", "In fact, it was originally designed for manufacturers seeking to begin human testing, not for physicians seeking use by single patients.\"", "\n\nHe announced that the FDA had created a new form that would be much easier for physicians to use. \"", "We estimate that physicians will be able to complete the finalized version of the [new] form in just 45 minutes, as compared to the 100 hours listed on the previous form,\" he wrote. \"", "Additionally, to further assist the physician seeking access to an experimental therapy, we have redesigned our website to make it easier to navigate and to explain the new proposed process in detail.\"", "\n\nFor Frank Burroughs of the Abigail Alliance, the announcement was vindication.", "\n\n\"We were right!\" ", "he says. \"", "It took too long!\"", "\n\nIn an interview, Dr. Woodcock proudly touted this reform. \"", "We have streamlined the process, which was excessively onerous.\"", "\n\nBut just a few months earlier, her then-boss, FDA Commissioner Hamburg, said it wasn't \"onerous\" at all—just a matter of \"checking off boxes.\"", "\n\nWhat suddenly changed?", "\n\nHere is what changed: by February 2015, five state legislatures had passed Right to Try laws eliminating the need for the FDA's compassionate use program. ", "Only in the face of this grassroots revolt did the FDA finally acknowledge what doctors and patients had been saying for years: that the forms were too difficult and the process was too complex. ", "Only after states started passing Right to Try laws did the FDA finally admit, after repeated public denials, that the application did in fact, take one hundred hours.", "\n\nAt this writing, the new, shorter application _still_ has not yet been put into effect. ", "An FDA spokesman says, \"We're hoping to have it launched by the end of the year.\" ", "But even if it is eventually put in place, a simplified form is only an incremental step forward.", "\n\nIt does not solve the fundamental problem: you still have to beg the federal government for the Right to Try to save your own life.", "\n\nThe problem is not just a hundred hours of paperwork; it is an entire system of federal disincentives that block and discourage access to investigational medicines. ", "Without deeper reforms, simplified paperwork will be nothing more than window dressing for an inhumane system that prevents hundreds of thousands of dying Americans from getting the drugs they need to survive.", "\n\nIf just five states passing Right to Try laws can force the FDA to eliminate ninety-nine hours of paperwork, imagine what can be accomplished when Right to Try is the law of the land in all fifty states. ", "We need to keep up the pressure until compassionate access is the rule for everyone facing a terminal illness, not the exception for a privileged few.", "\n\nAnd that requires not only removing the bureaucratic obstacles that discourage doctors from applying for compassionate use but also getting rid of the bureaucratic obstacles that discourage companies from making their drugs available to desperate patients.", "\n\nWHEN WE SPEAK WITH CEOs of biotech and pharmaceutical companies, the two biggest risks they cite in regard to expanding compassionate access are that it will (1) delay drug approvals and (2) drive patients out of clinical trials.", "\n\nBoth of these problems can be solved—but it will require changing the way the FDA does business.", "\n\nIf we want companies to dramatically increase compassionate use, they must have confidence that granting access to experimental treatments is not going to delay the approval of drugs and cost them millions of dollars in lost business.", "\n\nToday, that is not the case. ", "As one biotech CEO told me, \"Sponsors generally believe that the FDA puts the burden of proof on the company to convince the regulatory reviewers that any adverse event is not related to the company's drug. ", "While there may not be a lot of examples that suggest that adverse events uncovered in a compassionate use/expanded access situation [have] derailed a drug, it is one of the reasons that it has not been more widely adopted because of the theoretical risk that such adverse events will constitute a disproportionate amount of attention in the dialogue with regulatory reviewers in the effort to get a drug approved.\"", "\n\nFormer FDA commissioner Andy von Eschenbach (who supports dramatically increasing compassionate use through federal, not state-level, reforms) says that today \"there's no upside for the company other than doing a moral good. ", "But there is an awful lot of downside for them.\"", "\n\nFor some, simply doing a moral good is incentive enough. ", "One CEO of a major pharmaceutical company says it already does make its drugs available on a compassionate basis. \"", "I think it's really important that promising new drugs get to patients sooner. ", "I've worked all my life with that goal, not only in the US, but around the world.\"", "\n\nThis CEO says that while \"we certainly, in our programs, have found ways to address that compassionate need,\" there is a fear among others in the industry that \"if you use your product in really sick people, the illness the person has may be interpreted as side effects of the drug. ", "That's what people are worried about in many instances.\"", "\n\nTo address this concern, the FDA needs to create \"safe harbor\" for drug companies that provide their products to patients outside clinical trials, and make clear it will hold companies harmless in the regulatory process if they do the right thing and provide drugs for dying patients.", "\n\nYou can't just ignore the data if a patient dies, says Dr. von Eschenbach, but you can find \"a way to _sequester_ the data. . . . ", "In other words, it certainly has to be recorded and recognized. [", "But you] find a way to recognize the data but also recognize the circumstance and not allow it to inappropriately adversely influence the regulatory decision.\"", "\n\nThe FDA was supposed to make its policies on sequestration clear in 2009, when the agency last updated its compassionate access programs. ", "But according to the pharmaceutical industry, it still has not done so. ", "Speaking on NPR's _Diane Rehm Show_ in May 2014, Sascha Haverfield, the vice president for scientific and regulatory affairs at the Pharmaceutical Research and Manufacturers of America (PhRMA), said, \"You want to provide certainty to the process to drug developers to understand how data will be used. . . . ", "When the FDA put this process in place in 2009, we are still looking for final guidance on how FDA will facilitate the process and use data.\"", "\n\nFive years later, at the time of this writing, the FDA has still not provided clear guidance to companies on how it will treat data from compassionate use. ", "No wonder companies are reluctant to provide access.", "\n\nDr. Woodcock says the FDA is still working on it. \"", "We are completely aware [of those concerns] and we're working on sort of a statement that we get to say that we don't hold these experiences against the drug.\"", "\n\nHow many states will have to pass Right to Try laws before the FDA finally gets around to issuing it?", "\n\nSequestration is important, but it's only the first step. ", "If we want to dramatically increase the scope and scale of compassionate use, we also need to create _incentives_ for companies to cooperate with compassionate use requests.", "\n\n\"Making it easier is getting rid of the drag,\" Dr. von Eschenbach says. ", "But the bigger question is, \"How do you do the pull? ", "Is there a positive way of incentivizing it? ", "There's got to be a positive incentive as well as getting rid of the barriers.\"", "\n\nOne incentive he proposes is to reward drug companies that offer drugs on an \"off-label\" basis before FDA approval. ", "Today, patients are regularly rejected for clinical trials because they have the \"right\" kind of cancer in the \"wrong\" part of the body. ", "This is what happened to Mikaela Knapp and Abigail Burroughs. ", "They did not qualify for trials, because of the location of their cancer, even though the drugs they needed were the right ones to treat the type of cancer they had.", "\n\nSadly, Dr. von Eschenbach says, this happens all the time. ", "He explains that a drug manufacturer may be conducting clinical trials on a promising new drug for, say, lung cancer, when it is approached by a patient with pancreatic cancer who does not qualify for the clinical trial. ", "But it turns out the pancreatic tumor has the same genetic mutation that is apparently driving the lung cancer in the manufacturer's clinical trial.", "\n\nIf the drug were already approved, doctors would simply go ahead and use the lung cancer drug to treat pancreatic cancer—no special FDA permission would be required. ", "This is called using a drug off-label—because the FDA label says the drug is for lung cancer, but the doctor is confident it can work in pancreatic cancer as well. \"", "Oncology was built on off-label use,\" Dr. von Eschenbach says. \"", "What happens all the time with that scenario is, if the drug's already available, then it's simply used off-label and everybody's happy as a clam.\"", "\n\nHe believes we should do the same thing \"in the very, very early stages of clinical development, before a drug has been approved and [is] available on the market and everyone can get access to it by prescription.\"", "\n\nThis can be done by (1) promising to sequester the data from the pancreatic patient, so that it does not hurt the lung-cancer trial if something goes wrong and (2) promising that if the drug works, positive data will be collected and could be used to help the company win approval from the FDA to market the drug for pancreatic as well as lung cancer—which is very financially valuable for the company.", "\n\n\"If it pans out that that drug is active in that pancreatic patient, they're one step further along in developing another indication for their drug,\" he says. \"", "Rather than having to go all the way back to square one and doing another full-blown registration study for a completely different indication, you have sort of a shortcut and you can get an additional label indication with a minimal amount of required data. . . . ", "And then if a sufficient number of patients get access to the drug earlier, you take that back to the FDA and use it as a registry.", "\n\n\"If it doesn't work,\" he says, \"the data's recorded and recognized but it's not going to count against the lung-cancer registry protocol.\"", "\n\nNow, suddenly, compassionate use is a win-win for industry. ", "The company now has an economic reason, as well as a moral reason, to provide access.", "\n\nThis \"could get the companies and the sponsors to be much more liberal about their willingness to provide these drugs,\" Dr. von Eschenbach says. ", "But to make it happen \"you really have to incentivize the sponsor by protecting them and giving them an opportunity to advance their goal of drug development.\"", "\n\nSome companies already do this, even in the face of regulatory obstacles. ", "One CEO of a major pharmaceutical company described to me how his company many years ago offered a drug on a compassionate use basis to patients on a transplant list.", "\n\n\"We thought we could let them live longer until they could find an [organ],\" he says, \"but they in fact came off of the transplant list. ", "Their disease regressed.\" ", "His company had no idea its drug would be so effective in patients with advanced disease until it offered the drug to them under compassionate use.", "\n\nWe need to find ways to encourage more companies to take those kinds of risks. ", "We need policies that reward companies for doing the right thing, and change early access from a \"dilemma\" for industry into a tool of scientific discovery.", "\n\nThe second big obstacle that drug companies cite is the risk that expanding compassionate use will discourage patients from joining clinical trials. ", "The problem here, once again, is caused by the FDA and its overreliance on what are called \"double-blind placebo controlled trials\"—studies in which some patients get the experimental medicine and others do not.", "\n\nAs Steven Walker, cofounder of the Abigail Alliance, points out, the problem is \"the FDA's retention of obsolete clinical trial designs, in which terminal and seriously ill patients must be coerced to enroll in agency-required trials under the risk of randomization to a placebo, or an older, known to be inadequate drug, as the basis of its entire regulatory scheme.\"", "\n\nHe says, \"Enrolling in a randomized placebo control trial is far more dangerous to a patient with a terminal disease than it would be to simply be given the drug. ", "Because getting the placebo, under blinded conditions, is for many, many people a death sentence. ", "It's a gamble. ", "The company is betting that fewer people will die in the arm that gets the drug than in the placebo arm. ", "This pile of bodies is smaller than the placebo pile, that's what they want to see. ", "And that's literally what they are measuring. ", "That is our clinical research system for cancer.\"", "\n\nThe excruciating dilemma these studies create for patients and their families was recently brought to life in the Ken Burns documentary _Cancer: The Emperor of All Maladies_.", "\n\nIn one scene, the parents of a leukemia-stricken fourteen-month-old girl named Olivia Blair are discussing with her doctors whether to enroll her in a clinical trial for a new chemotherapy drug.", "\n\n\"This is probably the hardest decision along the way that you guys have to make,\" a doctor tells Olivia's parents.", "\n\nHer mom, Kelly, leans across the table and asks, almost in a whisper, \"So how do we find out if they get the [drug]? ", "How do we find that out? ", "It's randomized, right?\"", "\n\nThe doctor explains how the selection process work. ", "Names of patients are put into a computer that decides who gets the drug and who doesn't. \"", "There's a formula that spits out, 'OK, the next patient that consents is going to get it, the next patient is not going to get it.'\"", "\n\nKelly pauses with a confused look. \"", "That's like . . . ", "I don't . . . ", "I don't . . . ", "I don't feel comfortable with that.\"", "\n\nThe doctor tries to reassure her. \"", "The thought of your child's treatment being left up to a computer is a very hard concept to take. ", "It's OK if you decide not to be in the study.\"", "\n\n\"I don't know what to say,\" Kelly tells the doctors.", "\n\nThe doctors leave the room, and the family holds hands as Olivia's father, Marcus, leads them in prayer:\n\n\"Lord, what we ask of you now Father is just to kind of nudge us in the right direction, Lord, and put us at ease and at peace with the decision that is ultimately made. ", "And we just humbly ask for your guidance in making this decision, Lord. ", "Amen.\"", "\n\nIt is a moral outrage that any Americans with a life-threatening illness—much less the parents of a fourteen-month-old baby with cancer—should be forced by their own government to make this kind of decision.", "\n\nFor decades, patient advocates have been demanding that the government stop putting people facing terminal diagnoses in placebo trials. ", "When AIDS protesters chained themselves to the gates at FDA headquarters in the 1990s, one of their key demands was:\n\nNo more double-blind placebo trials. ", "Because giving a placebo to someone with a life-threatening illness is unethical, the FDA must inform designers of clinical trials that it will not accept data based on placebo trials. ", "Instead, new drugs must be measured against other approved drugs or, where there are none, against other experimental therapies, different doses of the same drug, or against what is already known of the natural progression of AIDS.", "\n\nThey were morally right then.", "\n\nBut the difference today is that there is no longer any scientific justification for continuing this unethical approach to clinical trials—because technology is increasingly making these trials unnecessary.", "\n\n\"The reason why we have randomized placebo control trials is it's an artifact of an age when you couldn't analyze large data sets effectively and look for, and tease out, one variable from all of the things that were changing in a large data set,\" says Dr. Scott Gottlieb, a former FDA deputy commissioner and a scholar at the American Enterprise Institute. \"", "But in today's age, when we have sophisticated computers that look at large data sets and tease out with high degrees of certainty statistical conclusions based on how different groups are being affected, you could be incorporating those tools into drug development. ", "And on the medical device side they actually do, but on the drug development side they don't.\"", "\n\nWhen Kianna Karnes was waging her unsuccessful campaign to get access to an experimental cancer drug, the _Wall Street Journal_ pointed out:\n\nThe problem here is the FDA's unethical—and let us stress, unscientific—insistence on gathering information about drugs by way of \"blinded\" placebo-controlled trials, in which a subset of study patients are knowingly denied the new treatment and in some cases denied access to any active treatment at all. ", "This may be moral with an antihistamine; it's certainly not with treatments for a terminal disease.", "\n\nWhat's more, it's entirely unnecessary. ", "We already know what happens to most cancer patients who don't get treated. ", "They die. ", "We generally know, on average, how long that will take. . . . ", "A deadly follow-on effect of the placebo fetish is that it gives companies a disincentive to run compassionate use programs for unapproved drugs. ", "That's because companies won't be able to satisfy FDA demands to enroll patients in placebo trials if patients know they can get the drug for sure (instead of running the risk of getting a sugar pill) through compassionate use. ", "Hence Mrs. Karnes's deadly predicament.", "\n\nThe time has come for the FDA to give up its placebo fetish and start relying more on open-label trials instead, trials in which all the patients are actually getting the experimental drug.", "\n\nOpen-label studies are more than sufficient to determine whether a drug is safe and effective. ", "Indeed, the FDA has relied on them in the past. \"", "A lot of breakthrough therapies were approved on the basis of open-label studies where everyone got the drug and FDA allowed you to match them against historical controls and basically discern whether there was drug effect by looking at how patients should have done relative to how they did in the trial,\" Dr. Gottlieb says.", "\n\nBut today, when technology is making placebo trials less necessary, he says, the FDA's insistence on them is growing. \"", "Now FDA wants these really pristine, tightly randomized experiments, what I call the perfect experiment . . . ", "clinical trial results that are so mathematically rigorous that they leave absolutely not a shred of a doubt that the magnitude of the benefit that you're observing in the clinical trial is the drug's true benefit. ", "And because they're requiring these kinds of trials, it forecloses the opportunity to give the drug away outside the trial.\"", "\n\nSo how do we fix this problem?", "\n\nAll it takes, Dr. Gottlieb says, is changing one word in the law.", "\n\nRight now, the FDA has all the legal authority it needs under the FDA Modernization Act to approve drugs on the basis of open-label studies. ", "The problem is that it rarely exercises that authority.", "\n\nSo the answer is for Congress to take that discretion away.", "\n\n\"Congress should reaffirm the provisions of the Modernization Act. ", "It should spell out in legislation that the FDA 'shall'—rather than 'may'—approve drugs for severe conditions on the basis of a single study, or a more lenient statistical orthodoxy than 'two, randomized, placebo controlled trials,'\" Dr. Gottlieb says. \"", "You change a single word in the statute and you've made a tremendous amount of difference, you've taken away FDA's discretion to require these ridiculous placebo controlled trials in settings where it doesn't make sense.\"", "\n\nDr. von Eschenbach, the former FDA commissioner, is in complete agreement. \"", "Scott's absolutely right. ", "I mean, there are ways now, different technologies and methodologies that are significantly reducing our dependence on phase III blinded randomization.\"", "\n\nThe fact is that we already know that the regulatory system can function without placebo-controlled trials, because the FDA already does it—in its medical device division. ", "As the _Wall Street Journal_ put it, \"Nobody gets placebo defibrillators in trials.\" ", "If open-label studies are the norm for medical devices, there is no reason why they can't be the norm for medicines as well.", "\n\nNot only would greater reliance on open-label studies increase compassionate access; it would also help drug companies increase participation in clinical trials. ", "If patients knew they were certain they would get the drug and not a placebo, more people would join trials. ", "And, given the choice, most would probably choose a trial over compassionate use—because drugs are expensive and the trial is free.", "\n\nSo again, it is a win-win for drug companies. ", "They get more trial participants and have an even greater incentive to grant early access as well.", "\n\nAnother obstacle to compassionate access is supply. ", "When the drug in question is a small molecule pill or the sponsor is a giant pharmaceutical company, supply is usually not an issue. ", "As one CEO put it, these products have \"a simple manufacturing process where scaling up for a larger volume of patients constitutes a rounding error on overall drug development and manufacturing costs.\"", "\n\nBut for more complex drugs and biologics—especially those produced by small companies operating on shoestring budgets—the companies depend on research-stage manufacturing capacity that typically is supply constrained. ", "Ramping up manufacturing to get more supply during the clinical development phase for compassionate use isn't possible. ", "There simply is no way, this CEO says, to justify \"the cost, resources, and risk in scaling up and preparing to offer a larger volume of drug than is needed for clinical trials prior to knowing if the drug has performed favorably in the pivotal trials.\"", "\n\nIf we want manufacturers to create more supply early in the clinical trial process, then we have to allow them to derive an economic benefit from making the drug available. ", "The simple fact is: these are companies, and money talks. \"", "The most potent incentive is to allow companies to charge for investigational drugs prior to approval,\" says Chris Garabedian, the Sarepta Therapeutics CEO whose company pioneered the Duchenne drug that saved Jenn McNary's son.", "\n\nToday, federal law prohibits companies from making a profit from emerging drugs (though they can recover costs). ", "This means early access is essentially an act of charity—one that many smaller companies on shoestring budgets can rarely afford, especially on a large scale. ", "Allowing companies to charge for investigational drugs would make compassionate use instantly more attractive. ", "For smaller companies operating on shoestring budgets, it might even be a way to help them finance their research and clinical trials.", "\n\nGarabedian says that for-profit compassionate use models already exist. ", "In France, for example, the government has a policy called temporary authorization for use (ATU), which allows companies to provide experimental drugs and charge for them at the expected market price or higher. \"", "The French ATU is widely used, and often the first step for a company to gain access to a market and generate revenues for providing early access,\" he says. \"", "Other countries also allow reimbursement (with profit) prior to approval.\" ", "But the United States does not.", "\n\nWithout the ability to charge for the drug, he says, no CEO could justify creating a large expanded access program to his or her investors. ", "He points out that most drug manufacturers are public companies and that many precommercial pharmaceutical and biotech companies are not yet profitable.", "\n\n\"Investors in these companies have an influence on deployment of capital and the appropriate use of resources,\" Garabedian says. ", "They \"do not want to see unnecessary (read: cash draining activity vs. cash generating activity) initiatives without a tangible link to the market value of the company.\"", "\n\nThis means that \"most CEOs would be criticized by investors and financial media, not hailed, by announcing a broad expanded access program. ", "It would be hard to justify the cost-risk benefit of such an approach.\" ", "As a result, Garabedian says, \"large-scale use and adoption of early access will not occur until we . . . ", "allow a profitable pricing model preapproval as in the case of France's ATU program.\"", "\n\nDr. von Eschenbach would go even further. ", "Rather than charging for treatments, he recommends that the FDA simply allow companies to put drugs out on the market much earlier in their clinical development, with a rigorous system of \"postmarket surveillance\" in place. ", "Once a drug's safety has been established, \"if you allowed the drug to go out on the market when you had less than 100 percent certainty [of efficacy], but you had a really good system of post-market surveillance . . . ", "you can continue to expand the experiential database so that you get closer and closer to certainty. . . . ", "But you don't have to be depriving people of that until you get to that 'I'm 99 percent certain I understand how it works because I forced you to put so many people on the trial and carry it out for such a long period of time that it's obvious as the nose on the end of your face.'\"", "\n\nThis way \"people won't have to wait eight years, they can get it earlier, and it's actually approved and it's actually eligible for compensation and reimbursement. ", "But you still continue to acquire data on its performance and you have the authority to modulate or change your regulatory decision.\" ", "You would end up \"with much broader access and a much more rational economic model for the developer.\"", "\n\nWe asked Dr. von Eschenbach whether what he is proposing is effectively a federal Right to Try with a program of postmarket surveillance attached. ", "Once the drug's safety is established, it would be made broadly available early in the development process to a wide patient population and the company would then continue to collect data to improve it as it went. ", "So the result would be the same—dying patients who currently can't get into trials could now go to their doctors and get the investigational drugs—but with the added benefit that their progress would be monitored and reported to FDA. \"", "That's a fair interpretation,\" he says (though he underscored his belief that the reforms should be made at the federal level).", "\n\nWith the right incentives in place, says Garabedian, smart drug companies would embrace large-scale early access programs. ", "Those who did would benefit over those who did not in a number of important ways.", "\n\nFirst, they would get an edge on the competition. ", "Garabedian says that expanded access would give innovative companies a chance to be the first to get their drugs into the hands of treating physicians. \"", "These are still the ultimate customer who prescribes the drug and it allows the primary customer to get hands-on experience with a drug.\" ", "He says most treating physicians are not involved in clinical trials, or have only a few patients who qualify. \"", "In a competitive scenario, especially with products that are not significantly differentiated, the product that physicians have the most experience [with] and knowledge [of] from their hands-on application of the drug will likely have a huge advantage over [a product from] a company that doesn't widely employ an early access program.\"", "\n\nSecond, Garabedian says, \"early access programs can act as a 'beta test' for what would typically happen in a commercial launch setting.\" ", "Once a product is unleashed in the marketplace, he explains, there is always a significant amount of learning by the company in how the customers interact with the product. \"", "Physicians and patients and caregivers will engage the company with various questions, highlight issues or concerns, and provide general commentary on their direct experience with the product.\"", "\n\nSoftware companies do this every day. ", "They get their product out to a sampling of the intended audience and use the feedback from these early adopters to improve the product and their marketing strategy. ", "By getting new drugs out to medical early adopters through a broad expanded access program, a company can get that kind of feedback and can use these early experiences to improve the product and adjust its marketing strategy.", "\n\n\"This 'beta test' would allow the official launch to have a more successful communications and customer engagement strategy,\" Garabedian says. \"", "Furthermore, this early feedback could have a direct impact on the negotiation of the package insert and label content with regulators.\"", "\n\nThird, Garabedian says, early access would be an opportunity for companies to build goodwill—and thus brand loyalty—in the patient community. \"", "The goodwill that an early access program would generate among the health-care provider community and patient community could be significant,\" he says. ", "Patients and the doctors who treat them will never forget that a particular company fought to get them life-saving drugs in time. ", "This would be especially valuable and attractive to companies that have multiple products in a specific disease area, and \"enable a loyalty and commitment to the company for the long term.\"", "\n\nFourth, Garabedian says, the FDA would benefit. ", "The information generated from wider use of expanded access programs would \"make their jobs easier as it enables more information to consider a drug's approval.\" ", "Regulators \"will get more comprehensive data sooner and more rapid assessments of how any drug would fare to treat a given disease\" that would allow the FDA to approve drugs faster.", "\n\nWith the right economic incentives, he says, \"it seems early access programs should be a win-win for industry and regulators alike.\"", "\n\nSo if companies would benefit, patients would benefit, and even regulators would benefit, why hasn't the FDA taken these and other steps to encourage broader access to compassionate use?", "\n\nBecause, Dr. von Eschenbach says, the FDA has \"a very risk-averse culture.\" ", "He says, \"The mind-set in the FDA is 'My job is first and foremost to protect the public and not let anything bad happen to them—and then, oh, by the way I'm also supposed to promote health.' ", "Well, the truth of the matter is the reverse is really what the charge is. ", "It's to promote and protect the public health. ", "The first reason for the FDA to be there is to promote. ", "And that means—promote means more rapid efficient access to lifesaving drugs and devices.\"", "\n\nUnfortunately, his old colleague Dr. Janet Woodcock, the director of the FDA's Center for Drug Evaluation and Research, disagrees. ", "Asked what the FDA is doing to speed drug development, Dr. Woodcock says, \"It's not about speed.\"", "\n\nBut if you are dying and waiting for a drug, it _is_ about speed.", "\n\n\"I don't agree, okay?\" ", "she says. \"", "I'm a doctor. ", "If I were dying I'd want—it's about quality. ", "Okay? ", "If I was going to try something I'd want to know it had a chance of helping me, right? ", "There are tons of quacks out there.\"", "\n\nShe points out that most emerging drugs fail. \"", "Eight out of ten times they probably wouldn't help because they'd be either too toxic or it wouldn't work,\" she says.", "\n\nThis is not entirely accurate. ", "While only about 20 percent of drugs that make it out of phase I and into phase II trials are eventually approved, according to the FDA about 60 percent of drugs in phase III trials do eventually succeed. ", "For a terminally ill patient with 100 percent chance of dying, access to a drug with a 20 to 60 percent chance of success is a big improvement. ", "Most dying patients would gladly take a 10 percent, or a 5 percent, or even a 1 percent chance—anything above zero.", "\n\nMoreover, doctors, patients, and patients' advocates are not stupid. ", "They are not choosing drugs by throwing darts at a wall. ", "Patients meticulously research the various treatments that are in clinical development. ", "Doctors carefully study the results of clinical trials. ", "They know which drugs are promising and which ones are not.", "\n\nFrank Burroughs of the Abigail Alliance points out that \"every drug for cancer and other serious life-threatening illnesses that we pushed for earlier access to, earlier approval of, every drug is now approved by the FDA. ", "There's not one drug we've pushed for earlier approval of that would not be able to make it through the clinical trial process.", "\n\n\"I think you call that batting a thousand,\" he says.", "\n\nDying patients are not looking for a 100 percent guarantee the drug is effective. ", "They are looking for hope. ", "They are looking for a fighting chance.", "\n\nUnfortunately, getting them that chance requires pressure—and sometimes it requires harnessing the power of shame. ", "Former secretary of defense Donald Rumsfeld—the former head of G. D. Searle and chairman of Gilead Sciences—says shame is a powerful motivator. \"", "People don't succeed in government by being anything other than risk averse. ", "But risk-aversion tends not to include the shame factor,\" he says. \"", "Shame is a killer. ", "People don't like to be shamed. ", "They don't like to look like jackasses even though their conduct results in jackass outcomes.\"", "\n\nToday, social media have empowered patients to fight for themselves and draw attention to \"jackass outcomes\"—like the ones experienced by Mikaela Knapp, Kianna Karnes, Nick Auden, Andrea Sloan, Diego Morris, Austin McNary, and countless other Americans fighting to save their lives.", "\n\nMoreover, social media are disrupting and democratizing the drug development and approval process. ", "It used to be that drug development was a closed ecosystem, in which drug companies and the FDA had a monopoly on information. ", "Parents in clinical trials didn't know each other, they could not compare stories of how they or their children were responding, and so they had no idea how a clinical trial was progressing.", "\n\nToday, thanks to social media, if a trial is working, the word spreads at the speed of Facebook. ", "Indeed, patients sometimes know that a drug is working before the drug companies do. ", "Chris Garabedian says the first time he had an inkling that Sarepta's drug eteplirsen was working was when Jenn McNary came up to him at the Duchenne conference and told him her son was getting better and demanded the drug for her other son. ", "She was online sharing that information with other Duchenne moms, who were telling similar stories. ", "The data later confirmed what the moms already knew thanks to the power of social media.", "\n\nWhen patients and parents know a drug is working, they are not going to sit back and wait for years for the FDA to satisfy itself with near–100 percent certitude about the efficacy of a drug. ", "Patients are demanding action. ", "They are demanding speed. ", "They are demanding access. ", "They are demanding the Right to Try.", "\n\nIn Europe, Ronald Brus has found a way to meet this demand, by creating an online clearinghouse that provides physicians and patients who are excluded from clinical trials access to drugs in development.", "\n\nBrus was the CEO of Crucell, a Netherlands-based biotech company that produced revolutionary vaccines, when his father came down with inoperable lung cancer. ", "He says, \"Being at the heart of the industry I felt that I could fix that, right?\" ", "So he called several people in the United States and asked whether they had any new, cutting-edge drugs for lung cancer. ", "They said yes, but he found it was impossible to get those innovative treatments to his father. ", "Here he was, the CEO of a major biotech company—a leader in his industry, with twenty-five years in drug development—and even _he_ could not get access to the experimental drugs he needed to save his father. ", "Before his father died, he promised him he would change that.", "\n\n\"Like my dad, there's about over a million people a year that basically hear from the doctors that there's no treatment option left. ", "And what they basically mean is that in their toolbox that's approved there's nothing left,\" he says. \"", "But if you assume that the next iPhone is better than the iPhone that you currently have . . . ", "you know that there is something in the pipeline that might be much better.\"", "\n\nHe sold his company, Crucell, to Johnson & Johnson for about $3 billion and together with other European biotech entrepreneurs started a new company called myTomorrows. ", "Brus describes myTomrrows as an iTunes for investigational drugs and treatments. ", "His company builds bridges among patients, doctors, and drug developers. ", "Doctors and patients can go to his site and find out what drugs are in development for a particular disease, how many patients are using them, and how they rate them. ", "Then myTomorrows helps facilitate requests for permission from governments in Europe for early access for physicians and pharmacists.", "\n\nBrus is creating an economic model through which patients can benefit, and drug manufacturers can profit, from early access. \"", "We are active in every country in Europe already,\" he says. ", "Now he wants to bring his model to America—and he thinks that he will eventually be able to do so because of the pressure from the Right to Try movement.", "\n\n\"Because of Right to Try there's pressure on the system and the FDA needs to bend,\" he says. \"", "It's like what Uber did to the cab world is put pressure on the system and say, 'Hey guys, the system was intended to protect patients but it became a system that just protects the establishment and is harmful to patients.'\"", "\n\nThe FDA is going to have to deal with the growing demand for investigational treatments. ", "It is going to have to accept that the information age is disrupting the model of drug development to which it and the drug companies have grown accustomed. ", "It is going to have to change its model or face a grassroots revolution that will change the model for it.", "\n\n\"We have to deal with it,\" says Dr. Woodcock. \"", "But people always say stuff like this but you have to realize that the drug development process is basically a scientific evaluation process, that's what it is. ", "It's not a vote.", "\n\n\"Everyone in the world who talked to each other four hundred years ago believed the world was flat; it didn't mean it was flat,\" she says. \"", "So science is different. ", "The scientific process is not changing.\"", "\n\nThe FDA right now is in resistance mode. ", "It sees those seeking earlier access and faster approval as \"flat-earthers\" and believes its job is to defend the scientific process against the onslaught. ", "It sees patients, parents, and advocates as a challenge to be managed. ", "It meets with them regularly and has them \"testify\" before its committees. ", "But while it \"listens\" to patients, too often it does not hear—and does not act.", "\n\nThat is going to have to change.", "\n\nThe truth is that today the FDA pays lip service to compassionate use but does not really support it. ", "When asked if it would be a good thing if hundreds of thousands of people were receiving investigational medicines on a compassionate basis, Dr. Woodcock sighs and says: \"Well, it would be another burden on the health-care system.\"", "\n\n\"Another burden.\"", "\n\nThat is how FDA sees dying patients seeking compassionate access to drugs?", "\n\nThese patients are not a \"burden.\" ", "They are human beings. ", "They are also American citizens. ", "The FDA works for them. ", "It is the FDA's job to help patients get access to drugs that could potentially save their lives.", "\n\nDoes Dr. Woodcock believe dying patients have the Right to Try?", "\n\n\"As I said, eight out of ten times [the drugs] probably wouldn't help because they'd be either too toxic or [they] wouldn't work. ", "However, for those individuals who wanted to try something, definitely. ", "We shouldn't look people in the face and say, 'Okay, you're dying and we have nothing to offer you' if there's something they could try.", "\n\n\"I believe that it's only fair that if you have a fatal disorder you should be able to try. ", "We, the federal government, shouldn't stand between people who are dying and treatments they think could help them. ", "That's what I believe,\" she says.", "\n\nThe FDA claims that it doesn't stand in the way of dying Americans' getting access. ", "We have seen how, in a myriad of ways, it does. ", "But \"not standing in the way\" is not good enough.", "\n\nThe bigger problem is that the FDA won't _fight_ to get them access.", "\n\nIf their own government won't fight for them, we will.", "\n\n# 8.", "\n\nWould You Use a Fifteen-Year-Old Cell Phone?", "\n\n_How to Get American Medicine Back on Top_\n\nDo you remember what your cell phone looked like fifteen years ago? ", "It was a big hunk of plastic with a large stub antenna, a black-and-white display, no camera, no video, no keyboard, no email, no text messaging, no Internet connection, no GPS, no apps, no music, and almost no memory.", "\n\nIf you showed it to your kids today, they would laugh and ask, \"Did people really use those?\"", "\n\nWell, if you wouldn't use fifteen-year-old cell phone technology to make a call today, why should you be forced to depend on fifteen-year-old medical technology to save your life?", "\n\nBecause that is exactly what you are getting when you put the latest FDA-approved drugs into your body.", "\n\nIn an age when the speed of technological innovation is accelerating in almost every aspect of our lives, the time it takes to bring a new drug from the laboratory to the pharmacy shelf has nearly doubled over the last five decades. ", "It now takes, on average, nearly fifteen years to bring a new drug to market.", "\n\nThis is not the fault of scientists. ", "As we have seen, they are pioneering incredible cures and treatments for diseases from ALS to muscular dystrophy that were once unimaginable. ", "No, the problem lies not with the innovators but with the regulators.", "\n\nToday, instead of speeding medical innovation, the government is routinely slowing it down—demanding more data, more tests, and more procedures on more subjects before it will approve a drug. ", "Clinical trials are getting longer, larger, and more complex. ", "As a result, the cost of developing new drugs is skyrocketing, while the time it takes to get these drugs to dying patients is slowing. ", "Even FDA commissioner Margaret Hamburg admitted in 2010, \"We are left relying on 20th century approaches for the review, approval and oversight of the treatments and cures of the 21st century.\"", "\n\nWhat do you think your iPhone would look like if it had to go through the same regulatory process as medical treatments? ", "Answer: you would not have an iPhone.", "\n\nToday, doctors and scientists routinely come up with novel ways to treat diseases only to run into delays at the FDA.", "\n\nHERE IS WHAT THE Obama administration says. ", "In September 2012 the President's Council of Advisors on Science and Technology (PCAST) issued its \"Report to the President on Propelling Innovation in Drug Discovery, Development and Evaluation.\" ", "The report found:\n\nEvidence indicates that the time and cost for conducting clinical trials of new drug candidates is rising. ", "Over the past 50 years, the time from drug discovery to drug approval has nearly doubled from 8 years in the 1960s to roughly 14 or more years now. ", "More recently, some experts conclude that the time required for drug development (from patent filing to commercialization) has increased from an average of 9.7 years for drugs launched during the 1990s to an average of 13.9 years for drugs launched since 2000.", "\n\nFactors include the increasing complexity of clinical trial protocols, including the procedures to be applied, the growing difficulty of recruiting and retaining patients that meet the criteria for clinical trials, the administrative burdens of setting up clinical trials, and increasing regulatory requirements for clinical trials in particular areas.", "\n\nThe report also notes that these anti-innovation policies disproportionately affect small companies:\n\nWhile the factors above are important to all innovators, they may be especially important to small biotechnology companies. ", "When the FDA determines that the available evidence is inadequate to support approval and that additional studies are required, a large pharmaceutical firm with many products in its pipeline can accommodate the delay more readily than a small biotech firm. ", "Small firms often have only a single drug under development. ", "Because such companies have no commercial sources of revenue to support their high \"burn rate,\" a two-year delay in drug approval can be a death knell.", "\n\nThe FDA denies that it is to blame.", "\n\n\"My analysis which I have pursued over many years is that the FDA is really not at the heart of this problem,\" says Dr. Janet Woodcock, the FDA's director of drug evaluation. ", "The FDA, she insists, is approving new drugs and treatments at a record pace.", "\n\nWriting in the newspaper _The Hill_ in April 2015, Dr. Woodcock and Dr. Karen Midthun, director of the FDA Center for Biologics Evaluation and Research, claimed that the FDA had achieved \"drastic reductions in the time it takes the agency to review new drugs.\" ", "They claimed that the \"FDA consistently reviews new drugs faster than all other advanced regulatory authorities around the world, including the European Medicines Agency.\"", "\n\nAs evidence of the FDA's supposed speed, Drs. ", "Woodcock and Midthun point to an FDA report, \"Novel New Drugs 2014 Summary,\" which claims that the agency \"approved a majority of the novel new drugs of 2014 (32 of 41, 78%) on the 'first cycle' of review, meaning without requests for additional information that would delay approval and lead to another cycle of review.\" ", "In each case, the FDA claims, the drugs were \"approved\" in a matter of months.", "\n\nThis is deeply misleading. ", "To understand why, imagine for a moment that you need to apply for a mortgage and there is only one bank in the entire world that can give it to you. ", "So you go to the bank and tell it you want to apply for a loan. ", "It says it needs you to go back and collect all your financial data. ", "So you collect all the information it wants, come back, and give it to the bank. ", "A few months later, it comes back and says: we need more data. ", "So you go back, collect the data it wants, and give it to the bank. ", "Then a few months later, it says: we need even more data. ", "You give it to the bank. ", "Then imagine the process repeats itself—over, and over, and over—until almost a decade has gone by. (", "There are no other banks you can go to, so you have no choice but to deal with this one bank.)", "\n\nThen one day the bank finally says: Okay, we have all the information we need, you can file your loan application. ", "So you file the application, and a few months later, the bank approves it.", "\n\nAnd the bank says: See how fast we are! ", "We approved your loan in just a few months!", "\n\nYou say: Are you kidding me? ", "We started this process nine years ago!", "\n\nThat is what the FDA is doing when it comes to drug approvals.", "\n\nA drug sponsor comes to the FDA and says: We have a new drug and we want to move from the lab into human trials. ", "The FDA asks for data from laboratory testing and, if it is promising, it allows the sponsor to begin to file what is called an Investigational New Drug (IND) application and start the clinical trials. ", "Then, as the trials go along, the FDA continues to demand more and more data each step of the way. ", "And the drug sponsor keeps producing it—waiting for the invitation from the FDA to file the NDA. ", "This process takes many years—sometimes a decade or more.", "\n\nThen, one day, the FDA finally says: Okay, we have all the data we need, you can file a new drug application. ", "The sponsor files the application and a few months later, the FDA approves it.", "\n\nAnd the FDA says: See how fast we are! ", "We approved the drug in just a few months!", "\n\nIn fact, the process took years.", "\n\nHere is a real-life example of how misleading the FDA's statistics are. ", "Remember the story in chapter 1 about Jenn McNary's fight to get the FDA to approve eteplirsen, the Duchenne muscular dystrophy drug her son, Austin, desperately needs? ", "The FDA kept playing \"Lucy with the football\" with the drug company, Sarepta Therapeutics. ", "For three years, the company kept providing the agency with data showing the drug was safe and effective. ", "And for three years, the FDA kept promising Sarepta it could apply for an NDA—only to pull back the invitation and demand more data. ", "As of April 2015, Sarepta was still waiting for the green light to submit its new drug application to the FDA.", "\n\nThat means, by the FDA's standards, the approval clock for eteplirsen _hadn't even started yet_.", "\n\nDoes anyone think the clock has not started for Jenn McNary? ", "Her son Austin has been waiting _for years_ to get access to the drug. ", "For him, the clock has been ticking and ticking and ticking, while his condition has been declining and declining and declining.", "\n\nEteplirsen is not unique. ", "Indeed, many of the FDA's most celebrated success stories of drugs it says were \"approved\" in a few months' time have in fact taken years.", "\n\nHere are seven examples of drugs the FDA claims it approved in 2014 under \"accelerated approval.\" ", "In each case, the FDA claims it approved the drugs a matter of months. ", "In each case, we went back into the FDA records and calculated the _actual_ time it took to approve the drug from the filing of an IND application to final approval:\n\n******• OPDIVO—** a drug to treat patients with unresectable (cannot be removed by surgery) or metastatic (widely spread) melanoma who no longer respond to other drugs.", "\n\n_FDA claimed approval time: 4 months, 22 days_\n\n_Actual approval time: 8 years, 5 months, 23 days_\n\n**• LYNPARZA—** a drug to treat advanced ovarian cancer.", "\n\n_FDA claimed approval time: 10 months, 16 days_\n\n_Actual approval time: 8 years, 3 months, 27 days_\n\n**• BLINCYTO—** a drug to treat patients with Philadelphia chromosome-negative precursor B-cell acute lymphoblastic leukemia (B-cell ALL).", "\n\n_FDA claimed approval time: 2 months, 14 days_\n\n_Actual approval time: 8 years, 3 months, 15 days_\n\n**• KEYTRUDA—** a drug for treatment of patients with advanced or unresectable melanoma who are no longer responding to other drugs.", "\n\n_FDA claimed approval time: 9 months, 13 days_\n\n_Actual approval time: 4 years, 8 months, 25 days_\n\n**• ZYDELIG—** a drug to treat patients with three types of blood cancers.", "\n\n_FDA claimed approval time: 10 months, 12 days_\n\n_Actual approval time: 5 years, 6 months, 22 days_\n\n**• BELEODAQ—** a drug to treat patients with peripheral T-cell lymphoma (PTCL).", "\n\n_FDA claimed approval time: 6 months, 24 days_\n\n_Actual approval time: 9 years, 7 months, 18 days_\n\n******• ZYKADIA—** a drug to treat patients with a certain type of late-stage (metastatic) non-small-cell lung cancer (NSCLC).", "\n\n_FDA claimed approval time: 4 months, 5 days_\n\n_Actual approval time: 3 years 6 months, 21 days_\n\nIn other words, the FDA's claims are grossly inaccurate.", "\n\nAnd all these are cancer drugs, which are among the fastest drugs to be approved. ", "The Neurological Division—the division reviewing Sarepta's Duchenne drugs—has not approved a single drug under accelerated approval since 2004, more than a decade.", "\n\nSo what can be done to speed the drug development and approval process? ", "Here are a few ideas.", "\n\nONE SIMPLE REFORM WOULD be to make it easier, not harder, for drug companies to get follow-on drugs approved.", "\n\nIn theory, once Sarepta gets FDA approval for its first exon-skipping drug, eteplirsen, that should logically pave the way for the speedy approval of Sarepta's follow-on Duchenne drugs—all of which are built around the same core technology.", "\n\nAll Sarepta's Duchenne drugs use the same chemical backbone, which acts as the delivery vehicle that sends genetic information to the cell. ", "In eteplirsen, scientists attach genetic information that instructs the cell to skip exon 51—which affects about 13 percent of Duchenne sufferers. ", "But scientists can just as easily attach different genetic information to the same chemical backbone, instructing the cell to skip other missing exons.", "\n\nSo once the first drug using this chemical backbone is approved, logic dictates that the follow-on drugs based on the same chemical backbone should speed through FDA approval, right? ", "If it works on exon-51, the exon Max and Austin McNary are missing, it should work on exon-53, the exon Jordan McLinn is missing.", "\n\nIn practice, that is not how FDA approval works. ", "Rather than making it easier to approve follow-on therapies, the agency often makes it harder and harder for each subsequent drug to get to market.", "\n\nAnd those delays have a terrible human price.", "\n\nThis is precisely what happened when the FDA considered new drugs targeting MPS diseases (mucopolysaccharidoses)—a cluster of terrible genetic disorders that cripple, and often kill, children. ", "Children with MPS diseases are born without the ability to produce enzymes that break down certain complex molecules in the body. ", "These molecules then accumulate in cells and tissues in places like the heart, brain, liver, joints, respiratory system, and central nervous system—disfiguring, debilitating, and eventually killing the children. ", "The diseases—including Gaucher, Hunter, and Pompe—are extremely rare, each with only a few thousand victims.", "\n\nWriting in _National Affairs_ , Dr. Scott Gottlieb, a former FDA deputy commissioner and a scholar at the American Enterprise Institute, explains that in the early 1990s, the first treatments for MPS diseases began to emerge as drugs were developed that could function as replacements for the missing enzymes.", "\n\nThe first drug, Ceredase, was designed to treat an MPS disorder called Gaucher disease, which kills most affected children before the age of five.", "\n\n\"Ceredase was approved by the FDA in 1991 on the basis of a single, six-month study of 12 patients,\" Dr. Gottlieb says. \"", "When regulators saw that the [abnormally enlarged] livers and spleens of these patients were shrinking, the FDA took it as evidence that the replacement enzyme was having its intended clinical benefit. ", "If the FDA had required statistically significant evidence that the drug enabled patients to function better or live longer, rather than settling for proof that it addressed the physical markers of the disease, the trial could have taken several years.", "\n\n\"But given the severity of the disease, as well as the absence of alternative treatments, the agency opted to approve Ceredase once the drug's safety was clearly established.\"", "\n\nIt was a good-news story. ", "The FDA acted with speed to save dying children suffering from a rare, debilitating, and deadly illness with no other available treatment or cure.", "\n\nIt was an example of government working as it should.", "\n\nFast-forward a decade. ", "Encouraged by both the success and the rapid approval of Ceredase, scientists and manufacturers have developed similar treatments for other MPS diseases. ", "They reasonably expected that each subsequent approval would be easier and faster. ", "After all, when the FDA approved Ceredase for Gaucher disease, it did not know whether or not restoring the missing enzyme was going to have a therapeutic effect. ", "But now, after years of treatment, doctors were certain that if you give the enzyme to MPS patients, and the enzyme stays in the blood, the patients are going to experience a therapeutic effect, slowing or even stopping the advance of the disease.", "\n\nSo most people in the MPS community expected that approving the next round of enzyme-replacement drugs would be easier, not harder.", "\n\nThey were wrong.", "\n\nInstead of speeding approval as follow-on drugs were developed, the FDA suddenly put on the brakes—holding up approvals while requiring larger, more complex, and more rigorous clinical trials.", "\n\nIn the early 2000s, Elaprase, a drug for another MPS condition called Hunter's syndrome, was discovered. ", "But instead of requiring a six-month twelve-patient trial, as it had for Ceredase, this time the FDA required a yearlong trial that involved ninety-six patients with Hunter's disease—which, Dr. Gottlieb says, amounted to \"some 20 percent of all Americans afflicted with the disease.\"", "\n\nIt was an exceptionally high number.", "\n\nBut the story gets worse. ", "Not only did the FDA require an unreasonably large trial, but \"for the first time in such a study of enzyme-replacement therapy, the FDA also insisted that patients be randomly assigned to receive either the experimental drug or an inert placebo,\" Dr. Gottlieb says.", "\n\nThat meant many families were traveling hundreds of miles in the hope that the drug would save their children from a debilitating disease—but were getting nothing more than sugar water.", "\n\nThis was not only cruel, Dr. Gottlieb says; it was scientifically unnecessary.", "\n\n\"The course of Hunter syndrome is well documented, and follows a very regular pattern in most afflicted children; the results for patients who got the experimental therapy could easily have been compared against readily available historical databases that track the normal course of the disease. ", "It is hard to see why a placebo was necessary in such circumstances, especially when the requirement for a placebo group meant that some of the kids involved wasted a full year of the most able portion of their short lives effectively going untreated.\"", "\n\nA decade earlier, the FDA had approved Ceredase as soon as it saw that the enlarged livers and spleens of the patients were shrinking, which it accepted as evidence that the replacement enzyme was working.", "\n\nIn the case of Elaprase, it had this same evidence that the drug was working eighteen weeks into the trial. ", "According to _Science Daily_ , \"Liver and spleen size decreased by more than 20 percent after 18 weeks of treatment in both groups that received Elaprase, whereas liver size remained unchanged and spleen size increased in the placebo group.\"", "\n\nBut instead of using that data to quickly approve the drug, the FDA insisted on letting the trial go on for a year, so it could wait to see whether the patients on the drug walked farther than patients on the placebo.", "\n\nThey did. ", "When the FDA finally approved Elaprase in July 2006, the agency boasted in its news release that \"patients who received Elaprase infusions experienced on average a 38-yard greater increase in the distance walked in six minutes compared to the patients on placebo.\"", "\n\nWhat it failed to mention was that the kids on the placebo were crippled. ", "After a year, many couldn't walk and their breathing had declined. ", "Even if they were eventually moved onto the drug, they would never regain all the function they had lost that year.", "\n\nThese were kids!", "\n\nThe FDA could have enrolled one hundred kids in an open-label study, given everyone the drug, and compared the results with historical databases for Hunter's disease. ", "Instead it knowingly allowed a group of children to lose their ability to walk and breathe.", "\n\nNone of this was to establish the safety of the drug. ", "It was all done, Dr. Gottlieb says, \"in an effort to satisfy an increasingly unreasonable hunger for statistical certainty on the part of the FDA.", "\n\n\"The story of the Elaprase trial is important not because it stands out as an exception,\" Dr. Gottlieb continues, \"but rather because it is increasingly characteristic of the FDA's drug-review culture. ", "That culture is the product of a poorly understood, but now well-established, attitude within the agency: an excessive desire for certainty . . . [", "that] is impeding the availability of safe, effective drugs that could today be helping real patients.\"", "\n\nToday, Dr. Gottlieb says, \"there are currently no new treatments in clinical development for Hunter syndrome.\" ", "Why? ", "He says, \"Potential new drug developers have looked at the conditions the FDA attached to the Elaprase trial and similar development procedures, and they have determined that any future studies would take too long and cost too much. ", "Even drug makers looking at developing 'biosimilar' copies of existing drugs have so far reasoned that the process would be infeasible.\"", "\n\nEven the original MPS drug—Ceredase—has not escaped the FDA's ever-increasing demands for statistical certainty. ", "In 2010, when the FDA reviewed an upgraded version of the drug, Dr. Gottlieb says, \"the agency required the drug to be tested in ninety-nine patients. ", "It also wanted the drug (named VPRIV) to be tested in some patients who had not received any prior treatment for their disease. ", "Given the availability of Ceredase, finding these 'treatment naïve' patients was no easy feat: Most people with the disease were already being treated. ", "To find enough patients who had never been treated for the disorder required an enormous, and expensive, multiyear search that has delayed access to the medicine.\"", "\n\nBased on this experience, anyone who thinks that once the FDA approves eteplirsen—Sarepta's drug for Duchenne patients missing exon 51—the agency is going to speed the approval of Sarepta's follow-on exons is likely in for a rude awakening.", "\n\nUnfortunately, this trend is not limited to MPS drugs. ", "The FDA is demanding more and more data, and requiring greater and greater statistical certainty, before it will approve a drug.", "\n\nAs a result, trials are getting larger, longer, and more complex.", "\n\nAccording to Kenneth Getz of the Tufts Center for the Study of Drug Development, in 2012 a typical phase III trial saw an average of 170 procedures performed on each study volunteer over 230 days. ", "Ten years earlier, the same trial required just 106 procedures over the course of 187 days. ", "That is a more than 60 percent increase in the number of procedures and a 23 percent increase in trial duration.", "\n\n\"Without exception we've seen a dramatic increase in the scope and demands of the study,\" Getz recently explained at a conference on reforming clinical trials. \"", "The total number of end points has nearly doubled. . . . ", "Total number of eligibility criteria has nearly doubled. . . . ", "If you just look at the volume of data that we're collecting for a typical phase III trial today, we're approaching a million data points. . . . ", "With every one of those data points that has to be monitored and source data verified.\"", "\n\nWhy are trials taking longer and getting more complex? ", "Drug manufacturers fear that \"failure to [follow FDA protocols] could potentially delay regulatory submission, product launch and product adoption,\" Getz says. ", "The result is \"higher development costs, longer study durations, and more protocol deviations and amendments.\"", "\n\nAgain, almost none of this is done in the name of safety. ", "It is in the name of guaranteeing efficacy. \"", "What the FDA is doing is reflecting societal values,\" says Dr. Janet Woodcock, director of the FDA Center for Drug Evaluation and Research, in an interview.", "\n\nDr. Woodcock points out that eight out of ten drugs fail and asks what people would say if the agency had let those drugs through. ", "Imagine, she says, \"if people who build bridges . . . ", "or skyscrapers, if they built them and eight out of ten times they fell down. ", "That would not be good.\"", "\n\nBut the difference is that a normal person walking across a bridge expects it to work 100 percent of the time. ", "A patient dying of ALS or cancer or some other terminal illness is not asking the FDA for a 100 percent guarantee.", "\n\nShe's asking for a _chance_.", "\n\n\"We get that,\" Dr. Woodcock says.", "\n\nBut really the FDA doesn't.", "\n\nWhen someone has a terminal illness and has no other options, he will gladly take a drug with a 50 percent chance of 20 percent effectiveness, over the 100 percent chance that he will die without the drug.", "\n\nBut Dr. Woodcock protests, \"If you want a 50 percent certainty that means half the drugs on the market wouldn't work. ", "Insurance companies would be paying for them, Medicare would be paying for them, they wouldn't work.\"", "\n\nThis is what the FDA does not seem to get: dying Americans are willing to take that risk.", "\n\nIt can't seem to distinguish between cough medicine and a treatment for a terminal illness. ", "When it comes to cough medicine, the FDA can take all the time in the world. ", "No one is going to die. ", "But when it comes to people with terminal illnesses, the FDA's often irrational quest for certainty is deadly.", "\n\nANOTHER REFORM THAT IS needed is to put an end to the situation in which Americans like Diego Morris have to go to Europe to get a safe and effective drug that is not available here in America—by making drug approvals reciprocal, so that drugs approved in Europe are automatically available here.", "\n\nIt is not just cancer patients who face this dilemma.", "\n\nIdiopathic pulmonary fibrosis (IPF) is a fatal lung disease with no known cure. ", "According to the National Heart, Lung, and Blood Institute, the \"tissue deep in your lungs becomes thick and stiff, or scarred, over time. . . . ", "As the lung tissue thickens, your lungs can't properly move oxygen into your bloodstream. ", "As a result, your brain and other organs don't get the oxygen they need.\"", "\n\n\"This disease is deadlier than 60 to 70 percent of malignancies,\" says Dr. Daniel M. Rose, chief executive of the Pulmonary Fibrosis Foundation.", "\n\nMost people live only three to five years after diagnosis.", "\n\n\"They suffocate from their lungs filling up with Jell-O,\" Dr. Paul W. Noble, an IPF expert at Duke University, told an FDA advisory committee.", "\n\nThere were no effective treatments for IPF until a drug company named InterMune developed a breakthrough therapy called pirfenidone (Esbriet) that reduces the scarring in the lungs and thus extends life. ", "It was approved by the FDA in October 2014. ", "The FDA hailed the approval in a press release, declaring the decision as evidence that \"[w]e continue to help advance medication therapies by approving products that treat conditions that impact public health.\"", "\n\nIn fact, it is evidence of the opposite.", "\n\nIn March 2010 four years and seven months earlier, an FDA advisory panel had recommended approval of pirfenidone, but the FDA rejected the drug.", "\n\nThere were three clinical trials done examining its safety and effectiveness—two in the United States and one in Japan. ", "One of the US trials showed the drug worked by a statistically significant margin, as did the Japanese trial. ", "The second US trial just barely missed statistical significance, but the FDA advisory panel realized it was because of a flaw in the trial. ", "Weighing the evidence of effectiveness, the safety data, and the unmet medical need, the panel voted overwhelmingly, 9 to 3, to recommend the drug for approval.", "\n\nBut the FDA rejected the drug. ", "The agency said it needed two trials showing effectiveness. ", "It had two trials, but it would not accept the Japanese trial—because all the patient-level case reports were in Japanese. ", "So even though the drug targeted a huge unmet medical need, even though there were two studies confirming its effectiveness, and even though its own advisory committee said it believed the data, the FDA refused to make the drug available—withholding an effective treatment that was desperately needed by approximately 100,000 patients with IPF. ", "It demanded that the company conduct yet another trial.", "\n\nThere was no doubt about the general safety of pirfenidone. ", "The FDA wasn't protecting anyone. ", "Quite the opposite: its delays were consigning many desperate patients to certain death.", "\n\nOn February 28, 2011, after looking at exactly the same data, the European Medicines Agency (EMA) approved the drug for use in all twenty-eight EU member states. ", "The following year, on October 1, 2012, Health Canada approved pirfenidone based on the same data. ", "And it has been approved for use in Japan since October 16, 2008.", "\n\nAfter its European approval, the drug took off across the Continent. ", "By 2012, 42 percent of all respiratory specialists in Europe were using pirfenidone as first-line treatment for newly diagnosed IPF.", "\n\nBut the FDA did not finally approve the drug until October 15, 2014.", "\n\nThat means the FDA needlessly withheld the drug from dying Americans for three years and eight months after the European Medicines Agency approved it. ", "It withheld it from dying Americans for two years after Health Canada approved. ", "It withheld it for four years and seven months after its own advisory committee voted overwhelmingly to approve it.", "\n\nTo understand the human costs of that decision, consider: About 40,000 Americans die each year of IPF. ", "That means an estimated 183,000 Americans lost their lives while the FDA was withholding the only known treatment for this disease.", "\n\nThat should never have happened. ", "And there is a simple solution to make sure it never happens again: The United States should institute a policy of regulatory reciprocity with countries that have a proven record of approving safe and effective drugs—including the European Union, Canada, Japan, and Australia.", "\n\nAs Dr. Tom Coburn—a physician, former US senator, and scholar at the Manhattan Institute's Project FDA—explains, \"We ought to say if it's approved in the European Union, its approved here. ", "If it's approved in Japan it's approved here. ", "That would markedly lower costs and markedly increase availability of new drugs and new devices.\"", "\n\nAs Dan Klein and Alex Tabarrok, two economists at George Mason University, explain, \"Such an arrangement would reduce delay and eliminate duplication and wasted resources. ", "By relieving itself of having to review drugs already approved in partner countries, the FDA could review and investigate NDAs more quickly and thoroughly.\"", "\n\nOf course, the FDA does not see it that way. ", "The agency resists the idea of reciprocity because, according to Manhattan Institute scholars Paul Howard and Yevgeniy Feyman, \"if access to the large and lucrative U.S. market could be obtained by going to the EMA rather than the FDA, there might be a mass exodus of drug applications to the E.U.\"\n\nBut that is precisely why we need reciprocity. ", "If FDA officials know that drug companies can go to the EMA instead, they will be more reasonable and rational in their decision making.", "\n\nDoes anyone think that if FDA officials knew that InterMune could simply go to the EMA to get reciprocal approval of pirfenidone, the agency would have overturned its own advisory panel's recommendation and rejected it in 2010? ", "That's unlikely. ", "Many thousands of lives could have been saved.", "\n\nJoe DiMasi and Christopher-Paul Milne of the Tufts Center for the Study of Drug Development, and Alex Tabarrok of George Mason University, shed some light on the FDA's culture in their 2014 _FDA Report Card_ :\n\nThe FDA faces asymmetrical incentives. ", "Damage can occur when bad drugs are approved quickly or when good drugs are approved slowly. ", "However, the cost to the FDA of these two outcomes is not the same. ", "When bad drugs are approved quickly, the FDA is scrutinized and criticized, victims are identified, and their graves are marked. ", "In contrast, when good drugs are approved slowly, the victims are unknown. ", "We know that some people who died would have lived had new drugs been available sooner, but we don't know which people. ", "As a result, premature deaths from drug lag and drug loss create less opposition than deaths from early approval, and the FDA's natural stance is one of deadly caution.", "\n\nSam Kazman, general counsel of the Competitive Enterprise Institute, says that even the victims of FDA delays usually don't realize their own government's culpability. \"", "All they know is that their doctors told them that nothing more could be done to help them. ", "Only a fraction of these people will understand the reason for this—namely, that a useful drug was bottled up at FDA. ", "Unlike in the first scenario, these people do not realize that they too are victims of FDA mistakes. ", "Their suffering or death is simply viewed, by them and others, as reflecting the state of medicine rather than the status of an FDA drug application.\"", "\n\nFormer FDA commissioner Alexander M. Schmidt once told Congress, \"In all of FDA's history, I am unable to find a single instance where a congressional committee investigated the failure of FDA to approve a new drug. ", "But, the times when hearings have been held to criticize our approval of new drugs have been so frequent that we aren't able to count them. . . . ", "The message to FDA staff could not be clearer.\"", "\n\nReciprocity would create a countervailing set of incentives to speed drug approvals. ", "If the FDA did not improve its regulatory process, manufacturers could simply go to Europe, Canada, Australia, or Japan to get their drugs approved.", "\n\nCritics say this might create a race to the bottom, with agencies lowering standards to attract applications and the application fees that come with them. ", "But the fact is there are plenty of ways to protect against this. ", "For example, as Paul Howard and Yevgeniy Feyman explain, \"Reciprocity could be limited to our highly developed trading partners, and to well-understood drug classes or products where there is a high unmet need, like cystic fibrosis or the myriad cancers that don't respond well to available therapies.\"", "\n\nMoreover, as Dr. Henry I. Miller, the founding director of the FDA's Office of Biotechnology and a fifteen-year agency veteran, points out, \"Reciprocity could be achieved, for example, simply by giving the FDA a finite period of time (say, 60 days) from the date of an EU, Japanese or Canadian approval to show cause why a product should not be approved. ", "In the absence of such evidence from the FDA (which would carry the burden of proof), the drug would be approved automatically.\"", "\n\nFurther, no regulatory agency—whether in Europe, Australia, Japan, or the United States—is going to grant approval to any drugs that have not passed phase I safety testing. ", "So the question is not one of lowering the bar on safety. ", "Rather it is how to get regulators to give promising drugs to patients facing terminal illnesses faster, without wasting years seeking near-perfect assurance of efficacy.", "\n\nThe FDA routinely drags its feet on the approval of drugs that are approved in Europe and advanced non-European countries. ", "We saw this in 2013 and 2014, when several American college campuses experienced meningitis B outbreaks. ", "According to the Meningitis Research Foundation, meningitis B \"leads to death in 10% of all cases and to long-term aftereffects in a further 36%,\" including amputations, brain damage, and hearing loss. ", "The US campus outbreaks took the lives of students at Georgetown University, Kalamazoo College, Princeton University, San Diego State University, and Drexel University, and caused a University of California–Santa Barbara lacrosse player to have his feet amputated. ", "Yet many parents were stunned to learn that a vaccine for meningitis B called Bexsero, manufactured by Novartis, was approved in the European Union, Australia, and Canada—but was not available in the United States.", "\n\n\"Officials at the affected campuses were forced to appeal to the federal government for special permission to import and administer it,\" Dr. Miller says. ", "They had to apply to the FDA for compassionate use of an unapproved drug. ", "According to Dr. Miller, it took nine months after the first meningitis B case appeared for the FDA to get the vaccine to Princeton University and it was never made available to students at Kalamazoo College and Drexel University.", "\n\nWhen she heard that the FDA was not going to give the drug to students at Kalamazoo, Alicia Stillman—whose daughter Emily died in the outbreak at Kalamazoo—finally had enough. ", "She organized a bus to take dozens of college-age students across the border to Canada to have the vaccine administered in Windsor, Ontario.", "\n\nAs Mrs. Stillman explained on Forbes.com: \"Last February, my nineteen year old healthy daughter contracted the B strain while away at college. . . . ", "She died within 30 hours of entering the hospital with a headache. ", "My life has been changed forever. ", "I have followed the 'compassionate release' of the Bexsero vaccine to those 'lucky' Princeton students—and can only hope the rest of us find it available soon. ", "If any of the decision makers at the FDA watched their sweet daughter die such a death, and if those decision makers had to go choose a coffin and a headstone for one of their children, I have a feeling the decision would be made a little quicker.\"", "\n\nEmily Stillman died in February 2013. ", "Yet it took the FDA almost two more years to finally approve Bexsero for use in the United States in January 2015.", "\n\nIf there had been reciprocity between the EMA and the FDA, there would have been no need for American college students facing a deadly outbreak of meningitis B to wait for months to get the vaccine under compassionate use.", "\n\nThe problem is not limited to drugs. ", "In November 2011 the FDA approved a revolutionary heart valve called the Sapien Transcatheter Heart Valve—the first artificial heart valve that can replace an aortic heart valve without open-heart surgery. ", "The artificial valve is compressed into the end of a long, thin, tube slightly wider than a pencil. ", "The tube is then inserted into the artery through a small cut in the leg and threaded up to the heart, where it is placed and released. ", "For patients who could not have open-heart surgery, it was a lifesaving development. ", "Clinical studies showed that after a year, almost 70 percent of patients who received the valve were alive, compared with 50 percent of those who received an alternative treatment.", "\n\nAs Dr. Andy von Eschenbach and Ralph Hall, a professor at University of Minnesota Law School, pointed out in the _Wall Street Journal_ , \"This would be a great story for American patients, but for one frustrating detail: The Sapien valve has been available in Europe since 2007, saving lives there but not here.\"", "\n\nThey added, \"Unfortunately, this delay was not exceptional. ", "American patients used to be the first to benefit from their country's enormous investments in basic medical research. ", "Today, Americans wait as much as 60% longer than they did in 2005 for new lifesaving and life-enhancing medical devices—such as stents that keep arteries open and defibrillators—to reach the market, according to a recent Government Accountability Office report. ", "During that wait, many remain sick or disabled. ", "Some die.\"", "\n\nReciprocity would have brought this revolutionary valve to the United States five years earlier.", "\n\nReciprocity would have allowed Diego Morris to get mifamurtide here at home, instead of having to move to London for nine months. ", "Reciprocity would have made pirfenidone accessible to some 183,000 Americans who died while the FDA demanded more data in its quest for statistical certainty. ", "Delay kills.", "\n\nFINALLY, WE NEED TO adapt the drug development and approval process to the era of personalized medicine.", "\n\nIn the world of national security, we are experiencing what has become known as the \"Revolution in Military Affairs,\" with new weapons so precise that they can take out a target in one floor of a building without damaging the other floors.", "\n\nToday, in the world of science, we are experiencing a Revolution in Medical Affairs _,_ with new treatments so precise that doctors can take out a patient's own cells, reprogram them, and then turn them into missiles that target disease cells without damaging healthy cells.", "\n\nWe saw how this works in the case of Emily Whitehead, the little girl in chapter 4 who was dying from leukemia—until doctors extracted her blood, separated out her T cells, genetically reprogrammed them to fight her cancer, and then infused them back into her body, curing her.", "\n\nWe are entering an era when new medical treatments will increasingly be like this—designed to fit each of our individual molecular biologies.", "\n\n\"Precision medicine is the future of medicine,\" says the Manhattan Institute's Peter Huber, the author of _The Cure in the Code_. ", "Yet the regulatory system is still clinging to antiquated twentieth-century approaches to the study and approval of drugs that cannot keep up with the revolutionary advances taking place in the field of medicine.", "\n\nEarlier we talked about reducing the overreliance on large, randomized placebo controlled studies—because forcing terminally ill patients into a system in which they may get a placebo instead of a drug is morally unacceptable.", "\n\nBut there is another reason to modernize study design: personalized medicine. ", "How, Huber asks, can such large, randomized placebo trials be used for \"approving a custom-made drug that will be prescribed to only one patient, in whom its safety and efficacy will be largely determined by how the patient's molecular biology interacts with itself?\" ", "In this circumstance, \"any scientific demonstration of both efficacy and safety must involve a single patient study.\"", "\n\nEven in larger disease groups, the old model often fails. ", "Take breast cancer, for example. \"", "There is no such thing as breast cancer,\" Huber says. \"", "For a while we thought there were four variations as we began exploring the molecular structures of these cancers.\" ", "Now, he says, scientists have discovered at least ten distinct variations.", "\n\nThis means you can't have a clinical trial for \"breast cancer,\" Huber explains, because \"if the molecular structure of the disease is different then you really aren't dealing with one disease, you're dealing with a bunch of different diseases. [", "If] you throw a drug indiscriminately at all breast cancer patients it's not going to perform well because you're actually throwing it at ten different diseases and it may do just fine against one of them but not the others.\"", "\n\nMoreover, today, Huber says, we are learning more and more that \"pharmacology isn't a science of one hand clapping. ", "The patient's chemistry matters as much as the drug's.\" ", "So not only are you trying to treat ten different breast cancers; you are doing so while interacting with an enormous number of unique personal chemistries that could affect the drug's performance as well.", "\n\nThis throws a giant wrench into the FDA's four-decades-old \"crowd science\" approach to drug development. ", "Personalized medicine is \"the antithesis of the FDA's long-standing, one-size-fits-all drug approval process,\" Huber says. \"", "It can't handle the complexity and torrents of data that now propel the advance of molecular medicine.\"", "\n\nThis presents a major challenge for the regulatory classes in Washington, because the truth is the FDA can't regulate personal medicine the way it has traditionally regulated treatments.", "\n\nThe solution is to rely more on \"adaptive\" clinical trials—studies that are constantly changing and adapting to new information. ", "In a traditional FDA trial, if a drug is helping only one in ten patients, it will be considered a failure and the drug rejected. ", "In an adaptive trial, scientists take that information and use it to adapt the trial to focus on that subset of patients and figure out why they are responding while the others are not. ", "Perhaps the researchers go out and find additional patients who are genetically similar to the patients who benefited and bring them into the study. ", "Or perhaps they test new combinations of drugs to see if they are even more effective in the responding patients. ", "As they explore multiple avenues, they continue to adapt and collect data and develop a set of statistically rigorous results.", "\n\nFor adaptive trials to work, the reins in Washington have to be loosened. ", "Huber says that in many ways, the adaptive trial process is like Right to Try. ", "The targeted drug would go through the standard FDA safety trials and \"then—I guess roughly what your Right to Try laws would say—just get it into the hands of the experts and let them learn from there. ", "And you can, as long as you keep gathering the data from more and more patients and that means both their molecular profiles and their clinical effects. ", "You will build databases that just keep getting better and better at fitting the same drug to large groups of patients who will benefit from it.\"", "\n\nThe evidence is mounting that the antiquated model of large, one-dimensional placebo studies with yes/no verdicts no longer works in many cases. ", "In 2014 the National Cancer Institute launched what it called the Exceptional Responders Initiative, in which researchers are going back over a decade of \"failed\" clinical trials to see whether it was the drugs that failed or the FDA.", "\n\nNCI researchers went through their database of early phase clinical trials in which fewer than 10 percent of the patients responded to the treatments being studied. ", "They looked to see how many exceptional responders—\"patients who have a unique response to treatments that are not effective for most other patients\"—they could find.", "\n\nThe results were astounding. ", "In the initial search, they discovered about one hundred exceptional responders in whom the drug in the \"failed\" FDA trial actually worked. ", "They are now going back to conduct molecular testing on these patients to figure out why they responded when others didn't. ", "The goal is to see whether the drugs that \"failed\" FDA testing could be resurrected to treat a genetic subgroup of patients who might respond.", "\n\nOne such exceptional responder is Ed Levitt, who was interviewed in a remarkable Manhattan Institute video. ", "In 2004 Levitt was diagnosed with metastatic lung cancer that had spread throughout his body. ", "He was given just months to live. ", "His nurse suggested he try a new drug called Iressa, which had recently been approved by the FDA. ", "She thought it would make his final days less painful.", "\n\nInstead, it cured his cancer. ", "In days his tumors disappeared. \"", "Within a matter of a month, he was back to normal,\" his wife Linda says.", "\n\n\"What is Iressa?\" ", "Ed asks. \"", "Iressa is magic!\"", "\n\nIressa worked on Ed because he had a genetic mutation that made his cells amenable to the drug. ", "But the drug did not work in patients who lacked this genetic mutation. ", "So a year later, in June 2005, the FDA withdrew its approval for Iressa, because it did not extend life in enough patients.", "\n\nRather than going back and looking at why Iressa worked in Ed and figuring out how to find other patients who might be similarly helped, the FDA took it off the market—allowing patients who were already receiving it to continue, but not allowing any others to get the drug regardless of their genetic makeup.", "\n\nThe decision puzzles and frustrates Ed.", "\n\n\"The FDA could be so great, but it chooses not to be,\" he says.", "\n\nNow the National Cancer Institute is going out to try to find all the Ed Levitts of the world so we can find and resurrect all the drugs that the FDA dismissed as failures when it was really the antiquated clinical-trial protocols that failed.", "\n\nIn 2007 a Colorado company called Regenerative Sciences, LLC, developed a procedure called Regenexx to treat orthopedic injuries using stem cells derived from a patient's own bone marrow. ", "The stem cells are removed, isolated, processed and grown over a period of a few weeks, and reinjected into the injured areas to promote healing. ", "According to the company website, \"These stem cell procedures utilize a patient's own stem cells or blood platelets to help heal damaged tissues, tendons, ligaments, cartilage, spinal disc, or bone.\"", "\n\nIn 2008 the FDA sent the company a letter directing it to stop performing the procedure because the patients' own cells \"are considered drugs\" and without an FDA license, \"such products may be distributed for clinical use in humans only if the sponsor has an investigational new drug application in effect.\"", "\n\nThe company rejected the FDA's claims. ", "In a combative blog post titled \"FDA: Your Body Is a Drug and We Want to Regulate It,\" the company vowed to fight, saying it was \"engaged in a David and Goliath struggle over a basic civil right—who gets to regulate your body.\"", "\n\nIn 2010 the FDA sued, and two years later the US District Court in Washington, DC, sided with the FDA. ", "Regenexx moved its treatment to a clinic in the Cayman Islands (but continues to offer other same-day stem-cell procedures not subject to the FDA lawsuit in the United States).", "\n\nHuber says the decision was probably inevitable under current law, but the idea that the FDA can regulate people's own stem cells as a drug is absurd. \"", "How the hell would you control a blinded randomized trial here? ", "You could try the process, but what you're not trying is the chemistry because your stem cells are not the same as mine. . . . ", "There's absolutely no guarantee that the combination of chemistry in how a stem cell therapy works in you will work the same way as it will in me.\"", "\n\nInstead of trying to regulate stem cells as a drug, he says, the FDA should treat this as an opportunity to conduct adaptive trials to study this new technology. \"", "The FDA [should] simply put out some general guidance saying, 'Look . . . ", "we're not defining this as a drug but you have got to feed your data, you got to collect this much data and you've got to be willing to pool it, get the patient's consent and then the profession can at least learn the conditions under which these things work and let's find out why some patients respond and others don't.'\"", "\n\nThe same advances in personalized medicine that are revolutionizing the development of new drugs are also revolutionizing the development of medical devices.", "\n\nIn 2012 doctors at the University of Michigan were struggling to save three newborn infants with a terminal form of tracheobronchomalacia (TBM), which causes the windpipe to periodically collapse and prevents normal breathing. ", "According to an article in _MIT Technology Review_ , \"the three infant boys were each near death. ", "They were all on ventilators. ", "All had airways so tiny that the breaths they tried to exhale couldn't get out.\"", "\n\nThe doctors came up with a novel solution. ", "They used 3-D printers to make models of the boys' tiny airways and then used them to design custom stents, modeled to their specific anatomy, that could open their blocked airways. ", "The doctors then printed out the custom stents with the 3-D printer and inserted them into the boys' tracheas and bronchi.", "\n\nThe custom devices worked. ", "All three boys recovered and were able to go home. ", "They did not even need follow-on procedures to remove the stents. ", "Doctors designed the stents to gradually dissolve as the boys grew.", "\n\nDr. Glenn Green, an associate professor of pediatric otolaryngology at the University of Michigan's C. S. Mott Children's Hospital, where the devices were designed, says, \"Before this procedure, babies with severe tracheobronchomalacia had little chance of surviving. ", "Today, our first patient Kaiba is an active, healthy 3-year-old in preschool with a bright future. ", "The device worked better than we could have ever imagined. ", "We have been able to successfully replicate this procedure and have been watching patients closely to see whether the device is doing what it was intended to do. ", "We found that this treatment continues to prove to be a promising option for children facing this life-threatening condition that has no cure.\"", "\n\nAs he explained to a medical journal, we are now entering an era when medical devices can be made to fit an individual patient's anatomy on the submillimeter scale.", "\n\nPersonalized medical devices pose challenges for the FDA similar to those posed by personalized drugs. ", "So far the agency has approved the use of these devices on an emergency basis. ", "But the technology is in its infancy. ", "How is the FDA going to regulate medical devices on a mass scale, where doctors are routinely designing and implanting custom stents and other devices, where no one is like any other? ", "The development of personalized medical devices is going to challenge the established way of doing things.", "\n\nAs we have seen with the rapid rise of the Right to Try movement, patients are clamoring for better and faster development of cures that could save them. ", "Encouraging follow-on drugs, embracing reciprocity, and supporting flexible, adaptive trials are simple steps the government could take to expand access to emerging drugs and help save lives.", "\n\n# 9.", "\n\nIf You Have the Right to Die, You Should Have the Right to Try\n\nIn 2005 the George W. Bush administration went to the Supreme Court to challenge an Oregon law, the Death with Dignity Act. ", "Such a statute, known as a Right to Die law, allows patients diagnosed with a terminal illness to request a prescription for a lethal dose of medication for the purpose of ending their own life.", "\n\nIn 2001 Attorney General John Ashcroft moved to suspend the licenses of doctors who prescribed lethal medications under the Oregon law, citing his powers under the federal Controlled Substances Act. ", "A federal judge blocked Ashcroft's order—a move that was upheld by the Ninth Circuit Court of Appeals—setting up an epic showdown at the Supreme Court.", "\n\nIn 2005 the justices heard arguments in the case of _Gonzales v. Oregon_ to determine the constitutionality of Ashcroft's order and the fate of the Death with Dignity Act. ", "United States solicitor general Paul Clement argued on behalf of the Bush administration that the state of Oregon did not have the power to regulate the practice of medicine when that practice entails prescribing federally controlled substances. ", "Oregon's senior assistant attorney general Robert Atkinson countered that Congress intended only to address recreational drug abuse when it passed the Controlled Substances Act and that because medical practices are regulated at the state level, Ashcroft's order was invalid and the Death with Dignity Act should be upheld.", "\n\n\"This is an issue of federalism, and the relationship between the sovereign states and the federal government,\" Atkinson told the justices. ", "Congress passed the Controlled Substances Act against the \"backdrop of 200 years of responsible regulation of the practice of medicine\" by the states, he said, and added, \"We think it's clear that Congress intended to respect the responsibility of the states to regulate their medical practices.\"", "\n\nOn January 17, 2006, the justices ruled 6 to 3 in favor of Oregon, upholding the law. ", "Considering \"the structure and limitations of federalism,\" the court observed that states have great latitude in regulating health and safety, including medical standards, which are primarily and historically a matter of local concern. ", "To hold otherwise, the court said, would mark \"a radical shift of authority from the states to the Federal Government to define general standards of medical practice in every locality.\"", "\n\nSo does the Supreme Court's decision in _Gonzales v. Oregon_ clear the way for states to permit the use of non-FDA-approved medications to help dying patients save their own lives?", "\n\nIf states have the authority to protect patients' Right to Die, don't they also have the power to protect the Right to Try?", "\n\nAt the Goldwater Institute, we believe they do.", "\n\nState Right to Try laws are based on the well-established legal principle that US states have inherent powers to regulate medical practice for terminal patients. ", "Moreover, Right to Try laws safeguard a constitutionally protected liberty interest—the right of a terminal patient to try to save his life by trying safe, investigational treatments.", "\n\nFederal regulations that violate our constitutional liberties can never trump state laws protecting those liberties. ", "The US Constitution provides a floor of protection for individual rights, not a ceiling. ", "As James Madison wrote in _Federalist_ number 51, our system of federalism provides \"a double security . . . ", "to the rights of the people.\" ", "The fifty states serve as shields for individual rights that the federal government fails to protect. ", "And states can harness these tools to protect the most personal, intimate right of all—the right to try to save one's life.", "\n\nA federal challenge to a Right to Try act would pit the concepts of federalism and individual rights against the expansive power of the federal government. ", "While the federal government often prevails in federalism clashes with states, the current Supreme Court is the most pro-federalism court in decades—particularly when it comes to protecting individual rights related to medical treatments.", "\n\nEssential to this appeal to federalism is the fact that the Right to Try is inseparable from the concept of liberty. ", "The Supreme Court has acknowledged that individuals have a constitutionally protected liberty interest in refusing unwanted medical treatment. ", "A patient's autonomy interest should be the same when she chooses to seek investigational treatment to fight for her life.", "\n\nSupport for Right to Try laws comes from the due process clauses of the Fifth and Fourteenth Amendments as well as the Ninth and Tenth Amendments to the US Constitution. ", "The right to medical self-preservation is so \"deeply rooted in the Nation's history and tradition\" and \"implicit in the concept of ordered liberty\" that its regulation by the FDA violates fundamental rights. ", "In other words, the right to self-preservation is a liberty so inherent and vital that no government can place limitations on it through regulation or otherwise.", "\n\nThe Supreme Court has never addressed the issue of investigational medication in the context presented by Right to Try.", "\n\nSome critics of Right to Try point to the 1979 case _United States v. Rutherford_ , in which the Supreme Court held that the government has an interest in regulating unsafe drugs. ", "But that case involved not a promising treatment that had passed FDA safety trials, but rather an ineffective drug called laetrile that the FDA had declared \"a public health menace.\"", "\n\nThe FDA called laetrile a \"highly toxic product that has not shown any effect on treating cancer.\" ", "According to the National Cancer Institute, laetrile mimics \"the signs and symptoms of cyanide poisoning. ", "These include: Nausea and vomiting; Headache; Dizziness; Blue color of the skin due to a lack of oxygen in the blood; Liver damage; Abnormally low blood pressure; Droopy upper eyelid; Trouble walking due to damaged nerves; Fever; Mental confusion; Coma; Death.\"", "\n\nThe concerns for safety expressed by the Supreme Court in _United States v. Rutherford_ do not apply in the case of Right to Try laws. ", "Under Right to Try, terminally ill patients can access investigational drugs _only_ if they have (1) passed an FDA-approved safety trial and (2) are still actively being developed in a clinical trial under the FDA umbrella. ", "In other words, the law relies heavily on the FDA's expertise and diligence and does not permit access to any drugs (like laetrile) that the agency has deemed unsafe. ", "Right to Try simply extends to all terminally ill patients the same opportunities as those lucky enough to enroll in clinical trials.", "\n\nIndeed, it is the very lack of access to safe investigational treatments that is actually driving dying patients into the hands of those promoting quack cures.", "\n\nFor example, today—thirty-six years after the _Rutherford_ decision—a clinic called Oasis of Hope is still offering laetrile treatment for desperate American cancer patients across the border in Mexico. ", "The clinic conducts admissions at the San Diego airport. \"", "We will pick you up at the baggage claim of your choice in a van and bring you to the hospital so there is no car to rent, no hotel expense, no food to buy, and you get a private room with two beds so a Companion can come with you,\" the website promises.", "\n\nCurrent FDA policy drives terminally ill patients to clinics like Oasis of Hope. ", "Right to Try laws help dying Americans get treatments the FDA says are safe enough for clinical trials, which means desperate patients are less likely to pursue dangerous ones like laetrile. ", "If anything, there is a public safety interest in upholding Right to Try laws.", "\n\nAnother case that is often incorrectly cited as evidence that Right to Try laws will be struck down is _Abigail Alliance v. von Eschenbach._ ", "This case was brought in 2006 by Frank Burroughs, the Virginia dad whose daughter Abigail died after she was unable to get access to an investigational cancer drug called Erbitux. ", "The drug was later approved by the FDA. ", "Frank went on to form the Abigail Alliance for Better Access to Developmental Drugs to help others like Abigail get the drugs they need before the clock runs out.", "\n\nThe Abigail Alliance sued the FDA, arguing that terminally ill patients with no remaining FDA-approved treatment options have a constitutionally protected due process right to seek access to investigational medications that the FDA concedes are safe and promising enough for substantial human testing.", "\n\nA three-judge panel of the US Circuit Court of Appeals for the District of Columbia agreed with the Abigail Alliance and ruled that the Constitution did guarantee terminally ill patients the right to seek access to experimental drugs without government permission. ", "After the FDA petitioned the court for a rehearing, the full circuit court reversed the decision of the three-judge panel, finding there is no fundamental right to access unapproved experimental drugs, even for the terminally ill. ", "The Supreme Court declined to hear the Abigail Alliance's appeal, leaving the lower court ruling in place.", "\n\nCase closed, say Right to Try's opponents.", "\n\nWhen asked if patients have a \"right\" to try, Dr. Janet Woodcock of the FDA says, \"Well, I believe that was litigated in court.\"", "\n\nNot so fast.", "\n\nFirst of all, since the Supreme Court has not decided the issue, the question of whether terminally ill patients have a fundamental right to seek access to investigational medicine has not yet been settled. ", "The _Abigail Alliance_ decision is not binding outside the DC Circuit. ", "The DC Circuit, while influential, is only one of twelve regional circuits, and none of the other circuit courts are required to follow it.", "\n\nSecond, many legal scholars believe that the DC Circuit's decision is wrong and that later decisions will go the other way. ", "Indeed, Judge Judith Rogers and Chief Judge Douglas Ginsburg dissented and explained very thoroughly in a twenty-nine-page opinion why their colleagues were wrong:\n\nIn the end, it is startling that the oft-limited rights to marry, to fornicate, to have children, to control the education and upbringing of children, to perform varied sexual acts in private, and to control one's own body even if it results in one's own death or the death of a fetus have all been deemed fundamental rights covered, although not always protected, by the Due Process Clause, but the right to try to save one's life is left out in the cold despite its textual anchor in the right to life. ", "This alone is reason the court should pause about refusing to put the FDA to its proof when it denies terminal patients with no alternative therapy the only option they have left, regardless of whether that option may be a long-shot with high risks.", "\n\nAmong other arguments, they explained that both the common law and the Constitution support a fundamental right to \"medical self-defense.\" ", "Self-defense is about the most firmly settled \"fundamental right\" that there is. ", "So if the government wants to infringe on that right, it must show an extremely compelling reason.", "\n\nMoreover, the Supreme Court has supported the right of medical autonomy in abortion, so by that logic, it should do the same when it comes to investigational drugs. ", "The esteemed UCLA law professor Eugene Volokh explains the principle at stake here in the _Harvard Law Review_ , using examples of two women:\n\nAlice is seven months pregnant, and the pregnancy threatens her life; doctors estimate her chance of death at 20%. ", "Her fetus has long been viable, so Alice no longer has the Roe/Casey right to abortion on demand. ", "But because her life is in danger, she has a constitutional right to save her life by hiring a doctor to abort the viable fetus. ", "She would have such a right _to a therapeutic abortion even_ if the pregnancy were only posing a serious threat to her health, rather than threatening her life. . . .", "\n\nEllen is terminally ill. ", "No proven therapies offer help. ", "An experimental _drug_ therapy seems safe, because it has passed Phase I FDA testing, yet federal law bars the therapy outside of clinical trials because it hasn't been demonstrated to be effective (and further checked for safety) through Phase II testing. . . .", "\n\nIt can't be that a woman has a constitutional right to protect her life using medical procedures, but only when those procedures kill a viable fetus. . . . ", "The Supreme Court has so far recognized the medical self-defense right only in abortion cases. ", "Yet the right can't logically be limited to situations in which the defensive procedure is abortion, and rejected when a woman needs to defend herself using experimental drugs.", "\n\nMoreover, Volokh says, Americans have an even broader right to lethal self-defense. ", "It is commonly accepted that self-defense is an exception to criminal laws against murder. \"", "Lethal self-defense is allowed even against those who threaten your life with little or no moral fault.\" ", "So, Volokh writes, \"if I may kill a human or an animal to protect my life, why shouldn't I be presumptively free to protect my life using medical procedures that don't involve killing, such as . . . ", "the use of experimental drugs?", "\n\n\"Medical self-defense,\" Volokh declares, \"is a constitutional right.\"", "\n\nWe believe that this is one of several arguments that would prevail if the Right to Try is brought before the Supreme Court.", "\n\nThe Right to Try movement is in many ways a direct response to the DC Circuit _Abigail Alliance_ majority's invitation to lawmakers to safeguard the Right to Try through the democratic process:\n\nAlthough in the Alliance's view the FDA has unjustly erred on the side of safety in balancing the risks and benefits of experimental drugs, this is not to say that the FDA's balance can never be changed. ", "The Alliance's arguments about morality, quality of life, and acceptable levels of medical risk are certainly ones that can be aired in the democratic branches, without injecting the courts into unknown questions of science and medicine. ", "Our Nation's history and traditions have consistently demonstrated that the democratic branches are better suited to decide the proper balance between the uncertain risks and benefits of medical technology, and are entitled to deference in doing so. . . . ", "Our holding today ensures that this debate among the Alliance, the FDA, the scientific and medical communities, and the public may continue through the democratic process.", "\n\nThat is exactly what the Right to Try movement has done. ", "Supporters of the Right to Try are now using the democratic process to expand access to investigational medicines—by going to the state legislatures, to which courts have generally deferred when it comes to regulating the practice of medicine.", "\n\nA complementary reform is for Congress to pass legislation explicitly protecting state Right to Try laws. ", "In July 2015, Republican representatives Matt Salmon and Paul Gosar of Arizona and Marlin Stutzman of Indiana introduced a federal Right to Try Act, which would bar the federal government from interfering with states and parties using properly enacted Right to Try laws.", "\n\nThe Goldwater Institute is also asking the FDA to explain to the American people how it decides who gets access to investigational medicines and who does not.", "\n\nIn chapter 5 we learned how an American medical missionary, Dr. Kent Brantly, contracted Ebola while caring for patients in Liberia and was given an antiviral drug called ZMapp. ", "The FDA never publicly explained how it decided to make this drug, which had never even been tested in human beings, available for use, while denying millions of Americans access to other promising drugs that actually have passed FDA safety trials.", "\n\nSo in August 2014, we filed a Freedom of Information Act Request seeking information about the FDA's decision-making process on the experimental Ebola drug. ", "The FDA denied the request, claiming that releasing the records would reveal the drugmakers' trade secrets (even though we asked for no proprietary commercial information). ", "We appealed to the Department of Health and Human Services, which also denied our request. ", "So in June 2015, we filed a lawsuit in the US District Court in Arizona, arguing that the FDA's arbitrary withholding of this public information violates federal law and undermines the public's right to know how the government makes decisions on life-and-death matters.", "\n\nAmericans deserve transparency. ", "They should not have to beg their government for the right to save their own lives, or stand by while the government makes decisions behind a veil of secrecy that allow some to live and leave others to die.", "\n\nAs we go to press, the FDA has not challenged Right to Try laws. ", "It would be unwise to do so. ", "If it does, it will lose twice—once in the court of law, and once in the court of public opinion.", "\n\nAll FDA enforcement litigation must be brought by the Department of Justice, which means the decision whether to bring a lawsuit to stop Right to Try is up to the attorney general and, ultimately, the president of the United States.", "\n\nAny president who goes to court to try to take away the rights of dying patients to save their own lives will pay a huge political price. ", "In this book, we have seen up close the human tragedy that takes place when people with terminal illnesses are denied their right to try. ", "A Supreme Court fight would draw national attention to stories like these and shine a bright spotlight on the myriad ways the federal government fails dying Americans.", "\n\nThe more attention these cases get, the more popular Right to Try will become. ", "Already, Right to Try laws are passing in the states by overwhelming margins. ", "It's not hard to see why. ", "Almost every American has lost a friend or loved one to a terminal illness or knows someone who has—and every one of us can imagine ourselves in a similar circumstance. ", "For most of us, the answer is simple: of course we have the right to try to save our own lives. ", "Those fighting to stop us from doing so will emerge from that fight diminished, whatever the legal outcome.", "\n\nBut if the powers that be in Washington do decide to take on this losing battle, they can rest assured that Goldwater Institute is prepared to defend Right to Try in court. ", "And our record shows that we are a formidable legal adversary.", "\n\nWe will stand up to defend the right of dying Americans to try to save their own lives.", "\n\nIf the powers that be in Washington want to take us—and the millions of Americans we represent—on, that is fine by us.", "\n\nThey have the right to try.", "\n\n# 10.", "\n\nWhere Do I Start?", "\n\n_A Step-by-Step Guide to Seeking an Investigational Treatment_\n\nIf you're among the majority of Americans who cannot participate in a clinical trial, and you'd like to try an investigational medicine or treatment, the following information may help you.", "\n\nI wish I could tell you that the process will be simple and easy, because it should be. ", "For a patient fighting for his or her life, the process should be as quick and accessible as getting any other prescription or treatment from your doctor. ", "I also wish I could tell you that Right to Try laws have cleared away all the institutional barriers created in Washington, DC, to patients seeking access. ", "As we have seen in this book, many of these barriers still exist. ", "And because Right to Try laws are brand-new, and doctors and manufacturers are still figuring out how to use the law, you may need an attorney to help you navigate the process.", "\n\n**Am I eligible?**", "\n\nThe Right to Try laws vary slightly from state to state, so you'll need to check the requirements where you live. ", "The website righttotry.org contains an up-to-date list of Right to Try laws. ", "If your state hasn't yet adopted a Right to Try law, you may be able to exercise your Right to Try in a different state.", "\n\nEligibility requirements generally include the following: you have a terminal diagnosis; no treatment is available, or you have exhausted the standard treatments for your condition; you aren't eligible for a clinical trial; your doctor has advised you that the use of an investigational treatment is the best medical option to extend or save your life; the investigational treatment has successfully completed basic safety testing (phase I clinical trials) and is in the development pipeline as part of the FDA's ongoing evaluation and approval process; you are willing to provide \"informed consent,\" acknowledging the potential risks associated with the use of the drug; and the company developing the treatment is willing to make it available.", "\n\n**How can my doctor and I learn more about emerging treatments that could help me?**", "\n\nPatient support and advocacy groups for particular conditions often receive up-to-date information on cutting-edge research and treatments. ", "The following is a list of groups and resources that share information on emerging treatments and clinical trials:\n\nThe Abigail Alliance for Better Access to Developmental Drugs\n\n8881 White Orchid Place, Lorton, VA 22079\n\nEmail: frankburroughs@abigail-alliance.org\n\nPhone: (703) 646-5306\n\nWebsite: http://www.abigail-alliance.org/\n\nAIDSinfo\n\nPO Box 4780\n\nRockville, MD 20849-6303\n\nEmail: ContactUs@aidsinfo.nih.gov\n\nPhone: (800) 448-0440\n\nMain website: www.aidsinfo.nih.gov\n\nTrials website: www.aidsinfo.nih.gov/clinical-trials\n\nTwitter: @AIDSinfo\n\nAlzheimer's Disease and Education Referral Center (at the National Institutes of Health's National Institute on Aging)\n\n31 Center Drive, MSC 2292, Bethesda, MD 20892\n\nEmail: adear@nia.nih.gov\n\nPhone: (800) 438-4380\n\nWebsite: www.nia.nih.gov/alzheimers\n\nTwitter: @Alzheimers_NIH\n\nThe Center for Information and Study on Clinical Research Participation\n\n56 Commercial Wharf East, Boston, MA 02110\n\nContact form: www.ciscrp.org/about-ciscrp/contact-us\n\nPhone: (877) MED-HERO\n\nMain website: www.ciscrp.org\n\nClinical trial database website: www.ciscrp.org/programs-events/search-clinical-trials/search\n\nCustom clinical trial search website: www.ciscrp.org/programs-events/search-clinical-trials\n\nTwitter: @CISCRP\n\nClinicalTrials.gov (National Library of Medicine)\n\n8600 Rockville Pike, Bethesda, MD 20894\n\nEmail: custserv@nlm.nih.gov\n\nPhone: (888) 346-3656\n\nWebsite: www.clinicaltrials.gov\n\nMedlinePlus (National Library of Medicine)\n\n8600 Rockville Pike, Bethesda, MD 20894\n\nEmail: custserv@nlm.nih.gov\n\nMain website: www.nlm.nih.gov/medlineplus\n\nWebsite: www.nlm.nih.gov/medlineplus/clinicaltrials.html\n\nTwitter: @medlineplus\n\nNational Cancer Institute\n\n9609 Medical Center Drive, Bethesda, MD 20892-9760\n\nContact form: www.cancer.gov/contact/email-us\n\nPhone: (800) 422-6237\n\nMain website: www.cancer.gov\n\nWebsite: www.cancer.gov/about-cancer/treatment/clinical-trials/search\n\nTwitter: @theNCI\n\nNational Heart, Lung, and Blood Institute \"Children in Clinical Studies\"\n\nPO Box 30105, Bethesda, MD 20824-0105\n\nEmail: ResearchAndKids@nhlbi.nih.gov\n\nPhone: (301) 592-8573\n\nMain website: www.nhlbi.nih.gov\n\nWebsite: www.nhlbi.nih.gov/childrenandclinicalstudies/index.php\n\nTwitter: @nih_nhlbi\n\nNational Institute on Aging \"Clinical Trials and Older People\"\n\n31 Center Drive, MSC 2292\n\nBethesda, MD 20892\n\nEmail: niaic@nia.nih.gov\n\nPhone: (800) 222-2225\n\nMain website: www.nia.nih.gov\n\nWebsite: www.nia.nih.gov/health/publication/clinical-trials-and-older-people\n\nNational Institutes of Health \"Clinical Trials and You\"\n\n9000 Rockville Pike, Bethesda, MD 20892\n\nEmail: NIHinfo@od.nih.gov\n\nPhone: (301) 496-4000\n\nMain website: www.nih.gov\n\nWebsite: www.nih.gov/health/clinicaltrials\n\nTwitter: @NIH\n\nResearchMatch\n\nContact form: www.researchmatch.org/contact\n\nWebsite: www.researchmatch.org\n\nTwitter: @ResearchMatch\n\n**What does my doctor need to do?**", "\n\nYour doctor should contact the drug manufacturer to request access to an emerging treatment.", "\n\n**What does the drug manufacturer need to do?**", "\n\nIf a company agrees to provide a treatment, it can work with your doctor to provide it to you under your doctor's supervision.", "\n\n**How do I pay for treatment?**", "\n\nMany companies provide investigational treatments to patients at no charge or at cost. ", "Unfortunately, most insurance companies will not pay for investigational treatments as of this writing. ", "The following groups may be able to assist with the cost of care, including treatments and travel:\n\nAir Charity Network\n\nPhone: (877) 621-7177\n\nWebsite: www.aircharitynetwork.org\n\nTwitter: @AngelFlightSE\n\nAngel Flight for Veterans\n\n6324 Culverhouse Court, Gainesville, VA 20155\n\nEmail: info@angelflightveterans.org\n\nPhone: (800) 550-1767\n\nWebsite: www.angelflightveterans.org\n\nCorporate Angel Network\n\nWestchester County Airport\n\nOne Loop Road, White Plains, NY 10604-1215\n\nEmail: info@corpangelnetwork.org\n\nPhone: (914) 328-1313\n\nWebsite: www.corpangelnetwork.org\n\nEdmond J. Safra Family Lodge at National Institutes of Health\n\n65 Center Drive, Bethesda, MD 20892\n\nEmail: cc-famlodge@cc.nih.gov\n\nPhone: (301) 496-6500\n\nWebsite: www.clinicalcenter.nih.gov/familylodge\n\nMercy Medical Angels\n\n4620 Haygood Road, Ste. ", "1, Virgina Beach, VA 23455\n\nEmail: info@MercyMedical.org\n\nPhone: (757) 318-9174\n\nWebsite: www.mercymedical.org\n\nTwitter: @MercyMedical\n\nMiracle Flights for Kids\n\n2764 N. Green Valley Pkwy. #", "115, Green Valley, NV 89014-2120\n\nEmail: info@miracleflights.org\n\nPhone: (800) FLY-1711\n\nWebsite: www.miracleflights.org\n\nTwitter: @miracleflights\n\nNational Association of Hospital Hospitality Houses\n\nPO Box 1439, Gresham, OR 97030\n\nEmail: jdavis@hhnetwork.org\n\nPhone: (800) 542-9730\n\nWebsite: www.nahhh.org\n\nNational Patient Travel Center\n\n4620 Haygood Rd, Ste. ", "1, Virginia Beach, VA 23455\n\nContact form: www.patienttravel.org\n\nPhone: (800) 296-1217\n\nWebsite: www.patienttravel.org\n\nPatient Advocate Foundation\n\n421 Butler Farm Road, Hampton, VA 23666\n\nEmail: cpr@patientadvocate.org\n\nPhone: (800) 532-5274\n\nWebsite: www.patientadvocate.org\n\nTwitter: @PatientAdvocFou\n\nRight to Try Foundation\n\nEmail: board@righttotryfoundation.com\n\nPhone: (801) 400-8160\n\nWebsite: www.righttotryfoundation.com\n\nTwitter: @_RightToTry\n\nFor more information, please contact the Goldwater Institute at info@goldwaterinstitute.org or visit www.goldwaterinstitute.org.", "\n\n## Afterword\n\n_Everyone Deserves the Right to Try: An Update on Jenn McNary, Ted Harada, and Diego Morris_\n\nAfter three years and three months of fighting, Jenn McNary finally succeeded in getting her son Austin into a clinical trial for eteplirsen.", "\n\n\"The FDA finally allowed the company to expand their trials to include a few older children,\" she says. \"", "I think it was specifically done because they wanted us off their backs.\"", "\n\nBut on the day Austin was to get his first infusion—the day Jenn had been fighting for, hoping for, praying for—she could not be there. ", "She had to get on a plane and take Max to Columbus, Ohio, for his six-month lab test.", "\n\nSo Christine McSherry, her friend and partner in the fight to get eteplirsen approved, offered to take Austin to the hospital to get the drug for the first time.", "\n\nAfter Jenn boarded the flight to Ohio, Christine's phone rang.", "\n\nIt was Chris Garabedian, the CEO of Sarepta.", "\n\n\"I understand Austin is getting his first infusion today,\" he said.", "\n\n\"Yeah, I'm on my way in,\" Christine said.", "\n\n\"Can you pick me up, because I really want to be there too,\" Chris said.", "\n\n\"Really?\" ", "Christine said. ", "She was floored.", "\n\n\"Yeah, I just got off a red-eye from Arizona. ", "If I can be there when the first nonambulatory boy get his dose, I'd really like to do that.\"", "\n\nChris had flown across the country just to be by Austin's side when he finally got the drug.", "\n\n\"Yep, I'll pick you up,\" Christine said.", "\n\nShe got Chris and took him to the hospital, where Austin was infused—the first new patient to receive eteplirsen since the twelve-patient study began in 2011.", "\n\nWhy was it so important for Garabedian to be there?", "\n\n\"Jenn McNary was the first mom who was convinced the drug was working,\" he says. \"", "The fact that she waited more than two years from that original request to get Austin on the drug, and channeled all of her energy into advocacy for accelerated approval so that all the boys who could benefit from eteplirsen could get access, was truly heroic in my eyes.\"", "\n\nSo how is Austin doing?", "\n\n\"He's been on the drug for eighteen weeks,\" Jenn says. ", "It usually takes about six months for the drug to have a discernible impact, but Jenn already sees signs that the drug is helping.", "\n\n\"He's able to take his sweatshirt off without assistance and is starting to be able to write a little bit.\" ", "Austin is also playing drums in his school band. \"", "The other night he was drumming up a storm,\" Jenn says.", "\n\nShe understands that the drug won't reverse the decline Austin experienced while fighting for access.", "\n\n\"It's not going to make him walk again, but it really could stabilize his progression so he doesn't get worse.\"", "\n\nAnd that is what is so tragic about the delay. ", "Austin waited 170 weeks before he could finally get on the drug. ", "For 170 weeks he watched his brother get better while he slowly got worse.", "\n\nWhat was the cost of that more than three-year wait?", "\n\n\"The skills he has lost while his brother has been on drugs have been really important life skills,\" Jenn says.", "\n\nHe lost the ability to transfer himself from chair to bed, from chair to toilet, the ability to wash his hair, the ability to dress himself, cut his own food, pick up his dog, open most doors. ", "Skills he [was] on the verge of losing [included] feeding himself, lifting his cell phone to his ear, lifting his arms for a hug, rolling to his side in bed.", "\n\nThe most frustrating part of the FDA is that they already have the tools that they need to be able to approve a drug like this. ", "So we weren't asking them to do something that was against the rules, against the law, and we weren't asking them to make an exception. ", "They've given that guidance to allow [Sarepta] to file [for accelerated approval] and then taken it back three times.", "\n\nEvery time the drug company got to a place where they had the data that they thought they needed to file for approval, the FDA changed their mind and moved the goalpost again. ", "They said, \"Okay, now we want more [data], or now we want different [data], or now we want more kids enrolled, we want more end points; we want you to measure the dystrophin differently.\"", "\n\nThe FDA's delays did not affect only Austin, she says. ", "Max and the other eleven boys in the first clinical trial have had to undergo repeated surgeries just to take biopsies of their muscle tissue to test whether the treatment was helping them produce dystrophin, the missing protein that causes Duchenne.", "\n\n\"The FDA was not happy with the first three muscle biopsies that were taken from the kids so they asked these twelve children to go for a fourth muscle biopsy,\" Jenn says. ", "It is major surgery that has no health benefits for the boys. \"", "They're fully under anesthesia, intubated; this is a huge surgery to take a piece of muscle, which is exactly the thing that these kids are losing.\"", "\n\nNone of this was to ensure the safety of the drug; it was all to get as close as possible to absolute certainty about the drug's efficacy before the FDA approved its release.", "\n\n\"We have a safe and effective drug. ", "We have a drug company that's ready to move forward. ", "We have laws that Congress has given them in order to allow them to approve this drug under accelerated approval and they're just refusing to do it.\"", "\n\nJenn thinks the FDA finally gave in and created a trial for which Austin qualified in hopes of shutting her up.", "\n\n\"Here's what we think happened. ", "We think the FDA got sick of hearing from us. . . . ", "So what they did was they said, Listen, we'll just do a 'safety' trial on these older boys. ", "You can just prove that it's safe in them. [", "The plan was] getting my kid on the drug so the FDA didn't have to hear from me as much.\"", "\n\nIf that was the plan, it didn't work.", "\n\n\"Little did they know I wasn't going to stop,\" Jenn says. \"", "We didn't even pause to get excited about it. ", "Our kids were on the drug, and we were back to the FDA a week later and said, 'Great, when are you going to approve it, because that's what we're looking for.' ", "They thought they were going to get rid of us when our kids were on the drug but that didn't happen.\"", "\n\nIn April 2015 Chris Garabedian resigned as CEO of Sarepta—a casualty of the company's struggles with the FDA.", "\n\nA few weeks later, on May 19, 2015, the FDA invited Sarepta to submit a new drug application that year—a process that was completed on June 26. ", "The company requested \"priority review,\" which could shorten the review period from ten months to about six.", "\n\n\"I'm cautiously optimistic,\" Christine says. \"", "I analogized it to a bad relationship yesterday—'Oh man, I've been down this road before, is it going to happen again?' ", "But the fact that they're already taking parts of the NDA tells us that it sounds like they're pretty serious about it. . . . ", "I'm just so nervous to get excited because I don't want the disappointment again.\"", "\n\nIf all goes well, and the drug is finally approved, it will be because an innovative CEO and a group of moms joined forces to fight for faster approval.", "\n\nYet even if the FDA does finally approve eteplirsen, the drug's roller-coaster path through the FDA approval process remains a cautionary tale.", "\n\n\"This is the classic story,\" Garabedian says. \"", "Once a drug moves forward and it's successful, everybody forgets about the delays, the inefficiency of the process, what boys could have been helped if this were approved a year ago. ", "Nobody ever talks about that, they only talk about 'Wow! ", "The FDA did the right thing in the end. ", "The FDA is letting the drug move forward. ", "Wow!' ", "But everybody quickly has short-term memory and doesn't remember that we were right more than two years ago when we were describing the merits of why this should be considered for accelerated approval.\"", "\n\nHe points out that even if eteplirsen is approved, the fight is not over. ", "Eteplirsen helps just 13 percent of Duchenne patients who are missing exon 51. ", "But the company has a suite of follow-on drugs that use exactly the same chemical backbone to treat Duchenne patients with other missing exons—boys like Jordan McLinn, the young fireman in Indiana.", "\n\nWill the FDA speed approval of those follow-on drugs based on its approval of eteplirsen? ", "Or will it put those Duchenne patients through the same delays that Jenn McNary and her family suffered, or worse?", "\n\nIf it does the latter, the FDA will face a patient backlash that will make the fight over eteplirsen look mild by comparison.", "\n\n\"Now that 13 percent of the Duchenne community may get access to the drug, imagine the other 87 percent who now feel left on the sidelines,\" Garabedian says. \"", "I mean, eteplirsen advocates are going to look small and feeble compared to those who might get activated who aren't going to get access to eteplirsen.\"", "\n\nJenn McNary and Christine McSherry will stay in the fight until all Duchenne patients get access to the drugs they need to save their lives.", "\n\nChristine is amazed by Jenn's resilience and determination. ", "She recalls coming back from one of their many trips to Washington, DC, sitting on the plane and looking at Jenn—and thinking about all the Duchenne groups that wanted nothing to do with her.", "\n\n\"[Here was this] mom who got pregnant at eighteen and had two kids before she was twenty-two. ", "Dropped out of high school. ", "Never went to college. ", "Yet, here is this girl. . . . ", "She was the catalyst and initiated change and a movement far beyond [what] all those other organizations [achieved]. ", "She really did. ", "And it just didn't matter what her education was. ", "It might have even been her lack of education that allowed her to get out front and do that. ", "It was just sheer passion that she had to fight for her son.\"", "\n\nFor her part, Jenn says simply, \"Everybody deserves to be involved, and not feel helpless, and not feel like they have to be quiet.\"", "\n\nYou can be sure of this: Jenn McNary won't be quiet until every boy with Duchenne gets access to the drugs he needs to save his life.", "\n\nON FEBRUARY 25, 2013, two and a half years after first being diagnosed with ALS, Ted Harada walked into a hearing room at the Food and Drug Administration headquarters in Silver Spring, Maryland, and took his seat at the witness table.", "\n\nBefore him on the dais sat the leadership of the FDA—the men and women who had the power to grant or deny other dying patients access to the treatment that had saved his life.", "\n\n\"My name is Ted Harada,\" he began. \"", "I am an ALS patient and advocate. ", "In the eight-plus hours that this meeting will take place, five people in the United States will die from ALS, and five more will be diagnosed with their death sentences.\"", "\n\nThe doctors who saved his life, Harada told the panel, have \"only been allowed to treat fifteen people in three-plus years. ", "I don't think that treating fifteen people goes hand in hand with the concept of doing everything you can for ALS patients.\"", "\n\nHe acknowledged that the FDA approval process was the \"gold standard.\" ", "But, he said, \"while the FDA applies its universal gold standard, eighteen thousand people have died from ALS since the trial inception in January 2010. ", "Nearly twelve thousand people have died from ALS since I was helped after my first surgery in March 2011.", "\n\n\"I had a chance. ", "I have hope. ", "What about everyone else?\"", "\n\nTed Harada had transitioned from ALS victim to ALS advocate—from patient number 11 to a champion for patients everywhere, and not just those suffering from ALS.", "\n\nBut he was only getting started.", "\n\n\"After I testified at the FDA, I didn't see a whole lot of change,\" Ted says. ", "So he used some contacts at the ALS foundation to get himself appointed to an official FDA patient advisory group. ", "He began attending meetings at FDA headquarters, but he didn't seem to be making much progress there either. ", "He found FDA officials defensive. ", "They spent their time trying to convince him that the drug-approval process was just fine.", "\n\nThen, one day, Ted was online looking at the Neuralstem website—he often checked CEO Richard Garr's blog for updates on how the clinical trial was doing—when he came across a blog post from Garr discussing the first Right to Try legislation that was then being considered by the Arizona legislature.", "\n\nSo Ted started looking into Right to Try—and the more he learned, the more sense it made.", "\n\n\"Right now, I don't need another treatment,\" Ted says. \"", "But what happens when I do? ", "Why should the FDA even have an opportunity to tell me no? ", "If I have a treatment that's proven, that's helped me two different times, why should I have to even ask and give the federal government the opportunity to tell me no?\"", "\n\nThis, he decided, would be his cause.", "\n\n\"I tried to exert outside pressure on the FDA from my testimony. ", "I tried to exert internal pressure from being part of the FDA representative program.\"", "\n\nNow, he says, he has a new strategy: \"I'm going to circumvent [the FDA] through Right to Try.\"", "\n\nTed decided to write an op-ed for his local paper, the _Atlanta Journal-Constitution_. ", "He shared his miraculous story in print for the first time, and declared, \"I am making it my personal mission to introduce 'Right to Try' to the Georgia General Assembly as part of next year's legislative session. . . . ", "I appreciate that the FDA is the gold standard in drug safety; however, if you or a loved one were facing mortality, would you be willing to settle for a silver standard?\"", "\n\nAfter his op-ed ran, state representative Mike Dudgeon emailed Ted and told him he would be happy to sponsor the legislation. ", "Ted connected Dudgeon with us at the Goldwater Institute, where we shared a draft of our model legislation and some of the bills that had been passed in other states.", "\n\nSoon Dudgeon introduced House Bill 34, the Georgia Right to Try Act.", "\n\nTed began lobbying for the bill, writing to legislators and meeting with the legislative staff to educate them about Right to Try. ", "He recruited another ALS patient in the Neuralstem study, Ed Tessaro, to join him in lobbying for Right to Try in Georgia.", "\n\nA retired Macy's executive, Ed was in Bangkok running a marathon seven years ago when he first noticed something was wrong. \"", "I was running a race there and for the first time in my life, after a lifetime of running, my left leg was performing differently. ", "I had a little flutter in it and it wasn't landing solid,\" he says.", "\n\nWhen he got home to Atlanta, he went to a doctor who diagnosed spinal stenosis. \"", "I was so happy to get that news, that it was a fixable thing, I didn't even get a second opinion,\" Ed says. \"", "I just said let's go fix that.\"", "\n\nHe had spinal-fusion surgery in February 2009. ", "It didn't work.", "\n\n\"Four months later I was getting worse—weaker in my legs—and then I became worried again and went to see a neurologist.\"", "\n\nHe was diagnosed with ALS. \"", "It just knocked the crap out of me because I've been a cyclist and a runner and a mountain climber for my entire life and you think you're bulletproof at that level and all of a sudden I get this.\"", "\n\nHe and Ted had lumbar surgery a month apart. ", "Because they responded so well, they were then among the three patients who got a second round of surgery in the upper spinal area that controls breathing.", "\n\nEd did not have the dramatic reversal of symptoms that Ted experienced—no one has yet. ", "But he is now stable in his disease, and for an ALS patient stability is life transforming. \"", "I can still walk a hundred yards with crutches, but I have a wheelchair,\" he says. ", "But five years after his ALS diagnosis, he has retained 100 percent of his lung function thanks to the surgery. \"", "It's breathing difficulties that eventually kill you,\" he says, adding, \"I'm in great shape. ", "I'm the best-conditioned guy with a fatal disease you've ever seen.", "\n\n\"Nobody really understands ALS,\" he says. \"", "They don't understand what it feels like to be a prisoner in your own body. ", "You know, your mind works, your eyes work, you're a hundred percent sharp but you can't move, you can't speak. ", "I mean that is a terror of a life sentence to be a prisoner in your own body.\"", "\n\nHe has testified four times before the Georgia legislature in support of Right to Try.", "\n\nEd says he told the lawmakers, \"You have to look at this as a patient rights bill. ", "I don't want you to give me a thing, I don't want a tax dollar. ", "I don't want anybody to do anything except allow me to take a risk to save my own life, to give me a chance at an experimental therapy or drug to save my own life.", "\n\n\"We like experimental. ", "We're not afraid of the word 'experimental,'\" Ed told the legislators. \"", "It's a personal sovereignty thing. ", "We know that something's safe but we know it's 'experimental only' and we're three years away from knowing whether or not I could buy it or ask my insurance company to buy it as a therapy. ", "Well, I don't have three years. ", "I'll foot the bill to do it right now.\"", "\n\nTed was recently invited to join the national board of the ALS Association and now flies to Washington several times a year to lobby Congress. ", "He has spoken at bioethics symposia and high school science classes, and he has helped patients in Indiana and Kansas get Right to Try introduced in their states.", "\n\n\"Ted is like an unstoppable force now,\" says Neuralstem CEO Richard Garr, who follows Ted's medical and political progress with pride.", "\n\nThe admiration is mutual. \"", "He's a brave, good man. ", "He cares,\" Ted says of Garr. ", "Ted says that when he recently completed his third ALS walk, Garr flew to Georgia just to join him. \"", "He donated to my walk team. ", "How many people do that? ", "How many people do that?\"", "\n\nHe plans to keep doing the ALS walk every year. \"", "It's two and a half miles and it wears me out,\" he says. \"", "It takes a few days for my legs to recover but I can do it. ", "And as long as I can do it, I'm going to keep doing it.\"", "\n\nHe says his wife told him this year that maybe he should skip the walk.", "\n\n\"And I'm like, 'Why? ", "I can still walk.' ", "She goes, 'I know, but do you see yourself the next few days afterward?' ", "But I said as long as I can it's a symbol that I can still do this. ", "And I think sometimes it provides a little hope for other people too. ", "In the ALS community hope has been a nonexistent commodity. ", "It doesn't exist. ", "So if this story, and me being able to do the walk, provides just an inkling of hope, then I'll deal with [the] few days that it takes to recuperate to provide that kind of hope.\"", "\n\nAt this writing, Ted's condition is holding steady. \"", "I'm doing good,\" he says. \"", "It's status quo. ", "I haven't gotten any worse. ", "I can't probably lift more than thirty pounds or so. ", "If I went to arm wrestle my eleven-year-old daughter, I couldn't beat her. ", "But I can do all my daily life activities. ", "I can live life every day.\"", "\n\nOn a recent checkup at Emory, Ted says, Dr. Glass told him something remarkable. \"", "You're the first ALS patient I ever told this to,\" Glass said, \"but right now you are not dying from ALS, you are living with it.\"", "\n\nTed looks back at the miracle he has undergone and wants to help others.", "\n\n\"I don't know why I was picked or why I was chosen,\" he says. \"", "It's tough for me to think that I'm no more deserving than anyone else. ", "But that kind of does drive my desire to help others because I feel like life is a gift you can't buy. ", "So if I've been given this gift, how selfish is it of me to keep that gift to myself and not do something good with it.", "\n\n\"We all wonder sometimes what our purpose is,\" he says. \"", "Maybe at the end of the day this is my purpose. ", "The easy thing is to take your ball and go home. ", "The hard thing is to do the work and try to make a difference even if it's an uphill battle and even if sometimes it impacts you physically. ", "But I think my faith also tells me that my moral compass is if God gave you a gift; who am I to waste God's gift?", "\n\n\"I haven't seen the burning bush,\" he says, \"but until I do I'm going to assume this is what He wants me to do.\"", "\n\nWould he have the surgery again if his ALS symptoms began to return?", "\n\n\"That's not up to me,\" Ted says. \"", "I wouldn't qualify for the trial anymore because it would be too long since my diagnosis, so if it gets to the point where I need it, if Right to Try doesn't exist, I'll be one of these people begging the FDA to give me a chance to live.\"", "\n\nHe says the government thinks it is protecting patients, but it's not.", "\n\n\"If you're on a plane that was crashing and there was a parachute, one parachute, and just because it didn't have a government stamp of approval on it, wouldn't you take your chance and try that parachute anyway? ", "You would. ", "If you looked at it and said, 'Oh, this thing's not certified, to heck with it, I guess I'll go down with the plane.' ", "No, that's not what people would do. ", "They'd take their chance with the parachute.", "\n\n\"I can go to Oregon and have the right to die, but it's not okay for me to try to save my life?\" ", "Ted says. \"", "It just doesn't make sense.\"", "\n\nSince word of his miraculous recovery spread, Ted has been inundated with requests for help from other patients.", "\n\n\"That's another reason why I'm so passionate,\" he says. \"", "I get letters and emails—people begging me for their daughter, their spouse; what can you do to help me get into this trial? ", "Obviously there's nothing I can do. ", "And I also explained to them, you know, there's no guarantee that you'd get the result I got. ", "And they say, 'Well, I know that, but I just want to try.' ", "And it is heartbreaking some of these requests you get. ", "And I just try to show them as much compassion as I can and give them as much support as I can.\"", "\n\nHe's also using the time he has been given to teach his kids important life lessons.", "\n\nWhen he first got his diagnosis, he thought, \"I could teach my kids how to deal with adversity, you know. ", "Maybe when something bad happens in their life later on—because bad stuff happens—they can really be like, this is how my dad dealt with it. ", "I wanted to show them that you have to hold your head high, and that was something that I wanted to impart to them.\"", "\n\nThen, when he experienced his miraculous turnaround, the lesson changed.", "\n\n\"Now that I've been helped, I'm modeling the way for them that if you're given gifts, it's not just about the gift you received and, great, now you're happy, and you can be done. ", "Now you have to see how you can help others. ", "Whatever your gift or talent is you really have to see now how you can help others. ", "And I try to impart that to them no matter what.\"", "\n\nRecently, Ted was at the local hospital, visiting people from his church\n\n\"I was walking down the hall, and a lady comes out of her room and says, 'Are you Ted?' ", "I said yes. ", "She said, 'My name is Katie, we are connected on Facebook, and my husband, Bruce, has ALS.' ", "She then told me that Bruce is in the hospital with pneumonia. ", "I asked if I could meet Bruce. ", "So she took me in their room and she told Bruce who I was and his eyes got big and he smiled. ", "We talked for fifteen minutes and prayed together. ", "His wife told me how hard they tried to get in the stem-cell trial but the timing didn't work out. ", "They thanked me for all I do, which is so humbling because I am in awe of these patients dying without hope.", "\n\n\"It was a blessing to meet these people,\" he says. \"", "We as a society need to do more than treat them as if their lives are a disposable commodity, and bicker over drug regulations for dying people.\"", "\n\nDIEGO MORRIS RECENTLY WENT back to St. Jude Children's Research Hospital to have his prosthetic adjusted. ", "Doctors at St. Jude had designed a special pediatric prosthetic that can be lengthened as he grows without additional surgeries.", "\n\n\"They put a ring around his leg; they put him under; they use heat and magnets and they pull the string and the prosthetic lengthens,\" his mom, Paulina, says.", "\n\nThe experience can be traumatic—imagine having your leg extended by an inch or more overnight. ", "But two years after his treatment, Diego is doing great. ", "Instead of going every three months for a body scan, he's able to go every six months now.", "\n\nMifamurtide—the drug the FDA denied him here at home—worked.", "\n\nHe's playing baseball again too. \"", "He's a great athlete. ", "He's not able to run, but that's really the only thing that slows him down,\" his father, Jason, says.", "\n\n\"We found him a super coach and team and it was very emotional for my husband and I to see him back on the pitching mound,\" says Paulina. \"", "It's not the preference of the surgical artist, but our surgeon has I think three sons and he understands Diego's desire to be athletic.\"", "\n\nAs he resumes a normal teenage life, Diego is still fighting for the Right to Try. ", "After his successful efforts to pass Right to Try in Arizona, he told us that he wanted to stay involved. ", "So now he is helping make the case for Right to Try laws in other states.", "\n\n\"I am so fortunate to be cancer free,\" he says. \"", "I want to help children who need medical treatment get the medicine they need at home. ", "I want to help others.\"", "\n\nDiego and his family recently traveled to Oregon to talk with legislators and encourage them to pass Right to Try. ", "He met members of the House Committee on Health Care and held a press conference in the state capitol with Representative Knute Buehler, an orthopedic surgeon who is the bill's principal sponsor.", "\n\n\"I told them that I think Right to Try needs to pass because it's important that everyone has the ability to save their lives with experimental drugs and to save their families, and I think it's important that we get the drugs in the US when we need them,\" Diego says.", "\n\nHe's become a pretty effective advocate. ", "Not long after Diego's visit, Right to Try passed the Oregon House by a unanimous 60 to 0 vote, and the Senate by a unanimous 29 to 0 vote.", "\n\nWhen Diego returned from his lobbying trip in Oregon, he was able to share his experiences with his social studies class. \"", "It was fun telling my social studies teacher after the trip about the whole experience,\" Diego says, \"because right now we're learning about the Arizona constitution and politics so it was fun telling about it.\"", "\n\nHe may have been the only kid in his class—or any eighth-grade class for that matter—who has actually changed the laws of his state.", "\n\nHis mom says the entire experience has transformed Diego.", "\n\n\"You never know how strong you are until you're faced with adversity,\" Paulina says. \"", "And the opportunity to try and help others and make a difference and change a very stringent bureaucratic process here in the United States just has been amazing.", "\n\n\"In the United States we should be able to have options. ", "We should be able to make informed decisions and have choices that we work in partnership with our doctor on in making informed choices, not just for ourselves but for our loved ones, for our children. ", "This is the United States; we should be able to do that.\"", "\n\nBut to this day, Diego's government still has not approved the medication that helped save his life. ", "And he is not the only one who needs it.", "\n\nSome sixty-four hundred people in the United States have been diagnosed with osteosarcoma since the FDA rejected mifamurtide in 2007—about half of them children. ", "Not all of them can afford to move overseas to get the medication they need to save their lives as Diego did.", "\n\nWhy, Diego asks, should people have \"to move five thousand miles away to receive treatment because our government could not approve a study after more than a decade? ", "It's not right and nobody should have to go through the struggle of doing that. ", "And not many people would even be able to do that. ", "We were lucky to get the opportunity to go to London but not many people can just leave the country and go get a drug that should be approved but isn't.\"", "\n\nPaulina's message to the FDA is simple:\n\n\"Listen up!\" ", "she says. \"", "Listen up to what's happening around this country.\"", "\n\nRight to Try has now passed in twenty-four states and counting, and the movement is showing no signs of slowing down.", "\n\n\"This is spreading like wildfire,\" she says. \"", "You need to hear the changes that people want.\"", "\n\nCHRIS GARABEDIAN, THE FORMER CEO of Sarepta, believes change is coming.", "\n\n\"What we've seen over the last couple of years is an increasing demand of patients across many disease areas of getting access to drugs that are in clinical development,\" he recently told the _Boston Business Journal_. \"", "There's an increasing voice from the community [saying] that it is their right to get access to these investigational drugs, consistent with the Right to Try legislation.\"", "\n\nGarabedian says, \"The demand's not going away.\"", "\n\nHe's right. ", "And neither is the Goldwater Institute . . . ", "or Diego Morris . . . ", "or Ted Harada . . . ", "or Frank Burroughs . . . ", "or any of the countless heroes we've met who are fighting to get life-saving treatments to their fellow Americans before time runs out.", "\n\nIn chapter 1, Tracy Seckler, one of the Duchenne moms, compared the plight of their kids to the passengers on the _Titanic_. ", "It's an apt analogy. ", "As a society, we can and should debate the best ways to make better, stronger lifeboats. ", "We can and should ensure the safety and reliability of lifeboats. ", "We can and should figure out the best ways to pay for lifeboats and make sure we have more of them.", "\n\nBut there is no argument for _withholding_ the lifeboats we do have from drowning kids.", "\n\nThrough the Right to Try movement, Americans are sending the powers that be an unmistakable message: Get those lifeboats in the water _right now_. ", "We are not okay with letting those kids drown. ", "Rescue those kids—and _then_ figure out how to make better lifeboats.", "\n\nAnd how are the opponents of Right to Try responding to this grassroots effort to rescue dying kids? ", "With excuses: \"We don't know if the lifeboats will work. . . . ", "We don't want to give the drowning kids 'false hope.' . . . ", "We don't have enough lifeboats for everyone, so we can't give them to anyone. . . . ", "We don't know how to pay for the lifeboats. . . . ", "It's not fair that the lifeboat manufacturers feel pressure to deploy them before they are ready. . . . ", "We need to form a committee to decide who gets rescued and who doesn't. . . . ", "We need to make sure there is a system in place to ensure people get in the lifeboats in an orderly fashion.\"", "\n\nGood grief.", "\n\nNo wonder Right to Try is passing unanimously almost everywhere it comes up for a vote. ", "On one hand, Americans see drowning kids. ", "On the other, they see the government and the pharmaceutical industry making excuses for why we can't rescue them.", "\n\nDoes anyone doubt how this debate is going to play out?", "\n\nThe dying children will win.", "\n\nThis is why Richard Garr—who is quite explicit about the very real challenges in implementing these new laws—is on the Right to Try team. ", "On the wall in his office, he keeps a reprint of a newspaper story about a young girl who had experimental gene therapy to treat a brain tumor. ", "It failed and the girl died. ", "He keeps the story, he says, to remind himself that \"every day is the last day for somebody, someplace.\"", "\n\nWe should all keep in mind the kids facing that last day as we debate these issues.", "\n\nHe's right. ", "Boys with Duchenne . . . ", "kids with osteosarcoma . . . ", "moms with multiple myeloma . . . ", "dads with Lou Gehrig's disease . . . ", "young girls with brain tumors—they are all drowning right now. ", "They don't have time to wait.", "\n\nLet's get the lifeboats in the water.", "\n\n## Acknowledgments\n\nLet's be honest: I'm the mother of three toddlers. ", "When a friend suggested that I write this book, the idea seemed preposterous. ", "Where would I find the time?", "\n\nMy thanks go first to my collaborator, Marc Thiessen; and to the beloved friend who introduced us, Wynton Hall. ", "Marc conducted dozens of interviews and flawlessly penned sentence after sentence to turn my ideas into this book. ", "His buoyant humor made the work joyful, and the book possible.", "\n\nFor the conception of the Right to Try, I'm indebted to my friend Chuck Warren, who invited us to meet with the Cancer Treatment Centers of America to learn about the barriers to receiving life-saving treatments, and who challenged us to find a solution.", "\n\nThe Right to Try became our answer and was developed over several months by my extraordinarily talented colleagues, namely Kurt Altman, Clint Bolick, Starlee Coleman, Christina Corieri, Adi Dynar, and Christina Sandefur.", "\n\nThrough exceptional strategic acumen, Victor Riches drove the Right to Try in five states in rapid succession, passing the torch to Kurt Altman, Craig Handzlik, and Michael Hunter, who made short work of taking the initiative to the next seventeen states.", "\n\nWe owe a great debt to our many on-the-ground partners, including the McLinn family, Linda Clark and Jehad Majed of PALS, Kelly Sawyer and her team at Change.org, Andi's Army and Michelle Wittenburg of the KK125 Ovarian Cancer Research Foundation, Lindsay Boyd and Justin Owen of the Beacon Center, Steve Buckstein of Cascade Policy Institute, Dr. Jameson Taylor of the Mississippi Center for Public Policy, Renae Cowley, and the State Policy Network.", "\n\nJustin Lang, Dan Lips, Naomi Lopez-Bauman, and Christina Sandefur were the principal researchers on the book, cheerfully and meticulously slogging through reams of data to pinpoint truth. ", "I'm also indebted to the UCLA law professor Eugene Volokh for his insightful review.", "\n\nI'd also like to thank friends and colleagues who have contributed to this book in countless ways, including Annica Benning, Carol Carter, Matt Gallaher, Richard Garr, Michael Kelley, Beau and Amanda Law, Erik Merkow, Jon Riches, Stephanie Rugolo, Kris Schlott, Le Templar, Blake Wilson, Roger Zetah, and the Goldwater Institute's talented law clerks and interns.", "\n\nThe Goldwater Institute is funded entirely through donations, and the Right to Try simply would not exist without the thousands of committed men and women who generously support us. ", "Thanks to Eric Crown, the Goldwater Institute board of directors, Tom and Sabina Sullivan, the JM Foundation, the Milbank Foundation, the Randolph Foundation, and Searle Freedom Trust for providing essential funding to turn the vision for the Right to Try into reality.", "\n\nThanks to the patients, family members, analysts, medical researchers, and physicians who shared their personal experiences for this book. ", "I did my best to convey your voices and stories honestly and accurately and take full responsibility for any omissions or errors.", "\n\nI've been blessed by many people in pursuit of this work but none so much as Norman McClelland, whose integrity and constancy provided light when dark skies appeared.", "\n\nAnd finally, my gratitude to Adam Bellow, FE, for taking a chance on a new author, for patiently guiding the manuscript's development, and for what has become a bright friendship that I cherish.", "\n\n## Notes\n\nINTRODUCTION\n\n. ", "Andrew von Eschenbach and Ralph Hall, \"FDA Approvals Are a Matter of Life and Death,\" _Wall Street Journal_ , June 17, 2012, accessed February 14, 2015, http://www.wsj.com/articles/SB10001424052702303753904577454163076760768.", "\n\n. \"", "Debate over 'Right-to-Try' Laws,\" _The Diane Rehm Show_ , National Public Radio, May 27, 2014, accessed March 14, 2015, http://thedianerehmshow.org/shows/2014-05-27/debate-over-right-try-laws.", "\n\n. \"", "Expanded Access Submission Receipts Report (October 1, 2011–September 30, 2012),\" US Food and Drug Administration, accessed March 4, 2015, http://www.fda .gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedand Approved/DrugandBiologicApprovalReports/INDActivityReports/UCM390564 .pdf.", "\n\n. \"", "Cancer Facts & Figures 2012,\" American Cancer Society, accessed February 16, 2015, http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2012/.\n\n. ", "Emily Rauhala, \"North Korea Elections: A Sham Worth Studying,\" _Time_ , March 10, 2014, accessed February 16, 2015, http://time.com/17720/north-korea-election -a-sham-worth-studying/.\n\n. \"", "Arizona Terminal Patients' Right to Try Referendum, Proposition 303 (2014),\" Ballotpedia, accessed March 3, 2015, http://ballotpedia.org/Arizona_Terminal_Patients %27_Right_to_Try_Referendum,_Proposition_303_%282014%29.", "\n\nCHAPTER 1: SOPHIE'S CHOICE\n\n. ", "Margaret Wahl, \"Exon Skipping in DMD: What Is It and Whom Can It Help?\" _", "Quest_ , October 1, 2011, accessed February 3, 2015, http://quest.mda.org/article/exon-skipping-dmd-what-it-and-whom-can-it-help.", "\n\n. ", "Balasubramanyam Seshan, \"EU Patent Dispute Outcome Limits DMD Opportunity for AVI Biopharma,\" _International Business Times_ , November 21, 2011, accessed February 23, 2015, http://www.ibtimes.com/eu-patent-dispute-outcome-limits-dmd-opportunity-avi-biopharma-372646.", "\n\n. ", "Paul M. Barrett, \"Moms, Regulators, Biotech Startups, and the Battle over a Potentially Life-Saving Drug,\" _Bloomberg Business_ , October 30, 2014, accessed February 18, 2015, http://www.businessweek.com/printer/articles/233350-moms-regulators-biotech-startups-and-the-battle-over-a-potentially-life-saving-drug.", "\n\n. ", "Luke Timmerman, \"Profiles in Long-Termism: Sarepta Therapeutics CEO Chris Garabedian,\" _Xconomy_ , June 10, 2013, accessed November 28, 2014, http://www .xconomy.com/national/2013/06/10/profiles-in-long-termism-sarepta-therapeutics-ceo-chris-garabedian/.\n\n. ", "Ibid.", "\n\n. ", "Don Seiffert, \"Transcript of Interview with Former Sarepta CEO Chris Garabedian,\" _Boston Business Journal_ , April 28, 2015, accessed May 3, 2015, http://www.bizjournals .com/boston/blog/bioflash/2015/04/transcript-of-interview-with-former-sarepta-ceo .html.", "\n\n. ", "Timmerman, \"Profiles in Long-Termism.\"", "\n\n. \"", "Sarepta Therapeutics Announces Eteplirsen Meets Primary Endpoint of Increased Novel Dystrophin and Achieves Significant Clinical Benefit on 6-Minute Walk Test After 48 Weeks of Treatment in Phase IIb Study in Duchenne Muscular Dystrophy,\" Sarepta Therapeutics, October 3, 2013, accessed February 10, 2015, http://investor relations.sarepta.com/phoenix.zhtml?c=64231&p=irol-newsArticle&ID=1741044.", "\n\n. \"", "Sarepta Letter to Patient Community,\" Parent Project Muscular Dystrophy, accessed April 25, 2015, http://www.parentprojectmd.org/site/DocServer/Sarepta_Letter_to _Patient_Community_082812.pdf?docID=13303.", "\n\n. ", "Seiffert, \"Transcript of Interview with Former Sarepta CEO Chris Garabedian.\"", "\n\n. ", "Barrett, \"Moms, Regulators, Biotech Startups, and the Battle over a Potentially Life-Saving Drug.\"", "\n\n. ", "Ibid.", "\n\n. ", "Seiffert, \"Transcript of Interview with Former Sarepta CEO Chris Garabedian.\"", "\n\n. \"", "Sarepta Therapeutics Announces FDA Will Consider Accelerated Approval for Eteplirsen after Further Review of Data on Dystrophin and Clinical Outcomes,\" Sarepta Therapeutics, April 15, 2013, accessed May 12, 2015, http://investorrelations.sarepta.com/phoenix.zhtml?c=64231&p=irol-mediaPressArticle&ID=1806913.", "\n\n. \"", "Sarepta Therapeutics Announces Plans to Submit New Drug Application to FDA for Eteplirsen for the Treatment of Duchenne Muscular Dystrophy in First Half of 2014,\" Sarepta Therapeutics, July 24, 2013, accessed May 12, 2015, http://investorrelations .sarepta.com/phoenix.zhtml?c=64231&p=irol-mediaPressArticle&ID=1840401.", "\n\n. ", "Barrett, \"Moms, Regulators, Biotech Startups, and the Battle over a Potentially Life-Saving Drug.\"", "\n\n. \"", "Sarepta Therapeutics Announces FDA Considers NDA Filing for Eteplirsen Premature in Light of Recent Competitive Drug Failure and Recent DMD Natural History Data,\" Sarepta Therapeutics, November 12, 2013, accessed May 13, 2015, http://investor relations.sarepta.com/phoenix.zhtml?c=64231&p=irol-mediaPressArticle&ID=1875187.", "\n\n. \"", "Petition: Urge the FDA to Say Yes to Accelerated Approval for Safe, Effective Therapies for Children with Duchenne,\" The White House, accessed February 17, 2015, https://petitions.whitehouse.gov/petition/urge-fda-say-yes-accelerated-approval-safe-effective-therapies-children-duchenne.", "\n\n. ", "Tracy Seckler, \"Needless Delay for a Medicine That Could Save Kids' Lives,\" _Huffington Post_ , March 5, 2014, accessed May 9, 2015, http://www.huffingtonpost.com/tracy-seckler/eteplirsen-duchenne_b_4904850.html.", "\n\n. \"", "Sarepta Therapeutics Announces Plans to Submit New Drug Application to FDA for Eteplirsen for the Treatment of Duchenne Muscular Dystrophy by Year End 2014,\" Sarepta Therapeutics, April 21, 2014, accessed May 12, 2015, http://investorrelations .sarepta.com/phoenix.zhtml?c=64231&p=irol-mediaPressArticle&ID=1920025.", "\n\n. \"", "Exon Skipping for Duchenne,\" Sarepta Therapeutics, accessed January 24, 2015, http://www.sarepta.com/pipeline/exon-skipping-duchenne.", "\n\nCHAPTER 2: FIVE THOUSAND MILES FOR A CURE\n\n. \"", "What Are the Survival Rates for Osteosarcoma?\" ", "American Cancer Society, accessed December 9, 2014, http://www.cancer.org/cancer/osteosarcoma/detailedguide/osteosarcoma-survival-rates.", "\n\n. \"", "Immune-Based Drug Approved in Europe for Pediatric Cancer Patients,\" MD Anderson Cancer Center, March 10, 2009, accessed February 5, 2015, http://www.mdanderson .org/newsroom/news-releases/2009/immune-based-drug-approved-in-europe-for-pediatric-cancer-patients.html.", "\n\n. ", "E. S. Kleinerman, P. A. Meyers, C. L. Schwartz, et al., \"", "Osteosarcoma: A Randomized, Prospective Trial of the Addition of Ifosfamide and/or Muramyl Tripeptide to Cisplatin, Doxorubicin, and High-Dose Methotrexate,\" _Journal of Clinical Oncology_ 23 (2005): 2004, accessed May 13, 2015, doi: 10.1200/JCO.2005.06.031.", "\n\n. \"", "The Journey of an Orphan Drug,\" _Children's Cancer Hospital Newsletter_ (MD Anderson Cancer Center), Spring 2013, accessed April 25, 2015, http://www.mdanderson.org/pub lications/children-s-cancer-hospital-newsletter/issues/2013-spring/mepact.html.", "\n\n. ", "Bonnie Mills, \"Oncologic Drugs Advisory Committee on MTP for Osteosarcoma,\" presentation, Silver Spring, MD, May 9, 2007, accessed March 18, 2015, http://www.power show.com/view1/1f9c35-ZDc1Z/Oncologic_Drugs_Advisory_Committee_on_MTP_for_Osteosarcoma_powerpoint_ppt_presentation.", "\n\n. \"", "FDA Briefing Document—NDA 022092,\" Oncologic Drugs Advisory Committee, May 9, 2007, accessed March 15, 2015, http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4301b1-02-FDA-redacted.pdf.", "\n\n. ", "Eugenie S. Kleinerman, \"Oncologic Drugs Advisory Committee Hearing,\" Center for Drug Evaluation and Research, 57, May 9, 2007, accessed February 18, 2015, http://www .fda.gov/ohrms/dockets/ac/07/transcripts/2007-4301t1-Part1.pdf.", "\n\n. \"", "IDM Pharma Receives Not Approvable Letter for Mifamurtide for Treatment of Osteosarcoma,\" _News Medical_ , August 28, 2007, accessed January 29, 2015, http://www .news-medical.net/news/2007/08/28/29154.aspx.", "\n\n. \"", "Mepact,\" European Medicines Agency, last modified January 10, 2013, accessed January 29, 2015, http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/med icines/000802/human_med_000899.jsp&mid=WC0b01ac058001d124.", "\n\n. ", "Lynne Taylor, \"PAS Reverses NICE Rejection of Takeda's Mepact,\" _PharmaTimes_ , October 27, 2011, accessed January 30, 2015, http://www.pharmatimes.com/Article/11-10-27/PAS_reverses_NICE_rejection_of_Takeda_s_Mepact.aspx.", "\n\n. \"", "Voters Approve Experimental-Drug Measure,\" KJZZ News, November 4, 2014, accessed April 21, 2015, http://kjzz.org/content/63525/voters-approve-experimental-drug-measure.", "\n\nCHAPTER 3: MAKING MEDICAL MIRACLES\n\n. \"", "Understanding Carcinoid Cancer,\" _Inside Mount Sinai_ , December 21, 2008, accessed January 17, 2015, http://www.mountsinai.org/vgn_lnk/Regular%20Content/File/Faculty %20Profile%20Pdfs/MSN_inside_121508_Warner.pdf.", "\n\n. ", "Walter Isaacson, _Steve Jobs_ (New York: Simon & Schuster, 2011), 480.", "\n\n. \"", "What Is an OctreoScan?\" ", "Carcinoid Cancer Foundation, accessed January 17, 2015, http://www.carcinoid.org/content/what-octreoscan.", "\n\n. ", "D. J. Kwekkeboom, B. L. Kam, M. van Essen, et al., \"", "Somatostatin Receptor-Based Imaging and Therapy of Gastroenteropancreatic Neuroendocrine Tumors,\" _Endocrine-Related Cancer_ 17 (2010): R53–R73, accessed January 7, 2015, doi: 10.1677/erc-09-0078.", "\n\n. \"", "What Is Peptide Receptor Radionuclide Therapy (PRRT)?\" ", "Society of Nuclear Medicine and Molecular Imaging, accessed March 20, 2014, http://snmmi.files.cms-plus.com/docs/fact_sheets/PRRT_Final.pdf.", "\n\n. ", "Lindsey Miller, \"Ich Bin Eine Lebe,\" _I Am a Liver_ (blog), May 24, 2013, accessed February 12, 2015, https://iamaliver.wordpress.com/2013/05/24/ich-bin-eine-lebe/.\n\n. ", "Lindsey Miller, \"Crowdfunding My Cancer Care,\" _Huffington Post_ , April 3, 2014, accessed February 13, 2015, http://www.huffingtonpost.com/lindsey-miller/crowdfunding-for-my-medic_b_5073305.html.", "\n\n. ", "Jaclyn Cosgrove, \"Oklahoma Vietnam Veteran with Cancer Asks Why VA Won't Cover His Care,\" _Daily Oklahoman_ , June 22, 2014, accessed May 1, 2015, http://newsok .com/oklahoma-vietnam-veteran-with-cancer-asks-why-va-wont-cover-his-care/article/4949250/?page=1.", "\n\n. \"", "Netter-1 Study,\" Advanced Accelerator Applications, accessed March 21, 2015, http://www.adacap.com/netter-1/.\n\n. ", "D. Wild, M. Fani, R. Fischer, et al., \"", "Comparison of Somatostatin Receptor Agonist and Antagonist for Peptide Receptor Radionuclide Therapy: A Pilot Study,\" _Journal of Nuclear Medicine_ 55 (2014): 1248–52, accessed January 9, 2015, doi: 10.2967/jnumed.114.138834.", "\n\n. ", "Marsha Shuler, \"'Dallas Buyers Club' Bill Signed into Law in La.,\" _The Advocate,_ June 2, 2014, accessed April 5, 2015, http://theadvocate.com/news/9317769-123/dallas-buyers-club-bill-signed.", "\n\nCHAPTER 4: WHAT STEVE JOBS SAW\n\n. \"", "Serendipity,\" Mayo Clinic, accessed February 26, 2015, http://www.mayoclinic.org/giving-to-mayo-clinic/your-impact/features-stories/serendipity.", "\n\n. ", "Ibid.", "\n\n. ", "Lindsey Seavert, \"Mayo Clinic Trial: Massive Measles Vaccine Attacks Blood Cancer,\" _KARE_ 11, May 15, 2014, accessed May 13, 2015, http://www.kare11.com/story/news/health/2014/05/14/mayo-clinic-trial-measles-vaccine-multiple-myeloma/9101893/.\n\n. ", "Lizzy Smith, \"An Interview with Stacy Erholtz on Getting the Measles Vaccine & Participating in Clinical Trials,\" _Myeloma Crowd_ , October 22, 2014, accessed January 27, 2015, http://www.myelomacrowd.org/interview-stacy-erholtz-getting-measles-vaccine-participating-clinical-trials/.\n\n. \"", "Serendipity,\" Mayo Clinic.", "\n\n. ", "Dan Browning, \"Mayo Clinic Trial: Massive Blast of Measles Vaccine Wipes Out Cancer,\" _Minneapolis_ _Star Tribune_ , December 18, 2014, accessed March 9, 2015, http://www.startribune.com/no-4-massive-blast-of-measles-vaccine-wipes-out-cancer-in-mayo-clinic-trial/259155541/.\n\n. ", "Lindsey Bever, \"Woman's Cancer Killed by Measles Virus in Unprecedented Trial,\" _Washington Post_ , May 15, 2014, accessed March 28, 2015, http://www.washing tonpost.com/news/morning-mix/wp/2014/05/15/womans-cancer-killed-by-measles-virus-in-unprecedented-trial/.\n\n. ", "Lecia Bushak, \"Measles Virus Cures Cancer in Woman with Multiple Myeloma; Stacy Erholtz Now Fundraising More Research,\" _Medical Daily_ , September 12, 2014, accessed March 12, 2015, http://www.medicaldaily.com/measles-virus -cures-cancer-woman-multiple-myeloma-stacy-erholtz-now-fundraising-more-302850.", "\n\n. ", "Jacque Wilson and William Hudson, \"Measles Virus Used to Put Woman's Cancer into Remission,\" CNN, May 18, 2014, accessed April 17, 2015, http://www.cnn .com/2014/05/15/health/measles-cancer-remission/.\n\n. ", "Scott Pelley, \"Killing Cancer,\" _60 Minutes_ , CBS, aired March 29, 2015, accessed March 30, 2015, http://www.cbsnews.com/news/polio-cancer-treatment-duke-university-60-minutes-scott-pelley/.\n\n. ", "Ibid.", "\n\n. ", "Ibid.", "\n\n. \"", "Providence Brain and Cancer Experts Begin First-in-World Novel Brain Tumor Vaccine Research Trial,\" _Providence Health & Services_, May 5, 2014, accessed April 2, 2015, http://oregon.providence.org/news-and-events/news/2014/05/providence-brain-and-cancer-experts-begin-first-in-world-novel-brain-tumor-vaccine-research-trial/.\n\n. ", "Ibid.", "\n\n. ", "Shannon O. Wells, \"'Luckiest Guy' Gets a New Lease on Life,\" _Beaverton Valley Times_ , July 2, 2014, accessed April 4, 2015, http://www.pamplinmedia.com/bvt/15-news/226045-88134-luckiest-guy-gets-a-new-lease-on-life.", "\n\n. ", "Browning, \"Mayo Clinic Trial.\"", "\n\n. \"", "Fire with Fire—Ross Kauffman—GE Focus Forward,\" YouTube video, 3:39, posted by \"General Electric,\" May 5, 2013, https://www.youtube.com/watch?v=h6SzI2ZfPd4.", "\n\n. \"", "Childhood Acute Lymphoblastic Leukemia Treatment—for Health Professionals (PDQ®),\" National Cancer Institute, last modified May 20, 2015, accessed May 26, 2015, http://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq#section/all.", "\n\n. \"", "Fire with Fire—Ross Kauffman—GE Focus Forward,\" YouTube video.", "\n\n. ", "Matthew Herper, \"Is This How We'll Cure Cancer?\" _", "Forbes_ , May 7, 2014, accessed May 20, 2015, http://www.forbes.com/sites/matthewherper/2014/05/07/is-this-how-well-cure-cancer/.\n\n. ", "Ibid.", "\n\n. \"", "How Many People Get Acute Lymphocytic Leukemia?,\" ", "American Cancer Society, last modified January 12, 2015, accessed April 15, 2015, http://www.cancer.org/cancer/leukemia-acutelymphocyticallinadults/overviewguide/leukemia-all-overview-key-statistics.", "\n\n. \"", "Glioblastoma Multiforme,\" _American Association of Neurological Surgeons_ , March 2015, accessed May 6, 2015, http://www.aans.org/Patient%20Information/Conditions%20and %20Treatments/Glioblastoma%20Multiforme.aspx.", "\n\n. \"", "How Many People Get Multiple Myeloma?\" ", "American Cancer Society, last modified June 19, 2014, accessed April 15, 2015, http://www.cancer.org/cancer/multiplemyeloma/overviewguide/multiple-myeloma-overview-key-statistics.", "\n\n. \"", "Fight to Live,\" _Gravitas Ventures_ , directed by Barbara Kopple (2014).", "\n\n. \"", "Dr. John C. Bell,\" Ottawa Hospital Research Institute, accessed April 16, 2015, http://www.ohri.ca/corporate/jbell.asp.", "\n\n. ", "John C. Bell, Caroline J. Breitbach, et al., \"", "Intravenous Delivery of a Multi-Mechanistic Cancer-Targeted Oncolytic Poxvirus in Humans,\" _Nature_ 477 (2011): 99–102, accessed May 1, 2015, doi:10.1038/nature10358.", "\n\nCHAPTER 5: INSIDE MAN\n\n. ", "Kathleen Doheny, \"When Depression Becomes Deadly,\" WebMD, August 14, 2014, accessed March 3, 2015, http://www.webmd.com/depression/news/20140812/depression-deadly.", "\n\n. \"", "FDA Approves Neuralstem to Treat Final Cohort in NSI-189 Phase Ib Trial in Major Depressive Disorder,\" Neuralstem Inc., accessed February 21, 2015, http://investor.neu ralstem.com/2013-04-22-FDA-Approves-Neuralstem-To-Treat-Final-Cohort-In-NSI-189-Phase-Ib-Trial-In-Major-Depressive-Disorder.", "\n\n. ", "David Frey, \"A Better Pill to Swallow,\" _Bethesda Magazine_ , November-December 2013, accessed March 2, 2015, http://www.bethesdamagazine.com/Bethesda-Magazine/November-December-2013/NSI-189/.\n\n. ", "Kim Kozlowski, \"UM Researcher Uses Stem Cells to Fight Alzheimer's,\" _Detroit News_ , November 11, 2014, accessed April 25, 2015, http://www.detroitnews.com/story/news/local/michigan/2014/11/11/um-researcher-uses-stem-cells-fight-alzheimers/18895621/.\n\n. ", "Richard Garr, \"Post: December 2, 2013,\" Neuralstem Inc. blog, December 2, 2013, accessed December 14, 2014, http://www.neuralstem.com/neuralstem-ceo-blog/208-every-man-gotta-right-to-decide-his-own-destiny.", "\n\n. ", "Andrew Pollack, \"Ebola Therapy from an Obscure Biotech Firm Is Hurried Along,\" _New York Times_ , August 6, 2014, accessed February 25, 2015, http://www.nytimes .com/2014/08/07/business/an-obscure-biotech-firm-hurries-ebola-treatment.html.", "\n\n. ", "Lenny Bernstein and Brady Dennis, \"Small Drugmakers Try to Scale Up to Meet Ebola Crisis,\" _Washington Post_ , October 9, 2014, accessed January 9, 2015, http://www .washingtonpost.com/national/health-science/2014/10/09/a594dec2-4fee-11e4-babe-e91da079cb8a_story.html.", "\n\n. ", "Sheri Fink and Rick Gladstone, \"Two Vaccines to Protect Against Ebola Could Be Available Within Weeks,\" _New York Times_ , September 5, 2014, accessed January 11, 2015, http://www.nytimes.com/2014/09/06/world/africa/ebola-vaccine-could-be-ready-by-november-who-says.html.", "\n\n. ", "Richard Garr, \"The FDA Is Not the Enemy,\" _The Chairman's Blog_ , June 9, 2014, accessed March 2, 2015, http://www.thechairmansblog.com/neuralstem/richard-garr/fda-enemy/.\n\n. ", "Amy Dockser Marcus, \"Frustrated ALS Patients Concoct Their Own Drug,\" _Wall Street Journal_ , April 15, 2012, accessed January 7, 2015, http://www.wsj.com/articles/SB10001424052702304818404577345953943484054.", "\n\nCHAPTER 6: WE ARE THE 99 PERCENT\n\n. ", "Linda Carroll, \"Mom's Heartache: Two Sons Have Deadly Disease, but Only One Can Get 'Miracle Drug,'\" NBC News, May 27, 2013, accessed May 1, 2015, http://www.today .com/health/moms-heartache-two-sons-have-deadly-disease-only-one-can-6C10077829.", "\n\n. ", "Kylee Wierks, \"Boy with Fatal Condition Gets Dream Job with IFD,\" Fox 59, December 24, 2014, accessed May 1, 2015, http://fox59.com/2014/12/24/boy-with-fatal-condition-to-interview-for-dream-job-with-ifd/.\n\n. ", "Derrik Thomas, \"5-Year-Old Gets Wish, 'Hired' by IFD,\" RTV6 ABC, December 25, 2014, accessed May 1, 2015, http://www.theindychannel.com/news/local-news/watch-5-year-old-gets-wish-hired-by-ifd.", "\n\n. ", "Matt Smith, \"Five-Year-Old Indiana Boy to Lawmakers: 'Please Say Yes' to Right to Try Bill,\" Fox 59, March 4, 2015, accessed May 1, 2015, http://fox59.com/2015/03/04/indiana-boy-to-lawmakers-please-say-yes-to-right-to-try-bill/.\n\n. ", "Jessica Firger, \"Indiana Governor Signs 'Right to Try' Drug Law,\" CBS News, March 24, 2015, accessed May 2, 2015, http://www.cbsnews.com/news/indiana-governor-signs-right-to-try-drug-law/.\n\n. \"", "The Little Boy Behind Indiana's 'Right to Try' Bill,\" CBS News, March 25, 2015, accessed May 3, 2015, http://www.cbsnews.com/news/jordan-mclinn-5-year-old-face-behind-indiana-right-to-try-bill-muscular-dystrophy/.\n\n. ", "Kevin Rader, \"Five-Year-Old Hero's Fight Begins as Pence Signs 'Right to Try' Bill,\" WTHR, March 24, 2015, accessed May 3, 2015, http://www.wthr.com/story/28598710/pence-set-to-sign-right-to-try-bill.", "\n\n. \"", "Save Locky's Dad,\" YouTube video, 3:25, posted by \"Savelockys Dadnick,\" August 28, 2013, https://www.youtube.com/watch?v=3teA62o5eLY.", "\n\n. ", "Sydney Lupkin, \"Dad Pleading for Unapproved Cancer Drug Dies,\" ABC News, November 25, 2013, accessed February 26, 2015, http://abcnews.go.com/Health/dad-pleading-unapproved-cancer-drug-dies/story?id=21004482&singlePage=true.", "\n\n. ", "Save Locky's Dad Facebook page, last modified November 24, 2013, accessed May 2, 2015, https://www.facebook.com/savelockysdad/photos/a.213259775503468 .1073741830.208927279270051/237716026391176/.\n\n. ", "Kurtis Lee, \"'Right to Try' Aims to Limit Bureaucracy for Colorado's Terminally Ill,\" _Denver Post_ , April 1, 2014, accessed May 2, 2015, http://www.denverpost.com/politics/ci_25463368/right-try-aims-limit-bureaucracy-colorados-terminally-ill.", "\n\n. ", "Kristen Wyatt, \"Governor Signs Ginal's 'Right to Try' Bill,\" _Coloradoan_ , May 17, 2014, accessed May 2, 2015, http://www.coloradoan.com/story/news/local/2014/05/17/gov-signs-ginals-right-try-bill/9232409/.\n\n. ", "Edie Bacon, \"My Life's Not FDA-Approved,\" _Wall Street Journal_ , November 29, 2002, accessed May 1, 2015, http://www.wsj.com/articles/SB1038535925179938868.", "\n\n. \"", "Yondelis,\" European Medicines Agency, last modified September 10, 2012, accessed May 4, 2015, http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000773/human_med_001165.jsp.", "\n\n. \"", "U.S. FDA Grants Priority Review for Yondelis (Trabectedin) for the Treatment of Patients with Advanced Soft Tissue Sarcoma,\" Drugs.com, February 3, 2015, accessed May 2, 2014, http://www.drugs.com/nda/yondelis_150203.html.", "\n\n. ", "Kristina Brogan, interviewed by Stephen Fee, \"'Right to Try' Law Gives Terminal Patients Access to Drugs Not Approved by FDA,\" _PBS News Hour_ , June 21, 2014, accessed April 29, 2015, http://www.pbs.org/newshour/bb/right-try-law-gives-terminal-patients-access-non-fda-approved-drugs/.\n\n. ", "Mike Sherry, \"Missouri Becomes Third State to Enact 'Right to Try' Drug Therapy Law,\" _KCPT_ , July 15, 2014, accessed December 19, 2014, http://kcpt.org/health/missouri-state-enact-right-try-drug-therapy-law/.\n\n. ", "Nick Swedberg, \"'Right to Try' Medical Measure Sent to Illinois Governor,\" Associated Press, May 19, 2015, accessed May 25, 2015, http://www.nwherald.com/2015/05/19/right-to-try-medical-measure-sent-to-illinois-governor/aa30hvt/.\n\n. \"", "Connelly and Harris Aim to Give Terminal Patients Options,\" Illinois Senate GOP, January 30, 2015, accessed March 15, 2015, http://senategop.state.il.us/News/Recent News/TabId/121/p/24811/v/2000/connelly-and-harris-aim-to-give-terminal-patients-options.aspx#sthash.", "TrEMtw6m.dpuf.", "\n\n. ", "Andi's Army Facebook page, accessed March 15, 2015, https://www.facebook.com/OfficialAndisArmy.", "\n\n. \"", "BioMarin Pharmaceutical: Give Andrea Sloan (@andi_sloan) Access to the Cancer Drug That Could Save Her Life,\" Change.org, accessed April 9, 2015, https://www .change.org/p/biomarin-pharmaceutical-give-andrea-sloan-andi-sloan-access-to-the-cancer-drug-that-could-save-her-life.", "\n\n. ", "Shannon Wolfson, \"Andrea Sloan Pleads with BioMarin CEO,\" KXAN-TV, September 25, 2013, accessed March 15, 2015, http://kxan.com/2013/09/25/andrea-sloan-pleads-biomarin-ceo/.\n\n. ", "Jason Cherkis, \"Andrea Sloan Wins Big Victory in Quest for Cancer Drug,\" _Huffington Post_ , October 3, 2013, accessed March 15, 2015, http://www.huffingtonpost .com/2013/10/03/andrea-sloan-victory-drug_n_4039633.html.", "\n\n. ", "Todd Ackerman, \"Texas Poised to Pass Right-to-Try Legislation,\" _Houston Chronicle_ , May 9, 2015, accessed May 6, 2015, http://www.houstonchronicle.com/news/health/article/Texas-poised-to-pass-right-to-try-legislation-6253623.php.", "\n\n. \"", "Joshua Hardy,\" CaringBridge, accessed May 7, 2015, http://www.caringbridge.org/visit/joshuahardy/mystory.", "\n\n. ", "Robert Griffin III, Twitter post, March 10, 2014, 9:47 a.m., https://twitter.com/rgiii/status/443065599863033857.", "\n\n. ", "Elizabeth Cohen, \"Company Denies Drug to Dying Child,\" CNN, March 11, 2014, accessed December 17, 2014, http://www.cnn.com/2014/03/10/health/cohen-josh/.\n\n. \"", "Company Denies Drug to 7-Year-Old Boy Struggling against Curable Virus,\" Fox News, March 10, 2014, accessed May 7, 2015, http://insider.foxnews.com/2014/03/10/drug-maker-chimerix-refuses-release-drug-7-year-old-josh-hardy-struggles-against-curable.", "\n\n. \"", "Charity Offers to Pay for 7-Year-Old's Lifesaving Treatment; Drug Maker Still Refuses,\" Fox News, March 11, 2014, accessed May 7, 2015, http://www.foxnews.com/health/2014/03/11/charity-offers-to-pay-for-7-year-old-lifesaving-treatment-drug-maker-still/.\n\n. \"", "Chimerix Board Member Blames FDA for 7-Year-Old Josh Hardy's Plight,\" Fox News, March 12, 2014, accessed May 4, 2015, http://www.foxnews.com/health/2014/03/12/chimerix-board-member-blames-fda-for-7-year-old-josh-hardys-plight/.\n\n. 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", "Hearing Before the Committee on Government Reform, House of Representatives, 107th Cong. ", "37-38 (2001) (Testimony of Frank Burroughs).", "\n\n. \"", "House, Senate Leaders Announce Agreement on Right to Try Legislation,\" _Augusta Free Press_ , February 23, 2015, accessed March 26, 2015, http://augustafreepress.com/house-senate-leaders-announce-agreement-on-right-to-try-legislation/.\n\n. ", "Robyn Sidersky, \"Governor Signs 'Right to Try' Bill Inspired by Josh Hardy,\" _Free Lance-Star_ , March 27, 2015, accessed May 8, 2015, http://www.fredericksburg.com/news/local/fredericksburg/governor-signs-right-to-try-bill-inspired-by-josh-hardy/article_978ee80e-d3ec-11e4-8beb-271596aa66ff.html.", "\n\n. \"", "Lawmakers and Parents Advocate for Right to Try Legislation,\" NBC29 WVIR-TV, last modified February 23, 2015, accessed May 8, 2015, http://www.nbc29.com/story/28177028/lawmakers-and-parents-advocate-for-right-to-try-legislation.", "\n\n. 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", "37-38 (2001) (Testimony of Frank Burroughs).", "\n\n. ", "US Food and Drug Administration, \"Expanded Access INDs and Protocols\" accessed April 6, 2015, http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugs areDevelopedandApproved/DrugandBiologicApprovalReports/INDActivityReports/ucm373560.htm.", "\n\n. \"", "Cancer Facts & Figures 2015,\" American Cancer Society, accessed January 17, 2015, http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2015/index.", "\n\n. ", "Institute of Medicine (US) Forum on Drug Discovery, Development, and Translation, \"Transforming Clinical Research in the United States: Challenges and Opportunities: Workshop Summary,\" Washington, DC: National Academies Press (US), 2010, 6, Clinical Trials in Cancer. ", "Available from: http://www.ncbi.nlm.nih.gov/books/NBK50895/.\n\n. ", "Emil J. Freireich, \"Should Terminally Ill Patients Have the Right to Take Drugs That Pass Phase I Testing? 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", "Frank Young, interview with Judy Woodruff, _The MacNeil/Lehrer NewsHour_ , PBS, February 16, 1988.", "\n\n. ", "Philip M. Boffey, \"Campaign to Find Drugs for Fighting AIDS Is Intensified,\" _New York Times_ , February 15, 1988, accessed May 1, 2015, http://www.nytimes.com/1988/02/15/us/campaign-to-find-drugs-for-fighting-aids-is-intensified.html.", "\n\n. \"", "Drugs to Fight AIDS Given Top Priority at FDA,\" _Associated Press_ , January 30, 1988, accessed May 1, 2015, http://articles.latimes.com/1988-01-30/news/mn-10189_1 _top-priority.", "\n\n. ", "Rebecca Kolberg, \"Protesters Demanding Faster Access to AIDS Treatments Were Arrested,\" United Press International, October 11, 1988, accessed May 13, 2015, http://www.upi.com/Archives/1988/10/11/Protesters-demanding-faster-access-to-AIDS-treatments-were-arrested/7539592545600/.\n\n. 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", "Scott Gottlieb, \"Changing the FDA's Culture,\" _National Affairs_ , Summer 2012, accessed April 20, 2015, http://www.nationalaffairs.com/publications/detail/changing-the-fdas-culture.", "\n\n. \"", "Enzyme Replacement Drug Found to Be Effective Treatment for Hunter Syndrome,\" University of North Carolina School of Medicine, August 21, 2006, accessed January 19, 2015, http://www.sciencedaily.com/releases/2006/08/060819115541.htm.", "\n\n. ", "US Food and Drug Administration, \"FDA Approves First Treatment for Hunter Syndrome,\" news release, July 24, 2006, accessed April 19, 2015, http://www.fda.gov/News Events/Newsroom/PressAnnouncements/2006/ucm108699.htm.", "\n\n. ", "Kenneth A. Getz and Kenneth I. Kaitin, \"Why Is the Pharmaceutical and Biotechnology Industry Struggling?\" ", "in _Re-Engineering Clinical Trials_ , ed. ", "Peter Schuler and Brendan M. Buckley (London: Academic Press, 2015), 9.", "\n\n. ", "Ibid., ", "10–11.", "\n\n. \"", "What Is Idiopathic Pulmonary Fibrosis?\" ", "National Heart, Lung, and Blood Institute, last modified September 20, 2011, accessed April 18, 2015, http://www.nhlbi.nih.gov/health/health-topics/topics/ipf.", "\n\n. ", "Andrew Pollack, \"InterMune Lung Drug Is Successful in New Trial,\" _New York Times_ , February 25, 2014, accessed April 19, 2015, http://www.nytimes.com/2014/02/26/busi ness/intermune-reports-successful-trial-for-lung-disease-drug.html.", "\n\n. ", "Andrew Pollack, \"F.D.A. Rejects InterMune's Drug for Fatal Lung Disease,\" _New York Times_ , May 4, 2010, accessed April 19, 2015, http://www.nytimes.com/2010/05/05/busi ness/05lung.html.", "\n\n. ", "US Food and Drug Administration, \"FDA Approves Esbriet to Treat Idiopathic Pulmonary Fibrosis,\" news release, October 15, 2014, accessed April 21, 2015, http://www.fda .gov/NewsEvents/Newsroom/PressAnnouncements/ucm418991.htm.", "\n\n. ", "Joyce Frieden, \"FDA Nixes Pirfenidone for Now, Wants New Trial,\" _MedPage Today_ , May 5, 2010, accessed April 20, 2015, http://www.medpagetoday.com/PublicHealthPolicy/FDAGeneral/19933.", "\n\n. \"", "InterMune Receives FDA Breakthrough Therapy Designation for Pirfenidone, an Investigational Treatment for IPF,\" Coalition for Pulmonary Fibrosis, accessed April 21, 2015, http://www.coalitionforpf.org/2014/07/17/ntermune-receives-fda-breakthrough-therapy-designation-for-pirfenidone-an-investigational-treatment-for-ipf/.\n\n. \"", "InterMune Reports Japanese Regulatory Approval of Pirfenidone in IPF,\" Coalition for Pulmonary Fibrosis, accessed April 21, 2015, http://www.coalitionforpf.org/2008/10/16/intermune-reports-japanese-regulatory-approval-of-pirfenidone-in-ipf/.\n\n. ", "Susan Mayor, \"Increasing Treatment of Idiopathic Pulmonary Fibrosis with Pirfenidone, European Survey Shows,\" _Medical News Today_ , last modified December 6, 2012, accessed April 21, 2015, http://www.medicalnewstoday.com/articles/253656.php.", "\n\n. ", "Alexander Tabarrok and Daniel Klein, \"Reform Options,\" FDAReview.org, accessed April 19, 2015, http://www.fdareview.org/reform.shtml.", "\n\n. ", "Paul Howard and Yevgeniy Feyman, \"If a Drug Is Good Enough for Europeans, It's Good Enough for Us,\" _Health Affairs_ , February 14, 2014, accessed April 20, 2015, http://healthaffairs.org/blog/2014/02/14/if-a-drug-is-good-enough-for-europeans-its-good-enough-for-us/.\n\n. ", "Joseph A. DiMasi, Christopher-Paul Milne, and Alex Tabarrok, \"An FDA Report Card: Wide Variance in Performance Found among Agency's Drug Review Divisions,\" Manhattan Institute, no. ", "7 (2014): 4, accessed April 27, 2015, http://www.manhattan-institute .org/pdf/fda_07.pdf.", "\n\n. ", "Sam Kazman, \"Drug Approvals and Deadly Delays,\" _Journal of American Surgeons_ 15, no. ", "4 (2010): 102, accessed April 26, 2015, http://www.jpands.org/vol15no4/kazman.pdf.", "\n\n. ", "Ibid., ", "102.", "\n\n. ", "Howard and Feyman, \"If a Drug Is Good Enough for Europeans, It's Good Enough for Us.\"", "\n\n. ", "Henry I. Miller, \"A Grieving Mother Acts, While the FDA Dithers,\" _Forbes_ , May 21, 2014, accessed April 28, 2015, http://www.forbes.com/sites/henrymiller/2014/05/21/3230/.\n\n. ", "Jonel Aleccia, \"Vaccine Run: Grieving Mom Heads to Canada for Lifesaving Shots,\" _NBC News_ , May 16, 2014, accessed April 27, 2015, http://www.nbcnews.com/health/health-news/vaccine-run-grieving-mom-heads-canada-lifesaving-shots-n106646.", "\n\n. ", "Miller, \"A Grieving Mother Acts, While the FDA Dithers.\"", "\n\n. ", "US Food and Drug Administration, \"FDA Approves a Second Vaccine to Prevent Serogroup B Meningococcal Disease,\" news release, January 23, 2015, accessed March 21, 2015, http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm431370 .htm.", "\n\n. ", "Andrew von Eschenbach and Ralph Hall, \"FDA Approvals Are a Matter of Life and Death,\" _Wall Street Journal_ , June 17, 2012, accessed February 14, 2015, http://www.wsj .com/articles/SB10001424052702303753904577454163076760768.", "\n\n. ", "Peter Huber and Paul Howard, \"Unlocking the Code of Health: Bridging the Gap Between Precision Medicine and FDA Regulation,\" _Project FDA Report_ 8 (2015), accessed April 9, 2015, http://www.manhattan-institute.org/pdf/fda_08.pdf.", "\n\n. ", "Peter Huber, \"Patient, Heal Thyself,\" _City Journal_ (Winter 2015), accessed March 29, 2015, http://www.city-journal.org/2015/25_1_cell-therapies.html.", "\n\n. ", "Huber and Howard, \"Unlocking the Code of Health.\"", "\n\n. 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Mott Children's Hospital, April 29, 2015, accessed May 10, 2015, http://www.mottchildren.org/news/archive/201504/3dprinting.", "\n\nCHAPTER 9: IF YOU HAVE THE RIGHT TO DIE, YOU SHOULD HAVE THE **RIGHT** TO TRY\n\n. _", "Cruzan v. Director, Missouri Department of Health_ , 497 U.S. 261, (1990).", "\n\n. _", "United States v. Rutherford_ , 442 U.S. 544 (1979).", "\n\n. ", "US Department of Health, Education, and Welfare, Food and Drug Administration, \"Laetrile: The Commissioner's Decision,\" 77-3056 (HEW Publication), accessed May 11, 2015, http://www.cancertreatmentwatch.org/q/laetrile/commissioner.pdf.", "\n\n. 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", "Caroline Chen and Danielle Burger, \"Sarepta CEO Quits; Successor Pledges to Work Better with FDA,\" _Bloomberg Business_ , March 31, 2015, accessed June 6, 2015, http://www.bloomberg.com/news/articles/2015-04-01/duchenne-biotech-firm-sarepta-s-ceo-chris-garabedian-resigns.", "\n\n. \"", "Sarepta Therapeutics Completes NDA Submission to FDA for Eteplirsen for the Treatment of Duchenne Muscular Dystrophy Amenable to Exon 51 Skipping,\" Sarepta Therapeutics, June 29, 2015 accessed July 3, 2015, http://investorrelations.sarepta.com/phoenix.zhtml?c=64231&p=irol-newsArticle&ID=2063150.", "\n\n. \"", "Right to Try Stories: Diego Morris,\" Goldwater Institute, November 30, 2014, accessed December 12, 2015, http://goldwaterinstitute.org/en/work/topics/healthcare/right-to-try/right-to-try-life-stories-diego-morris/.\n\n. ", "Saerom Yoo, \"Cancer Survivor, 14, Advocates for Right to Try Bill,\" _Statesman Journal_ , February 26, 2015, accessed June 6, 2015, http://www.statesmanjournal.com/story/news/health/2015/02/26/cancer-survivor-advocates-right-try-bill/24095681/.\n\n. \"", "Oregon House Votes 59–0: Passes Right to Try Act to Effectively Nullify Some FDA Restrictions on Terminally-Ill,\" Tenth Amendment Center, April 8, 2015, accessed May 30, 2015, http://blog.tenthamendmentcenter.com/2015/04/oregon-house-votes-59-0-passes-right-to-try-act-to-effectively-nullify-some-fda-restrictions-on-terminally-ill/.\n\n. \"", "What Are the Key Statistics about Osteosarcoma?\" ", "American Cancer Society, last modified January 6, 2015, accessed May 22, 2015, http://www.cancer.org/cancer/osteosarcoma/detailedguide/osteosarcoma-key-statistics.", "\n\n. ", "Andrew Pollack, \"Races for a Cure, Straight from the Heart,\" _New York Times_ , May 27, 2001, accessed January 18, 2015, http://www.nytimes.com/2001/05/27/business/races-for-a-cure-straight-from-the-heart.html.", "\n\n## Index\n\nThe pagination of this electronic edition does not match the edition from which it was created. ", "To locate a specific entry, please use your e-book reader's search tools.", "\n\nAbbot, Greg, 94\n\nThe Abigail Alliance for Better Access to Developmental Drugs, 167, 178–79, 182, 254\n\n_Abigail Alliance v. von Eschenbach_ , 247, 248\n\naccelerated approval 42, 43, 44, 54, 55, 56, 57, 117, 167, 219, 221, 262, 263, 264, 265\n\nacute lymphoblastic leukemia (ALL), 114–17, 220\n\n\"adaptive\" clinical trials, 237\n\nadenovirus, 161\n\nAdvanced Accelerator Applications, 93\n\naging, potential treatment for, 124–25\n\nAIDS, 152, 192–93\n\nAIDSinfo, 254–55\n\nAir Charity Network, 257\n\nAlabama, 170–71\n\nALS\n\napproved medication, 5\n\nclinical trials, 127\n\ninvestigational intraspinal injection of stem cells, 8, 10, 11–16, 18\n\nas manageable condition, 270\n\nprogression, 6–7\n\nAltman, Kurt, 143, 148, 153–55, 158, 159, 168\n\nAlzheimer's disease, 125\n\nAlzheimer's Disease and Education Referral Center, 255\n\nAmerican Cancer Society, 184\n\nAndi's Army, 157–58\n\nAngel Flight for Veterans, 258\n\nanti-PD-1 immunotherapy, 145, 176, 181\n\nArizona, 81–82\n\nAuden, Amy, 145, 146–47, 148–49\n\nAuden, Lachlan \"Locky,\" 146\n\nAuden, Nick, 145–47\n\nB-cell ALL, 220\n\nBacon, Edie, 150–51\n\nBahjat, Keith, 112–13\n\nBAY 43-9006 for kidney cancer, 181\n\nBayer, 181\n\nBecker's muscular dystrophy, 32, 136\n\nbeleodaq, 220\n\nBell, Jonathan, 118–20\n\nBentley, Robert, 170–71\n\nBexsero, 233\n\nBienaimé, Jean-Jacques, 156\n\nBioMarin, 155–56\n\nbiotechnology companies. _", "See_ pharmaceutical companies\n\nBiotechnology Industry Organization, 188–90\n\nblincyto, 220\n\nblockbuster drugs, 116\n\nblood cancer, 100–108, 117\n\nBMN-673, 155–56\n\nbone-marrow transplants, 101\n\nBonner, Steve, 19, 20, 22\n\n_Boston Business Journal_ , 275\n\nBoulis, Nick, 8\n\nbrain cancer, 110–13, 117\n\nBrantly, Kent, 129, 250–51\n\nBrogan, Kristina, 149–50, 151–52\n\nBRCA gene mutation, 156\n\n\"breakthrough therapies\" designation, 43\n\nbreast cancer, 148, 170\n\nBreedlove, Regina, 162\n\nbrincidofovir, 161–62, 163–65\n\nBristol-Meyers Squibb, 145, 148, 176, 177\n\n_British Medical Journal_ , 185\n\nBrus, Ronald, 212–13\n\nBuehler, Knute, 274\n\nBurroughs, Abigail, 166–67, 247\n\nBurroughs, Frank, 166–67, 169, 178–79, 182, 210–11, 247\n\nBurton, Dan, 182\n\nCamp Promise, 44–45, 49\n\ncancer, 20, 184. _", "See also_ specific diseases\n\n_Cancer: The Emperor of All Maladies_ (documentary), 201\n\nCancer Treatment Centers of America (CTCA), 19, 20, 99\n\ncancer treatments, bogus, 246\n\ncancer treatments, investigational\n\nfor B-cell ALL, 220\n\nfor breast cancer, 148\n\nfor colon cancer, 150–51, 166, 247\n\ncurrent number of phases II and III clinical trials, 20\n\nfor glioblastoma, 112–13\n\ninformation about obtaining, 254–59\n\nfor kidney cancer, 181–82\n\nfor melanoma, 113–14, 145, 220\n\nfor metastatic lung cancer, 238\n\nfor multiple myeloma, 101–8\n\nfor NSCLC, 221\n\nfor ovarian cancer, 155–56\n\nfor pancreatic cancer, 113\n\npercent of patients receiving, in clinical trials, 99\n\nfor peripheral T-cell lymphoma (PTCL), 220\n\nsafety of viral therapies, 118–19\n\ncancer treatments, standard. _", "See also_ chemotherapy\n\nfor kidney cancer, 176, 181\n\nfor melanoma, 145\n\nfor multiple myeloma, 101, 104, 107\n\nside effects, 160\n\nCelgene, 38\n\nThe Center for Information and Study on Clinical Research Participation, 255\n\nCeredase, 222–23, 225–26\n\nChampion, Janet, 171\n\nChampion, Sid, 171\n\nCharley's Fund, 53\n\nchemotherapy\n\neffect on ALL, 114–15\n\neffect on NET cancer, 85, 86, 90\n\neffect on osteosarcoma, 65–66\n\neffect on osteosarcoma with mifamurtide, 68, 69\n\nside effects, 77, 80, 86\n\nChildren's Hospital (Philadelphia), 114–17\n\nChimerix, 161–62, 161–64, 161–65\n\nCiba Geigy (now Novartis), 68\n\nclinical trial eligibility requirements\n\nabsence of complications or coexisting illnesses, 146, 152\n\nabsence of previous health conditions, 152\n\nage, 161\n\nlocation of cancer, 176, 182\n\nfor phase II trials, 185\n\nspecific symptoms and level of deterioration, 35, 52, 176\n\nclinical trials\n\n\"adaptive\" as future of, 237\n\ncompassionate use and, 150–51, 180, 189–90\n\ncosts of negative outcomes, 132\n\ndouble-blind placebo controlled tests as unnecessary, 200–203\n\nin Europe, 30–31\n\nexceptional responders, 238–39\n\nFDA dosage specifications, 17\n\nFDA scientific data requirements, 133, 226\n\nincrease in time and cost of, 216–17\n\nof medical devices, 205\n\noff-label use during, 199–200\n\npercent of drugs approved, 210\n\npersonalized medicine and, 236–37\n\nphase I safety and purpose, 9\n\nphase II, 185\n\nphase III, 204, 226\n\nresources for obtaining information about, 254–57\n\nclinical trials, current\n\naltered polio virus to treat brain glioblastoma, 111\n\neteplirsen for muscular dystrophy, 39–41\n\ngallium scans, 87\n\nherpes simplex virus to treat pancreatic cancer, 113–14\n\n_Listeria_ to treat cancers, 112–13\n\nmifamurtide for osteosarcoma, 67–69\n\nneural stem cell treatment for cognitive deficit in schizophrenia, 124\n\nneural stem cell treatment for depression, 124\n\nneural stem cell treatment for spinal cord injuries, 123\n\nnumber of phases II and III cancer, 20\n\npercent of cancer patients in, 20, 99, 184\n\nPRRT for NET cancer, 92–93\n\nradial viral therapy for multiple myeloma, 104–5\n\ntransplantations for ALS, 127\n\nClinicalTrials.gov (National Library of Medicine), 255\n\nCoburn, Tom, 230\n\ncognitive deficit in schizophrenia, treatment for, 124\n\ncolon cancer, 150–51, 166, 247\n\nColorado, 145–49, 183\n\ncompassionate use\n\nannual number and percent of requests approved by FDA, 183–84\n\nannual number granted by Kaiser Permanente, 183\n\nas burden to health care system, 214\n\nclinical trials and, 150–51, 180, 189–90\n\ndrugs supplied by manufacturers, 42, 97, 117\n\neconomics of, 205–8\n\nFDA application process, 194–95\n\nFDA early access programs, 189, 208, 209\n\nFDA as obstacle to pharmaceutical companies, 188–91, 196–97\n\nFDA as obstacle to physicians, 187–88\n\nFDA attempts to help patients get, 191–92\n\nFDA policy, 20–21, 109, 131\n\nFDA program for mifamurtide ended, 75\n\nfirst formal programs, 153\n\nincentivizing, 198\n\nof measles virus for multiple myeloma, 108\n\npermit off-label use during trials, 199–200\n\nphysicians and, 109, 117–18, 186, 187–88, 194–95\n\npolicies of pharmaceutical companies, 156, 161–62, 163, 177, 191\n\nConnelly, Mike, 153–55\n\nCorporate Angel Network, 258\n\nCrimp, Douglas, 193\n\nCrittenden, Marka, 112\n\n_Daily Oklahoman_ , 91\n\n_Dallas Buyers Club_ , 152–53\n\nDana-Farber Cancer Institute, 148\n\ndata sequestration, 197–98\n\nDayton, Mark, 170\n\nDeath with Dignity Act (Oregon), 243–44\n\nDelpassand, Ebrahim, 92–93, 94\n\nDepartment of Veterans Affairs (Virginia), 91, 92\n\ndepression, treatment for, 123, 124\n\nDesjardins, Annick, 112\n\n_Detroit News_ , 125\n\nDillon, Sir Andrew, 71–72\n\nDiMasi, Joe, 231\n\nDuchenne muscular dystrophy\n\ncause, 30\n\neteplirsen and, 34, 39–41, 43–44, 54–59, 137, 219\n\nexon skipping explained, 30–31\n\npercent of boys exon-skipping could help, 59\n\n\"Race to Yes\" campaign, 53, 56\n\nsymptoms, 28, 45\n\nDudgeon, Mike, 268\n\nDuke University, 110–13\n\nEbola, treatment for, 129, 130, 250–51\n\nEdmond J. Safra Family Lodge at National Institutes of Health, 258\n\nElaprase, 223–25\n\nEmory University, 8, 18\n\n\"end point,\" 43\n\nErbitux, 166, 247\n\nErholtz, Stacy\n\ndiagnosed, 100–101\n\neffects of multiple myeloma on, 99–100\n\nas patient advocate, 110\n\nradial viral therapy, 105–6\n\nstandard treatment, 101, 104\n\nET-743 (Yondelis in Europe) (trabectedin), 150–51\n\neteplirsen, 54–59, 262–65\n\napproval clock for, 219\n\nclinical trial, 39–41\n\ndevelopment of, 34\n\nFDASIA and, 43–44\n\nmedical action of, 137\n\nEuropean Medicines Agency (EMA), 71, 229\n\nExcel Diagnostics & Nuclear Oncology Center, 92–93\n\nexceptional responders, 238–39\n\nExceptional Responders Initiative, 238, 239\n\nexon skipping treatment, 30–31. _", "See also_ eteplirsen\n\nexpanded access programs (EAPs), 189–90\n\nfederalism, 23, 244–45\n\n_Federalist_ (Madison and Hamilton), 23, 244–45\n\nFeldman, Eva, 125\n\nFeyman, Yevgeniy, 230, 232\n\nFidler, Josh, 66–67\n\nFood and Drug Administration (FDA). _", "See also_ _clinical trial_ entries; compassionate use\n\napproval of breakthrough drugs on basis of surrogate outcomes, 43–44\n\napproval time for medications and medical devices, 20, 217–21, 223, 234–35\n\napprovals shortly after compassionate use denied, 181, 182\n\nbelief that policies do not protect people, 120\n\nCenter for Biologics Evaluation and Research, 217\n\nCenter for Drug Evaluation and Research, 55, 190, 210, 227\n\ncompassionate use application, 194–95\n\nemergency requests, 158, 191\n\neteplirsen and, 54–56, 58–59, 262–65\n\ngallium scans and, 87\n\nincrease in time and cost of clinical trials, 216–17\n\nlawsuit against, 167\n\nmedical device trials, 205\n\nmifamurtide and, 69–71, 72\n\nNew Drug Application, 54, 55, 57, 58, 219, 239, 264\n\noff-label use during trials, 199–200\n\nPhase 1b, 124\n\nPhase II, 17, 20, 39, 67, 73, 124, 126, 127, 130, 133, 185, 210, 249\n\nPhase III, 20, 67, 113, 116, 130, 133, 185, 204, 210, 226\n\npriority review, 151\n\nPRRT and, 86, 87, 88–89, 92–93, 96\n\nradial viral therapy and, 104–5\n\nrefusal to approve reciprocity, 230–32\n\nrisk-averse culture of, 209–10\n\nrole in Right to Try laws, 131\n\nsequestration of data, 197–98\n\nsupervision of clinical trials, 17\n\nuse of open-label studies, 204–5\n\nuses 20th-century approach in 21st century, 215–16\n\nZMapp and, 129–30, 250–51\n\nFood and Drug Administration Safety and Innovation Act (FDASIA, 2012), 43–44, 167–68\n\nfor-profit compassionate use, 206\n\n_Forbes_ , 116\n\nFrance, 206\n\nFreireich, Emil, 115, 117–18, 185, 186–87\n\nFriedman, Henry, 112\n\nfund-raising for treatment, 90\n\ngallium scans, 87\n\nGarabedian, Chris\n\ndealings with FDA, 44, 54\n\nhealth of Sarepta when became CEO, 38–42\n\non increasing demand for Right to Try laws, 276\n\nJenn McNary and, 40, 261–62\n\non reforming compassionate use, 206, 207, 208, 209\n\nresignation from Sarepta, 264\n\nGarr, Lisa, 123\n\nGarr, Matthew, 121–22\n\nGarr, Richard\n\nas advocate for Right to Try laws, 126–29, 134, 277\n\non contagion as reason FDA allowed use of ZMapp, 130\n\non FDA's role in Right to Try laws, 131\n\non neural stem cell treatments, 124\n\non Neuralstem, 123\n\nson's tumor, 121–23\n\nTed Harada and, 270\n\nGaucher disease, 222, 225–26\n\nGenentech, 176, 177\n\nGeorgia, 268\n\nGetz, Kenneth, 226–27\n\nGilead Sciences, 38\n\nGinal, Joann, 147\n\nGinsburg, Douglas, 248\n\nGiveForward.com, 90, 178\n\nGlass, Jonathan, 5, 9, 271\n\nglioblastoma, 110–13, 117\n\nGoldwater Institute. _", "See also_ Altman, Kurt; Right to Try campaign and laws\n\nbackground of, 18–19\n\nCancer Treatment Centers of America and, 19, 21, 99\n\ncontact information, 259\n\ndrafting of Right to Try law, 126\n\npetition to FDA about access to investigational drugs, 250\n\n_Gonzales v. Oregon_ , 243–44\n\nGordon, Josh, 183\n\nGosar, Paul, 250\n\nGottlieb, Scott, 202–3, 204, 222, 223–24, 225–26\n\nGreen, Glenn, 241\n\nGriffin, Gabe, 170–71\n\nGriffin, Robert III, 162\n\nGromeier, Matthias, 112\n\nHall, Ralph, 234\n\nHamburg, Margaret, 20–21, 192–93, 194, 216\n\nHamilton, Alexander, 23\n\nHandzlik, Craig, 171\n\nHanify, Tom, 141–42\n\nHarada, Michelle, 1, 2\n\nHarada, Ted\n\nas advocate for Right to Try law, 266–68, 270–73\n\ndiagnosed with ALS, 5–6\n\non fear of quacks, 132–33\n\nprogression of ALS, 6–7\n\nsymptoms, 1–3\n\nHardy, Aimee, 160–61, 162, 164–66, 168, 169\n\nHardy, Josh, 160–64\n\nHardy, Todd, 160–61, 165\n\nHarris, Greg, 152–55\n\n_Harvard Law Review_ , 248–49\n\nHaverfield, Sascha, 198\n\nHealth Canada, 229\n\nHerbert, Bob, 170\n\nherpes simplex virus, 113\n\nHickenlooper, John, 149\n\n_Houston Chronicle_ , 160\n\nHoward, Paul, 230, 232\n\nHuber, Peter, 235–37, 240\n\n_Huffington Post_ , 90\n\nHunter syndrome, 223–25\n\nidiopathic pulmonary fibrosis (IPF), 228\n\nIDM Pharma, 68, 71\n\nIllinois, 152–55\n\nImClone, 166\n\nimmune phase, 104\n\ninformed consent 17, 24, 134, 254\n\nindividual rights in federal system, 243–45\n\nInterMune, 228–29\n\ninvestigational treatments, obtaining\n\ngeneral eligibility requirements, 254\n\npatient support and advocacy groups, 254–57\n\nresources to help cover costs, 257–59\n\nIressa, 238–39\n\nIsaacson, Walter, 84\n\nischemic stroke treatment in China, 123\n\n_JAMA: The Journal of the American Medical Association_ , 189–90\n\nJames Cancer Hospital, 113\n\nJenner Biotherapies, 68\n\nJett Foundation, 44–45, 47, 52\n\nJimenez, Joseph, 116\n\nJindal, Bobby, 96\n\nJobs, Steve, 83–84\n\nJohe, Arthur, 122, 124–25\n\nJohe, Karl, 122, 123\n\nJohnson, Dennis, 122\n\nJohnson & Johnson, 150–51\n\nJolley, Kenneth, 90–93\n\nJoshi, Janak, 147\n\nJune, Carl, 114, 115–16\n\nKacal, Kyle, 158\n\nKaiser Permanente, 148, 183\n\nKalley, Arlene, 170\n\nKalley, Terry, 170\n\nKarnes, Kianna, 181–82\n\nKazman, Sam, 231\n\nKelly, Crystal, 9\n\nkeytruda, 220\n\nkidney cancer, 176–82\n\nKieny, Marie-Paule, 129\n\nKing, Ken, 158\n\nKlein, Dan, 230\n\nKlein, Richard, 175\n\nKleinerman, Eugenie, 66–68, 70–71, 72, 73–74\n\nKnapp, Keith, 176–81\n\nKnapp, Mikaela, 176–81\n\nKuhlik, Bruce, 189–90\n\nKulsrud, Lane, 171\n\nKulsrud, Tanner, 171\n\nKulsrud, Ty, 171\n\nLeffler, Aidan, 33–34, 52–53\n\nLeffler, Mindy, 33–34, 52–53\n\nlethal self-defense right, 249\n\nleukemia, 114–17\n\nLevenback, Charles, 155–56, 159–60, 186\n\nLevitt, Ed, 238–39\n\nLipscomb, Stephanie, 111–12\n\n___Listeria_ phase I trials, 112–13\n\nLou Gehrig's disease. _", "See_ ALS\n\nLurie, Peter, 194–95\n\nlynparza, 220\n\nMacAuliffe, Terry, 169\n\nMadison, James, 23, 244–45\n\nmajor depressive disorder (MDD) treatment, 124\n\nMalone, Ernest, 138, 140\n\nMapp Biopharmaceutical, 129\n\nMax Cure Foundation, 163\n\nMayo Clinic, 101–7, 108, 110\n\nMcCartin, Lorraine, 148\n\nMcClaren, Don, 192\n\nMcLinn, Jordan, 136–44\n\nMcLinn, Laura, 136–44\n\nMcNary, Austin, 27–30, 32, 33, 36, 40, 261–62\n\nMcNary, Jenn\n\nas advocate for eteplirsen, 50–52, 59–60\n\non Austin's losses waiting for trial, 262–63\n\non FDA allowing use of ZMapp, 130\n\nGarabedian and, 38, 40, 261–62\n\non getting FDA to act, 263–64\n\nMax in trial, 35–36\n\nsons diagnosed, 27–30\n\nMcNary, Max\n\ndecline, 33\n\ndiagnosed with Duchenne muscular dystrophy, 30\n\ngetting into trial, 34–36\n\nimprovement from eteplirsen, 41, 49–50, 51\n\nMcSherry, Christine, 45–53, 55, 58, 265–66\n\nMcSherry, Jett, 45–48\n\nMD Anderson Cancer Center, 155–56\n\nmeasles virus, 101–6\n\nmedical autonomy and self-defense, 248–49\n\nMedlinePlus (National Library of Medicine), 255–56\n\nmelanoma, 113–14, 145, 220\n\nMemorial Sloan Kettering Cancer Center, 67\n\nMendell, Jerry, 34, 41, 137\n\nmeningitis B vaccine, 233\n\nMerck, 145, 176, 177, 179–81\n\nMercy Medical Angels, 258\n\nmetastatic lung cancer, 238\n\nMeyers, Paul, 67–71, 73, 76, 80–81\n\nMichigan, 170\n\nMidthun, Karen, 217–18\n\nmifamurtide (also known as MEPACT or MPT)\n\nadministration of, 66\n\navailability, 71–72, 73, 74, 75–79\n\nclinical trials of, 67–69\n\nPrix Galien Award, 72\n\nsuccess rate, 69\n\nused with chemotherapy on osteosarcoma, 68, 69\n\nMight, Bertrand, 170\n\nMiller, Henry I., 232, 233\n\nMiller, Lindsey, 89–90\n\nMilne, Christopher-Paul, 231\n\nMinnesota, 170\n\nMiracle Flights for Kids, 258\n\nMississippi, 171\n\nMissouri, 149–52\n\n_MIT Technology Review_ , 240\n\nMoch, Kenneth, 163, 164\n\nMorris, Diego\n\nas advocate for Right to Try law, 81–82, 273–75\n\ndiagnosed with osteosarcoma, 61–63\n\ninability to get compassionate use of mifamurtide, 74\n\nrecovery, 80\n\ntreatment in London with mifamurtide, 76–79\n\nMorris, Jason, 61, 62, 74–82\n\nMorris, Mateo, 62\n\nMorris, Paulina, 61, 62, 74–80, 81–82, 274, 275\n\nMPS diseases (mucopolysaccharidoses), 222–26\n\nmultiple myeloma, 100–108, 117\n\nmuscular dystrophy. _", "See also_ Duchenne muscular dystrophy\n\nBecker's, 32, 136\n\nmyTomorrows, 212–13\n\n_National Affairs_ , 222\n\nNational Association of Hospital Hospitality Houses, 259\n\nNational Cancer Institute (NCI), 238, 239, 256\n\nNational Heart, Lung, and Blood Institute \"Children in Clinical Studies,\" 256\n\nNational Institute on Aging \"Clinical Trials and Older People,\" 256\n\nNational Institutes of Health \"Clinical Trials and You,\" 257\n\nNational Patient Travel Center, 259\n\nNeely, Jim, 149, 150, 151–52\n\nneural stem cell treatments, 123–25\n\nNeuralstem, 8, 123–24\n\nneuroendocrine carcinoma (NET cancer), 83–86, 90–93\n\nNGLY1 (genetic disease), 170\n\nNixon, Jay, 152\n\nNoble, Paul W., 228\n\nnon-small-cell lung cancer (NSCLS), 221\n\nNorth Dakota, 171\n\nNovartis, 116–17, 233\n\n\"Novel New Drugs 2014 Summary\" (FDA), 218\n\nOasis of Hope, 246\n\nOctreoScan, 84, 86–87\n\noctreotide, 86, 90\n\nO'Dorisio, Sue, 86, 88, 96\n\nO'Dorisio, Tom\n\non chemotherapy for NET cancer, 90\n\non cost of PRRT treatment, 87–88\n\non PRRT treatment in Europe, 86, 93, 94\n\nsupport for Right to Try laws, 96\n\noff-label use, 199\n\noncolytic phase, 104\n\noncolytic viral therapy. _", "See_ viral therapies\n\nopdivo, 220\n\nopen-label studies, 204\n\nOregon, 274\n\nosteosarcoma\n\nannual number of children diagnosed with, 70\n\ndiagnosing, 62–63\n\nmifamurtide as standard treatment except in US, 73\n\nmifamurtide clinical trials, 67–69\n\nmortality rate, 66\n\nrecurrence of, 65–66\n\nstandard chemo and surgical treatment, 63–65\n\novarian cancer, 155–56, 220\n\npancreatic cancer, 113–14\n\nPatient Advocate Foundation, 259\n\npatient autonomy, 245\n\nPelley, Scott, 111\n\nPence, Mike, 143\n\nPenrod, Joseph, 53\n\nPenrod, Marissa, 53, 59\n\nPerlmutter, Roger, 181\n\npersonalized medicine\n\nexceptional responders and, 238–39\n\nlarge, randomized placebo trials and, 236–37\n\nmedical devices, 240–41\n\nusing patients' stem cells, 239\n\nPfizer, 181\n\npharmaceutical companies\n\ncompassionate use policies, 156, 161–62, 163, 177, 191\n\ncosts of investigational treatments, 131–32, 227\n\nFDA as obstacle to compassionate use, 188–91, 196–97\n\nincrease in time and cost of clinical trials and, 216–17\n\npotential profits from successful drugs, 179–81\n\nrequirements to have Right to Try laws work, 132, 205–9\n\nphysicians\n\ncompassionate use and, 109, 117–18, 186, 187–88, 194–95\n\nsupport for Right to Try laws, 94–97, 120, 147, 149\n\npirfenidone (Esbriet), 228–30\n\nPKAN (metabolic disorder), 171\n\nPlotkin, Richard, 163\n\npolio vaccine, 111–12\n\npost-traumatic stress disorder (PTSD) treatment, 124\n\npostmarket surveillance system, 207–8\n\nprecision medicine. _", "See_ personalized medicine\n\nPresident's Council of Advisors on Science and Technology (PCAST), 216–17\n\nProvidence Cancer Center, 112–13\n\nPRRT (Peptide Receptor Radionuclide Therapy)\n\nclinical trials, 92–93\n\ncost, 87–88, 91\n\nFDA and, 86, 87, 88–89, 92–93, 96\n\nnew technique using, 93–94\n\nside effects, 86\n\nas treatment for NET cancer, 84–85\n\nworldwide use, 86, 89, 91\n\nquacks, fear of, 119, 132–33\n\n\"Race to Yes\" campaign, 53\n\nradiation therapy, 107\n\nradio viral therapy, 103–4, 106–7, 108\n\nrandomized placebo trial, 189, 236\n\nRansone, Margaret, 165, 168\n\nRawlins, Sir Michael, 72\n\nreciprocal drug approvals\n\nas creating race to bottom, 232\n\nFDA reasons for opposing, 230–32\n\nmeningitis B outbreak and, 233–34\n\npirfenidone example, 228–30\n\nSapien Transcatheter Heart Valve example, 234–35\n\nReeves, Bryce, 165\n\nRegenerative Sciences, LLC, 239\n\nRegenexx, 239\n\nReolysin, 113\n\n\"Report to the President on Propelling Innovation in Drug Discovery, Development and Evaluation\" (PCAST), 216–17\n\nResearchMatch, 257\n\nRiches, Victor, 158–59, 173\n\nRight to Die laws, 243–44\n\nRight to Try Foundation, 259\n\nRight to Try laws. _", "See also_ specific states\n\n_Abigail Alliance v. von Eschenbach_ , 247\n\nconstitutional basis of, 244–45\n\ndirect patients away from false cures, 133\n\ndue process clauses of, 245, 248\n\neligibility in, 117, 185, 226, 254\n\nfederal challenge to, 245\n\n_Gonzales v. Oregon_ , 243, 244\n\nintroduction of federal, 250\n\nlethal self-defense of, 249\n\nmedical autonomy and, 248\n\nmedical self-defense and, 248, 249\n\nneed for, 99\n\nnext steps toward, 253–59\n\nNinth Amendment and, 245\n\nopposition by Kaiser Permanente, 148, 183\n\npayments in, 257–59\n\npharmaceutical companies and, 121, 132\n\nphysicians support, 94–97, 120, 147, 149\n\nprovisions, 24, 94, 126, 131\n\nquacks and, 119, 132–33\n\nscientists support, 147\n\nstates attempting to pass, 173\n\nstates with, 24–25, 135, 170–72\n\nSupreme Court and, 244, 245–46\n\nTenth Amendment and, 245\n\ntreatment and, 254–56\n\n_United States v. Rutherford_ 245, 246\n\nRobinson, Tim, 139\n\nRogers, Judith, 248\n\nRose, Daniel M., 228\n\nRosenblatt, Michael, 189–90\n\nRowe, John, 181–83\n\nRussell, Stephen\n\nclinical trials, 104–5, 107\n\ndesire to treat dying patients outside of clinical trials, 109\n\non herpes simplex virus for pancreatic cancer, 113\n\nrequests to treat multiple myeloma patients, 108\n\ntreatment of Erholtz, 105–6\n\nuse of measles virus for multiple myeloma, 101–4\n\nSaint Mary's Hospital (Rochester, Minnesota), 105–7\n\nSalmon, Matt, 250\n\nSapien Transcatheter Heart Valve, 234–35\n\nSarepta Therapeutics\n\neteplirsen, 34, 39–41, 43–44, 54–56, 57–59, 219\n\nhealth of, when Garabedian became CEO, 38–42\n\nrequest for priority review, 264\n\nuse of FDASIA, 43\n\nSaveLockysDad.com, 146\n\nSchmidt, Alexander M., 232\n\n_Science Daily_ , 224\n\nSeckler, Charley, 53\n\nSeckler, Tracy, 53, 57, 58\n\nSloan, Andrea, 155–57\n\nSmith, Vincent, 3\n\nSnyder, Rick, 170\n\nsocial media, effect of, 211\n\nSolove Research Institute, 113\n\nsomatostatin, 84\n\nspinal cord injury trials, 123\n\nSt. Jude Children's Research Hospital, 63, 161–62\n\n_Star Tribune_ (Minneapolis newspaper), 113\n\nstate constitutions, individual rights in, 23\n\nstem cell treatments\n\nfor ALS, 8, 10, 11–16, 18\n\nfor multiple myeloma, 101, 104\n\nfor orthopedic injuries, 239\n\nStephenson, Mary Brown, 19\n\nStephenson, Richard, 19, 20\n\nStillman, Alicia, 233–34\n\nStillman, Emily, 233–34\n\nStutzman, Marlin, 250\n\nSU11248 for kidney cancer, 181\n\n\"surrogate\" outcomes measurement, 43\n\nT-cell immunotherapy to treat leukemia, 114–17\n\nTabarrok, Alex, 230, 231\n\nTakeda, 72\n\ntemporary authorization for use (ATU), 206\n\nterminal illness, 18, 26, 82, 117, 135, 142, 153, 154, 167, 173, 183, 185, 193, 196, 227, 232, 243, 251, 252\n\nTessaro, Ed, 268–69\n\nTexas, 94, 155–60\n\ntracheobronchomalacia (TBM), 240–41\n\ntraumatic brain injury treatment, 124\n\n_United States v. Rutherford_ , 245–46\n\nUniversity of Basel Hospital (Switzerland), 87–88, 93–94\n\nUniversity of California—San Francisco Medical Center, 176\n\n_USA Today_ , 128\n\nUtah, 170\n\nVelcade, 110\n\nviral therapies\n\nherpes simplex to treat melanoma, 113–14\n\nmeasles to treat multiple myeloma, 101–6\n\npolio to treat glioblastoma, 110–12\n\nside effects, 118–19\n\nsmallpox, 118\n\nVirginia, 160–69\n\nVolokh, Eugene, 248–49\n\nvon Eschenbach, Andy\n\non compassionate use from companies' viewpoint, 197\n\non incentivizing compassionate use for companies, 198–200, 207\n\non phase III blinded randomization, 204\n\non postmarket surveillance, 207–8\n\non risk-averse culture of FDA, 209–10\n\non Sapien Transcatheter Heart Valve availability, 234\n\nWahl, Margaret, 31\n\nWalker, Steven, 200–201\n\n_Wall Street Journal_ , 133, 150–51, 182, 203, 205, 234\n\n\"War Fighter of the Future\" project, 124\n\nWarner, Richard, 84–85, 88–89\n\n_Washington Post_ , 129\n\nWhited, Mike, 141–42\n\nWhitehead, Emily, 114\n\nWhitehead, Tom, 115, 120\n\nWild, Damian, 89, 93–94\n\nWilliams, David, 4–5\n\nWittenberg, Michelle, 156–60\n\nWollaeger, Tim, 163\n\nWoltering, Eugene, 95–96\n\nWoodcock, Janet\n\non compassionate use as burden on health system, 214\n\nconcerns about failure, 210\n\non drug companies as obstacles to compassionate use, 191–92\n\non drug development process, 213\n\non FDA and compassionate use, 190–91, 195\n\nhonored by EveryLife Foundation, 55\n\nmeetings with Duchenne moms, 55, 56\n\non need for thorough scrutiny of drugs, 227\n\non patients' right to try, 247\n\non rate of FDA approval of new drugs, 217–18\n\non Right to Try, 214\n\non sequestration of data, 198\n\non trial for eteplirsen, 57\n\nYondelis (trabectedin), 151\n\nYoung, Frank, 192\n\nYoung, Scott, 117\n\nZerwas, Nick, 170\n\nZMapp, 129–30, 250–51\n\nzykadia, 221\n\n## **Photographs**\n\nTed Harada celebrates his miraculous recovery from ALS by completing Atlanta's two-and-a-half mile \"Walk to Defeat ALS.\" ", "Ted is one of just thirty-two Americans allowed to try the experimental ALS therapy. ", "Some others in the trial saw the progression of the disease slowed or maintained the same level of functionality they had had years before the procedure. ( _", "Courtesy of the Harada family_ )\n\n\"Right now I don't need another treatment,\" said Ted. \"", "But what happens when I do? ", "If I have a treatment that's helped me twice, why should I have to go hat in hand to the FDA asking for their permission?\" ", "Under current FDA guidelines, Ted cannot undergo the procedure again. ( _", "Courtesy of the Harada family_ )\n\nAustin and Max, Jenn McNary's sons, were both diagnosed with a deadly form of Duchenne muscular dystrophy. ", "Max received access to a clinical trail, and Austin, Max's older brother, watched as Max's condition improved, while Austin's only got worse. ( _", "Courtesy of Justin Ferland_ )\n\n\"It is one thing if your child is dying from an untreatable disease,\" said Jenn McNary, the boys' mother. \"", "But to have your child dying from a treatable disease is devastating. ", "I never thought it would be the government I was working against.\" ( _", "Courtesy of Justin Ferland_ )\n\nFourteen-year-old Diego Morris and his family had to travel five thousand miles overseas to combat osteosarcoma, a deadly form of bone cancer. ", "The lifesaving treatment Diego received is still not approved in the United States. ( _", "Courtesy of the Goldwater Institute_ )\n\n\"We tried everything,\" said Paulina Morris, Diego's mother. \"", "We talked to the drug manufacturer, political representatives, and the FDA. ", "We tried every avenue to get the drug here. ", "We realized that if we were going to get this drug for Diego, we would have to move to a foreign country.\" ( _", "Courtesy of the Goldwater Institute_ )\n\nJordan McLinn, a five-year-old with Duchenne muscular dystrophy, was granted his wish to become a fireman, then rallied fellow firefighters and legislators to pass the Right to Try law in Indiana. ( _", "Courtesy of Chris Bergin Photography_ )\n\n\"I believe God gives us miracles in many different ways,\" said Laura McLinn, Jordan's mother. \"", "He is helping people and giving people hope at just six years old. ", "We pray that something, anything, comes through for Jordan.\" ( _", "Courtesy of Chris Bergin Photography_ )\n\nTo bring joy to Jordan and raise awareness for Duchenne, Laura McLinn posted her son's résumé to Facebook. ", "Within hours, Jordan received job offers from fire stations all across the country. ( _", "Courtesy of the McLinn Family_ )\n\nAndrea Sloan of Texas, unable to qualify for a clinical trial, sought \"compassionate use\" access to BMN-673, an experimental cancer drug. ", "Despite widespread public support, the drug manufacturer BioMarin refused to engage in a dialogue or even to look at her medical records. ( _", "Courtesy of the Sloan family_ )\n\nFDA approval was too little too late. \"", "Andrea's scans showed the drug was having incredible success,\" said Karen Sloan, Andrea's mother. \"", "But the months of trying to engage BioMarin had taken its toll; the pneumonia proved insurmountable to her physical body.\" ", "Andrea passed away on New Year's Day 2014. ( _", "Courtesy of the Sloan family_ )\n\nNick Audin petitioned for and was denied access to PD-1, a potentially lifesaving experimental drug. ", "Nick's wife, Amy, launched SaveLockysDad.com, a website with a moving video featuring Nick's towheaded seven-year-old son, Lachlan \"Locky\" Audin. ( _", "Courtesy of the Auden family_ )\n\n\"We needed hope but didn't receive it through our battle,\" said Amy. \"", "For the patients and for their families, Right to Try offers some hope.\" ( _", "Courtesy of the Auden family_ )\n\nAbigail Burroughs's inability to gain access to the investigational cancer drug Eribitux may have contributed to her death. ", "Abigail's father, Frank, formed Abigail Alliance, then sued the FDA to help others like Abigail get the lifesaving drugs they need. ( _", "Courtesy of Frank Burroughs_ )\n\nChris Garabedian resigned his position as CEO of Sarepta after struggles with the FDA. \"", "Once a drug moves forward, and it's successful, everybody forgets about the delays, the inefficiency of the process, what boys [with Duchenne] could have been helped if this were approved a year ago.\" ( _", "Courtesy of Chris Garabedian_ )\n\nColorado becomes the first state in the nation to sign Right to Try into law when governor John Hickenlooper signs House Bill 1282, sending a strong message to Washington. ", "Republicans and Democrats agree on little these days, but there is unanimity in Colorado when it comes to defending the Right to Try. ( _", "Courtesy of KCNC-TV Denver_ )\n\nGovernor Robert Bentley signs Senate Bill 357, the Gabe's Right to Try Act, into law. ", "The bill was inspired by ten-year-old Gabe Griffin, who has Duchenne muscular dystrophy. ( _", "Courtesy of the State of Alabama Governor's Office_ )\n\nFive-year-old honorary fireman Jordan McLinn, the McLinn family, and local firemen from IFD Station 13 look on as Indiana governor Mike Pence signs the Right to Try bill into law. ( _", "Courtesy of the Indiana State Republican Caucus_ )\n\n## About the Author\n\n**DARCY OLSEN** is the president of the Goldwater Institute, a leading national policy and litigation organization that has changed more than two hundred laws nationwide over the last several years. ", "The group is leading the national campaign to pass Right to Try laws.", "\n\nDiscover great authors, exclusive offers, and more at hc.com.", "\n\n## Credits\n\nCover design by Milan Bozic\n\nCover photographs: © by Dejan Stanisavljevic / Shutterstock\n\n(lock); © David Smart / Shutterstock (medicine bottle)\n\n## Copyright\n\nTHE RIGHT TO TRY. ", "Copyright © 2015 by Darcy Olsen. ", "All rights reserved under International and Pan-American Copyright Conventions. ", "By payment of the required fees, you have been granted the nonexclusive, nontransferable right to access and read the text of this e-book on-screen. ", "No part of this text may be reproduced, transmitted, downloaded, decompiled, reverse-engineered, or stored in or introduced into any information storage and retrieval system, in any form or by any means, whether electronic or mechanical, now known or hereafter invented, without the express written permission of HarperCollins e-books.", "\n\nFIRST EDITION\n\nISBN: 978-0-06-240752-8\n\nEPub Edition November 2015 ISBN 9780062407542\n\n15 16 17 18 19 OV/RRD 10 9 8 7 6 5 4 3 2 1\n\n## About the Publisher\n\n**Australia**\n\nHarperCollins Publishers Australia Pty. ", "Ltd.\n\nLevel 13, 201 Elizabeth Street\n\nSydney, NSW 2000, Australia\n\nwww.harpercollins.com.au\n\n**Canada**\n\nHarperCollins Canada\n\n2 Bloor Street East - 20th Floor\n\nToronto, ON M4W 1A8, Canada\n\nwww.harpercollins.ca\n\n**New Zealand**\n\nHarperCollins Publishers New Zealand\n\nUnit D1, 63 Apollo Drive\n\nRosedale 0632\n\nAuckland, New Zealand\n\nwww.harpercollins.co.nz\n\n**United Kingdom**\n\nHarperCollins Publishers Ltd.\n\n1 London Bridge Street\n\nLondon SE1 9GF, UK\n\nwww.harpercollins.co.uk\n\n**United States**\n\nHarperCollins Publishers Inc.\n\n195 Broadway\n\nNew York, NY 10007\n\nwww.harpercollins.com\n" ]

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[ "Q:\n\nThe type or namespace name 'FacebookSessionClient' could not be found (are you missing a using directive or an assembly reference?)", "\n\nI am following http://facebooksdk.net/docs/phone/tutorial/ for logging into my Windows Phone 8 app through Facebook. ", "Upon going through the article when I try to run the application, it gives me error-\n\nThe type or namespace name 'FacebookSessionClient' could not be found (are you missing a using directive or an assembly reference?)", "`\n\nand,\n\nThe type or namespace name 'FacebookSession' could not be found (are you missing a using directive or an assembly reference?)", "\n\nI am sure I have added all references and namespaces. ", "So what I am doing wrong?", "\n\nA:\n\nThis happens because of the version of the Facebook SDK and the Facebook.", "Client.", "\nAbove problem can be resolved by installing the Facebook SDK version 6.3.2 and the Facebook.", "Client version 0.40-alpha\nYou can download and install using the Package Manager Console and the command can be found in here and here too.", "\n\n" ]

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[ "So Much For The Violent Femmes Reunion Gig At Riot Fest!", "\n\nThis just in from Violent Femmes drummer Victor DiLorenzo:\"It's always hard to write a eulogy for a lost loved one. ", "In this case, I sadly lament the loss of a dream and an ideal that was once Violent Femmes.", "When I first heard the news about the possibility of the original Violent Femmes reuniting, I was excited that once again our group might be able to play music for the fans that love us and for the new fans that have never had the chance to see us create the music live. ", "The only conditions that I had were that the three of us move forward to repair our relationships within the band, and that we would strive to attain a fair business agreement that would reflect a new way of handling the business that wouldn't be 'business as usual.' ", "Sadly, my open-hearted approach to finding a way to move forward wasn't shared by Violent Femmes. ", "What was finally being offered to me was, 'business as usual,' with a great deal of disrespect, dishonesty and greed.", "After having found out that the promoters of our recent concerts weren't interested in booking our group unless it was, 'the reunion of the original band,' I spoke to two of the biggest concert promoters in the world that handled two of our shows, and they told me directly that this was true. ", "So it confuses me that fans and the promoters see the value in presenting the original band, but not the band itself. ", "I realize that I'm no longer part of the copyright after having given up my business interest in Violent Femmes years ago, but I will always be part of the birthright of Violent Femmes, for which I will always be very proud! ", "I'm sorry and I apologize that the fans, promoters and agents won't get to see the Violent Femmes show that was being offered and that people bought tickets to see.", "As John Lennon once said, 'the dream is over.' ", "In regards to my history with Violent Femmes, the dream never quite got there.", "So on the evening of June 26th, 2013, on the stage of the Marcus Amphitheater at Summerfest, I gave to the world my last performance with Violent Femmes. ", "Milwaukee, we were yours for the night, and now forever!Sincerely and with warm regards,Victor DeLorenzo\"As much as I respect the Violent Femmes for the level of success they achieved despite being, well, HORRIBLE fucking musicians - arguably the most important component of the punk aesthetic - I'm having a hard time figuring out why Victor DiLorenzo, arguably the worst drummer to ever have a mental breakdown over the prospect of being paid huge amounts of money to play a big-time festival gig, is quitting Violent Femmes AGAIN.I mean, is he suddenly surprised all over again that Gordan Gano's an a-hole? ", "And why the fuck would he relinquish ownership of his portion of the band's copyright? ", "Was he drunk when he agreed to that? ", "If not, he's an idiot. ", "I mean, you can quit the band, even sell your drums on Craigslist, but you NEVER give up ownership of your copyright. ", "Hell, why do you think Steve Perry is still drawing a paycheck anytime Journey plays a show despite not having performed with the band in ages?Makes absolutely no fucking sense.", "Of course, this means that those who bought tickets to Riot Fest (taking place in Humboldt Park Sept 13-14-15) to see a \"reunited Violent Femmes\" will have to settle for 2/3 of the band and Dresdon Dolls drummer Bryan Viglione subbing for DiLorenzo. ", "It's one thing to be dissatisfied by the less-than-ideal circumstances that DiLorenzo helped create by expecting others to do the \"honorable thing\", but none of this is reason enough to bail on the show. ", "Whether you;re in a punk band, or Journey, the professional thing to do is to honor your commitments and play the shows you've agreed to pay, no matter how big a jerk Gordan Gano or Brian Ritchie may be at any given moment. ", "I hate to say it, but DiLorenzo is the one pulling the ultimate dick move of all by taking his ball and going home." ]

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[ "/*\nCopyright The Kubernetes Authors.", "\n\nLicensed under the Apache License, Version 2.0 (the \"License\");\nyou may not use this file except in compliance with the License.", "\nYou may obtain a copy of the License at\n\n http://www.apache.org/licenses/LICENSE-2.0\n\nUnless required by applicable law or agreed to in writing, software\ndistributed under the License is distributed on an \"AS IS\" BASIS,\nWITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.", "\nSee the License for the specific language governing permissions and\nlimitations under the License.", "\n*/\n\n// Code generated by informer-gen. ", "DO NOT EDIT.", "\n\npackage v1\n\nimport (\n\ttime \"time\"\n\n\trbacv1 \"k8s.io/api/rbac/v1\"\n\tmetav1 \"k8s.io/apimachinery/pkg/apis/meta/v1\"\n\truntime \"k8s.io/apimachinery/pkg/runtime\"\n\twatch \"k8s.io/apimachinery/pkg/watch\"\n\tinternalinterfaces \"k8s.io/client-go/informers/internalinterfaces\"\n\tkubernetes \"k8s.io/client-go/kubernetes\"\n\tv1 \"k8s.io/client-go/listers/rbac/v1\"\n\tcache \"k8s.io/client-go/tools/cache\"\n)\n\n// RoleInformer provides access to a shared informer and lister for\n// Roles.", "\ntype RoleInformer interface {\n\tInformer() cache.", "SharedIndexInformer\n\tLister() v1.RoleLister\n}\n\ntype roleInformer struct {\n\tfactory internalinterfaces.", "SharedInformerFactory\n\ttweakListOptions internalinterfaces.", "TweakListOptionsFunc\n\tnamespace string\n}\n\n// NewRoleInformer constructs a new informer for Role type.", "\n// Always prefer using an informer factory to get a shared informer instead of getting an independent\n// one. ", "This reduces memory footprint and number of connections to the server.", "\nfunc NewRoleInformer(client kubernetes.", "Interface, namespace string, resyncPeriod time.", "Duration, indexers cache.", "Indexers) cache.", "SharedIndexInformer {\n\treturn NewFilteredRoleInformer(client, namespace, resyncPeriod, indexers, nil)\n}\n\n// NewFilteredRoleInformer constructs a new informer for Role type.", "\n// Always prefer using an informer factory to get a shared informer instead of getting an independent\n// one. ", "This reduces memory footprint and number of connections to the server.", "\nfunc NewFilteredRoleInformer(client kubernetes.", "Interface, namespace string, resyncPeriod time.", "Duration, indexers cache.", "Indexers, tweakListOptions internalinterfaces.", "TweakListOptionsFunc) cache.", "SharedIndexInformer {\n\treturn cache.", "NewSharedIndexInformer(\n\t\t&cache.", "ListWatch{\n\t\t\tListFunc: func(options metav1.ListOptions) (runtime.", "Object, error) {\n\t\t\t\tif tweakListOptions !", "= nil {\n\t\t\t\t\ttweakListOptions(&options)\n\t\t\t\t}\n\t\t\t\treturn client.", "RbacV1().Roles(namespace).List(options)\n\t\t\t},\n\t\t\tWatchFunc: func(options metav1.ListOptions) (watch.", "Interface, error) {\n\t\t\t\tif tweakListOptions !", "= nil {\n\t\t\t\t\ttweakListOptions(&options)\n\t\t\t\t}\n\t\t\t\treturn client.", "RbacV1().Roles(namespace).Watch(options)\n\t\t\t},\n\t\t},\n\t\t&rbacv1.Role{},\n\t\tresyncPeriod,\n\t\tindexers,\n\t)\n}\n\nfunc (f *roleInformer) defaultInformer(client kubernetes.", "Interface, resyncPeriod time.", "Duration) cache.", "SharedIndexInformer {\n\treturn NewFilteredRoleInformer(client, f.namespace, resyncPeriod, cache.", "Indexers{cache.", "NamespaceIndex: cache.", "MetaNamespaceIndexFunc}, f.tweakListOptions)\n}\n\nfunc (f *roleInformer) Informer() cache.", "SharedIndexInformer {\n\treturn f.factory.", "InformerFor(&rbacv1.Role{}, f.defaultInformer)\n}\n\nfunc (f *roleInformer) Lister() v1.RoleLister {\n\treturn v1.NewRoleLister(f.", "Informer().GetIndexer())\n}\n" ]

{ "pile_set_name": "Github" }

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[ "I've always loved Bruce Banner and of course, the Hulk! ", "You did a great job in portraying his power and intense emotions. ", "I know, he may need to take some anger management classes, but that wouldn't make him The Hulk! ", "You used a nice shade of green and incorporated very Cool details throughout, like his popping veins and hairy fingers! ", "Very nice work!", "\n\nThis comment is brought to you by" ]

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[ "1. ", "Introduction\n===============\n\nMarine organisms (including invertebrates and microorganisms) constitute a vast reservoir of bioactive molecules exhibiting potential anticancer activities \\[[@B1-marinedrugs-12-00779],[@B2-marinedrugs-12-00779]\\]. ", "Despite this, several marine-based molecules have reached Phase II and III cancer clinical trials with encouraging results. ", "In addition, Ecteinascidin 743 (*a.k.a* Trabectedin, Yondelis^®^), an antitumor compound extracted from sea quirts and tunicates, has been approved for the treatment of advanced soft tissue sarcomas in European countries \\[[@B3-marinedrugs-12-00779],[@B4-marinedrugs-12-00779]\\]. ", "Many marine compounds with antitumor effects are natural poisons involved in defense mechanisms and are therefore potentially cytotoxic to cancer cells. ", "For instance, Kahalalide F, a peptide isolated from molluscs, represents a lysosomal poison that promotes non-apoptotic cell death by oncosis in several tumor cells \\[[@B5-marinedrugs-12-00779]\\]. ", "Despite real advances, in most of cases, mechanisms of anticancer effects of marine-derived drug candidates remain to be determined. ", "Over the past decade, there has been a growing interest in a promising family of natural marine products called lamellarins. ", "Lamellarins were initially isolated from the marine prosobranch mollusc *Lamellaria* sp. ", "and afterward from ascidians (tunicates) that are considered as food supply by *Lamellaria* (for review \\[[@B6-marinedrugs-12-00779],[@B7-marinedrugs-12-00779]\\]). ", "To date, more than 40 lamellarins, which share a common hexacyclic alkaloid skeleton, have been described \\[[@B7-marinedrugs-12-00779]\\]. ", "Lamellarins have complex mechanisms of action and exert pleiotropic bioactivities including antiviral properties, antioxidative activities, antiproliferative and cell death-inducing effects (for review \\[[@B6-marinedrugs-12-00779]\\]). ", "Lamellarin D (LamD) ([Figure 1](#marinedrugs-12-00779-f001){ref-type=\"fig\"}) is undoubtedly one of the most active lamellarins with high potential for cancer therapy \\[[@B8-marinedrugs-12-00779]\\]. ", "LamD is a multitarget drug endowed with important antitumor activities in a wide variety of cancer cells including multidrug-resistant tumor cell lines \\[[@B9-marinedrugs-12-00779]\\]. ", "LamD targets several serine/threonine kinases that contribute to the tumorigenesis \\[[@B10-marinedrugs-12-00779]\\]. ", "Morevoer, LamD preferentially targets cancer cell mitochondria \\[[@B8-marinedrugs-12-00779]\\], leading to prominent reduction in mitochondrial activity \\[[@B11-marinedrugs-12-00779]\\]. ", "The mitochondrial targeting depends upon the presence of hydroxyl groups attached to the basic skeleton of LamD \\[[@B11-marinedrugs-12-00779]\\]. ", "Mitochondrial dysfunctions are observed with micromolar concentrations of LamD and promote rapid mitochondrial permeability culminating in apoptotic cell death \\[[@B8-marinedrugs-12-00779],[@B11-marinedrugs-12-00779],[@B12-marinedrugs-12-00779]\\]. ", "Thus, there are cumulative evidences that LamD triggers cancer cell apoptosis through direct activation of the canonical intrinsic mitochondrial cell death pathway \\[[@B8-marinedrugs-12-00779],[@B12-marinedrugs-12-00779]\\]. ", "Interestingly, cytotoxicity of LamD is totally dependent on the presence of functional mitochondria and is dissociated from nuclear signaling pathways such as those dependent on p53 \\[[@B12-marinedrugs-12-00779]\\]. ", "While the cytotoxic effects of LamD have been largely deciphered \\[[@B8-marinedrugs-12-00779],[@B11-marinedrugs-12-00779],[@B12-marinedrugs-12-00779]\\], mechanisms and molecular pathways involved in the antiproliferative activities of LamD are still not elucidated. ", "Of note, LamD has also been identified as a potent inhibitor of DNA topoisomerase I \\[[@B9-marinedrugs-12-00779]\\]. ", "This effect is presumably responsible for the antiproliferative activity observed with sublethal concentrations of LamD \\[[@B12-marinedrugs-12-00779]\\]. ", "Consequently, in this paper, we investigated the growth inhibition profile of several cancer cell lines exposed to sublethal doses of LamD. Our results add senescence-associated growth arrest to the wide spectrum of anticancer activities of LamD and indicate that LamD-induced senescence is largely dependent on the effect of LamD on topoisomerase I and ROS generation.", "\n\n{#marinedrugs-12-00779-f001}\n\n2. ", "Results and Discussion\n=========================\n\n2.1. ", "Lamellarin D Induces Senescence-Like Growth Arrest in Cancer Cells\n-----------------------------------------------------------------------\n\nWe aimed to determine the phenotype of several cancer cells exposed to sublethal concentrations of LamD \\[[@B8-marinedrugs-12-00779],[@B12-marinedrugs-12-00779]\\]. ", "While 5 µM LamD mainly reduced cell viability by induction of an apoptotic phenotype, morphological examination of P388 leukemia cells exposed to 0.2 µM LamD revealed growth arrest with the appearance of \"giant\" cells over time ([Figure 2](#marinedrugs-12-00779-f002){ref-type=\"fig\"}A). ", "LamD-induced cell enlargement was associated with vacuolated cytoplasm, the presence of enlarged nuclei and sometimes multiple nuclei ([Figure 2](#marinedrugs-12-00779-f002){ref-type=\"fig\"}A). ", "In addition, DAPI-stained nuclei appeared enlarged with the presence of multiple foci ([Figure 2](#marinedrugs-12-00779-f002){ref-type=\"fig\"}B), a feature consistent with the presence of DNA damage \\[[@B13-marinedrugs-12-00779]\\]. ", "Confirming previous observations \\[[@B9-marinedrugs-12-00779],[@B12-marinedrugs-12-00779]\\], cell cycle analysis indicated that 0.2 µM LamD induced a transient S-phase blockage (\\>12--18 h of exposure) followed by an accumulation of cells in G2/M phase ([Figure 2](#marinedrugs-12-00779-f002){ref-type=\"fig\"}C). ", "The quasi-totality of cells was arrested in G2/M phase upon 48 h of treatment. ", "Since microscopic examination revealed mitoses only infrequently ([Figure 2](#marinedrugs-12-00779-f002){ref-type=\"fig\"}A), the presence of enlarged cells observed after LamD exposure probably corresponded to cells arrested at the G2 checkpoint and not during mitosis. ", "In an attempt to determine if growth-arrested cells remained metabolically active, determination of intracellular ATP level was performed in P388 cells exposed to LamD. Contrasting with the effect observed at higher concentrations, 0.2 µM LamD, a dose that induced leukemia growth arrest ([Figure 2](#marinedrugs-12-00779-f002){ref-type=\"fig\"}A,C), did not profoundly curtail intracellular ATP production ([Figure 2](#marinedrugs-12-00779-f002){ref-type=\"fig\"}D). ", "Since the above morphological changes were reminiscent of cellular senescence \\[[@B14-marinedrugs-12-00779],[@B15-marinedrugs-12-00779]\\], this prompted us to analyze the presence of senescence-associated β-galactosidase (SA-β-gal), the typical marker of senescent cells \\[[@B16-marinedrugs-12-00779]\\], in LamD treated cells. ", "As shown in [Figure 3](#marinedrugs-12-00779-f003){ref-type=\"fig\"}A, LamD exposure caused the time-dependent induction of SA-β-gal activity as determined by flow cytometry in P388 cells stained with the fluorescent β-galactosidase substrate, C12FDG ([Figure 3](#marinedrugs-12-00779-f003){ref-type=\"fig\"}A). ", "To confirm this result, we also subjected other cancer cell lines (such as the human melanoma cell line HBL and the human osteosarcoma SAOS2) to sublethal concentrations of LamD. Strikingly, the cytochemical assessment of SA-β-gal also revealed significant increase in the senescent marker after treatment with LamD ([Figure 3](#marinedrugs-12-00779-f003){ref-type=\"fig\"}B). ", "Like LamD-treated P388 cells, HBL and SAOS2 cells positive for SA-β-gal were enlarged ([Figure 3](#marinedrugs-12-00779-f003){ref-type=\"fig\"}B). ", "As shown in [Figure 3](#marinedrugs-12-00779-f003){ref-type=\"fig\"}C, LamD also induced the apparition of SA-β-gal activity *in vivo* in HBL melanoma tumor model in SCID mice \\[[@B17-marinedrugs-12-00779]\\]. ", "In this preclinical tumor model, treatment with LamD reduced tumor growth ([Figure 3](#marinedrugs-12-00779-f003){ref-type=\"fig\"}C). ", "Altogether, these results indicate that LamD is an inducer of senescence-associated growth arrest in several cancer cells.", "\n\n{#marinedrugs-12-00779-f002}\n\n{#marinedrugs-12-00779-f003}\n\n2.2. ", "Senescence-Associated Growth Arrest Induced by Lamellarin D Is Dependent on Its Effect on Topoisomerase I\n--------------------------------------------------------------------------------------------------------------\n\nDNA topoisomerase I has been the first identified target of LamD \\[[@B9-marinedrugs-12-00779]\\]. ", "LamD has been unveiled as a potent inhibitor of topoisomerase I responsible for DNA damage, p53 activation and growth inhibition \\[[@B9-marinedrugs-12-00779],[@B12-marinedrugs-12-00779]\\]. ", "In contrast, we have previously reported that the cytotoxic activity of LamD is independent on topoisomerase I \\[[@B12-marinedrugs-12-00779]\\]. ", "Indeed, high concentrations of LamD maintained a sustained level of apoptosis in the topoisomerase I-mutated cells (P388CPT5) that are resistant to cell death induced by the prototype inhibitor of topoisomerase I, camptothecin (CPT) \\[[@B8-marinedrugs-12-00779]\\]. ", "Here, we addressed the question whether the inhibition of topoisomerase I could be involved in the senescence-associated growth arrest induced by sublethal concentration of LamD. First, we studied the apparition of growth arrest in P388CPT5 upon LamD exposure and used camptothecin as control ([Figure 4](#marinedrugs-12-00779-f004){ref-type=\"fig\"}A). ", "Contrasting what was observed in P388 cells, kinetic studies revealed that LamD, as well as CPT, was devoid of any antiproliferative effect in P388CPT5 ([Figure 4](#marinedrugs-12-00779-f004){ref-type=\"fig\"}A). ", "Confirming these results, LamD and the prototype topoisomerase I inhibitor CPT arrested P388 cells in G2 phase, a situation not observed in P388CPT5 ([Figure 4](#marinedrugs-12-00779-f004){ref-type=\"fig\"}B). ", "G2 arrest was associated with a decline in the protein level of the phospatase Cdc25c in P388 cells exposed to drugs. ", "Once again, this effect was absent in the topoisomerase I-mutated cells exposed to LamD or CPT ([Figure 4](#marinedrugs-12-00779-f004){ref-type=\"fig\"}C). ", "Besides, growth arrest was associated with the induction of cellular senescence in P388 cells treated with LamD as deemed by the percentage of C12FDG+ cells ([Figure 5](#marinedrugs-12-00779-f005){ref-type=\"fig\"}A). ", "A nearly identical percentage was observed for P388 cells after treatment with CPT. ", "Conversely, LamD, as well as CPT, did not elicit any SA-gal activity in the topoisomerase I-mutated cells ([Figure 5](#marinedrugs-12-00779-f005){ref-type=\"fig\"}A). ", "Of note, the rate of senescence induced by LamD was comparable to that observed after CPT exposure ([Figure 5](#marinedrugs-12-00779-f005){ref-type=\"fig\"}A). ", "The CDK inhibitor, p21, can be considered as a senescence marker that links cell cycle arrest and cellular senescence. ", "Additionally, evidence shows that CPT induced the expression of p21 in colon cancer cells, and this expression is required for senescence \\[[@B18-marinedrugs-12-00779]\\]. ", "Confirming these data, LamD, as well as CPT, induced p21 mRNA expression exclusively in wild-type P388 cells. ", "Western blot analysis confirmed the p21 increase at the protein level, and immunofluorescence data revealed its nuclear localization in P388 treated with LamD ([Figure 5](#marinedrugs-12-00779-f005){ref-type=\"fig\"}B). ", "Taken together, these results suggest that senescence-like growth arrest induced by LamD is strictly dependent on its inhibition of DNA topoisomerase I.\n\n{#marinedrugs-12-00779-f004}\n\n{#marinedrugs-12-00779-f005}\n\nGenotoxic agents such as conventional chemotherapeutic agents induce senescence by different mechanisms and some of them have been associated with suppression of telomerase activity \\[[@B19-marinedrugs-12-00779]\\]. ", "We evaluated telomerase activity in cells exposed to LamD using the PCR-based telomeric repeat amplification protocol. ", "LamD treatment of P388 cells did not result in an important reduction in telomerase activity within the first 24--72 h of drug exposure. ", "No effect was observed with CPT for 24 h. Thus, telomere shortening probably does not constitute the principal mechanism resulting in senescence induced by LamD.\n\n2.3. ", "Lamellarin D Induced Extra-Mitochondrial ROS Accumulation in Senescent Cells\n---------------------------------------------------------------------------------\n\nRecent studies have suggested that reactive oxygen species (ROS) can mediate senescence induced by anticancer drugs \\[[@B19-marinedrugs-12-00779]\\]. ", "We first studied the pro-oxidant cell response to LamD. The generation of ROS in P388 cells was determined by flow cytometry with the general redox-sensitive fluorescent dye, H2DCFHDA. ", "As shown in [Figure 6](#marinedrugs-12-00779-f006){ref-type=\"fig\"}A, LamD stimulated the intracellular generation of ROS over time, beginning after 18 h of exposure concomitantly withthe apparition of senescence-like growth arrest ([Figure 2](#marinedrugs-12-00779-f002){ref-type=\"fig\"} and [Figure 3](#marinedrugs-12-00779-f003){ref-type=\"fig\"}). ", "LamD-induced ROS was limited by the pre-incubation with the antioxidant vitamin C ([Figure 6](#marinedrugs-12-00779-f006){ref-type=\"fig\"}A). ", "A similar increase in ROS was observed in HBL cells upon LamD exposure ([Figure 6](#marinedrugs-12-00779-f006){ref-type=\"fig\"}D). ", "ROS increase was not accompanied by changes in GSH content in LamD-treated P388 cells ([Figure 6](#marinedrugs-12-00779-f006){ref-type=\"fig\"}B). ", "Since mitochondrial electron transport chain is considered the principal source of intracellular ROS \\[[@B20-marinedrugs-12-00779]\\], we examined whether LamD could promote mitochondrial ROS production detected with the mitochondrial anion superoxide detector, MitoSox. ", "Under conditions in which LamD significantly increased H2DCFHDA fluorescence, MitoSox fluorescence was not affected by exposition to LamD ([Figure 6](#marinedrugs-12-00779-f006){ref-type=\"fig\"}C). ", "To confirm the existence of extra-mitochondrial sources of LamD-induced ROS, we used the partially respiration-deficient cell line HBL ρ0 that produces less mitochondrial ROS than its parental cell line, HBL \\[[@B21-marinedrugs-12-00779]\\]. ", "Unlike the mitochondrial pro-oxidant, elesclomol, which promoted ROS quasi-exclusively by active mitochondria \\[[@B21-marinedrugs-12-00779]\\], LamD induced about the same extent of ROS production in HBL and HBL ρ0 ([Figure 7](#marinedrugs-12-00779-f007){ref-type=\"fig\"}A), indicating that LamD can induce ROS in absence of intact electron transport chain and confirming that mitochondria are not the major source of ROS upon LamD exposure. ", "To get insight into the potential sources of ROS induced by LamD, we incubated P388 cells with various inhibitors of ROS-producing enzymes before treatment with LamD then ROS generation was evaluated after H2DCFHDA staining ([Figure 7](#marinedrugs-12-00779-f007){ref-type=\"fig\"}B). ", "LamD-induced ROS was significantly inhibited by diphenylene iodonium (DPI), a classical inhibitor of flavoenzymes, by apocynin, a more specific inhibitor of NADPH oxidase and by allopurinol an inhibitor of xantine oxidase activity. ", "In contrast, the mitochondrial ROS inhibitors, rotenone and antimycin A did not prevent ROS generation by LamD. No effect was observed with the inhibitor of NOS, L-NAME or with the inhibitor of cytochrome P450, ketoconazole. ", "Interestingly, a strong inhibitory effect of DPI on LamD-induced ROS generation was also observed in HBL cells ([Figure 7](#marinedrugs-12-00779-f007){ref-type=\"fig\"}C). ", "Altogether, the aforementioned data indicate that LamD generates extra-mitochondrial ROS in cancer cells.", "\n\n{#marinedrugs-12-00779-f006}\n\n{#marinedrugs-12-00779-f007}\n\n2.4. ", "Role of ROS Production in Senescence and DNA Damage Induced by LamD\n------------------------------------------------------------------------\n\nWe next studied whether the generation of ROS can contribute to the senescent phenotype induced by LamD ([Figure 8](#marinedrugs-12-00779-f008){ref-type=\"fig\"}). ", "Pre-treatment of P388 or HBL cells with DPI remarkably minimized the LamD-induced apparition of the senescent marker, SA-β-gal ([Figure 8](#marinedrugs-12-00779-f008){ref-type=\"fig\"}A,B), also as it prevented the generation of ROS ([Figure 6](#marinedrugs-12-00779-f006){ref-type=\"fig\"} and [Figure 7](#marinedrugs-12-00779-f007){ref-type=\"fig\"}). ", "Moreover, HBL ρ0 cells, which responded to LamD exposure by increasing intracellular ROS ([Figure 6](#marinedrugs-12-00779-f006){ref-type=\"fig\"} and [Figure 7](#marinedrugs-12-00779-f007){ref-type=\"fig\"}), displayed a classical senescent phenotype (demonstrated by significant increase in C12FDG positive cells ([Figure 8](#marinedrugs-12-00779-f008){ref-type=\"fig\"}B) and the presence of typical morphological changes ([Figure 9](#marinedrugs-12-00779-f009){ref-type=\"fig\"}A)). ", "Accordingly, upon LamD exposure, the topoisomerase I-mutated cell line, P388 CPT5, which was resistant to the apparition of senescence ([Figure 2](#marinedrugs-12-00779-f002){ref-type=\"fig\"} and [Figure 3](#marinedrugs-12-00779-f003){ref-type=\"fig\"}), did not produce intracellular ROS ([Figure 9](#marinedrugs-12-00779-f009){ref-type=\"fig\"}B). ", "All these data underscore the strict correlation between ROS production and senescence in LamD-treated cells indicating that LamD can promote the senescent phenotype through ROS generation.", "\n\n{#marinedrugs-12-00779-f008}\n\n{#marinedrugs-12-00779-f009}\n\nFinally, we investigated the role of ROS in DNA damage induced by LamD ([Figure 10](#marinedrugs-12-00779-f010){ref-type=\"fig\"}). ", "Exposure of P388 cells to DPI at concentrations that inhibited ROS production ([Figure 7](#marinedrugs-12-00779-f007){ref-type=\"fig\"}A) partially reduced the onset of DNA damage induced by LamD as estimated by nuclear foci and the detection of the phosphorylated form of histone H2AX (H2AXγ), a good indicator of double-strand DNA breaks ([Figure 10](#marinedrugs-12-00779-f010){ref-type=\"fig\"}A). ", "Moreover, DPI had only minimal protective effects on LamD-induced G2 arrest ([Figure 10](#marinedrugs-12-00779-f010){ref-type=\"fig\"}B).", "\n\n{#marinedrugs-12-00779-f010}\n\n2.5. ", "Proposed Mechanisms of LamD-Induced Senescence\n---------------------------------------------------\n\nLamD is an uncommonly potent anticancer agent that displays cytotoxic effects against a large panel of cancer cell lines and tumor xenografts \\[[@B8-marinedrugs-12-00779],[@B9-marinedrugs-12-00779]\\]. ", "The anticancer effect of LamD results from its unique mitochondrial effect leading to cancer cell death \\[[@B11-marinedrugs-12-00779]\\].", "\n\nHere, we demonstrated that LamD induced cellular senescence at sublethal doses correlating with IC50 value for antiproliferative activity \\[[@B9-marinedrugs-12-00779],[@B12-marinedrugs-12-00779]\\]. ", "Cellular senescence is a state of cell cycle arrest +ly triggered by telomere shortening (*a.k.a.* ", "replicative or mitotic senescence) or by intracellular stresses (*a.k.a.* ", "accelerated or premature senescence). ", "Thus, senescence of cancer cells can occur in response to DNA damaging agents and results in proliferation arrest associated with a specific morphological and biochemical phenotype (for review \\[[@B19-marinedrugs-12-00779]\\]). ", "Herein, we provided strong evidence for adding LamD to the list of senescence-inducing agents including many chemotherapeutic agents such as topoisomerase I and II inhibitors \\[[@B19-marinedrugs-12-00779]\\]. ", "Thus, it has been observed that the major cellular response to nonlethal concentrations of the topoisomerase II inhibitor, doxorubicin, was senescence observed in almost all tumor cell lines *in vitro* \\[[@B22-marinedrugs-12-00779]\\] as well as *in vivo* in human tumors xenografted in nude mice and even in biopsies from patients \\[[@B23-marinedrugs-12-00779]\\]. ", "We observed that LamD provokes growth arrest in the G2 stage of the cell cycle sustained by the increased expression of the cyclin-dependent kinase inhibitor, p21 \\[[@B24-marinedrugs-12-00779]\\]. ", "This is accompanied by a distinguishable morphological phenotype consisting of flattened and enlarged cells with cytoplasmic granules and a large nucleus associated with increased SA-β-gal staining. ", "However, the absence of major alteration in telomerase activity suggests that LamD caused DNA damage- and stress-induced senescence rather than the classical replicative senescence \\[[@B25-marinedrugs-12-00779]\\]. ", "Interestingly, senescence is considered as a major antiproliferative response that determines treatment outcome in apoptosis-resistant cancer \\[[@B23-marinedrugs-12-00779]\\]. ", "Senescence can be viewed as a tumor-suppressive mechanism and therefore efficient senescence-inducing agents, like LamD, could have a significant advantage in the clinical treatment of cancer. ", "Cellular senescence may represent an alternative outcome to anticancer therapies, and senescence, which requires much less concentrations of drugs, may be associated with fewer or less severe side effects than cytotoxicity \\[[@B19-marinedrugs-12-00779]\\].", "\n\nOur results also shed light on the potential mechanisms associated with the senescence-associated growth arrest induced by LamD. Firstly, we demonstrated a requirement for topoisomerase I in the senescence response to LamD. Moreover, LamD can produce significant levels of single \\[[@B9-marinedrugs-12-00779]\\] and double strand breaks (DSB) as shown by the presence of H2AX phosphorylation. ", "This is in agreement with the senescence observed with campthotecin (another topoisomerase I inhibitor) in colon cancer \\[[@B18-marinedrugs-12-00779]\\]. ", "Treatment of cells with nonlethal concentrations of camptothecin induced limited DNA damage, then p53 activation, which in turn up-regulated the expression of p21 \\[[@B18-marinedrugs-12-00779]\\]. ", "This is in line with the effects of LamD on p21 expression ([Figure 6](#marinedrugs-12-00779-f006){ref-type=\"fig\"} and [Figure 7](#marinedrugs-12-00779-f007){ref-type=\"fig\"}), suggesting that the cellular senescence response to topoisomerase I inhibitors depends on p21. ", "Secondly, we also demonstrated that ROS are required for senescence induced by LamD. Many anticancer drugs generate excessive intracellular ROS that participate in their cytotoxic effects \\[[@B26-marinedrugs-12-00779]\\]. ", "Furthermore, senescent cells caused by chemotherapeutic agents also exhibited a significantly higher level of ROS \\[[@B27-marinedrugs-12-00779]\\]. ", "The significant contribution of oxidative stress to premature senescence was confirmed by the observations that inhibition of ROS largely attenuated senescence induced by anticancer agents \\[[@B28-marinedrugs-12-00779]\\]. ", "Mitochondria are considered to be the major source of intracellular ROS. ", "Surprisingly, pharmacological evidences presented herein suggest an extra-mitochondrial origin of ROS in LamD-induced senescence. ", "Since the onset of senescence was sensitive to the NADPH oxidase (NOX) inhibitor, DPI, one can envisage that NOX-derived ROS may be involved in LamD-induced senescence. ", "There are growing evidences that enzymes of the NOX family play an important role in the redox signaling in healthy and tumor cells \\[[@B29-marinedrugs-12-00779]\\]. ", "Consistent with our data, the NADPH oxidase, NOX4, has been identified as a good candidate for ROS production in senescent cells \\[[@B30-marinedrugs-12-00779]\\]. ", "Interestingly, NOX4-dependent ROS also regulated P21 expression \\[[@B30-marinedrugs-12-00779]\\].", "\n\nHow are ROS and DNA damage interconnected in LamD-induced senescence? ", "Typically, increased ROS generation can trigger oxidative DNA damage then creates DNA DSB leading to premature senescence. ", "Accordingly, radiotherapy can induce senescence in cancer cells through ROS-mediated DNA damage \\[[@B31-marinedrugs-12-00779]\\]. ", "However, it is likely that induction of senescence by LamD does not follow this typical cascade. ", "Indeed, we observed that the protection of DPI on LamD-induced DNA damage was only partial. ", "Moreover, kinetic studies indicate that DNA damage induced by LamD occurred before the onset of ROS (\\[[@B12-marinedrugs-12-00779]\\] and data not shown). ", "Moreover, in topoisomerase I-mutated cells, no increase of the level of ROS was observed upon LamD exposure suggesting that DNA damage caused by LamD resulted in the induction of ROS. ", "Similarly, it has been demonstrated that DNA damage can induce ROS generation, which is fully prevented by pre-incubation of cells with DPI, through activation of the H2AX NOX1/Rac1 pathway, \\[[@B32-marinedrugs-12-00779]\\]. ", "However, we cannot exclude other mechanisms of regulation and, of note, our results suggest the existence of a signal amplification loop involving ROS and DNA damage that may favor the persistence of LamD-induced DNA damage ([Figure 11](#marinedrugs-12-00779-f011){ref-type=\"fig\"}). ", "Finally, based on above evidences and previous data \\[[@B8-marinedrugs-12-00779],[@B9-marinedrugs-12-00779],[@B12-marinedrugs-12-00779]\\], one can envision the speculative multistep scenario forcing LamD-treated cells toward senescence-associated growth arrest ([Figure 11](#marinedrugs-12-00779-f011){ref-type=\"fig\"}): (i) sublethal doses of LamD inhibit topoisomerase I and induce limited DNA damage; (ii) DNA damage activates NOX leading to ROS generation; (iii) DNA damage activates p21 and provokes G2 growth arrest. ", "All these events contribute to the onset of morphological and biochemical signs of senescence.", "\n\n{#marinedrugs-12-00779-f011}\n\n3. ", "Experimental Section\n=======================\n\n3.1. ", "Chemicals\n--------------\n\nLamellarin D was synthesized at Pharmamar (Madrid, Spain). ", "LamD was initially dissolved in DMSO at 10 mM. Drug stock solution was aliquoted, kept at −20 °C and freshly diluted with PBS to the desired concentration immediately before use. ", "All fluorochromes including 4′,6-diamidino-2-phenylindole (DAPI), 5-dodecanoylaminofluorescein di-β-[d]{.smallcaps}-galactopyrano-side (C12FDG), 6-carboxy-2′,7′-dichlorodihydrofluorescein diacetate (H2DCFHDA) and MitoSoxRed reagent were purchased from Life Technologies, Grand island, NY, USA. ", "Other reagents were purchased from Sigma-Aldrich (St. Louis, MO, USA) unless otherwise stated.", "\n\n3.2. ", "Cell Culture\n-----------------\n\nThe mouse leukemia cell line P388, its topoisomerase I-mutated subclone (P388CPT5) resistant to camptothecin (\\[[@B33-marinedrugs-12-00779]\\], a gift from JF Riou, Rhône-Poulenc Rorer, France) and the HBL cutaneous melanoma cell \\[[@B8-marinedrugs-12-00779],[@B9-marinedrugs-12-00779],[@B12-marinedrugs-12-00779]\\] line (kindly provided by Pr. ", "G. Ghanem, Universite Libre de Bruxelles, Institut Jules Bordet, Bruxelles, Belgium) were routinely cultured in RPMI 1640 medium (Invitrogen, Carlsbad, CA, USA) supplemented with l-glutamine, antibiotics and 10% heat-inactivated FCS. ", "We have also generated human melanoma cells lacking mitochondrial DNA (HBLρ0) from the HBL cell line based on standard protocols \\[[@B11-marinedrugs-12-00779]\\].", "\n\n3.3. ", "Microscopic Analysis of Cells\n----------------------------------\n\nMorphological examination was performed after May Gruenwald Giemsa staining and visualization of SA-β-gal activity was detected following the classical cytochemical protocol \\[[@B34-marinedrugs-12-00779]\\]. ", "For fluorescence microscopy, P388 cells were fixed in 4% paraformaldehyde for 10 min then permeabilized with 0.1% Triton X-100 for other 10 min. ", "After washing twice with PBS + 2% FCS, cells were incubated with the monoclonal anti-p21 antibody (1:250; F-5, SantaCruz Biotechnology Inc., Santa Cruz, CA, USA) on ice overnight. ", "After three washes in PBS, cells were incubated with AlexaFluor488-conjugated antibody (1:800; Life Technologies) for 1 h at room temperature. ", "Cells were counterstained with 4′,6-diamidino-2-phenylindole (DAPI, 5 mg/mL) to label nuclear DNA. ", "All samples were viewed using a Leica DMR microscope.", "\n\n3.4. ", "Flow Cytometric Analysis\n-----------------------------\n\nFor cell cycle determination, cells were fixed overnight at 4 °C using 70% ice-cold ethanol-PBS followed by propidium iodide (50 µg/mL) staining and cell cycle data were analyzed using the relevant Cell Cycle Analysis software (FlowJo, Tree Star, Ashland, OR, USA). ", "For measurement of SA-β-gal activity, cells were incubated with a non-fluorescent substrate of SA-β-gal, C12FDG at 30 µM, washed, and the level of green fluorescent product was detected by flow cytometry as described \\[[@B13-marinedrugs-12-00779],[@B34-marinedrugs-12-00779]\\]. ", "Detection of ROS was assessed with several oxidation-sensitive fluorescent probes such as mitochondria-targeted hydroethydine (Mito-SOX, 2.5 µM for 20 min at 37 °C) and H2CFHDA (50 nM for 20 min at 37 °C) following classical protocols \\[[@B17-marinedrugs-12-00779]\\]. ", "For evaluation of double strand breaks, the H2AX Phosphorylation Assay kit (Upstate, Lake Placid, NY, USA) was used according to previous reports \\[[@B35-marinedrugs-12-00779]\\]. ", "Cells were stained with the anti-phospho-histone H2AX-FITC conjugate, which recognizes H2AX phosphorylated at serine 139, or with normal mouse IgG conjugate used as control. ", "All samples were analyzed on a FACS Canto II cytofluorometer (Beckton Dickinson, Franklin Lakes, NJ, USA).", "\n\n3.5. ", "Determination of Intracellular Glutathione\n-----------------------------------------------\n\nThe total glutathione content was determined with the glutathione sensitive probe, monochlorobimane (40 µM for 30 min) as described \\[[@B12-marinedrugs-12-00779]\\]. ", "Fluorescence was measured at 460 nM using a microplate-reading fluorometer (Fluorocount, Packard Instrument Company, Meriden, CT, USA) with excitation at 360 nM.\n\n3.6. ", "RT-PCR Analysis\n--------------------\n\nTotal RNA was isolated with the TRIzol reagent (Invitrogen, Carlsbad, CA, USA) then cDNA was synthesized as previously described \\[[@B36-marinedrugs-12-00779]\\]. ", "RT-PCR experiments were performed using P21 forward primers (5′-GGAGCAAAGTGTGCCGTTGTC-3′) and P21 reverse primers (5′-GAGGAAGTACTGGGCCTCTTG-3′); Bax forward primers (5′-GGCGAATTGGAGATGAACTGG-3′) and Bax reverse primers (5′-GCTAGCAAAGTAGAAGAGGGC-3′). ", "The primer set used to amplify β-tubulin was: Forward 5′-CAACGTCAAGACGGCCGTGTG-3′ and reverse: 5′ GACAGAGGCAAACTGAGCACC-3′. The cycling conditions were as follows: 94 °C for 4 min, then 30 cycles consisting of 30 s at 94 °C, 30 s at 58 °C, and 1 min at 72 °C. ", "RT-PCR reaction mixtures were electrophoresed on 2% agarose gel stained with ethidium bromide.", "\n\n3.7. ", "Immunoblot Analysis\n------------------------\n\nTwenty micrograms of proteins of cell extracts were subjected to 12% SDS-PAGE and transferred onto nitrocellulose membranes (Amersham Life Science, Buckinghamshire, UK) which were probed with antibodies against cdc25c (1:1000, C-20 sc-327; SantaCruz Biotechnology Inc., Santa Cruz, CA, USA), or against p21 (1:1000; F-5, SantaCruz Biotechnology Inc.). ", "Protein loading was checked using a rabbit anti-G3PDH (1:1000; Trevigen, Gaithersburg, MD, USA) antibody. ", "Primary antibodies binding was then detected with secondary horseradish peroxidase-conjugated-specific antibodies (1:1000; Biorad, Hercules, CA, USA) and visualized by enhanced chemiluminescence following the manufacturer's protocol (Amersham Pharmacia Biotech, Piscataway, NJ, USA).", "\n\n3.8. ", "Measurement of Intracellular ATP\n-------------------------------------\n\nOne hundred and five cells/mL were incubated with LamD for the indicated times then cells were washed with PBS for bioluminescent ATP content evaluation with the cell-titer Glow assay kit (Promega, Madison, WI, USA) following manufacturer's instructions.", "\n\n3.9. ", "Telomerase Repeat Amplification Protocol (TRAP) Assay\n----------------------------------------------------------\n\nTo determine telomerase activity, the TRAPeze kit (Intergen, Purchase, NY, USA) was used in agreement with manufacturer's recommendations as previously depicted \\[[@B37-marinedrugs-12-00779]\\].", "\n\n3.10. *", "In Vivo* Experiments\n---------------------------\n\nAll procedures with animals were conducted in accordance with the Institutional guidelines following the procedure detailed elsewhere \\[[@B17-marinedrugs-12-00779]\\]. ", "Briefly, nine female severe combined immunodeficient (SCID) mice were injected with 1 × 10^6^ HBL cells, mixed (1:1 volume) with BD Matrigel Basement Membrane Matrix. ", "When tumors reached a palpable volume, mice were ramdomly divided into three groups: one control group mice were treated with PBS with the same schedule as the treated animals; two LamD groups with mice treated with LamD at 10 mg/kg or 1 mg/kg (i.v. ", "injection for 5 day/week). ", "After two weeks of treatment, mice were sacrificed, and tumors were measured and removed for histological analysis.", "\n\n3.11. ", "Statistics\n----------------\n\nData were evaluated using GraphPad program (GraphPad Software, San Diego, CA, USA). ", "Data are presented as the mean ± SD. ", "The student's *t*-test was used to compare data sets. ", "Statistical significant differences were determined for *p* values of less than 0.05.", "\n\n4. ", "Conclusions\n==============\n\nIn essence, our findings establish the marine drug, LamD, as a potential pro-senescent therapy against cancer and define the senescence program as a cellular stress response elicited by LamD. These results should reinforce our therapeutic interest for the lamellarin family of marine natural products.", "\n\nThis work was financially supported by INSERM, UNIVERSITE DE LILLE II, Société Française de Dermatologie (to PM), Ligue contre le Cancer (Comité de l'Aisne) (to PM), Société de Recherche Dermatologique (to LM). ", "We are especially indebted to the Association pour l'Etude des Anomalies Congénitales Neurodev of Pr. ", "B. Poupard (to PM) for the special financial support.", "\n\nThe authors declare no conflict of interest.", "\n" ]

{ "pile_set_name": "PubMed Central" }

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[ "The word Storytelling seems to be in common usage these days in reviews, writings and blog postings about Jazz, yet what does it really mean?", "\n\nReasoning by analogy is dotted with pitfalls, but in a narrative, written form, storytelling denotes an account of imaginary or real people and events told for entertainment with a beginning-middle-end progression.", "\n\nSo by analogy, storytelling in Jazz refers to an improvisation which provides the listener with a coherent expression of melodic phrases which similarly evolve through a starting point, expansion and conclusion, although in this case, the ear is the primary sense rather than the eye.", "\n\nOne of the accounts in the Jazz literature of how of Jazz soloists actually develop their storytelling abilities is contained in the following excerpts from Paul F. Berliner, Thinking in Jazz: The Infinite Art of Improvisation:\n\nTaken as a whole, I’ve always considered the half dozen tracks that make up Julian “Cannonball” Adderley’s Blue Note recording Somethin’ Else [CDP 7 46338 2]to be one of the best expressions of storytelling in Jazz ever recorded. ", "Thanks to the audio-visual efforts of Federico Zecca, you can listen to it in its entirety at the conclusion of this piece.", "\n\nThe recording gets its name from Miles’ reference to Cannonball as being …. ", "Somethin’ Else … words of high praise in Jazz parlances. ", "This 1958 LP also has the distinction of representing the last time that Miles recorded as a sideman.", "\n\n“In part, the metaphor of storytelling suggests the dramatic molding of creations to include movement through successive events \"transcending\" particular repetitive, formal aspects of the composition and featuring distinct types of musical material.", "\n\nFor early jazz players like Louis Armstrong and Sidney Bechet, and for swing players like Lester Young, storytelling commonly involved such designs for multiple choruses as devoting an initial chorus to interpreting a piece's melody, devoting the next to expressive liberties varying it, and then returning to the melody or proceeding on to other events such as single-note riffing patterns.", "\n\nFor contemporary players, who may place less emphasis on the melody, the considerations of shaping remain just as essential. ", "Typically, when it comes time for Buster Williams to solo, he \"wants to tell a story, and the best way to tell a story is to set it up.\" ", "If someone who is \"very excited about something that just happened\" comes running to Williams \"saying, 'Buster, blah-blah-Mah-blah,' the first thing I'm going to say is, 'Look, wait a minute. ", "Calm down and start from the beginning.'\" ", "Williams's plan is the same for solo work. \"", "Start from the beginning,\" he advises. \"", "It's also like playing a game of chess. ", "There's the beginning game, the middle game, and then there's the end game. ", "Miles is a champion at doing that. ", "So is Trane. ", "To accomplish this, the use of space is very important—sparseness and simplicity—maybe playing just short, meaningful phrases at first and building up the solo from there.\"", "\n\nSimilarly, [pianist] Kenny Barron tries \"to start the solo in a way that's sparse or low key\" so that he has \"somewhere to go, so that the solo can build.\" ", "From listening to Dizzy Gillespie when he performed in Gillespie's band, Barron earned how to \"save\" himself in his playing. \"", "You don't have to play everything you know every minute,\" Barron says.", "\n\nYou can leave some spaces in the music. ", "You're not going to start off a solo double-timing. ", "You start off just playing very simply and, as much as possible, with lyrical ideas. ", "And as the intensity builds, if it does, your ideas can become a little more complicated. ", "They can become longer. ", "The way I look at it is that you're going to start down so that you have somewhere to go. ", "It can build to different points in different parts of the solo. ", "It's hills and valleys. ", "That's what it is anywhere. ", "There are certain sections of the tune which build harmonically and suggest that the intensity should also build at that particular point. ", "That's a very natural thing to happen, and what you play will always build there. ", "Other times, it's a matter of wherever it occurs, wherever you feel it coming. ", "It could happen in different spots within the tune at different times.", "\n\nA related feature of storytelling involves matters of continuity and cohesion. ", "Paul Wertico advises his students that in initiating a solo they should think in terms of developing specific \"characters and a plot. . . . ", "You introduce these little different [musical] things that can be brought back out later on; and the way you put them together makes a little story. ", "That can be [on the scale of] a sentence or a paragraph.. . . ", "The real great cats can write novels.\" ", "Wertico expresses admiration for the intellectual prowess of these players. ", "Throughout a performance, they creatively juxtapose ideas that they introduced in their initial \"character line,\" and at just \"the right time\" in their story, they can \"pull out\" and develop ideas that they \"only hinted at\" earlier in the performance but have borne in mind all along. \"", "That's what's really fantastic about a solo,\" Wertico maintains.", "\n\nTo develop the skills of expert storytellers, artists find it essential to devote some practice time to improvising under conditions that simulate formal music events, thereby imposing maximum constraints upon performances. ", "Negotiating a composition's structure as \"one cohesive string,\" with each chord leading to the next in strict rhythm, they formulate complete solos, pausing but momentarily to reflect on their inventions. \"", "To learn to play a song better,\" Art Farmer would \"work on its chords, chorus after chorus, trying to play whatever came to mind. ", "Even if it didn't come out right, I'd keep playing,\" he says. \"", "At certain times, it's not good to stop.\"", "\n\nMusicians commit themselves to the rigors of developing the ideas that occur to them at the moment, cultivating powers of concentration upon which larger-scale invention depends. \"", "After a lot of practice, you find that the phrases just begin to fall in the right place,\" Harold Ousley recalls. \"", "You are able to play a whole chorus of phrases together, and you are ready for the next chorus. ", "The more you do it, the smoother and the easier it gets. ", "When you begin to feel proficient at this, you feel a certain sense of freedom, and you get the inspiration to really get into your horn and to try out different things. ", "There's a great excitement about that.\"", "\n\nAs Ousley's remarks imply, the improviser's world of imagination considers more than musical abstractions. ", "Emotion serves as a partner to intellect in the conception and expansion of ideas. ", "Beyond emotional responses to their evolving creations, artists speak generally of \"tapping an emotional reservoir,\" whose \"energy\" represents a distillation of their experiences with life (Emily Remler). ", "Roberta Baum considers emotion to be \"the biggest part of singing. ", "It has become an extension of how it is to be alive,\" she says. ", "In this sense, performances can reflect the individual's characteristic scope of expression, including extreme fluctuations of feeling.", "\n\nAs alluded to earlier, artists can also draw upon the extramusical associations of the compositions that serve as vehicles. ", "They sometimes set up for performances by dwelling momentarily on a piece's moods and meanings, recalling, perhaps, the sense of personal identification with the theme of a standard piece that prompted its incorporation into their repertory, or envisioning the characters and incidents depicted in their own original compositions. ", "At times, Dexter Gordon actually sang a few lines of a ballad's lyrics to invoke its meaning, before switching to saxophone improvisations.26 With song texts, or in their absence, the emotional sentiment and the imagery suggested by titles and musical features also offer direction.", "\n\nOverall, a piece's precise mood has a powerful tempering effect on improvisers, guiding their personal feelings to blend with those appropriate for the performance. ", "For Arthur Rhames, \" 'God Bless the Child' [evokes] one set of moods about the remorse of not being on your own or having to depend on others, while a tune like 'Giant Steps' may be about advancing yourself\"; each provides \"different perspectives, different feelings, different moods. ", "And those moods govern a lot of what's going to come out in your interpretation of the chord changes in your improvising.\" ", "Chuck Israels also routinely takes the mood of the piece into account when he prepares to solo. ", "Over the course of an evening, \"I'll play a tune like 'The Preacher' that has a certain gospel flavor; then a tune like Bill Evans's 'Peri's Scope,' which is an outgoing, dancing, lighthearted tune. [", "Next, I will] play something melancholy, like 'Nardis.'\"", "\n\nThere is a constant spending and replenishment of a player's emotional reserves. ", "Israels performs \"tunes that have different emotional states\" in order to give himself \"different things to think about, different things to feel and to play\" when he improvises. ", "Each tune has \"its own feelings, its own shapes and patterns that occupy me when I play it,\" he explains. \"", "You just jump from one emotional mood to another because the moods change with each piece.\" ", "Sometimes, Emily Remler says, \"when I play a ballad like 'I'm in a Sentimental Mood,' I feel almost sick to my stomach because it is so heartrending and takes so much from me.\" ", "A piece's emotional associations commonly influence an artist's rhythmic approach or selection of tonal materials, in the latter instance suggesting, perhaps, an emphasis upon blues-inflected melodies rather than brighter, un-inflected melodies or upon tense rather than relaxed harmonies.", "\n\nThroughout the piece, artists may prepare themselves to respond to each of its varied nuances, beyond its most general tenor. ", "Emily Remler, looking forward to \"a gig tonight,\" knows \"that there are sections where I'll feel a lot of different emotions. ", "The [composition] breaks into a real happy part, and it makes me feel really happy. ", "Then there are other parts where I'll just feel determined.\" ", "In some instances, the elements of a piece combine to reinforce a particular emotional shape overall, suggesting that improvisers structure their own creations accordingly. ", "In a blues, an artist may build toward peaks of intensity at the same point as the harmony and poetic text reach a dramatic climax.", "\n\nVarious aspects of the meanings of compositions are also tied to their performance histories, especially the ways in which earlier improvisers have handled their original compositions (Barry Harris). ", "When Jimmy Robinson prepares to solo, he \"thinks about the things that have been done on the tune in the past\" and what he would \"like to do on it.\" ", "Of course, he says, if he has \"never heard the tune before\" or is performing his own pieces, he \"just strikes out\" on his own. ", "If it is a recent piece by someone like Dizzy Gillespie, however, he wants \"to know what Dizzy did on it just to give me an idea to start with, so I won't be too far off with it.\" ", "Robinson's intention is to be respectful to \"the idea\" of the composer. \"", "That also shows that I've been influenced by Dizzy,\" he says, \"since he did some very intricate things on it that I wish I had come up with [he laughs]. ", "You try to play in relationship to that to learn what he's doing, and then you try to build and improve on it.\"", "\n\nRenowned artists have sometimes improvised so effectively within the framework of other composers' works, bringing fresh interpretations to them, that they leave an indelible mark upon the works' performance traditions and on those of pieces with comparable styles. ", "Walter Bishop Jr. learned the general principles for formulating solos within modal compositions by analyzing Miles Davis's solos.", "\n\nAnother trumpeter admitted that after \"Miles's playing on 'Sketches of Spain,' it is impossible to improvise on any Spanish-type piece without using some of Miles's inflections.\" ", "A composition \"like 'Nardis' also has a lot of connotation because Bill Evans played it so much,\" Fred Hersch observes. ", "Along similar lines, even if Roberta Baum \"were to give my own interpretation of a song by Cole Porter, there is no way that I could forget how Ella Fitzgerald had phrased something.\" ", "A commemorative piece lends itself particularly to an interpretation imbued with the stylistic traits of the honored namesake. ", "In rendering the ballad \"I Remember Clifford,\" Lee Morgan integrates his own personal blues-oriented commentaries into the ballad's theme, at times adopting Clifford Brown's wide, singing vibrato, unique articulation devices, and characteristic embellishments. ", "Sometimes, it is in the very act of improvising that players discover and pursue the deep connections that compositions and the individual styles of soloists reveal to them.", "\n\nFor improvisers, the meaning of a piece incorporates layers of nuance derived from intimacy with its imagery, its rhythmic and tonal associations, its performance history, and its relatives within the wider repertory of pieces. ", "Among the myriad resources that soloists filter through their imaginations, one of the most striking is the vibrancy of the human connections that inhabit the piece—myriad inflections, personalities, voices, fingerings, and stances, coursing through the mind and into the musical performance. ", "Such varied imagery informs and deepens every story in the telling. ", "In a sense, each solo is like a tale within a tale, a personal account with ties of varying strength to the formal composition.", "\n\nWhile absorbing the conventions associated with idea formulation and storytelling in the jazz tradition, artists place different emphases upon the conventions. ", "They apply them uniquely according to each individual's temperament, personal style of jazz oratory, emotional response to compositions, and specific goals for the solo under formulation. ", "As expected, the differing emphases result in correspondingly varied transformations of jazz vocabulary and in different formal characteristics among the solos produced by improvisation .", "\n\nUnderlying their efforts to achieve such diversity of expression is rigorous practice on the part of jazz learners, as they develop flexibility in the use of initially limited stores of vocabulary, devise a systematic way of relating vocabulary patterns one to another, and absorb the aesthetic principles that guide vocabulary usage.", "\n\nStudents with such comprehensive training are in a far better position as improvisers than are those among their counterparts who may have acquired a large store of vocabulary patterns, chords, scales, and the like, but yet fail to appreciate these other critical aspects of jazz knowledge. ", "Ultimately, learning the tools and techniques of the art provides only the ground for the student's development.", "\n\nTo build the foundation, aspiring musicians must commit endless hours to practicing improvisation—mentally simulating the conditions of live performance events—if they are to acquire the cumulative experience upon which effective storytelling rests. ", "Among the challenges practicers confront in their earliest efforts are improvisation's capricious aspects, which can operate as powerful forces to influence a work's musical outcome.”", "\n\nPhil Woods 5tet Feat. ", "Tom Harrell - \"Azure\"\n\nFeatured Post [Click on Title]\n\nCelebrating the Legacy of Art Farmer 1928-1999\n\nThis year will be the 90th Birthday Anniversary of Art Farmer. ", "We are pleased to announce that The Art Farmer Website is now live. ", "Please click on the image of Art to be re-directed to his site replete with discography.", "\n\nGoogle Translator\n\nFollow JazzProfiles by Email\n\nJazzProfiles\n\nThis blog is my gift to my friends.", "\n\nBassist Chuck Israels on alto saxophonist Phil Woods\n\nQuincy Jones had a band that was preparing to tour Europe in the summer of 1959. ", "The band was rehearsing in the mezzanine of the Olympia Theatre and I somehow wrangled an invitation to attend a rehearsal. ", "It was a great hand with some of Quincy's friends from Seattle, like Buddy Catlett and Patti Brown. ", "Les Spann was the guitarist and played some flute solos. ", "Sahib Shihab was in the saxophone section and Joe Harris played drums. ", "I listened to a number of pieces in which there were solos played by various members of the band. ", "It would be unfair to say that those solos were perfunctory, but later, when Phil Woods stood up from the lead alto chair to play his solo feature, the atmosphere changed. ", "Phil played as if there were no tomorrow. ", "The contrast was striking and I have always remembered the impression it left. ", "If you practice rehearsing, then when the lime comes to perform, you are ready to rehearse. ", "Phil practiced performing.", "\n\nLegendary 1980 Weckl-Gadd-Colaiuta DRUM SHOWDOWN\n\nLarry Bunker's Advice to a Young Drum Student\n\n\"Be yourself, keep good time, play musically and don't show off your \"chops\" [technique]. ", "The only people who can appreciate them are other drummers, and nobody likes them anyway.\"", "\n\nJazzProfiles Readers Forum\n\nYou have done a great service by reproducing this article. ", "Gene really created a great portrait of Miller, especially with his new (for the time) interviews.", "\n\nI was a great admirer of Gene's writing, and can say we were friends. ", "If you like, I can send you a link to a memorial article I wrote for Doug Ramsey's blog Rifftides that I wrote after Gene died. ", "He could be quite frustrating at times, but I learned a lot from him, and he definitely helped me to become a better writer.", "\n\nHi. ", "I have been visiting his blog for a few months almost daily and I have to thank him for his work, contributing interesting articles about music and Jazz musicians which is helping me discover new things, to value others that I did not appreciate at the time and to recover some that I enjoyed. ", "and I have forgotten. ", "-Greetings and many thanks from Toledo Spain.", "\n\nGreat write up of one helluva release by Bill Lichtenauer of Tantara Productions. ", "Magnificent list, great technology, and fantastic Kenton sounds. ", "Thanks Steve...and thanks, Bill. ", "And the liner notes were done superbly by Michael Sparke of the UK. ", "Tony Agostinelli\n\nThanks Steven for making this available to a wider readership. ", "This book was like a \"bible\" to me when I first started collecting aged 16. ", "I still have my original copy ... complete with marginalia as I filled in my collection. ", "I had to wait until I moved to London in 1958 to acquire many of these albums on the British labels like Esquire .... this brings back so many pleasant memories, but it also reminds me that time does proceed, relentlessly.", "\n\nGarth.", "\n\nThis book was like a \"bible\" to me when I was a serious collector, aged 16 .... I still have my original copy, in excellent condition after all these years, over three continents complete with marginalia as I built my collection. ", "Bravo to you Steve for making these early observations available for others to read. ", "Raymond Horricks followed this book up with \"These Jazzmen Of Our Time\" (Gollancz, 1959), which contained some great early portraits by Herman Leonard.", "\n\nI met him twice. ", "He was playing at a mall with the Westchester jazz band. ", "That was around 97 or so. ", "They were taking a break and I started talking to him. ", "He was super nice. ", "I mention my grandfather was a jazz trumpet player Bunny Berigan. ", "I did not know who Bill was but like the way he played bass that day. ", "I ran across his book on jazz in the white plains library. ", "I was surprise at knowledge and who he played with in jazz. ", "I seen him again at the same place a year later and got to talk to him.", "Very nice again to me. ", "I asked him about Zoot Sims. ", "And about Benny Goodman which he your with in Russian . ", "My grandfather played with Benny too at one time. ", "Seems they both found him hard to deal with. ", "What a fine man Bill is.", "\n\nI discovered Oliver Nelson in 1977 and could not believe my ears. ", "At the time it was obviously a vinyl record and belonged to somebody else. ", "However, thanks to the technology of today I can listen to my cd of Blues and the Abstract Truth to my heart's content. ", "You have told me so much more about this wonderful man's unique style. ", "If I want to feel good, I just listen to Stolen Moments. ", "Thank you.", "\n\nI have been listening to 1 of greatest piece of orchestration of Stan Kenton style music I've ever listened too arranged by a young trumpet player & arranger Bill Mathieu it's Kenton it Mathieu but mostly a great music . ", "the complexed overlays , blending , fitting in soloists at just the right moment , plus the swelling of the whole orchestra to create the Kenton sound without losing his own indemnity is outstanding . ", "Thank Bill Thank you Stan ... Jim Shelton\n\nPeter Haslund has left a new comment on your post \"Mark Murphy: 1932-2015, R.I.P.\":\n\nJust discovered Mr. Murphy. ", "Gotta say it leaves me speechless that I listened to jazz since the 80s and never once heard his name. ", "All the stuff that sounded so contrived with Sinatra (who obviously knew he was really singing black people's music) is fresh and free with Mark. ", "RIP.", "\n\nHi Steven,\n\nI read with interest your recent piece about the Boss Brass. ", "I live in Toronto, and when it comes to the Canadian jazz scene, it's hard to overstate how influential this band was. ", "Besides the quality of McConnell's arrangements, the musicians were all top-name guys in the city (many with vigorous solo careers). ", "What has always floored me about their playing is the tightness and especially intonation in the woodwinds -- the skill of the horn players at playing doubles (flutes and clarinets) is legendary.", "\n\nI feel fortunate to have been able to hear them live, on a number of occasions. ", "From the stories I've heard, either third-hand or right from former Boss Brass members, Rob was a really hard guy to work with, but certainly pushed his group toward excellence.", "\n\nI also liked your recent piece on Pat Martino. ", "I'm a big fan of his style. ", "If you haven't read his autobiography, I highly recommend it! ", "His personal story is, of course, fascinating and inspiring.", "\n\nSpeaking of guitarists, someone you may want to profile someday is the Canadian jazz guitarist Ed Bickert. ", "He was the guitarist for the Boss Brass for many decades. ", "He is now quite elderly and no longer playing, but is another of those guys who was phenomenally influential, though I think he largely flew under-the-radar south of the border.", "\n\nThanks for putting together such a great site, and best wishes.", "\n\nJordan Wosnick\n\nYou can share your thoughts, observations and general remarks in the Readers Forum by contacting JazzProfiles via scerra@roadrunner.com\n\nHi Steve...I'm not a Facebook or Twitter guy so here's hoping this email reaches you...\n\nYou indicated that you were not aware of published Mulligan biographies in your recent post on Gerry and I wanted to bring one to your attention that I think you will like:\n\nJERU'S JOURNEY by Sanford Josephson. ", "It was published in 2015 by Hal Leonard Books. ", "It's part of the Hal Leonard Biography Series which also includes bios of Cannonball Adderley, Herbie Mann & Billy Eckstine.", "\n\nI own the Adderley and Mann bios and also recommend them.", "\n\nJeru's Journey is an easy read and covers Mulligan's life from birth to his passing. ", "It is a very good overview and the author--who knew Mulligan and interviewed him before his passing--tells Gerry's story completely including Mulligan's drug addiction, domestic (wives) issues, etc. ", "along with good musical analysis and insights both of the author's and other musicians. ", "In addition to a good discography there are many photographs.", "\n\nThe list price is $19.99. ", "A good buy.", "\n\nIn closing, I would like to tell you how much I have enjoyed your blog over the years. ", "I have recommended it to many musician friends and all have thanked me. ", "Thanks again for helping to keep the jazz alive...\n\nBruce Armstrong\n\nYou can share your thoughts, observations and general remarks in the Readers Forum by contacting JazzProfiles via scerra@roadrunner.com\n\nLes Koenig was clearly a GIANT despite his obvious preference to be low-key, himself. ", "THANK YOU, Steven Cerra!!! ", "The world is a better place because of people like Les! ", "Like Laurie(Pepper) & the list goes on & on forever! ", "Like YOU, Steven! ", "Thanks to ALL who work behind the scenes, on or off-stage, etc. ", "etc. ", "etc... -in support of the featured \"Player\" & \"Sidemen\" so that \"We the people...\" can be out in the audience having the time of our lives enjoying \"the show\" or \"Artistry, Talent, Efforts\" and so on! ", "My attitude is one of gratitude!! ", "THIS art form & ALL original American Art forms must be preserved and encouraged to not only survive, but to thrive!!!", "\n\nDiz\n\n\"Jazz is a gift. ", "If you can hear it, you can have it.\"", "\n\nPiano Players: Dick Katz on Erroll Garner\n\n“Unique is an inadequate word to describe Erroll Garner. ", "He was a musical phenomenon unlike any other. ", "One of the most appealing performers in Jazz history, he influenced almost every pianist who played in his era, and even beyond. ", "Self-taught, he could not read music, yet he did things that trained pianists could not play or even imagine. ", "Garner was a one-man swing band, and indeed often acknowledged that his main inspiration was the big bands of the thirties – Duke, Basie, Lunceford, et al. ", "He developed a self-sufficient, extremely full style that was characterized by a rock-steady left-hand that also sounded like a strumming rhythm guitar. ", "Juxtaposed against this was a river of chordal or single note ideas, frequently stated in a lagging, behind-the-beat way that generated terrific swing.” [", "\n\nPaul Desmond\n\nCannonball Adderley, who was at one point a rival of Paul's in the various polls and whose robust gospel-drenched playing was worlds apart once said: ‘He is a profoundly beautiful player.’ ", "Writer Nat Hentoff said. \"", "He could put you in a trance, catch you in memory and desire, make you forget the garlic and sapphires in the mud.\"", "\n\nDrummers Corner: Larry Bunker on Shelly Manne\n\n“In a truly formal sense, Shelly could barely play the drums. ", "If you gave him a pair of sticks and a snare drum and had him play rudi­ments—an open and closed roll, paradiddles, and all that kind of thing—he didn't sound like much. ", "He never had that kind of training and wasn't inter­ested in it. ", "For him it was a matter of playing the drums with the music. ", "He could play more music in four bars than almost anyone else. ", "His drums sounded gorgeous. ", "They recorded sensationally. ", "All you had to hear was three or four bars and you knew it was Shelly Manne. - ", "Larry Bunker, Jazz drummer and premier, studio percussionist\n\nThe 1954 Birdland Recordings of Art Blakey and The Jazz Messengers\n\nThe 1954 Birdland recordings on Blue Note provided the stylistic foundation for the rest of Art Blakey's career. ", "His style had completely crystallized. ", "His pulsation was undeniable, a natural force; the counter-rhythms he brought to the mix made what he played that much more affecting. ", "There was a purity about what he did—and always motion. ", "He was spontaneous, free, creating every minute. ", "That he was in the company of peers, all performing in an admirable manner, had a lot to do with making this \"on-the-spot\" session such an important musical document. ", "The band never stops burning. ", "The exhilarating Clifford Brown moves undaunted through material, fast, slow, in between, playing fantastic, well-phrased ideas that unfold in an unbroken stream. ", "His technique, almost perfect; his sound, burnished. ", "He's a gift to the senses. ", "Lou Donaldson, an underrated alto player in the Bird tradition, offers much to think about while you're tapping your foot. ", "Horace Silver is crucial to the effect of this music, much of it his own. ", "Certainly the rhythms that inform his piano playing and writing make it all the more soulful. ", "On this and other records he serves as a catalytic agent, provoking swing and engaging intensity. ", "Hard-hitting, unpretentious, communicative, Silver has little use for compositional elements or piano techniques that impede his message. ", "A live-in pulse permeates his music and his playing, strongly affecting the shape, content, and level of excitement of his performances and those of his colleagues. ", "An original and tellingly economic amalgam of Parker, the blues, shuffling dance rhythms, and a taste of the black church for flavor, Silver is quite undeniable. ", "Listen to his delightful \"Quicksilver\" on A Night at Birdland With the Art Blakey Quintet, Vol. ", "1 (Blue Note). ", "It capsulizes what he does. ", "On this album, Curly Russell shows once again he can play \"up\" tempos and interesting changes. ", "He ties in well with Blakey. ", "But Silver and Blakey, in combination, determine the rhythmic disposition of the music. ", "Blakey's natural time and fire raise the heat to an explosive level before the listener realizes how hot the fire has become. ", "Perhaps more than other recordings Blakey has made, the Birdland session documents his great strengths and technical failings. ", "At almost every turn, he shows what an enviably well coordinated, buoyantly confident, rhythmically discerning player he is.", "\n\nBOP AND DRUMS—A NEW WORLD\n\nFrom the Introduction to Burt Korall, “Drummin’ Men: The Bebop Years”\n\n“It is difficult for young musicians and jazz devotees to fully comprehend the tumultuous effect that the advent of bop had on drummers. ", "The new music demanded new, relevant, trigger-fast, musical, well-placed reactions from the person behind the drum set—an entirely revamped view of time and rhythm, techniques, and musical attitudes.", "\n\nHow well did drummers deal with bop? ", "The innovators, like Kenny Clarke and Max Roach, opened the path and showed how it was done. ", "Young disciples—if they had talent, sensitivity, and the necessary instincts— caught on and made contributions. ", "Other drummers stylistically modified the way they played, trying to combine the old with the new. ", "This was tricky at best. ", "Sometimes it worked; sometimes it was a matter of apples and oranges. ", "Still others fought change and what it implied.", "\n\nNot welcomed by many swing drummers and their more traditional predecessors, the new wave was looked upon as the enemy, sources of disruption and unnecessary noise. ", "Those stuck in the past could not accept breaking time, using the drum set as both color resource and time center. ", "The structural and emotional differences essential to bebop, the need for virtuosity, and the ability to think quickly and perform appropriately intimidated them. ", "The demands of the music were strange and often devastating; a feeling of hostility built up in them. ", "The basic reasons were quite clear. ", "The new music could ultimately challenge their earning ability and position in the drum hierarchy.\"", "\n\nGerry Mulligan 1927-1996\n\n“… Gerry Mulligan lived through almost the entire history of jazz. ", "It is against that background that he should be understood.” – ", "Gene Lees\n\nGunther Schuller on Sonny Rollins\n\n“Rhythmically, Rollins is as imaginative and strong as in his melodic concepts. ", "And why not? ", "The two are really inseparable, or at least should be. ", "In his recordings as well as during several evenings at Birdland recently [Fall/1958] Rollins indicated that he can probably take any rhythmic formation and make it swing. ", "This ability enables him to run the gamut of extremes— from almost a whole chorus of non-syncopated quarter notes (which in other hands might be just naive and square but through Rollins' sense of humor and superb timing are transformed into a swinging line) to asymmetrical groupings of fives and sevens or between the-beat rhythms that defy notation. ", "As for his imagination, it is prodigiously fertile. ", "And indeed I can think of no better and more irrefutable proof of the fact that discipline and thought do not necessarily result in cold or un-swinging music than a typical Rollins performance. ", "No one swings more (hard or gentle) and is more passionate in his musical expression than Sonny Rollins . ", "It ultimately boils down to how much talent an artist has; the greater the demands of his art both emotionally and intellectually the greater the talent necessary.”", "\n\nArtie Shaw on Louis Armstrong as told to Gene Lees\n\nArtie said, \"You are too young to know the impact Louis had in the 1920s,\" he said. \"", "By the time you were old enough to appreciate Louis, you had been hearing those who derived from him. ", "You cannot imagine how radical he was to all of us. ", "Revolutionary. ", "He defined not only how you play a trumpet solo but how you play a solo on any instrument. ", "Had Louis Armstrong never lived, I suppose there would be a jazz, but it would be very different.\"", "\n\nPops\n\nBill Crow on Louis Amstrong\n\nLouis Armstrong transformed jazz. ", "He played with a strength and inventiveness that illuminated every jazz musician that heard his music. ", "Louis was able to do things on the trumpet that had previously been considered impossible. ", "His tone and range and phrasing became criteria by which other jazz musicians measured themselves. ", "He established the basic vocabulary of jazz phrases, and his work became the foundation of every jazz musician who followed him.", "\n\nBassist Eddie Gomez on Pianist Bill Evans\n\n“Bill's music is profoundly expressive. ", "It is passionate, intellectual, and without pretense. ", "Eleven years with his trio afforded me the opportunity to perform, record, travel, and most importantly learn. ", "My development as an artist is largely due to his encouragement, support, and patience. ", "He instilled confidence in me, while at the same time urging me to search for my own voice and for new ways to make the music vital and creative. ", "And Bill believed that repertoire, both new and old, would organically flourish in repeated live performance. ", "In fact, there were precious few rehearsals, even before recording sessions. … ", "When Bill passed away late in 1980, it was clear that all of us in the jazz world had sustained a huge loss. ", "I was shocked and saddened; in my heart I had always felt that some day there would be a reunion concert. ", "Had I been able to look into a crystal ball and foresee his death, perhaps I might have stayed in the trio for a longer period. ", "I still dream about one more set with Bill. ", "He closes his eyes, turns his head to one side, and every heartfelt note seems etched and bathed in gold. ", "How I miss that sound.”", "\n\nJohn Coltrane on Stan Getz\n\nColtrane himself said of the mellifluous Stan Getz, \"Let's face it--we'd all sound like that if we could.\"", "\n\nPeter Bernstein on Bobby Hutcherson\n\nI got to play with Bobby Hutcherson at Dizzy's a few years ago, which ended up on a CD [2012's Somewhere In The Night on Kind of Blue Records]. ", "I was four feet away from him, thinking, \"How is this man just hitting metal bars with wooden sticks with cotton on the end and making such an expressive statement?\" ", "The instrument is just like ... it's him! ", "He's imbuing it with his thoughts and feelings. ", "That's a miraculous thing. ", "The instrument itself disappears when you're talking about a master on that level.", "\n\nRalph Bowen\n\n“In a way, the entire act of music is mind put into sound. ", "It has to go through some sort of physical medium in order to be heard. ", "I chose the saxophone, but the whole issue is to have such control over the instrument and over what you hear that the instrument physically doesn't get in the way of visualizing sound. ", "Technique to me means dealing with an instrument in the most efficient manner possible so that it's no more than peripheral to expression.\"" ]

{ "pile_set_name": "Pile-CC" }

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[ "/**\n * @file\n * VP5 compatible video decoder\n *\n * Copyright (C) 2006 Aurelien Jacobs <aurel@gnuage.org>\n *\n * This file is part of FFmpeg.", "\n *\n * FFmpeg is free software; you can redistribute it and/or\n * modify it under the terms of the GNU Lesser General Public\n * License as published by the Free Software Foundation; either\n * version 2.1 of the License, or (at your option) any later version.", "\n *\n * FFmpeg is distributed in the hope that it will be useful,\n * but WITHOUT ANY WARRANTY; without even the implied warranty of\n * MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. ", " See the GNU\n * Lesser General Public License for more details.", "\n *\n * You should have received a copy of the GNU Lesser General Public\n * License along with FFmpeg; if not, write to the Free Software\n * Foundation, Inc., 51 Franklin Street, Fifth Floor, Boston, MA 02110-1301 USA\n */\n\n#include <stdlib.h>\n#include <string.h>\n\n#include \"avcodec.h\"\n#include \"dsputil.h\"\n#include \"get_bits.h\"\n\n#include \"vp56.h\"\n#include \"vp56data.h\"\n#include \"vp5data.h\"\n\n\nstatic int vp5_parse_header(VP56Context *s, const uint8_t *buf, int buf_size,\n int *golden_frame)\n{\n VP56RangeCoder *c = &s->c;\n int rows, cols;\n\n vp56_init_range_decoder(&s->c, buf, buf_size);\n s->framep[VP56_FRAME_CURRENT]->key_frame = !", "vp56_rac_get(c);\n vp56_rac_get(c);\n vp56_init_dequant(s, vp56_rac_gets(c, 6));\n if (s->framep[VP56_FRAME_CURRENT]->key_frame)\n {\n vp56_rac_gets(c, 8);\n if(vp56_rac_gets(c, 5) > 5)\n return 0;\n vp56_rac_gets(c, 2);\n if (vp56_rac_get(c)) {\n av_log(s->avctx, AV_LOG_ERROR, \"interlacing not supported\\n\");\n return 0;\n }\n rows = vp56_rac_gets(c, 8); /* number of stored macroblock rows */\n cols = vp56_rac_gets(c, 8); /* number of stored macroblock cols */\n vp56_rac_gets(c, 8); /* number of displayed macroblock rows */\n vp56_rac_gets(c, 8); /* number of displayed macroblock cols */\n vp56_rac_gets(c, 2);\n if (!", "s->macroblocks || /* first frame */\n 16*cols !", "= s->avctx->coded_width ||\n 16*rows !", "= s->avctx->coded_height) {\n avcodec_set_dimensions(s->avctx, 16*cols, 16*rows);\n return 2;\n }\n } else if (!", "s->macroblocks)\n return 0;\n return 1;\n}\n\nstatic void vp5_parse_vector_adjustment(VP56Context *s, VP56mv *vect)\n{\n VP56RangeCoder *c = &s->c;\n VP56Model *model = s->modelp;\n int comp, di;\n\n for (comp=0; comp<2; comp++) {\n int delta = 0;\n if (vp56_rac_get_prob(c, model->vector_dct[comp])) {\n int sign = vp56_rac_get_prob(c, model->vector_sig[comp]);\n di = vp56_rac_get_prob(c, model->vector_pdi[comp][0]);\n di |= vp56_rac_get_prob(c, model->vector_pdi[comp][1]) << 1;\n delta = vp56_rac_get_tree(c, vp56_pva_tree,\n model->vector_pdv[comp]);\n delta = di | (delta << 2);\n delta = (delta ^ -sign) + sign;\n }\n if (!", "comp)\n vect->x = delta;\n else\n vect->y = delta;\n }\n}\n\nstatic void vp5_parse_vector_models(VP56Context *s)\n{\n VP56RangeCoder *c = &s->c;\n VP56Model *model = s->modelp;\n int comp, node;\n\n for (comp=0; comp<2; comp++) {\n if (vp56_rac_get_prob(c, vp5_vmc_pct[comp][0]))\n model->vector_dct[comp] = vp56_rac_gets_nn(c, 7);\n if (vp56_rac_get_prob(c, vp5_vmc_pct[comp][1]))\n model->vector_sig[comp] = vp56_rac_gets_nn(c, 7);\n if (vp56_rac_get_prob(c, vp5_vmc_pct[comp][2]))\n model->vector_pdi[comp][0] = vp56_rac_gets_nn(c, 7);\n if (vp56_rac_get_prob(c, vp5_vmc_pct[comp][3]))\n model->vector_pdi[comp][1] = vp56_rac_gets_nn(c, 7);\n }\n\n for (comp=0; comp<2; comp++)\n for (node=0; node<7; node++)\n if (vp56_rac_get_prob(c, vp5_vmc_pct[comp][4 + node]))\n model->vector_pdv[comp][node] = vp56_rac_gets_nn(c, 7);\n}\n\nstatic void vp5_parse_coeff_models(VP56Context *s)\n{\n VP56RangeCoder *c = &s->c;\n VP56Model *model = s->modelp;\n uint8_t def_prob[11];\n int node, cg, ctx;\n int ct; /* code type */\n int pt; /* plane type (0 for Y, 1 for U or V) */\n\n memset(def_prob, 0x80, sizeof(def_prob));\n\n for (pt=0; pt<2; pt++)\n for (node=0; node<11; node++)\n if (vp56_rac_get_prob(c, vp5_dccv_pct[pt][node])) {\n def_prob[node] = vp56_rac_gets_nn(c, 7);\n model->coeff_dccv[pt][node] = def_prob[node];\n } else if (s->framep[VP56_FRAME_CURRENT]->key_frame) {\n model->coeff_dccv[pt][node] = def_prob[node];\n }\n\n for (ct=0; ct<3; ct++)\n for (pt=0; pt<2; pt++)\n for (cg=0; cg<6; cg++)\n for (node=0; node<11; node++)\n if (vp56_rac_get_prob(c, vp5_ract_pct[ct][pt][cg][node])) {\n def_prob[node] = vp56_rac_gets_nn(c, 7);\n model->coeff_ract[pt][ct][cg][node] = def_prob[node];\n } else if (s->framep[VP56_FRAME_CURRENT]->key_frame) {\n model->coeff_ract[pt][ct][cg][node] = def_prob[node];\n }\n\n /* coeff_dcct is a linear combination of coeff_dccv */\n for (pt=0; pt<2; pt++)\n for (ctx=0; ctx<36; ctx++)\n for (node=0; node<5; node++)\n model->coeff_dcct[pt][ctx][node] = av_clip(((model->coeff_dccv[pt][node] * vp5_dccv_lc[node][ctx][0] + 128) >> 8) + vp5_dccv_lc[node][ctx][1], 1, 254);\n\n /* coeff_acct is a linear combination of coeff_ract */\n for (ct=0; ct<3; ct++)\n for (pt=0; pt<2; pt++)\n for (cg=0; cg<3; cg++)\n for (ctx=0; ctx<6; ctx++)\n for (node=0; node<5; node++)\n model->coeff_acct[pt][ct][cg][ctx][node] = av_clip(((model->coeff_ract[pt][ct][cg][node] * vp5_ract_lc[ct][cg][node][ctx][0] + 128) >> 8) + vp5_ract_lc[ct][cg][node][ctx][1], 1, 254);\n}\n\nstatic void vp5_parse_coeff(VP56Context *s)\n{\n VP56RangeCoder *c = &s->c;\n VP56Model *model = s->modelp;\n uint8_t *permute = s->scantable.permutated;\n uint8_t *model1, *model2;\n int coeff, sign, coeff_idx;\n int b, i, cg, idx, ctx, ctx_last;\n int pt = 0; /* plane type (0 for Y, 1 for U or V) */\n\n for (b=0; b<6; b++) {\n int ct = 1; /* code type */\n\n if (b > 3) pt = 1;\n\n ctx = 6*s->coeff_ctx[vp56_b6to4[b]][0]\n + s->above_blocks[s->above_block_idx[b]].not_null_dc;\n model1 = model->coeff_dccv[pt];\n model2 = model->coeff_dcct[pt][ctx];\n\n for (coeff_idx=0; coeff_idx<64; ) {\n if (vp56_rac_get_prob(c, model2[0])) {\n if (vp56_rac_get_prob(c, model2[2])) {\n if (vp56_rac_get_prob(c, model2[3])) {\n s->coeff_ctx[vp56_b6to4[b]][coeff_idx] = 4;\n idx = vp56_rac_get_tree(c, vp56_pc_tree, model1);\n sign = vp56_rac_get(c);\n coeff = vp56_coeff_bias[idx+5];\n for (i=vp56_coeff_bit_length[idx]; i>=0; i--)\n coeff += vp56_rac_get_prob(c, vp56_coeff_parse_table[idx][i]) << i;\n } else {\n if (vp56_rac_get_prob(c, model2[4])) {\n coeff = 3 + vp56_rac_get_prob(c, model1[5]);\n s->coeff_ctx[vp56_b6to4[b]][coeff_idx] = 3;\n } else {\n coeff = 2;\n s->coeff_ctx[vp56_b6to4[b]][coeff_idx] = 2;\n }\n sign = vp56_rac_get(c);\n }\n ct = 2;\n } else {\n ct = 1;\n s->coeff_ctx[vp56_b6to4[b]][coeff_idx] = 1;\n sign = vp56_rac_get(c);\n coeff = 1;\n }\n coeff = (coeff ^ -sign) + sign;\n if (coeff_idx)\n coeff *= s->dequant_ac;\n s->block_coeff[b][permute[coeff_idx]] = coeff;\n } else {\n if (ct && !", "vp56_rac_get_prob(c, model2[1]))\n break;\n ct = 0;\n s->coeff_ctx[vp56_b6to4[b]][coeff_idx] = 0;\n }\n\n cg = vp5_coeff_groups[++coeff_idx];\n ctx = s->coeff_ctx[vp56_b6to4[b]][coeff_idx];\n model1 = model->coeff_ract[pt][ct][cg];\n model2 = cg > 2 ? ", "model1 : model->coeff_acct[pt][ct][cg][ctx];\n }\n\n ctx_last = FFMIN(s->coeff_ctx_last[vp56_b6to4[b]], 24);\n s->coeff_ctx_last[vp56_b6to4[b]] = coeff_idx;\n if (coeff_idx < ctx_last)\n for (i=coeff_idx; i<=ctx_last; i++)\n s->coeff_ctx[vp56_b6to4[b]][i] = 5;\n s->above_blocks[s->above_block_idx[b]].not_null_dc = s->coeff_ctx[vp56_b6to4[b]][0];\n }\n}\n\nstatic void vp5_default_models_init(VP56Context *s)\n{\n VP56Model *model = s->modelp;\n int i;\n\n for (i=0; i<2; i++) {\n model->vector_sig[i] = 0x80;\n model->vector_dct[i] = 0x80;\n model->vector_pdi[i][0] = 0x55;\n model->vector_pdi[i][1] = 0x80;\n }\n memcpy(model->mb_types_stats, vp56_def_mb_types_stats, sizeof(model->mb_types_stats));\n memset(model->vector_pdv, 0x80, sizeof(model->vector_pdv));\n}\n\nstatic av_cold int vp5_decode_init(AVCodecContext *avctx)\n{\n VP56Context *s = avctx->priv_data;\n\n vp56_init(avctx, 1, 0);\n s->vp56_coord_div = vp5_coord_div;\n s->parse_vector_adjustment = vp5_parse_vector_adjustment;\n s->parse_coeff = vp5_parse_coeff;\n s->default_models_init = vp5_default_models_init;\n s->parse_vector_models = vp5_parse_vector_models;\n s->parse_coeff_models = vp5_parse_coeff_models;\n s->parse_header = vp5_parse_header;\n\n return 0;\n}\n\nAVCodec vp5_decoder = {\n \"vp5\",\n AVMEDIA_TYPE_VIDEO,\n CODEC_ID_VP5,\n sizeof(VP56Context),\n vp5_decode_init,\n NULL,\n vp56_free,\n vp56_decode_frame,\n CODEC_CAP_DR1,\n .long_name = NULL_IF_CONFIG_SMALL(\"On2 VP5\"),\n};\n" ]

{ "pile_set_name": "Github" }

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[ "Looking at the sales for Taylor Swift's 1989, it would appear that reports of the death of the music industry have been greatly exaggerated. ", "SoundScan reported Tuesday night that Swift's fifth album sold 1.287 million copies in its first week, the highest out-of-the-box bow for any album release since The Eminem Show sold a hair more than that 12 years ago. ", "She now goes down in history as the first artist in history to have three million-selling opening weeks. ", "This would have been impressive even in 1999, when Backstreet Boys walked the pre-Napster earth like lumbering giants. ", "But in 2014? ", "It's like we've just seen a ghost — the ghost of a happy, healthy music biz that can apparently only be summoned by Swift.", "\n\nSwift was too busy promoting 1989 in Japan this week to immediately toast the sales or critical plaudits. ", "But we caught up with her by transatlantic phone for her first interview since she achieved these fairly stunning figures. ", "Topics of discussion included her unusual DIY marketing ideas… the album's sure-to-be-controversial second single… and a new over-the-counter medicine you might have heard of called Swiftamine.", "\n\nThere's also that little matter of her having just removed her entire catalog from Spotify, after having previously only withheld new releases from free streaming services. ", "Some news accounts in the business pages have claimed that her label had some secret Machiavellian scheme in mind, but as Swift makes clear here, she's in control of her own business moves as well as her heart.", "\n\n[Related: Roughly 1,989 Words About Taylor Swift's '1989'! ", "A Track-by-Track Guide]\n\nYAHOO MUSIC: This album had the highest first-week sales since 2002. ", "Then there is also the fact that you're the first artist to have a million-selling week three times in a row. ", "And then there's also just the idea of this being a personal best, just for you. ", "Do any of these ways of looking at the initial success of the album mean more to you than others?", "\n\nTAYLOR SWIFT: Well, my huge dream in this whole thing, which I was told many times was an unrealistic… I was told many times to keep my expectations in check, so I did. ", "But the ultimate dream was, \"Can we ring that bell? ", "Can we get a million; can we do this for the third time?\" ", "Because we were all very well aware that if we sold a million records this time, it would be the only time in history that someone had done that three times. ", "That was the most insane thing, when we got the first hint that we might end up actually getting to do it. ", "And then my second biggest hope was, \"Hey, wouldn't it be insane if we topped what we did with Red?\" ", "And then the fans ended up making that happen, so it's been just kind of like a dream scenario all the way around. ", "And I just feel so lucky that people seem to understand what I was doing with this album and loved the new direction of it.", "\n\nYou put something up on Instagram where you pointed out that some of the so-called experts had initially been projecting it might only sell 650,000. ", "When you heard that back then, were you thinking, \"Oh, come on, guys? ", "This is me, Taylor — you know I can do better than that\"? ", "Or did you ever give in a bit to the diminished expectations of 2014?", "\n\nWell, I understand there's been a huge shift in this economic landscape, and the perception of music has changed a lot in the last two years. ", "And so when I saw that number that was lower than what we've done before as a prediction, I didn't really know what to expect anymore. ", "Because I hoped that I had created something that people would want to buy, but I didn't know what's been happening in people's minds… I just was hoping and praying that people still perceived there to be a value to someone's musical creation.", "\n\n\n\nThat leads to the streaming question. ", "We've played the game of wondering whether you would have sold hundreds of thousands of fewer copies last week if the album had been available to people for free via those services. ", "To a lot of people, you're a hero for reinforcing that music still has a value. ", "And then there are some people who think you're standing in the way of progress by not giving in to the streaming model. ", "What are your thoughts on all that?", "\n\nIf I had streamed the new album, it's impossible to try to speculate what would have happened. ", "But all I can say is that music is changing so quickly, and the landscape of the music industry itself is changing so quickly, that everything new, like Spotify, all feels to me a bit like a grand experiment. ", "And I'm not willing to contribute my life's work to an experiment that I don't feel fairly compensates the writers, producers, artists, and creators of this music. ", "And I just don't agree with perpetuating the perception that music has no value and should be free. ", "I wrote an op-ed piece in the Wall Street Journal this summer that basically portrayed my views on this. ", "I try to stay really open-minded about things, because I do think it's important to be a part of progress. ", "But I think it's really still up for debate whether this is actual progress, or whether this is taking the word \"music\" out of the music industry. ", "Also, a lot of people were suggesting to me that I try putting new music on Spotify with \"Shake It Off,\" and so I was open-minded about it. ", "I thought, \"I will try this; I'll see how it feels.\" ", "It didn't feel right to me. ", "I felt like I was saying to my fans, \"If you create music someday, if you create a painting someday, someone can just walk into a museum, take it off the wall, rip off a corner off it, and it's theirs now and they don't have to pay for it.\" ", "I didn't like the perception that it was putting forth. ", "And so I decided to change the way I was doing things.", "\n\n" ]

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[ "Top 5 fragrances for father’s Day\n\nWell I am sure you are all aware that fathers day is approaching, you can usually tell when you walk into your local supermarket and see all the cards and the presents all laid out neatly for you to choose your selected item.", "\n\nOne thing that I always find really hard is actually choosing a present and with so much to choose from it can become rather complicated…. ", "Unless dad has told you what he wants.", "\n\nAnd I am pretty sure dad is a bit bored of the ties, socks and little bits and pieces that tends to be the “stereotypical” present.", "\n\nYou could say that perhaps fragrances fall into that category… but think again, with so many options of different fragrances with some great smells… at least you know this present will be used and usually last a little while… lets just hope when spraying your dad is not as generous as myself.", "\n\nSo below is a list of my top 5 fragrances that I am sure dad would love to have!", "\n\nTom ford noir, my all time favourite! ", "And I have finally got my hands on some! ", "This fragrance is great because its long lasting and the smell is just perfect! ", "Not to heavy but not to light, this is great as an evening fragrance and if lightly spritzed you can get away with it for the day! ", "Every man should have this fragrance in there collection! ", "You can purchase the Noir from House of Fraser for £64 for 50ml for the Parfum.", "\n\nDavidoff horizon, Davidoff’s newest fragrance for men and one fragrance I just love spraying, its not like your classic musky Coolwater, this has a handsome smell to it, but nothing heavy! ", "You can purchase this from John Lewis for £58.50 for 125ml.", "\n\nAbercrombie and Fitch First Instinct, one of my new fragrances added to the collection, great as a day fragrance with some musk, but also a hint of sweet in their, Dad would love this if he loves a bit of musk in his scents, you can purchase this from the perfume shop for £57 for 100ml again another bargain.", "\n\nVersace Eros, This is currently one of my favourites as its long lasting and the smell is definitely eye catching, dad will love it!", "\n\nYou can purchase this fragrance at john Lewis for £47.50 for 100ml, which is a bargain!", "\n\nHERMES Terre D’ Hermes -I have always had a love for this fragrance since I smelt it on my best friend, which was a mistake for him as I cleared out his bottle… (sorry rick) this is a perfect sent for anyone that is looking to add some class into the fragrance collection! ", "I would be happy if someone purchased this for me.", "\n\nFor prices have a look around, they really can vary depending which size you get but at House of Fraser you can buy this fragrance for £84 for the 70ml Parfum." ]

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[ "Gaia: 'Go' for science\n\n29 July 2014\n\nVideo is not supported\n\nThe satellite was launched on 19 December 2013, and is orbiting a virtual location in space 1.5 million kilometres from Earth.", "\n\nGaia's goal is to create the most accurate map yet of the Milky Way. ", "It will make extremely accurate measurements of the positions and motions of about 1% of the total population of roughly 100 billion stars in our home Galaxy to help answer questions about its origin and evolution.", "\n\nRepeatedly scanning the sky, Gaia will observe each of its billion stars an average of 70 times each over five years. ", "Small apparent motions in the positions of the stars will allow astronomers to determine their distances and movements through the Milky Way.", "\n\nIn addition, Gaia will also measure key physical properties of each star, including its brightness, temperature and chemical composition.", "\n\nGaia spins slowly once every six hours, sweeping its two telescopes across the sky and focusing the light from their separate fields simultaneously onto a single focal plane – the largest digital camera ever flown in space, with nearly a billion pixels.", "\n\nAs the stars drift across the camera, the relative positions of all detected stars are measured and downlinked to Earth. ", "Over time, a complete network of positions of stars covering the whole sky is built up, before being analysed to yield a highly accurate 3D map.", "\n\nThe accuracy required is astonishing: Gaia must be able to measure positions to a level equivalent to the width of a human hair seen at 2000 km. ", "In turn, these measurements demand a very rigorous calibration of the satellite and its instruments, a painstaking procedure that has taken the first part of the year to complete.", "\n\nGaia is now ready to begin its five-year science phase, but the commissioning also uncovered some unexpected anomalies.", "\n\nOne problem detected early in the commissioning was associated with water freezing on some parts of the optics, causing a temporary reduction in transmission of the telescopes.", "\n\nThis water was likely trapped in the spacecraft before launch and emerged once it was in a vacuum. ", "Heating the affected optics to remove the ice has now largely solved this problem, but it is likely that one or two more 'decontamination' cycles will be required during the mission to keep it in check.", "\n\nAnother problem is associated with 'stray light' reaching Gaia's focal plane at a level higher than predicted before launch. ", "This appears to be a mixture of light from the Sun finding its way past Gaia's 10 m-diameter sunshield and light from other astronomical objects, both making their way to the focal plane as a diffuse background.", "\n\nThe effect on Gaia's performance is negligible for brighter objects at magnitude 15 and above, and a slight degradation in the positional accuracy is seen for fainter stars, reaching 50% for stars at Gaia's nominal faint limit of magnitude 20.", "\n\nThere is also some effect on the accuracy to which stellar brightnesses will be measured.", "\n\nThe impact of the stray light should, in principle, be more significant for faint stars seen by Gaia's Radial Velocity Spectrometer (RVS).", "\n\n\"However, we are optimising the onboard software to mitigate as much as possible the impact caused by these higher background levels of light, and we are confident that we will not be far off our initial and somewhat conservative estimate of studying 150 million stars with RVS, as planned,\" says Giuseppe Sarri, ESA's Gaia Project Manager.", "\n\n\"We will still be able to analyse one billion – if not more – stars with the astrometry and photometry instruments, measuring each star's position and motion up to 100 times more accurately than Gaia's predecessor Hipparcos and for a far larger number of stars.\"", "\n\nFurther tests made during commissioning have shown that it may be possible to extend Gaia's reach to stars even fainter than magnitude 20, while at the other end, software changes enable Gaia to measure almost all of the brightest stars in the sky, previously ruled out as being too bright for such a sensitive system. ", "Both of these extensions will need further analysis before being implemented.", "\n\nFinally, Gaia also contains a laser device called the 'basic angle monitor', designed to measure the angle of separation between Gaia's two telescopes to an extremely high level of accuracy. ", "This is necessary in order to correct for expected periodic variations in the separation angle caused by thermal changes in the payload as Gaia spins.", "\n\nAlthough this system is working, the detected variations in the basic angle are larger than expected. ", "Further efforts are being made to measure and accurately calibrate the variations, with the aim of largely eliminating them during the overall data analysis.", "\n\nThe commissioning has not only focused on the spacecraft performance, but also on the flow of data on the ground, testing procedures that will be used to process and analyse the vast amount of data that will be transmitted to Earth on a daily basis for the next five years.", "\n\nThus, after extensive testing and analysis of systems both in space and on the ground, Gaia is now in a position to begin routine operations.", "\n\n\"The commissioning phase has been challenging, and although some activities are ongoing, all in all Gaia is in good shape to fulfil its promise – all of the core scientific goals are still achievable, as hoped,\" says Timo Prusti, ESA's Project Scientist for Gaia.", "\n\n\"Given the somewhat longer-than-expected commissioning and taking into account the time needed to develop some new software, we anticipate that the first intermediate catalogue of science data will be released to scientists and the public in summer 2016.", "\n\n\"However, if rapidly-changing objects such as supernovas are detected, open alerts will be made as soon as possible – a service we hope to have up and running before the end of this year.\"", "\n\nFor a full quantitative analysis of Gaia's expected science performance based on the results of commissioning, see http://www.cosmos.esa.int/web/gaia/news_20140729.", "\n\nFor updates published during the commissioning period, please refer to the Gaia blog.", "\n\nFor more information, please contact:\n\nMarkus Bauer\n\nESA Science and Robotic Exploration Communication Officer\n\nTel: +31 71 565 6799\n\nMob: +31 61 594 3 954\n\nGiuseppe Sarri\n\nGaia Project Manager\n\nEmail: giuseppe.sarri esa.int\n\nTimo Prusti\n\nGaia Project Scientist\n\nEmail: timo.prusti esa.int\n\n(This article was originally published on ESA's Space Science Portal)" ]

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[ "Osteosarcoma of the lumbosacral spine invading the central venous pathways, right-sided cardiac chambers, and pulmonary artery.", "\nWe report an unusual case of lumbosacral osteogenic sarcoma with cauda equina syndrome and invasion into the central venous and cardiac system. ", "A 41-year-old Hispanic man presented to the emergency department complaining of severe low back pain, cauda equina syndrome, bilateral lower extremity edema, and an extra heart sound on physical examination. ", "CT of the lumbosacral spine done in the emergency department demonstrated a sclerotic lesion in the sacrum with cortical destruction, extension into the spinal canal and a bulky soft tissue mass containing calcifications. ", "Supplemental MRI demonstrated marrow replacement of L4, L5, and the sacrum, soft tissue extension of the tumor, and invasion iliac veins extending into the IVC; however, the full extent of the intravascular tumor was not seen on this examination. ", "Surgical laminectomy and biopsy of the spinal tumor provided the diagnosis of osteogenic sarcoma. ", "A transthoracic echocardiogram was performed while the patient was recovering due to nonsustained ventricular tachycardia, which showed an echogenic mass within the right atrium and ventricle. ", "CT pulmonary angiogram confirmed the echocardiogram showing a tumor extending through the pulmonary valve into the main pulmonary artery. ", "The patient underwent en bloc resection of the tumor from the venous and cardiac systems. ", "Histologic examination of the tumor confirmed osteogenic sarcoma. ", "While vertebral osteogenic sarcoma is uncommon, invasion of the spinal canal is common in these tumors. ", "However, tumor extending into the central venous and cardiac system is rare. ", "The previously reported cases of central venous and cardiac involvement have been related to distant metastases or primary cardiac osteosarcomas. ", "There is only one other reported case of direct extension into the venous system by an iliac bone osteosarcoma in an adolescent; however, the tumor did not extend into the pulmonary circulation." ]

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[ "The Two Moors Way\n\nby\nSue Viccars\n\nPublisher:\nCicerone Press\n\nPrint ISBN:\n9781852847142, 185284714X\n\neText ISBN:\n9781783621507, 1783621508\n\nThe Two Moors Way Edition by Sue Viccars and Publisher Cicerone Press. ", "Save up to 80% by choosing the eTextbook option for ISBN: 9781783621507, 1783621508. ", "The print version of this textbook is ISBN: 9781852847142, 185284714X." ]

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[ "Echolaryngography in cats.", "\nTwenty-five cats with clinical signs of upper respiratory tract disease and five cats without upper respiratory signs underwent echolaryngography. ", "Direct inspection of the larynx under general anesthesia was undertaken in all cats and used as the 'gold standard' for the diagnosis of laryngeal diseases. ", "The aims were to: (a) establish which anatomic structures of the larynx are visible ultrasonographically in cats without upper respiratory tract disease, (b) establish which laryngeal abnormalities can be detected and accurately localised using ultrasonography and (c) evaluate in which conditions the technique may provide complementary information or an alternative method of investigation. ", "The ultrasound investigation accurately indicated the presence and location of cysts and masses. ", "Abnormal laryngeal movements were also detected, although it was difficult to confirm whether these were unilateral or bilateral. ", "Vocal cord thickening was seen but the underlying cause could not be established with this technique." ]

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[ "Title\n\nAuthor\n\nAbstract\n\nSpeciation – the process by which new species arise – is of fundamental importance in the biological sciences. ", "The means by which new species arise, and the relationship among living species, has been a topic that has captivated both lay and scientific observers for centuries. ", "In recent years, the study of speciation has enjoyed increased attention, resulting in significant advances in our understanding of how species form. ", "Although our understanding of the processes that contribute to speciation has increased dramatically in recent years, our knowledge of how reproductive barriers accumulate as speciation proceeds is still limited. ", "Thus, studies that evaluate trait divergence and its consequences at early verses late stages of divergence can provide valuable insight into the speciation process. ", "Chapter 1 of my dissertation focuses on the role of animal personality in the speciation process. ", "Animal personality – defined as consistent individual differences in behavioral tendencies – has been identified as a key player in several ecological and evolutionary processes, yet the role of personality in speciation remains unexplored. ", "In this chapter I discuss the ways by which personality can contribute to a suite of reproductive barriers and drive the speciation process. ", "Chapters 2 through 5 provide a case study evaluating how selection acts on traits at early and late stages of speciation, using the Neotropical Livebearing fish genus Brachyrhaphis as a model system. ", "Brachyrhaphis is ideally suited for this research because several species pairs and population pairs within species occur in similarly divergent selective regimes. ", "I first present results from a field demographic study that shows that the strength of divergent selection acting on life-history traits in populations from divergent predation environments diminishes as speciation proceeds. ", "I then show that population pairs at different stages of divergence are evolving similar morphological patterns along parallel trajectories. ", "At both early and late stages of divergence, populations from environments with dense predator populations have a body shape that appears to be optimized for burst-speed swimming, and important component of predator escape. ", "In contrast, populations from environments lacking predators have a body shape optimized for endurance swimming ability, which is important in environments where competition for foods and mates is high. ", "Next, I show that populations from divergent predation environments do indeed differ in their swimming abilities according to our predictions, reflecting a population level trade-off between burst and endurance swimming ability. ", "Although population level trade-offs were strong, I found no evidence of within population level trade-offs, suggesting that populations have arrived at novel solutions to between population trade-offs that were not present within ancestral populations. ", "Finally, I show that these specialized swimming modes are locally adaptive, and that divergent ecology selects against immigrants, effectively reducing gene flow between populations from divergent environments. ", "Together, these studies provide a valuable glimpse into the repeatability and predictability of trait divergence at different stages of speciation.", "\n\nDegree\n\nPhD\n\nCollege and Department\n\nLife Sciences; Biology\n\nRights\n\nhttp://lib.byu.edu/about/copyright/\n\nBYU ScholarsArchive Citation\n\nIngley, Spencer J., \"Repeated Trait Evolution Driven by Divergent Natural Selection at Early and Late Stages of Speciation\" (2015). ", "All Theses and Dissertations. ", "6150.", "\nhttps://scholarsarchive.byu.edu/etd/6150" ]

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[ "Dalat, Sarawak\n\nDalat is the administrative town of the Dalat district in Mukah Division, Sarawak, Malaysia. ", "It is situated by the Oya river.", "\n\nEtymology\nAccording to Heidi Munan's book \"How Dalat Got Its Name\", Dalat was named following a bloodshed among three brothers as the village chief did not name a successor. ", "Many people died in the war. ", "Corpses lying in the village attracted flies. \"", "Dalat\" means fly in the Melanau language, and therefore, the locals named the village Dalat, which is now a small town.", "\n\nHistory\n\nGovernment\nDalat is represented at the State Legislative Assembly by Dato' Sri Hajah Fatimah Abdullah @ Ting Sai Ming, from Parti Pesaka Bumiputera Bersatu. ", "She won the seat in the 18th State Election 2016 for the fourth time. ", "For Parliament, Dalat district is under Parliament 213: Mukah.", "\n\nGeography and climate\nSimilar to most areas in the Rajang Delta, Dalat town and its land district is located on peat land that is categorized as deep peat (more than 150 cm).", "\n\nDemographics\n\nAccording to the 2010 National Census, Dalat townland has a population of 619.", "\n\nMost of the people use Melanau language to communicate here. ", "There is a slight difference of the language between each villages, yet they can understand each other very well. ", "Other languages such as Malay, Sarawak Malay, Iban, Mandarin, Hokkien and English are also widely spoken.", "\n\nMain religions practised in Dalat are Islam, Christianity (Roman Catholic, Methodist and SIB), Buddhism, and Malaysian Chinese religion.", "\n\nEconomy\nDalat is reputed to be the largest sago flour producer in the world. ", "The district has four modern sago factories with a total output of more than 74 tonnes per day.", "\n\nThe importance of the sago palm tree is evident in the district tagline.", "\n\nTransport\n\nRoad\nDalat is connected by a single-carriage road to Mukah. ", "There are daily express bus services connecting Dalat and Miri via Bintulu and Mukah.", "\n\nAir\nThe nearest airport is Mukah Airport. ", "The locals however prefer to use either Bintulu Airport or Sibu Airport to fly to Kuala Lumpur particularly.", "\n\nWater\nRiver transportation is still very vital in Dalat. ", "There are speed boats connecting Dalat and Sibu with a fee of MYR 25. ", "The journey takes approximately 2 hours.", "\n\nOther utilities\n\nEducation\nDalat town has four secondary schools namely SMK Dalat, SMK Oya, SMK Batang Igan and SMK Agama Igan. ", "In the town proper, there are three primary schools namely SJK (C) Chin Hua, SK Saint Bernard and SK Kampung Sungai Ud .", "\n\nIn January 2018, Centre Of Technical Excellence Sarawak (CENTEXS) Temporary Campus was officially launched by Dato Sri Fatimah Abdullah offering Textile & Hospitality courses for the first intake. ", "She also announced the plan to build a new CENTEXS campus costing RM 50 million will be built near Dalat Welfare Complex.", "\n\nHealthcare\n\nThe town is served by an eight-bedded public hospital, Dalat Hospital. ", " Despite having the least number of beds among 22 public hospitals in Sarawak, it is equipped with facilities such as X-ray laboratory and a dialysis centre. ", "\n\nSince there is a good system of transportation, any needs which Dalat Hospital could not handle would be referred to Mukah Hospital or even Sibu Hospital.", "\n\nOthers\nDalat town also has a post office, district office, a hospital, a stadium (Stadium Perpaduan Dalat), a few blocks of shop-houses, a Catholic church (St. Bernard Church), a Methodist Church, a Chinese temple (age more than a century) and a district mosque. ", "A Senior Citizens’ Activity Centre (PAWE) was established by the Ministry of Women, Family and Community Development in Dalat with 439 registered members. ", "In June 2017, a voluntary fire station was launched. ", "The fire station is an interim measure to respond swiftly to fires as the nearest facility is in Mukah, some 40 minutes’ drive away.", "\n\nThere is only one bank in Dalat which is a branch of RHB Bank.", "\n\nCulture and leisure\n\nThe people here particularly the Melanaus are still practising their culture. ", "The Melanaus are famous for their traditional food such as umai, sago worms and the sago pearls. ", "Also, there is a carnival named Karnival Balau (Balau is the Sago palm in Melanau language) which is held annually, and also a regatta, held few years once. ", "Some major celebrations here are Christmas, Hari Raya Aidilfitri, Chinese New Year and the Kaul Festival. ", "The Kaul Festival is celebrated on different dates for different villages.", "\n\nAssociations/ Clubs \n The Dalat Melanau Association was registered on 9 September 2010 under Association Act 1966-33 with Registrar Of Societies Number PPM-002-13-09092010. ", "The association aims to encourage Melanau at Dalat district to be more proactive and while helping to promote progress for local Melanau people. ", "The club also aims to protect Melanau Dalat heritage and culture.", "\n Dalat Photography Club - Co-founded by well known freelance photographer Naising Bega who is famous for his artwork. ", "Naising also acts as one of the instructors in this club. ", "The club was registered on 6 November 2012 with ROS PPM014-13-06112012. ", "The club initially known as Melanau Dalat Photography Club which made it early present on Pesta Bersaug Dalat on October 2010. ", "It later renamed to Dalat Photography Club to encourage more people enter the club. ", "The Patron of the club is Dalat state assembly woman Datuk Hajah Fatimah Abdullah @ Ting Sai Ming.", "\n\nLiterature\n Heidi Munan's short story 'How Dalat Got Its Name' is published in the book Melanau stories (2005) Utusan Publications. ", "The short story was included in the Malaysian lower secondary school English literature curriculum from 2000 to 2009.", "\n The Kut Canal and Medong Village are also featured in the book Melanau stories (2005), in 'The Story of Kut Canal'.", "\n\nNotable people\n Dato' Sri Hajah Fatimah Abdullah @ Ting Sai Ming - State Assembly Representative of Dalat and the current Minister of Welfare, Community Well Being, Women, Family and Childhood Development (Sarawak). ", "She was born and raised in Kampung Teh, Dalat.", "\n Rozie Khan - fashion designer and founder of \"Rozie Khan Couture\". ", "She is the winner of the Best Designer award during the 2018 Borneo Fashion Week.", "\n\nReferences\n\nCategory:Towns in Sarawak" ]

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[ "Pennsylvania: Mother of seven dies while jailed for unpaid fines\n\nBy Samuel Davidson\n\n16 June 2014\n\nThe death last Saturday of a 55-year-old mother of seven in a Pennsylvania jail is a tragic demonstration once again of the brutalization of the working class and the poor in the American justice system.", "\n\nEileen DiNino, 55, the impoverished mother of seven children, was found dead in her cell on Saturday, June 7, less than 24 hours after being placed in jail for being unable to pay mounting truancy fines imposed upon her when several of her children had missed too many days from school.", "\n\nAccording to the politicians of both the Democrat and Republican parties, the answer to every social problem in America is more police, more prisons and more repression.", "\n\nIn 1995, the Pennsylvania legislature amended the Pennsylvania Truancy Act to hold parents responsible if their children fail to attend school by imposing fines and possible jail time. ", "The law states that a parent can be fined up to $300 per violation and sent to jail for five days. ", "The act was signed into law by then governor Tom Ridge, who went on to become the first US secretary of Homeland Security under the G.W. Bush administration.", "\n\nThe No Child Left Behind Act of 2001 required school districts to report truancy rates, which forced districts to become more aggressive in pursuing truancy violations or risk losing federal and state funds. ", "Pennsylvania also ties state funding to attendance rates and budget cuts are forcing cash-strapped school districts to become more pernicious in imposing fines on parents.", "\n\nWhile debtors’ prison was supposedly abolished in the United States in 1830, tens of thousands of poor people are routinely placed in jail for failing to pay fines and other court costs.", "\n\nMs. DiNino had no income. ", "She was living in a home owned by another family member in Reading, Pennsylvania, on the eastern end of the state, about 65 miles northwest of Philadelphia. ", "Her three older children had already moved out of the home, but she was still raising the four younger ones.", "\n\nThe county coroner has performed an autopsy but has not yet released a cause of death, saying that he is awaiting a toxicology report. ", "Ms. DiNino suffered from high blood pressure and was taking medication for it and other health problems, but prison officials reported that they had not given her any medication.", "\n\nWhen Ms. DiNino presented herself to the Berks County judge who sent her to jail for the weekend, she had over $2,000 in fines that she could not pay. ", "Not all of the money was a result of truancy violations. ", "Once in the legal system, court costs and other fees are quickly added on. ", "An Associated Press examination of Ms. DiNino’s fines shows that for one truancy violation $10.00 was added for postage, $60.00 for the county constables and $8.00 for a “computer project.”", "\n\nExpressing the real contempt and hostility showed for the poor, and mothers in particular, according to the AP, District Judge Dean R. Patton, who sent Ms. DiNino to prison, said that while he had lost sleep over her death he felt “that a short jail stint can sometimes ‘break the habit’ of parents who’d rather party into the night than take their children to school the next day.”", "\n\nIt is likely that the “short jail stint” would not have been the end of her dilemma. ", "More than likely, had she lived she would have soon been visited by the county youth service agency, which may have tried to take her remaining children away from her and place them in foster care on the claim that she wasn’t caring for them.", "\n\nMs. DiNino’s plight is not an isolated one. ", "The Reading Eagle reported that since the year 2000 more than 1,600 parents have been jailed in Berks county alone for truancy violations or the fines associated with them. ", "More than two thirds of them are women and most are single parents living in poverty.", "\n\nIn 2011, the Public Interest Law Center of Philadelphia and the Pennsylvania NAACP filed a lawsuit against the Lebanon School District, which in the 2008-2009 school year alone fined parents over $500,000, more than 10 times per parent than neighboring Lancaster School District.", "\n\nThe tragic death of Ms. DiNino underscores one of the thousands of brutal indignities that the working class and the poor are subjected to in American society every day.", "\n\nPlease enable JavaScript to view the comments powered by Disqus." ]

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[ "Pacific Northwest Ballet\n\nPacific Northwest Ballet (PNB) is a ballet company based in Seattle, Washington, in the United States. ", "It is said to have the highest per capita attendance in the United States, with 11,000 subscribers in 2004. ", "The company consists of 49 dancers; there are over 100 performances throughout the year. ", "\n\nPNB performs in McCaw Hall at the Seattle Center. ", "It is especially known for its performance of the Stowell/Maurice Sendak Nutcracker, which it had presented from 1983 through 2014, as well as made into a feature film. ", "In 2006, the company was chosen to perform in the Fall for Dance Festival at New York's City Center Theatre and at the Jacob's Pillow Dance Festival.", "\n\nHistory\n\nPacific Northwest Ballet was founded in 1972, after the two-month residency of First Chamber Dance Company, as part of the Seattle Opera and named the Pacific Northwest Dance Association. ", " Under the directorship of Kent Stowell and Francia Russell, originally of New York City Ballet, it broke away from the Opera in 1977 and took its current name in 1978. ", " Stowell and Russell left at the end of the 2004–2005 season. ", "A portrait by artist Michele Rushworth was painted of Stowell and Russell and installed in the Phelps Center, Seattle, to commemorate their careers and retirement. ", "Both had studied with and danced for George Balanchine.", "\n\nIn July 2005, Peter Boal succeeded Stowell and Russell as artistic director following their retirement. ", "After dancing with the New York City Ballet for 22 years, he had been a full-time faculty member at The School of American Ballet from 1995-2005.", "\n\nIn 2013, the company and its orchestra toured to New York for the first time in sixteen years. ", " The New York Times dance critic Alastair Macaulay, stated of their presentation that \"This is a true company,\" more \"unified in its understanding of Balanchine\" than the New York City Ballet.", "\n\nIn 2012, PNB brought in Twyla Tharp as its first artist in residence for a year-long residency.", "\n\nPacific Northwest Ballet School\n\nThe Pacific Northwest Ballet School was founded in 1974. ", "Formerly directed by Francia Russell, and now directed by Peter Boal, it has been considered to be \"one of the leading, if not the definitive, professional training school in the country.\" ", "The teaching is structured on that of the School of American Ballet. ", "Pacific Northwest Ballet holds an annual summer course in the month of July and is considered one of the leading summer dance education facilities in the country.", "\n\nDancers \n\nPacific Northwest Ballet is noted for choosing dancers that have physique, expressivity and a variety of body shapes.", "\n\nPrincipals \n\n Leta Biasucci\n Kyle Davis\n Lindsi Dec\n Benjamin Griffiths\n William Lin-Yee\n\n James Moore\n Elizabeth Murphy\n Seth Orza\n Noelani Pantastico\n Lucien Postlewaite\n\n Lesley Rausch\n Sarah Ricard Orza\n Jerome Tisserand\n Laura Tisserand\n\nSoloists \n\n Angelica Generosa\n Joshua Grant\n Steven Loch\n\n Elle Macy\n Leah Merchant\n Margaret Mullin\n\n Price Suddarth\n Ezra Thomson\n Dylan Wald\n\nCorps de ballet \n\n \n Madison Rayn Abeo\n Guillaume Basso\n Ryan Cardea\n Nancy Casciano\n Dammiel Cruz\n Mark Cuddihee\n Christopher D'Ariano\n Abby Jayne DeAngelo\n Luther DeMyer\n\n Cecilia Iliesiu\n Angeli Kiana Mamon-Urrea\n Amanda Morgan\n Sarah Pasch\n Miles Pertl\n Christian Poppe\n Juliet Prine\n Calista Ruat\n\n Clara Ruf Maldonado\n Sarah-Gabrielle Ryan\n Emma Love Suddarth\n Yuki Takahashi\n Madison Taylor\n Leah Terada\n Sarah Villwock\n Genevieve Waldorf\n\nNotable former dancers \n\n Patricia Barker\n Chalnessa Eames\n\n Carla Körbes\n Louise Nadeau\n\n Kaori Nakamura\n\nReferences\n\nReviews \n\n NY Times by Alastair Macaulay, November 5, 2007\n\n NY Times by Alastair Macaulay, September 25, 2007\n\nExternal links \n \n Pacific Northwest Ballet at HistoryLink\n\nCategory:Culture of Seattle\nCategory:Ballet companies in the United States\nCategory:Pacific Northwest\nCategory:1972 establishments in Washington (state)\nCategory:Performing groups established in 1972\nCategory:Dance in Washington (state)\nCategory:Non-profit organizations based in Washington (state)\nCategory:Organizations based in Seattle" ]

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[ "Q:\n\nHow to check whether shared preferences is null or not in android?", "\n\nIn my apps for login and logout functionality, I am checking whether the shared preferences is null or not when activity starts, but I am still getting a NullPointerException.", "\nHere is my code for HomeActivity.java: \n// Username And Password Editbox\nString eusername;\nString epassword;\n\n// Shared Preferences String declaration\nString spusername;\n\n@Override\npublic void onCreate(Bundle savedInstanceState) {\n super.onCreate(savedInstanceState); \n\n SharedPreferences spreferences = PreferenceManager.getDefaultSharedPreferences(getApplicationContext());\n spusername=spreferences.getString(\"spusername\",\"\");\n\n if(!spusername.equals(\"\"))\n { \n Log.e(\"Spusername not null\",\"-->\"+spusername);\n }\n if(spusername==null)\n {\n Log.e(\"Spusername null\",\"-->\"+spusername);\n }\n}\n\nA:\n\nYou have contains method on SharedPreferences.", "\nboolean isSpUsernameDefined = spreferences.contains(\"spusername\");\n\nA:\n\nyou are giving eusername without initializing this variable so getting null pointer exception\nSo try like this\nspusername = preferences.getString(\"spusername\", \"n/a\");\n\nif(spusername!= null && !", "spusername.equals(\"\"))\n { \n Log.e(\"Spusername !", "= null\",\"-->\"+spusername);\n\n }\n else{\n // your code is here\n }\n\n" ]

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[ "About\n\nRandom, witty, and a whole lot of fun. ", "The Snappy Scribe is a reflection of me: irrelevant and messy, with a few failed attempts at humor, and even fewer moments of clarity when it comes to this whole adulting thing. ", "Love it or hate it, I can tell you this: you will never be bored." ]

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[ "ZERO U.S. Measles Deaths in 10 Years, but Over 100 Measles Vaccine Deaths Reported\n\nBrian Shilhavy\nHealth Impact News Editor\n\nWith the measles and measles vaccine debate reaching a near frenzy on the Internet, it is always nice to throw some cold hard facts on the firestorm currently raging in the measles debate.", "\n\nSo here are some easily verifiable facts regarding deaths due to measles in the United States for the past 10 years, and deaths due to measles vaccines during the same 10 year period.", "\n\nFirst, the Centers for Disease Control and Prevention (CDC) keeps a weekly tally of disease outbreaks, including deaths. ", "According to a statement made by Dr. Anne Schuchat, the director of CDC’s National Center for Immunization and Respiratory Diseases, in an Associated Press story picked up by Fox News on April 25, 2014:\n\nThere hs been no measles deaths reported in the U.S. since 2003. [", "1]\n\nThe weekly CDC Morbidity and Mortality Weekly Reports (MMWR) since that date have not revealed any measles deaths either.", "\n\nAnd while health authorities are blaming measles outbreaks in recent years on unvaccinated children, when you mention the fact that nobody is dying from measles in the U.S., they are quick to turn around and claim vaccines have eliminated measles deaths (even though they cannot eliminate the disease itself apparently.)", "\n\nBesides the obvious contradiction in reasoning with such a claim, the historical evidence just does not support it either:\n\nDeath by Measles Vaccines\n\nWhat about deaths due to the measles vaccine during the same time period?", "\n\nThe U.S. Government keeps a database of reports called The Vaccine Adverse Event Reporting System (VAERS). ", "The database is available to the public, and there is a search portal the public can use at Medalerts.org.", "\n\nWe ran a search for a ten year period for deaths due to all measles vaccines, including a few that are no longer in production. ", "The search result contained 108 deaths over this period, resulting from four different measles vaccines sold in the United States during the past 10 years.", "\n\nToday, one can only purchase a measles vaccine in combination with the mumps and rubella vaccines (MMR Vaccine).", "\n\nWhen searching for just the MMR vaccine during the past 10 years, 96 deaths were reported:\n\nAnybody with a computer and Internet access can search this database by visiting MedAlerts.org.", "\n\nThis database reflects only deaths that were reported during the time frame, and therefore probably reflects a much lower number than actual deaths, since most doctors and health authorities believe vaccines are safe, and would not normally attribute a death to a vaccine and actually report it.", "\n\nThe U.S. Government Settlements on Measles Vaccine Injuries\n\nThe other place to find facts regarding injuries and deaths due to the measles vaccine is to look at U.S. Government settlements for MMR vaccine injuries and deaths. ", "The U.S. public is largely unaware that manufacturers of vaccines have been given legal immunity from being prosecuted in civil court for vaccine injuries and deaths, since 1986. ", "If someone is injured or killed by a vaccine, they have to sue the U.S. Government in a special “vaccine court.”", "\n\nAs search here for “measles” returns a result of 111 claims settled for the MMR vaccine since 2004. ", "Some of them are for settlements due to deaths related to the MMR vaccine, as determined by the judge.", "\n\nWe did not click on and read each decision to find out how many resulted in deaths, but if we get a few reports from others who are willing to do so, and the numbers match, we will update this story with the actual death figure.", "\n\nIt takes many years to win a case in this vaccine court, so this probably represents only a tiny fraction of actual injuries and deaths due to the MMR vaccine.", "\n\nConclusion: Measles Vaccine Enthusiasm based Largely on Fear and Beliefs\n\nWe fully realize that those who believe in the value of vaccines will probably not be persuaded by these facts, which anyone with a computer and Internet access can verify from U.S. Government sources.", "\n\nHaving now published a few stories on the measles issue, and having received many hundreds of comments, it has become very clear to us that those who have strong opinions on the measles vaccine are based more on fear and beliefs, than they are on facts or science. ", "Any attempt by these vaccine proponents to force their beliefs on the rest of the U.S. public should be vigorously opposed.", "\n\n1. ", "Statement from Dr. Anne Schuchat, the director of CDC’s National Center for Immunization and Respiratory Diseases: Deaths from measles outbreak may be ‘inevitable’ as cases surge in US, Associated Press, published by Fox News on April 25, 2014.", "\n\n* EDIT – Since publishing this article, some have pointed out to us that some pro-vaccine sites are claiming that the CDC’s National Vital Statistics Reports show 2 deaths associated with measles for 2009, and 2 deaths listed in the same report for 2010. ", "That would make 4 deaths due to measles according to the the CDC’s National Vital Statistics Reports, and not zero, as reported by the CDC’s Dr. Anne Schuchat in the Associated Press interview of 2014. ", "Were her public statements in error?", "\n\nAnother reader has now sent us an email they received from the CDC, Division of Viral Diseases, stating that there has been no measles deaths in the U.S. since 2003. ", "So that appears to be the “official” position of the CDC.", "\n\nDr. Andrew Moulden: Every Vaccine Produces Harm\n\neBook – Available for immediate download.", "\n\nCanadian physician Dr. Andrew Moulden provided clear scientific evidence to prove that every dose of vaccine given to a child or an adult produces harm. ", "The truth that he uncovered was rejected by the conventional medical system and the pharmaceutical industry. ", "Nevertheless, his warning and his message to America remains as a solid legacy of the man who stood up against big pharma and their program to vaccinate every person on the Earth.", "\n\nDr. Moulden died unexpectedly in November of 2013 at age 49.", "\n\nBecause of the strong opposition from big pharma concerning Dr. Moulden’s research, we became concerned that the name of this brilliant researcher and his life’s work had nearly been deleted from the internet. ", "His reputation was being disparaged, and his message of warning and hope was being distorted and buried without a tombstone. ", "This book summarizes his teaching and is a must-read for everyone who wants to learn the “other-side” of the vaccine debate that the mainstream media routinely censors." ]

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[ "'use strict'\n\n//{{{ Imports\nvar util = require('util')\n , path = require('path')\n , events = require('events')\n , cocos = require('cocos2d')\n , nodes = cocos.nodes\n\nvar Director = cocos.", "Director\n , Scene = nodes.", "Scene\n//}}} Imports\n\n/**\n * @class\n * Runs a set of tests\n */\nfunction TestSuite () {\n TestSuite.superclass.constructor.call(this)\n this.tests = []\n}\n\nTestSuite.inherit(Object, /** @lends TestSuite# */ {\n /**\n * Array of tests to run\n * @type TestCase[]\n */\n tests: null\n\n /**\n * Index of current test\n * @type Integer\n */\n , currentTest: 0\n\n , getTest: function () {\n return new this.tests[this.currentTest]\n }\n\n /**\n * Start running the tests\n */\n , run: function () {\n var test = this.getTest()\n\n events.addListener(test, 'next', this.next.bind(this))\n events.addListener(test, 'back', this.previous.bind(this))\n events.addListener(test, 'restart', this.restart.bind(this))\n\n\n var director = Director.sharedDirector\n , scene = new Scene()\n\n scene.addChild(test)\n director.replaceScene(scene)\n\n return test\n }\n\n /**\n * Run the next test. ", "Loops back to the first when reaching the end.", "\n */\n , next: function () {\n this.currentTest++\n this.currentTest = this.currentTest % this.tests.length\n\n this.run()\n }\n\n /**\n * Run the previous test. ", "Loops back to the end when reaching the beginning.", "\n */\n , previous: function () {\n this.currentTest--\n if (this.currentTest < 0) {\n this.currentTest += this.tests.length\n }\n\n this.run()\n }\n\n /**\n * Restart the current test.", "\n */\n , restart: function () {\n this.run()\n }\n})\n\nmodule.exports = TestSuite\n\n// vim:et:st=4:fdm=marker:fdl=0:fdc=1\n" ]

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[ "Stomatodexia\n\nStomatodexia is a genus of parasitic flies in the family Tachinidae. ", "There are about six described species in Stomatodexia.", "\n\nSpecies\nThese six species belong to the genus Stomatodexia:\n Stomatodexia cothurnata (Wiedemann, 1830)\n Stomatodexia longitarsis (Macquart, 1843)\n Stomatodexia obscura (Walker, 1853)\n Stomatodexia quadrimaculata (Walker, 1853)\n Stomatodexia similigena Wulp, 1891\n Stomatodexia tinctisquamae Curran, 1926\n\nReferences\n\nFurther reading\n\n \n \n \n \n\nCategory:Flies\nCategory:Articles created by Qbugbot" ]

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[ "Glenn Richardson\n\nJames Glenn Richardson (commonly known as Glenn Richardson) (born January 12, 1960) is the former Speaker of the Georgia House of Representatives, in the state of Georgia. ", "In late 2009, following the announcement of a suicide attempt and revelations of marital strife involving an affair with a lobbyist, Richardson announced that he would resign as Speaker, and as a member of the House, effective Jan. 1, 2010.", "\n\nBiography\n\nEarly life\nRichardson was born on January 12, 1960 in Douglas County, Georgia, where he graduated from Douglas County High School in 1978. ", "In 1981, Richardson earned a Bachelor of Arts in Political Science from Georgia State University and earned his Juris Doctor in 1984 as a member of the first graduating class from the Georgia State University College of Law.", "\n\nIn 1985, Richardson joined the firm of Vinson & Osborne and made partner two years later. ", "Now known as Talley, Richardson & Cable, he continues to practice with the same firm. ", "In 1989, he was appointed to serve as County Attorney for Paulding County and served in that position for 16 years. ", "In 2005, he was appointed Special Projects and Litigation Attorney for Paulding County.", "\n\nPolitical career\nIn 1996, Richardson became the first Republican from Paulding County elected to the Georgia House of Representatives since Robert McWhorter in 1870 during Reconstruction. ", "In 2003, Governor Sonny Perdue hand-picked Richardson to serve as the Administration Floor Leader in the House and in November 2003, the Republican Caucus chose Richardson to serve as Minority Leader. ", " He was elected to his sixth consecutive term in 2006 to represent House District 19. ", "As a result of his role in securing Republican control of the House for the first time since Reconstruction, in 2005 he was chosen by his colleagues to serve as the first Republican Speaker of the House in over 130 years.", "\n\nThe Republican Party of Georgia named him the 2003 Legislator of the Year. ", "He was the recipient of the 2003 American Cancer Society Capitol Dome Award. ", "The March of Dimes recognized him \"for providing extraordinary leadership in passing legislation to reduce the number of premature births in Georgia.\" ", "Insider Advantage's James Magazine named him the 2005 \"Man of the Year.\" ", "He was also the recipient of the prestigious 2005 Wayne Shackelford Award from the Association of County Commissioners of Georgia and the James A. Coffman Award by the Medical Association of Georgia.", "\n\nIn 2006, Richardson became chairman of the Southern Legislative Conference (SLC) and the Republican Legislative Campaign Committee (RLCC). ", " As chairman of the SLC, he works with other southern states to foster greater intergovernmental cooperation and communication to address regional issues. ", "Richardson was re-elected Speaker of the Georgia House on January 8, 2007, with the support of several Democrats.", "\n\nOn September 12, 2012, Richardson announced he would be running for office in the Georgia State Senate District 30. ", "In the Republican primary, Richardson finished third in a field of four.", "\n\nLegislation \nRichardson was a major supporter of legislation in 2004 to pass a Constitutional Amendment to prohibit gay marriage. ", "In addition, Richardson is known for saying that legislation will not pass in the Georgia House unless it passes a four-prong test: it must shrink state government, cut taxes, encourage personal responsibility, or strengthen the state.", "\n\nRichardson's accomplishments in the 2007 legislative session include attempting to ensure that PeachCare, the State's health insurance program for children, remains solvent. ", "When asked about cuts to PeachCare, Richardson said that \"Peachcare and health care is not a constitutional right.\" ", "In addition, Richardson has proposed increasing the sales tax in Georgia from 4% to 5.75%. ", "This increase in the sales tax is meant to replace property taxes in Georgia.", "\n\nControversies\n\nAffair with lobbyist\nThe Atlanta Journal-Constitution reported that the Democratic Party of Georgia had filed an ethics complaint about Richardson based on an allegation that Richardson engaged in an \"inappropriate\" and \"personal\" relationship with a female lobbyist from Atlanta Gas Light in 2006, while the company was seeking legislative approval for a $300 million pipeline across the state. ", "Richardson only responded by stating that \"(t)he bad news for those that manufactured, dispensed and stirred unreasonably the poison is that I survived. ", "And I'm looking for those that manufactured that poison.\" ", " Despite the controversy, Richardson was re-elected Speaker of the Georgia House in January 2007.", "\n\nSpeedy divorce\nOn February 11, 2008, the Atlanta Journal-Constitution reported that \"House Speaker Glenn Richardson and his wife filed for divorce, completed the dissolution of their marriage and got court records of the proceedings sealed.\" ", "According to the AJC, this was done by Paulding Superior Court Judge James Osborne, a former law partner of Richardson's, who then sealed the records in apparent violation of the rules that govern the state's superior courts. ", "State law requires a 30-day waiting period before uncontested divorces become final, but a judge may grant an immediate divorce after finding circumstances such as spousal abuse, incurable mental illness or adultery. ", "The handling of the divorce raised questions as to whether the speaker of the state House received preferential treatment from Judge James Osborne, who was not initially assigned the case but signed the order placing it under wraps.", "The judge, once the speaker's law partner, is now weighing a request to unseal the divorce file. ", "He said that he has treated the Richardsons' request like any other. ", "First Amendment advocates note there is a strong presumption to access to proceedings and records to ensure courts are treating both parties to a dispute fairly.", "\"Public access protects litigants both present and future, because justice faces its gravest threat when courts dispense it secretly\", the Georgia Supreme Court said in 1988, ordering court records unsealed in a paternity suit against a Roman Catholic priest.", "\n(Atlanta Journal-Constitution July 13, 2008)\n\nSee also\n List of Speakers of the Georgia House of Representatives\n\nReferences\n\n|-\n\n|-\n\n|-\n\nCategory:Living people\nCategory:Members of the Georgia House of Representatives\nCategory:Georgia (U.S. state) lawyers\nCategory:Georgia State University College of Law alumni\nCategory:Georgia (U.S. state) Republicans\nCategory:21st-century American politicians\nCategory:Speakers of the Georgia House of Representatives\nCategory:1960 births" ]

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[ "Justice News\n\nBrevard County Man Sentenced To 50 Years In Federal Prison For Production Of Child Pornography\n\nOrlando, Florida – U.S. District Judge Roy B. Dalton, Jr. has sentenced Roberto Oquendo (38, Brevard County) to 50 years in federal prison for conspiracy to produce child pornography and production of child pornography. ", "The court also ordered Oquendo to forfeit two cellphones that he had used in connection with the offense.", "\n\nOquendo had pleaded guilty on January 30, 2019.", "\n\nAccording to the plea agreement, on September 15, 2016, Oquendo was the subject of a traffic stop. ", "During the traffic stop, deputies from the Brevard County Sheriff’s Office received a tip that Oquendo possibly had child pornography in his possession. ", "As a result, task force agents with the FBI and Homeland Security Investigations interviewed Oquendo. ", "During the interview, Oquendo admitted that, for several years, he had used a cellphone to search for and view child pornography. ", "Oquendo also disclosed that while residing in Brevard County, he had used a cellphone to take explicit photos of two female children in his custody.", "\n\nFurther investigation led to the seizure of several items of computer media from a place in Brevard County where Oquendo had resided. ", "The computer media contained thousands of images and videos of the two young girls, who were toddlers at the time, as well as other children engaged in sexually explicit conduct. ", "Oquendo’s collection of child pornography contains depictions of infants, toddlers, and young children engaged in sexual activity, including sadistic conduct.", "\n\nIn addition, Oquendo had used a social media application to engage in live chats with a co-conspirator, Rose Beth Litzky, during which Litzky engaged two female children in sexually explicit conduct for Oquendo’s viewing and sexual gratification. ", "At the time, Oquendo resided in Virginia, and Litzky resided in Florida. ", "Oquendo created screenshots of the visual depictions involving the two girls.", "\n\nA federal jury previously found Litzky guilty of conspiracy to produce child pornography, production of child pornography, and possession of child pornography. ", "Her sentencing hearing is set for October 15, 2019.", "\n\nThis case was brought as part of Project Safe Childhood, a nationwide initiative launched in May 2006 by the Department of Justice to combat the growing epidemic of child sexual exploitation and abuse. ", "Led by United States Attorneys’ Offices and the Criminal Division’s Child Exploitation and Obscenity Section (CEOS), Project Safe Childhood marshals federal, state, and local resources to locate, apprehend, and prosecute individuals who sexually exploit children, and to identify and rescue victims. ", "For more information about Project Safe Childhood, please visit www.justice.gov/psc.", "\n\nThis case was investigated by the Federal Bureau of Investigations, Homeland Security Investigations, and the Brevard County Sheriff’s Office. ", "It is being prosecuted by Assistant United States Attorney Ilianys Rivera Miranda." ]

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[ "Knowledge of, and beliefs about, access to screening facilities and cervical cancer screening behaviors among low-income women in New Jersey.", "\nRacial/ethnic disparities in cancer outcomes have been well documented. ", "Access to Pap testing may account for some of the variation in the racial and socioeconomic differences in cervical cancer outcomes. ", "Literature exploring perceived access to care as it relates to women of color and low-income women is lacking. ", "The goal of the study was to evaluate and characterize the relationship between what respondents believe about access to free/low-cost screening facilities and screening behaviors among low-income women in New Jersey. ", "We used multivariate logistic regression to investigate belief about access to affordable screening on cancer screening behaviors using data from a cross-sectional study of low-income women in New Jersey (n = 430). ", "Having had a Pap test in the past 3 years was inversely associated with age (OR 0.94, 95% CI 0.92-0.97) and was positively associated with having had insurance in the previous 2 years (OR 32.48. ", "95% CI 1.04-5.91), higher perceived risk of cervical cancer (OR 2.59, 95% CI 1.29-5.66), and knowing where to go to get a check-up that includes a cancer test (OR 1.97, 95% CI 1.11-3.49). ", "These results suggest that insurance status continues to be a predictor of screening behavior but also that perceived risk awareness of where to go to get cancer screenings in general may influence the likelihood of utilizing screening, which can be important in developing targeted prevention strategies." ]

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[ "Q:\n\nHow to add noise only to a part of the image in Matlab?", "\n\nI know how to add noise to the image using the 'imnoise' function, but I was not getting how to add noise patch only to a part of the image, leaving the rest of the image untouched.", "\nCould you please help?", "\n\nA:\n\nYou can add noise \"in-place\" without assigning an addition variable, for example like that:\n% Test image.", "\nimg = uint8(repmat([zeros(20), 255*ones(20); 255*ones(20) zeros(20)], 5, 5));\n\n% Show test image before noise.", "\nfigure(1);\nimshow(img);\n\n% Add noise only to part of image.", "\nimg(20:60, 20:80) = imnoise(img(20:60, 20:80), 'gaussian');\n\n% Show test image after noise.", "\nfigure(2);\nimshow(img);\n\n" ]

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[ "(AP) -- AT&T is countering the U.S. government's attempt to block its $39 billion acquisition of T-Mobile by depicting the deal as a way to provide consumers with better cell phone service at lower prices.", "\n\nThe argument, submitted in a Friday court filing, is AT&T Inc.'s first legal response to a lawsuit that the Department of Justice filed last week in an effort to ensure T-Mobile remains independent. ", "AT&T's 25-page document echoed the company's previous contention that buying rival T-Mobile will enable it to expand its mobile communications network so there are fewer dropped connections in a world where constant online access is becoming the norm.", "\n\nThe Justice Department believes there wouldn't be enough competition if AT&T devours T-Mobile, creating a void that would increase prices and reduce the incentive to develop new technology.", "\n\nAT&T's lawyers contend that the Justice Department's analysis reflects a misunderstanding of the market. ", "They say T-Mobile, the fourth largest cell phone carrier with 33.6 million customers, isn't a significant competitive threat to AT&T, the No. ", "2 carrier with nearly 100 million customers. ", "T-Mobile has been losing market share in recent years, a trend that AT&T argues will discourage its German parent, Deutsche Telekom, from investing to improve its own wireless network.", "\n\nIn contrast, AT&T says it spent more than $30 billion in network upgrades from 2008 through 2010, yet still can't keep up with customers' growing demand to transfer data over phones and other wireless devices, according to the court documents. ", "But if it can snap up T-Mobile, AT&T believes the added capacity will put it in a better position to deliver better services. ", "AT&T already has pledged to invest at least $8 billion and transfer 5,000 jobs currently in overseas call centers back to the U.S. if the T-Mobile purchase goes through.", "\n\nThe court filing also seeks to counter the Justice Department's theory that the U.S. cell phone market would be dominated by just three carriers - AT&T, Verizon Wireless and Sprint Nextel Corp, if T-Mobile disappears from the market. ", "AT&T's filing cites \"innovative upstarts\" MetroPCS and Leap/Cricket and regional carriers such as US Cellular and Cellular South as viable alternatives for most consumers.", "\n\n\"The (Justice) Department does not and cannot explain how, in the face of all these aggressive rivals, the combined AT&T/T-Mobile will have any ability or incentive to restrict output, raise prices, or slow innovation,\" the AT&T's lawyers wrote.", "\n\nIt's unusual for the Justice Department to challenge a proposed acquisition in court. ", "Most companies back out of deals to avoid tangling with the government. ", "But AT&T has a huge incentive to fight: It will have to pay a $3 billion termination fee if its agreement with T-Mobile unravels.", "\n\nThe first hearing in the case is set for Sept. 21 in Washington before U.S. District Court Judge Ellen Huvelle.", "\n\nAT&T, which is based in Dallas, is seeking a quick resolution to the case.", "\n\n©2011 The Associated Press. ", "All rights reserved. ", "This material may not be published, broadcast, rewritten or redistributed." ]

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[ "1 of 4 View Caption\n\nA Syrian refugee holds her daughter while standing outside her tent during a rainfall at an informal tented settlement near the Sy A Syrian refugee carries her child as she heads back to her tent through muddy slippery ground during a rainfall at an informal te Mormon author Neylan McBaine Credit: Scott Lunt A Syrian refugee boy stands at an informal tented settlement near the Syrian border on the outskirts of Mafraq, Jordan, Tuesday, M" ]

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[ "Thorarinn G. Petursson\n\nThorarinn G. Petursson (born July 2, 1966), is an Icelandic economist. ", "Since September 15, 2009, he is the Chief Economist of the Central Bank of Iceland.", "\n\nEducation\nPetursson received his PhD degree in economics from Aarhus University, Denmark, in 1998. ", "He has the M.S. degree in economics from the University of Essex in the UK in 1992 and a Cand. ", "Oecon. ", "degree in economics from the University of Iceland in 1991.", "\n\nCareer\nPrior to his appointment as Chief Economist, Petursson was Acting Chief Economist of the Bank from the end of February 2009 and became at the same time a member of the Bank's Monetary Policy Committee. ", "He began his career at the Bank as an economist at the Economics Department in January 1994, but has served as the Deputy Chief Economist and the Head of Research and Forecasting at the Bank from June 2004. ", "He has a long career as a university lecturer in economics.", "\n\nBibliography\nHe has published numerous articles in domestic and international academic journals on monetary policy and macroeconomics. ", " From 2001 to 2006, he led an effort to develop the Central Banks‘ new Quarterly Macroeconomic Model (QMM) of the Icelandic economy.", "\n\nReferences\n\nExternal links\nCentral Bank of Iceland's website\n\nThorarinn G. Petursson\nCategory:1966 births\nCategory:Living people\nCategory:Aarhus University alumni\nCategory:Alumni of the University of Essex\nThorarinn G. Petursson" ]

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[ "\"When relatives and villagers saw the man collapsed at the well's bottom, they subsequently got into the well to help him and they all also fainted and died in the well,\" Capt. ", "Muy Norn told Koh Santepheap Daily." ]

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[ "Comments\n\nGreat fight! ", "The rumors about Yarde having a weak chin were definitely not true, he took a lot of damage from Kovalev in this fight. ", "Yarde should have taken the step aside money, he definitely has the ability as a contender but he didn't have the experience or stamina to go deep in the fight versus Kovalev. ", "Kovalev is in the final stage of his career but his jab looked great in this fight. ", "Credit to Kovalev for digging deep after nearly being stopped given his reputation as a front runner. ", "His first knockout after eight rounds. ", "Looking forward to Canelo vs. Kovalev, hopefully Kovalev has a good camp with a quick turn around and we see a good fight.", "\n\nYou say that like it's a done deal, would be a very interesting fight, PPV for sure, but it's not guaranteed is it? ", "I would have said Canelo should stay at 160 and fight Andrade in unification fight, but I suppose money talks.", "\n\nSeems like it is more or less the formalities of getting the details done. ", "The big problem before was putting up enough money with Yarde's step aside money and Kovalev's purse, but that isn't an issue anymore. ", "Both sides want the fight and have something to gain from it. ", "It will be DAZN in the US if it happens, not PPV. ", "I don't know what the arrangement would be in the UK\n\nThere have been fights we've had to pay for over here that have been free in the US, but if it is just on DAZN, and not PPV, then I would imagine just like the card in Mexico tonight, Sky would cover the fight. ", "Both fighters have good reason to want the fight, because ifyiu are either fighter, you must be very confident you win.", "\n\nHave Canelo's past few DAZN fights been PPV in the UK? ", "I think that would be a good judge of if it will be PPV in the UK. ", "The fight makes a lot more sense for Canelo right now than the Andrade fight does. ", "Kovalev is a bigger name than Andrade, it boosts Canelo's legacy further, and Kovalev has an action style. ", "For Kovalev, it's either this or wait when he is aging to try to get the Gvozdyk vs. Beterbiev winner which wouldn't pay as much, so why not go for it versus Canelo?", "\n\nNo, only the Golovkin fights, but Jacobs, Fielding etc aren't the big money fights that Kovalev would be, that's why I assumed it would be PPV. ", "I agree it makes sense for both fighters, Andrade may or may not be higher risk because he is a lot smaller and less dangerous but is younger, fresher, may or may not be a better boxer, but although he has a belt, so does Kovalev, it is the chance to win a belt in another weight, build his legacy like you said, and make more money, so Kovalev is higher reward. ", "I wonder if Andrade will fight the winner of GGG vs Derevyanchenko, what better options are there? ", "Charlo is with PBC, Saunders is at 168 for now, Munguia isn't moving up just yet, it would be a unification fight, in house as well.", "\n\nI think if Canelo beats Kovalev and Golovkin beats Derevyanchenko we'll get the third match between Canelo and Golovkin, there will be enough pressure for it. ", "I think Canelo would be more willing to fight Andrade than Golovkin but I think Andrade will have to sit on the shelf or fight someone like Saunders because he's not a desirable opponent.", "\n\nDoes Canelo want Golovkin again though? ", "And will he gain lean muscle for Kovalev? ", "How will he do the weight in terms of moving up and then coming back down?, ", "because would he go down to 168 and fight Smith or Saunders? ", "I know Andrade is relatively low reward, but he has a belt, and sometimes fighters take the risky option that isn't necessarily high reward, for their pride, less often than not, but it's still an option. ", "If he moves up, Munguia might fight Andrade, if Golovkin has a belt, that makes more sense, still, what if the IBF have ordered another fight and the Andrade fight is his best option? ", "Hopefully Andrade won't be another Russell, Stevenson, where he defends his belts, but isn't in many big fights.", "\n\nI don't think he wants to fight Golovkin again but I think they'll be able to make it worth his while. ", "I think we've gone over this before but I don't think Canelo will try to bulk up versus Kovalev. ", "If it happens when it is supposed to it will only be in three months. ", "Not enough to gain significant mass. ", "Whether Canelo fights Andrade or not I don't know, but I can tell you it won't be Andrade vs. Munguia. ", "The moves Zanfer has made with Munguia's career have shown they want to cash him out on Canelo or Golovkin rather than try to build him up. ", "I don't think the IBF will order anything given Derevyanchenko was supposed to be the mandatory, but you never know with the IBF. ", "What you are saying is theoretically possible. ", "I think Andrade will get the big fight later on versus Canelo, but he doesn't do himself any favors with his style and name value.", "\n\nPossible, but it is personal, which is bad for negotiations, still, Canelo might take the fight for enough money, knowing the biggest difference is the age aspect which is well in his favour. ", "Yes we dicussed that, and I agree, he won't try to match Kovalev for size, and not just because he doesn't have enough time, but he might gain some mass, and making 160 wouldn't be as easy, not saying he won't come back down, but it might be a struggle to get back down straight after the Kovalev fight, and he has other options, because there are fights for him at 168. ", "Such as? ", "He fights often, Munguia, and given that making 154 is obviously touch and go, why is he still at 154 if his handlers want to cash him out against Canelo or GGG? ", "And logically, why would a 22 year old fighter need to cash out? ", "He isn't like Andrade style wise, he is an entertaining fighter, he could be built up and be in a lot of big fights in the future? ", "I'd say it is old fighters like Joyce who might want to cash out, because they are under time pressure. ", "Andrade's style is his style, we will never agree on Andrade as a fighter, I agree he could be more aggressive, but fighters should listen to their trainers, and although I understand it's important, fighters just can't think about money and being marketable when they are in the ring and being tested, they have to listen to what their trainer tells them.", "\n\nPersonally, if I were Canelo I wouldn't bother versus Smith. ", "He is kind of like the Danny Jacobs of Super Middleweight, really big and has skills but a good part of his success is his size. ", "Eventually, he will have issues with the weight and will have to move up at 6'3. ", "I would like to see Bivol vs. Smith for Smith's title if Bivol signs with Matchroom. ", "Zanfer has tried to match Munguia against Canelo and Golovkin for their upcoming bouts, if he fights one of them it is a huge payday, worth more than him making many title defenses versus low-level opponents or grinding as a contender at Middleweight. ", "Look at the matchmaking Munguia has had recently and he nearly lost versus Hogan at home. ", "They are trying to protect his zero, having him be a title raises his profile though. ", "He can keep going on after Canelo or Golovkin, but if they wanted to build him up they would have given him more challenges after Liam Smith, but they didn't. ", "Andrade should be more aggressive, knockouts sell and everyone knows that. ", "If he was fighting top-level opposition and winning with his style that would be one thing, but coasting versus lower level guys is entirely uninteresting.", "\n\nI wouldn't either, but some fighters have that pride, they want to keep taking the hard fights. ", "Smith and Jacobs are nowhere near as relient on size as Hurd, Easter. ", "Smith is a defensive puncher, counter puncher, it is harder to get rid of light heavyweights than super middleweights, but when it comes to the boxing IQ aspect, it's nothing to do with size, Jacobs and Smith have proven that their skills are much bigger factors than their size. ", "I get that, I am not saying 10 fights against Hogans and Alloteys is more money than one fight against Golovkin or Canelo, I was just saying, as he keeps fighting, improving, these fights can be built up, and he has a better shot of winning, and one thing I don't buy is that it's now or never, I understand Golovkin is old and Canelo has a lot of weight options, and a few years down the line those fights might not be options, but by then there will be other fighters who are draws, who are big money opponents.", "\n\nCorrect me if I'm wrong, you are saying Munguia is what he is, is not that good, not got a lot of improvement ahead of him, taking more time to keep winning isn't going to improve him as a fighter or build his reputation, so they might as well just cash him out now? ", "That makes sense, but I think Munguia, although he isn't the beast he was made to look like against Ali, is better than we saw if him in his last 2 fights, I think he fights too often and is killing himself to make a weight he doesn't need to make, he will improve, but it is more than likely a Canelo or Golovkin payday wouldn't ruin his career, so I suppose his handlers aren't putting his career on the line.", "\n\nTwo questions, if Munguia is so protected, why does he fight so often? ", "And if they are trying to put him in against Canelo and Golovkin, why is he still at 154? ", "He admitted he was drained against Hogan.", "\n\nThere isn't much more we can say on Andrade, agree to disagree, but one thing I will say is that I am talking like a trainer and you are talking like a promoter, do you agree on that?", "\n\nI agree that they aren't as reliant as Hurd and Easter, but having a large reach, height, and weight advantage are noteworthy for Jacobs and Smith. ", "They both can punch down on guys from range. ", "Right, and I agree that if they wanted to build him they should do what you are saying. ", "I wouldn't say it is now or never either but it is Zanfer, Munguia's promoter, that is making it a now or never.", "\n\nI think Munguia can improve if they built him up, but Zanfer, his promoter, wants to cash him out on Canelo/Golovkin while he is undefeated. ", "I don't know what they will do with him after that, but I'm sure he won't just retire.", "\n\nIt is possible to fight often and be protected, I would say Farmer has been protected fighting low level guys as well, for example. ", "I have no idea why he is taking this last fight at Super Welterweight, it makes no sense other than trying to get a final defense out of it.", "\n\nI agree with what you are saying, if you are Andrade's trainer you'd just want to focus on winning and maximizing his potential to win, which is what you have been suggesting he does. ", "As you said though, that doesn't line up with what will get him the big paydays the quickest." ]

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[ "CIA Director Mike Pompeo, who once cheered on WikiLeaks as it sunk the Hillary Clinton campaign, now says that Julian Assange's website is a conduit for stolen documents and should be deemed a \"hostile intelligence service.\"", "\n\n\"It is time to call out WikiLeaks for what it really is, a non-state hostile intelligence service often abetted by state actors like Russia,\" Pompeo said in a speech at the Center for Strategic and International Studies in Washington.", "\n\nAdvertisement:\n\nHe also called Assange a \"fraud\" and a \"coward\" before confirming that Russia's GRU military intelligence serviced used Wikileaks to publish the hacked emails from the Democratic National Committee during the election.", "\n\nIn July, when WikiLeaks dumped emails showing potential bias toward Clinton, the establishment front-runner, Pompeo, than a Republican member of the House of Representatives, alerted his Twitter followers of the new information.", "\n\n\"Need further proof that the fix was in from Pres. ", "Obama on down? ", "BUSTED: 19,252 Emails from DNC Leaked by WikiLeaks,\" Pompeo wrote in the now-deleted tweet.", "\n\nAdvertisement:\n\nBut now the CIA director is denouncing the organization, which, just last month, distributed secret documents pertaining to the CIA and NSA's cyber capabilities.", "\n\nTwo days before Pompeo's first public speech, Assange penned a column in The Washington Post trying to explain his vision of WikiLeaks and its mission.", "\n\n\"Vested interests deflect from the facts that WikiLeaks publishes by demonizing its brave staff and me,\" Assange wrote. \"", "We are mischaracterized as America-hating servants to hostile foreign powers. ", "But in fact I harbor an overwhelming admiration for both America and the idea of America. ", "WikiLeaks’ sole interest is expressing constitutionally protected truths, which I remain convinced is the cornerstone of the United States’ remarkable liberty, success and greatness.\"", "\n\nAdvertisement:\n\nhttp://media.salon.com/2017/04/2df8b55cb2ec374d50bcebeda1aa3ead.mp4" ]

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[ "UBS puts up decent PR show\n\nLast week I had coffee with a PR executive who helped manage Thursday’s UBS shareholders’ meeting in Lucerne. ", "We met at Sprüngli on the Paradeplatz, the branch of the posh chocolate, cake and coffee shop favoured by wives of Zurich gnomes. ", "He gave me an insider’s account of his work to restore trust in the Swiss icon.", "\n\nHe said the bank’s strategy was to rebuild trust in its competence piece by piece, issue by issue. ", "He described how UBS was managing a series of crises ranging from toxic debt, excessive executive bonuses, plunging share price and accusations of facilitating tax evasion and abusing banking secrecy rules in the US.", "\n\nThis was the fourth shareholders’ meeting of 2008. ", "Besides ratifying a government bailout, he told me how Thursday’s meeting was about communicating that UBS’s culture is changing. ", "It was about saying sorry again, and trashing the image of arrogance. ", "It was also about reassuring stakeholders that investments in UBS were safe and about setting out the new course for the bank.", "\n\nHe stated that UBS was developing a formula for managing executive bonuses that the rest of the banking industry was sure to emulate. ", "UBS chairman Peter Kurer certainly tackled the controversial bonus question head-on. ", "He renounced his own bonus entitlement this year and announced:\n\nWe want to give shareholders a greater say in decisions on compensation. ", "Starting with the general meeting in 2009, we will make our decisions on the principles and guidelines for compensation within the framework of a consultative vote.", "\n\nThis time around the sceptical audience was more subdued than at the other shareholder meetings. ", "News that former UBS chairman Marcel Ospel and two colleagues had renounced their right to collect CHF33 million in bonus won some applause. ", "But chairman Peter Kurer’s enthusiasm to clawback the bonuses of others won still more. ", "However most of Peter Kurer’s speech was heard in silence.", "\n\nMy friend explained that on some issues the bank will just have to take the blows. ", "For instance, when Peter Kurer praised board member Rainer-Marc Frey for his contribution to the bank, there were whistles of derision – this being the man who sold all his UBS shares before the worst of the you-know-what hit the fan. ", "There was no news on the level of recent withdrawals from the bank, which fueled speculation that yet more taxpayer-cash would be required soon.", "\n\nBut Peter Kurer was certainly a contrite CEO. ", "He said:\n\nWe have admitted to our mistakes several times in recent months – and have also apologized for them.", "\n\nSome letters have accused us of arrogance and say that we need to get off of our high horse.", "This, too, may have had an element of truth in it in the past – at all levels.", "\n\nBut let me reassure you, ladies and gentlemen, there is no room for arrogance in the UBS of today – nor will there be in the UBS of tomorrow.", "\n\nPeter Kurer, it seems, values the role of PR in ensuring UBS’s recovery. ", "He even praised the around the clock work of his communications department to shareholders in Lucerne. ", "My friend had nothing but praise for his chairman’s commitment to communication.", "\n\nThey would both agree, I think, with what Leslie Gaines-Ross says in her timely bookCorporate Reputation, 12 Steps to Safeguarding and Recovering Reputation, recovering a lost reputation is a marathon task, not a sprint." ]

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[ "New Pokemon Go Hack, Update Reveal And also Pokemon Go Plus Make use of.", "\n\nPokecoins offer you a HUGE advantage over other fitness instructors since you could get as many incenses as you wish and as a result will not even need to leave your house! ", "Acquired this for my child as a followup approximately another hack book, due to the fact that he and also his pals are obsessed with Pokemon. ", "Currently you could erase the tutu application if you wish to. ", "Appreciate the hacked variation of Pokemon Go on Android without origin. ", "Besides that, this gadget can execute basic feature such as catching a Pokemon by pressing its button. ", "Hope you guys appreciate this pokemon go hack for the 0.35.0 upgrade to use joystick, faucet to stroll and teleport! ", "Simply release the Pokemon Go game after downloading and also you should be able to alter GPS place (GPS-spoofing) and also a joystick will show up so you can quickly play the video game without leaving your home.", "\n\nExact same thing below, I began using the service, I got like 3 pokestops and captured a magikarp, then suddenly no pokestops job as well as every pokemon breaks put as well as runs right away. ", "If you uncover any type of Pokemon Go Hack pests, offer us a buzz to make sure that you can correct it asap kindly. ", "Thankfully, for some of the gamers, preferred mobile video gaming site has actually developed rip off software program which they guarantees to be 100% trusted and also undetectable from the Pokemon Go web servers. ", "When u pick with Joystick for Pokémon Go, I am additionally using Redmi Keep in mind 4G with MIUI 8 on it as well as fly general practitioners does not work provides a mistake. ", "Doing this makes an environment-friendly ring show up on the pokemon and also it becomes a definite hit. ", "Currently, go back to settings, and go to Programmer Options, there will certainly be many choices yet you have to disable the Mock Place choice. ", "Our Pokemon Go Hack has been in development for months, also before the launch of Pokemon Go.", "\n\nStep 7: Â Select any of the web browsers or mount directly from the browser which is built-in in TuTuApp. ", "Once it loads on the 2nd tab, the pokemon from the fitness instructor you are fighting on the first tab will certainly be where the wild pokemon was in tab two. ", "Once you have Cydia impactor, go to this, this or this web link and download and install the hacked IPA data of Pokemon enter your Computer system. ", "If you are the owner of an Android device, either a mobile phone or tablet computer, as well as intend to obtain entailed with the most up to date customized Pokemon experience, then you can follow our previous overview on the subject.", "\n\nChief amongst the changes that this customized variation of Pokemon Go gives the table is the ability to walk around making use of absolutely nothing more than a joystick. ", "Examine some reviews clash of clans hack the website you are using, or bothering with using, then go ahead as well as play should you want to. ", "Given that the TuTuApp site remains in Chinese, simply click Android photo and download the APK. ", "Pokemon Go has come to be a joke and also it”s due to the fact that individuals that are doing this (unfaithful) are a joke themselves.", "\n\nOur Pokemon GO money hack is 100% risk-free and also here is why, first of all we never need your password or any type of login information, the only piece of information we need from you is your username so we understand where to send the Poke Coins. ", "Prior to really making use of the tool or downloading and install online, the gamers ought to be assured that nothing harm will certainly take place to their expensive Android or iOS tool. ", "For Pokemon Go Pokecoins HACK Players around the world, we have some excellent news to reveal.", "\n\nPokemon Go is an online game where we should accumulate the various other characters from the game. ", "Jailbreak users, keep in mind: This version calls for the current 0.61.0 Pokemon Go application because of extra modifications from Niantic. ", "Before relocating in the direction of the real subject; all readers need to be understanding that jail break or root detection is there in Pokemon Go so before going additionally in advance in this message the viewers should follow the below pointed out steps to hide their prison break or origin from the game. ", "My mobile was rooted, even if of this I unrooted my device, still I am not able to play the game, I utilized to play on 0.35 variation, and now its requesting for upgrade and also not allowing to play on old variation, anybody plz recommend me, I entirely eliminated my origin as well as still not able to use this variation. ", "Histoire/originalit é: Pokémon GO obtient une note de 10 sur 10 à cette section.", "\n\nText Widget\n\nThis is a text widget. ", "The Text Widget allows you to add text or HTML to your sidebar. ", "You can use a text widget to display text, links, images, HTML, or a combination of these. ", "Edit them in the Widget section of the Customizer." ]

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[ "Just in time for this week's release of, Curt Franklin and artist Chris Haley of Let's Be Friends Again have broken down the history of Marvel Comics' esteemed Sentinel of Liberty. ", "Read all about the fabled ascent of Steve Rogers from weakling to Nazi-smasher to Avengers Leader to head of S.H.I.E.L.D. after the jump." ]

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[ "Q:\n\nproblem with jscrollpane in java\n\nI add a jtextarea to my jscrollpane but I dont know why it's not working!", "\nwould u please help me?", "\nproblem is my text go down, but scroll not working in GUI.", "\nI upload all of the code because it easy for u to run it, just create a main file & set size it. ", "u can track problem for these Jscrollpane : jScrollPane1 ,jScrollPane16 jScrollPane4\nimport java.awt.*;", "\nimport java.awt.event.*;", "\n\nimport javax.swing.*;", "\n\nimport com.borland.jbcl.layout.*;", "\n\npublic class Frame1 extends JFrame {\n JPanel contentPane;\n BorderLayout borderLayout1 = new BorderLayout();\n JMenuBar jMenuBar1 = new JMenuBar();\n JMenu jMenuFile = new JMenu();\n JMenuItem jMenuFileExit = new JMenuItem();\n JMenu jMenuHelp = new JMenu();\n JMenuItem jMenuHelpAbout = new JMenuItem();\n JToolBar jToolBar = new JToolBar();\n JButton jButton1 = new JButton();\n JButton jButton2 = new JButton();\n JButton jButton3 = new JButton();\n ImageIcon image1 = new ImageIcon(masterproject.", "Frame1.class.getResource(\n \"openFile.png\"));\n ImageIcon image2 = new ImageIcon(masterproject.", "Frame1.class.getResource(\n \"closeFile.png\"));\n ImageIcon image3 = new ImageIcon(masterproject.", "Frame1.class.getResource(\n \"help.png\"));\n JLabel statusBar = new JLabel();\n JSplitPane jSplitPane1 = new JSplitPane();\n JPanel jPanel1 = new JPanel();\n JPanel jPanel2 = new JPanel();\n DynamicTree jtProjectList = new DynamicTree();\n BorderLayout borderLayout2 = new BorderLayout();\n JToolBar jToolBar1 = new JToolBar();\n JToolBar jToolBar2 = new JToolBar();\n JButton jbAdd = new JButton();\n JButton jbRemove = new JButton();\n int newNodeSuffix = 0;\n JToolBar jToolBar3 = new JToolBar();\n BorderLayout borderLayout3 = new BorderLayout();\n JPanel jpCore = new JPanel();\n JPanel jpExclusion = new JPanel();\n JLabel jLabel1 = new JLabel();\n JTextArea jTextArea1 = new JTextArea();\n BorderLayout borderLayout4 = new BorderLayout();\n JTable jTable1 = new JTable();\n JPanel jpScope = new JPanel();\n JLabel jLabel2 = new JLabel();\n JTextArea jTextArea2 = new JTextArea();\n JTable jTable2 = new JTable();\n BorderLayout borderLayout5 = new BorderLayout();\n VerticalFlowLayout verticalFlowLayout1 = new VerticalFlowLayout();\n JPanel jpDeliverable = new JPanel();\n JTable jTable3 = new JTable();\n JLabel jLabel3 = new JLabel();\n JTextArea jTextArea3 = new JTextArea();\n BorderLayout borderLayout6 = new BorderLayout();\n JPanel jpAcceptance = new JPanel();\n JPanel jpConstraints = new JPanel();\n JPanel jpAssumption = new JPanel();\n JPanel jpRisk = new JPanel();\n BorderLayout borderLayout7 = new BorderLayout();\n BorderLayout borderLayout8 = new BorderLayout();\n BorderLayout borderLayout9 = new BorderLayout();\n JTable jTable4 = new JTable();\n JTable jTable5 = new JTable();\n JTable jTable6 = new JTable();\n JLabel jLabel4 = new JLabel();\n JLabel jLabel5 = new JLabel();\n JLabel jLabel6 = new JLabel();\n JTextArea jTextArea4 = new JTextArea();\n JTextArea jTextArea5 = new JTextArea();\n JTextArea jTextArea6 = new JTextArea();\n JLabel jLabel7 = new JLabel();\n JTextArea jTextArea7 = new JTextArea();\n JTable jTable7 = new JTable();\n BorderLayout borderLayout10 = new BorderLayout();\n JScrollPane jScrollPane1 = new JScrollPane();\n JScrollPane jScrollPane2 = new JScrollPane();\n JScrollPane jScrollPane3 = new JScrollPane();\n JScrollPane jScrollPane4 = new JScrollPane();\n JScrollPane jScrollPane5 = new JScrollPane();\n JScrollPane jScrollPane6 = new JScrollPane();\n JScrollPane jScrollPane7 = new JScrollPane();\n JScrollPane jScrollPane8 = new JScrollPane();\n JScrollPane jScrollPane9 = new JScrollPane();\n JScrollPane jScrollPane10 = new JScrollPane();\n JScrollPane jScrollPane11 = new JScrollPane();\n JScrollPane jScrollPane12 = new JScrollPane();\n JScrollPane jScrollPane13 = new JScrollPane();\n JScrollPane jScrollPane14 = new JScrollPane();\n JScrollPane jScrollPane15 = new JScrollPane();\n JScrollPane jScrollPane16 = new JScrollPane();\n public Frame1() {\n try {\n setDefaultCloseOperation(EXIT_ON_CLOSE);\n jbInit();\n } catch (Exception exception) {\n exception.printStackTrace();\n }\n }\n\n /**\n * Component initialization.", "\n *\n * @throws java.lang.", "Exception\n */\n private void jbInit() throws Exception {\n contentPane = (JPanel) getContentPane();\n contentPane.setLayout(borderLayout1);\n this.setFont(new java.awt.", "Font(\"Tahoma\", Font.", "BOLD, 14));\n setSize(new Dimension(753, 483));\n setTitle(\"Master Project\");\n statusBar.setText(\" \");\n jMenuFile.setText(\"File\");\n jMenuFileExit.setText(\"Exit\");\n jMenuFileExit.addActionListener(new Frame1_jMenuFileExit_ActionAdapter(this));\n jMenuHelp.setText(\"Help\");\n jMenuHelpAbout.setText(\"About\");\n jMenuHelpAbout.addActionListener(new\n Frame1_jMenuHelpAbout_ActionAdapter(this));\n jPanel1.setLayout(borderLayout2);\n jbAdd.setMaximumSize(new Dimension(51, 25));\n jbAdd.setPreferredSize(new Dimension(51, 25));\n jbAdd.setText(\"Add\");\n jbAdd.addActionListener(new Frame1_jbAdd_actionAdapter(this));\n jbRemove.setText(\"Remove\");\n jbRemove.addActionListener(new Frame1_jbRemove_actionAdapter(this));\n contentPane.setMinimumSize(new Dimension(400, 600));\n contentPane.setPreferredSize(new Dimension(400, 600));\n jSplitPane1.setMinimumSize(new Dimension(200, 55));\n jSplitPane1.setPreferredSize(new Dimension(200, 355));\n jSplitPane1.setLastDividerLocation(300);\n jtProjectList.setPreferredSize(new Dimension(200, 324));\n jPanel2.setLayout(borderLayout3);\n jLabel1.setText(\"Exclusion :\");\n jTextArea1.setPreferredSize(new Dimension(280, 60));\n jTextArea1.setText(\"jTextArea1\");\n jTextArea1.setLineWrap(true);\n jpExclusion.setLayout(borderLayout4);\n jLabel2.setText(\"Scope :\");\n jTextArea2.setPreferredSize(new Dimension(280, 60));\n jTextArea2.setText(\"jTextArea1\");\n jTextArea2.setLineWrap(true);\n jpScope.setLayout(borderLayout5);\n jpCore.setLayout(verticalFlowLayout1);\n jLabel3.setText(\"Deliverable :\");\n jTextArea3.setPreferredSize(new Dimension(280, 60));\n jTextArea3.setText(\"jTextArea3\");\n jTextArea3.setLineWrap(true);\n jpDeliverable.setLayout(borderLayout6);\n jpAssumption.setLayout(borderLayout7);\n jpConstraints.setLayout(borderLayout8);\n jpAcceptance.setLayout(borderLayout9);\n jLabel4.setText(\"Assumption :\");\n jLabel5.setText(\"Constraints :\");\n jLabel6.setText(\"Acceptance :\");\n jTextArea4.setMinimumSize(new Dimension(80, 18));\n jTextArea4.setPreferredSize(new Dimension(280, 60));\n jTextArea4.setText(\"jTextArea4\");\n jTextArea4.setLineWrap(true);\n jTextArea5.setMinimumSize(new Dimension(80, 18));\n jTextArea5.setPreferredSize(new Dimension(280, 60));\n jTextArea5.setText(\"jTextArea5\");\n jTextArea5.setLineWrap(true);\n jTextArea6.setMinimumSize(new Dimension(80, 18));\n jTextArea6.setPreferredSize(new Dimension(280, 60));\n jTextArea6.setText(\"jTextArea6\");\n jTextArea6.setLineWrap(true);\n\n jpScope.setToolTipText(\"\");\n jLabel7.setText(\"Risk :\");\n jTextArea7.setPreferredSize(new Dimension(280, 60));\n jTextArea7.setText(\"jTextArea7\");\n jTextArea7.setLineWrap(true);\n jpRisk.setLayout(borderLayout10);\n jpRisk.setMinimumSize(new Dimension(280, 60));\n jScrollPane6.setPreferredSize(new Dimension(284, 44));\n jScrollPane16.setPreferredSize(new Dimension(284, 44));\n jScrollPane5.setPreferredSize(new Dimension(284, 44));\n jScrollPane7.setPreferredSize(new Dimension(284, 44));\n jScrollPane14.setPreferredSize(new Dimension(284, 44));\n jScrollPane12.setPreferredSize(new Dimension(284, 44));\n jScrollPane10.setPreferredSize(new Dimension(284, 44));\n jScrollPane3.setVerticalScrollBarPolicy(JScrollPane.", "\n VERTICAL_SCROLLBAR_ALWAYS);\n jScrollPane9.setVerticalScrollBarPolicy(JScrollPane.", "\n VERTICAL_SCROLLBAR_ALWAYS);\n jScrollPane11.setVerticalScrollBarPolicy(JScrollPane.", "\n VERTICAL_SCROLLBAR_ALWAYS);\n jScrollPane13.setVerticalScrollBarPolicy(JScrollPane.", "\n VERTICAL_SCROLLBAR_ALWAYS);\n jScrollPane8.setVerticalScrollBarPolicy(JScrollPane.", "\n VERTICAL_SCROLLBAR_ALWAYS);\n jScrollPane4.setVerticalScrollBarPolicy(JScrollPane.", "\n VERTICAL_SCROLLBAR_ALWAYS);\n jScrollPane15.setVerticalScrollBarPolicy(JScrollPane.", "\n VERTICAL_SCROLLBAR_ALWAYS);\n jScrollPane1.setVerticalScrollBarPolicy(JScrollPane.", "\n VERTICAL_SCROLLBAR_ALWAYS);\n jMenuBar1.add(jMenuFile);\n jMenuFile.add(jMenuFileExit);\n jMenuBar1.add(jMenuHelp);\n jMenuHelp.add(jMenuHelpAbout);\n setJMenuBar(jMenuBar1);\n jButton1.setIcon(image1);\n jButton1.setToolTipText(\"Open File\");\n jButton2.setIcon(image2);\n jButton2.setToolTipText(\"Close File\");\n jButton3.setIcon(image3);\n jButton3.setToolTipText(\"Help\");\n jToolBar.add(jButton1);\n jToolBar.add(jButton2);\n jToolBar.add(jButton3);\n contentPane.add(statusBar, BorderLayout.", "SOUTH);\n contentPane.add(jSplitPane1, java.awt.", "BorderLayout.", "CENTER);\n jSplitPane1.add(jPanel1, JSplitPane.", "LEFT);\n jSplitPane1.add(jPanel2, JSplitPane.", "RIGHT);\n jToolBar1.add(jtProjectList);\n jPanel1.add(jToolBar1, java.awt.", "BorderLayout.", "CENTER);\n jPanel1.add(jToolBar2, java.awt.", "BorderLayout.", "NORTH);\n jToolBar2.add(jbAdd);\n jToolBar2.add(jbRemove);\n jPanel2.add(jToolBar3, java.awt.", "BorderLayout.", "CENTER);\n jToolBar3.add(jScrollPane3);\n jScrollPane3.getViewport().add(jpCore);\n jpScope.add(jScrollPane1, java.awt.", "BorderLayout.", "CENTER);\n\n jScrollPane1.getViewport().add(jTextArea2);\n\n jScrollPane16.getViewport().add(jTable1);\n jScrollPane14.getViewport().add(jTable5);\n jScrollPane12.getViewport().add(jTable6);\n jScrollPane10.getViewport().add(jTable7);\n jScrollPane8.getViewport().add(jTextArea4);\n jScrollPane6.getViewport().add(jTable2);\n jScrollPane5.getViewport().add(jTable3);\n jScrollPane4.getViewport().add(jTextArea3);\n\n contentPane.add(jToolBar, java.awt.", "BorderLayout.", "NORTH);\n jpDeliverable.add(jScrollPane4, java.awt.", "BorderLayout.", "CENTER);\n jpDeliverable.add(jScrollPane5, java.awt.", "BorderLayout.", "SOUTH);\n jpDeliverable.add(jLabel3, java.awt.", "BorderLayout.", "NORTH);\n jpScope.add(jScrollPane6, java.awt.", "BorderLayout.", "SOUTH);\n jpScope.add(jLabel2, java.awt.", "BorderLayout.", "NORTH);\n jScrollPane7.getViewport().add(jTable4);\n jpAcceptance.add(jLabel6, java.awt.", "BorderLayout.", "NORTH);\n jScrollPane9.getViewport().add(jTextArea7);\n jpRisk.add(jScrollPane10, java.awt.", "BorderLayout.", "SOUTH);\n jpRisk.add(jScrollPane9, java.awt.", "BorderLayout.", "CENTER);\n jpRisk.add(jLabel7, java.awt.", "BorderLayout.", "NORTH);\n jScrollPane11.getViewport().add(jTextArea6);\n jpAssumption.add(jLabel4, java.awt.", "BorderLayout.", "NORTH);\n jpAssumption.add(jScrollPane12, java.awt.", "BorderLayout.", "SOUTH);\n jpAssumption.add(jScrollPane11, java.awt.", "BorderLayout.", "CENTER);\n jScrollPane13.getViewport().add(jTextArea5);\n jpConstraints.add(jLabel5, java.awt.", "BorderLayout.", "NORTH);\n jpConstraints.add(jScrollPane14, java.awt.", "BorderLayout.", "SOUTH);\n jpConstraints.add(jScrollPane13, java.awt.", "BorderLayout.", "CENTER);\n jScrollPane15.getViewport().add(jTextArea1);\n jpExclusion.add(jLabel1, java.awt.", "BorderLayout.", "NORTH);\n jpExclusion.add(jScrollPane16, java.awt.", "BorderLayout.", "SOUTH);\n jpExclusion.add(jScrollPane15, java.awt.", "BorderLayout.", "CENTER);\n\n jpAcceptance.add(jScrollPane8, java.awt.", "BorderLayout.", "CENTER);\n jpAcceptance.add(jScrollPane7, java.awt.", "BorderLayout.", "SOUTH);\n\n jpCore.add(jpScope, 0);\n jpCore.add(jpExclusion, 1);\n jpCore.add(jpDeliverable, 2);\n jpCore.add(jpAcceptance, 3);\n jpCore.add(jpConstraints, 4);\n jpCore.add(jpAssumption, 5);\n jpCore.add(jpRisk, 6);\n jSplitPane1.setDividerLocation(230);\n }\n\n /**\n * File | Exit action performed.", "\n *\n * @param actionEvent ActionEvent\n */\n void jMenuFileExit_actionPerformed(ActionEvent actionEvent) {\n System.exit(0);\n }\n\n /**\n * Help | About action performed.", "\n *\n * @param actionEvent ActionEvent\n */\n void jMenuHelpAbout_actionPerformed(ActionEvent actionEvent) {\n Frame1_AboutBox dlg = new Frame1_AboutBox(this);\n Dimension dlgSize = dlg.getPreferredSize();\n Dimension frmSize = getSize();\n Point loc = getLocation();\n dlg.setLocation((frmSize.width - dlgSize.width) / 2 + loc.x,\n (frmSize.height - dlgSize.height) / 2 + loc.y);\n dlg.setModal(true);\n dlg.pack();\n dlg.setVisible(true);\n }\n\n public void jbRemove_actionPerformed(ActionEvent actionEvent) {\n jtProjectList.removeCurrentNode();\n }\n\n public void jbAdd_actionPerformed(ActionEvent actionEvent) {\n String response = \"\";\n while(response.trim().equals(\"\")){\n response = JOptionPane.showInputDialog(this,\n \"Please enter name of node?\",", "\n \"Enter your name\",\n JOptionPane.", "QUESTION_MESSAGE);\n //System.out.println(response);\n if( response !", "= null && response.trim().equals(\"\"))\n JOptionPane.showMessageDialog(this,\"Please enter valid name\",\n \"Error\",JOptionPane.", "ERROR_MESSAGE);\n }\n jtProjectList.addObject(response);\n\n }\n }\n\n class Frame1_jbAdd_actionAdapter implements ActionListener {\n private Frame1 adaptee;\n Frame1_jbAdd_actionAdapter(Frame1 adaptee) {\n this.adaptee = adaptee;\n }\n\n public void actionPerformed(ActionEvent actionEvent) {\n adaptee.jbAdd_actionPerformed(actionEvent);\n }\n }\n\n class Frame1_jbRemove_actionAdapter implements ActionListener {\n private Frame1 adaptee;\n Frame1_jbRemove_actionAdapter(Frame1 adaptee) {\n this.adaptee = adaptee;\n }\n\n public void actionPerformed(ActionEvent actionEvent) {\n adaptee.jbRemove_actionPerformed(actionEvent);\n }\n }\n\n class Frame1_jMenuFileExit_ActionAdapter implements ActionListener {\n Frame1 adaptee;\n\n Frame1_jMenuFileExit_ActionAdapter(Frame1 adaptee) {\n this.adaptee = adaptee;\n }\n\n public void actionPerformed(ActionEvent actionEvent) {\n adaptee.jMenuFileExit_actionPerformed(actionEvent);\n }\n }\n\n class Frame1_jMenuHelpAbout_ActionAdapter implements ActionListener {\n Frame1 adaptee;\n\n Frame1_jMenuHelpAbout_ActionAdapter(Frame1 adaptee) {\n this.adaptee = adaptee;\n }\n\n public void actionPerformed(ActionEvent actionEvent) {\n adaptee.jMenuHelpAbout_actionPerformed(actionEvent);\n }\n }\n\nA:\n\nI believe the reason your code is so messy is because it was generated automatically by some GUI builder. ", " With the large number of components and the complexity of your interface, you might want to write it manually. ", " There must be some kind of pattern here that you can exploit to reduce the amount of code and make it easier to understand and maintain.", "\nWith that aside, I think the problem could be down to the way the components are 'added' to the JScrollPanes. ", " You used\njScrollPaneX.getViewport().add(comp);\nwhich is not the usual way of assigning a view to a scroll pane. ", " The standard ways are by choosing the view component at construct time such as by calling\njScrollPanex = new JScrollPane(comp)\nor if you need to set it later, call\njScrollPaneX.setViewportView(comp).", "\n(Internally, this calls getViewport().setView(view) which is similar, but not the same as the way you were doing it.)", "\n\nA:\n\nI solved my problem by small review on my codes:\nI just remove this line:\njTextArea1.setPreferredSize(new Dimension(280, 60));\n\nDo not forget, if you set size (any size) for your Jtextarea scrollpane will not appear on screen for you :)\njob done, enjoy it....\n\n" ]

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[ " \nRoland Thorne\n\n# SAMURAI FILMS\n\n_For Mum, Dad and Sal._", "\n\n# CONTENTS\n\nTitle Page\n\nDedication\n\nAcknowledgements\n\nIntroduction\n\n1. ", "Who were the Samurai?", "\n\n2. ", "What makes a Samurai Film?", "\n\n3. ", "Other Recurring Themes and Plot Elements\n\n4. ", "The Directors\n\n5. ", "The Stars\n\n6. ", "The Influence of Samurai Films on World Cinema\n\n7. ", "Beginnings and the 1950s\n\n8. ", "The 1960s\n\n9. ", "The 1970s\n\n10. ", "The 1980s, 90s and Current Cinema\n\nBibliography\n\nCopyright\n\n# ACKNOWLEDGEMENTS\n\nSpecial thanks to Craig Cormick, for his vital help and encouragement during the early stages of this project. ", "Thanks also to those who have taught me the most about film and writing: Dave Watson, Francesca Rendle-Short and Felicity Packard. ", "Thanks to my good friend Chris 'Quaddy' Williams for his invaluable help with the frame grabs. ", "Thanks to those who have already written on this fascinating subject, mainly Mitsuhiro Yoshimoto, Alain Silver and Patrick Galloway. ", "Thanks to Eastern Eye for making so many of these wonderful films available in Australia. ", "And, of course, a big thanks to Hannah Patterson, for seeing the potential of a Kamera Book on samurai films. ", "\n\n# INTRODUCTION\n\nImagine a mountain top, with long grass undulating in the unrelenting wind. ", "Two figures come into view, a few short paces away from each other. ", "Their firm stance conveys pride, determination and a strange sort of calm. ", "In a flurry of motion, one of the men draws his sword, quickly followed by the other. ", "With a flash of blades, and a mist of blood, it is over. ", "One man walks away, the other doesn't. ", "Who are these men? ", "How did they get to the point where violence was the only way to settle their dispute? ", "And why did they both seem unafraid to die? ", "Welcome to the world of the samurai film.", "\n\nSamurai films come in many flavours: there are the basic action movies, beautiful in their brutal simplicity, the meaningful and moving tales of the individual's struggle to survive, and the expansive, epic films that tell tales of famous personalities. ", "In short, there's something to please every fan of genre cinema. ", "Within the pages of this book you'll find everything you need to begin or continue an interest in this highly entertaining and unique genre. ", "There's basic information on the samurai and their world, details on the major directors and stars, and reviews of some of the finest films in the genre.", "\n\nEvery film reviewed here is easily available. ", "This is a rule I've stuck to fervently while writing this book. ", "It meant excluding some great films, such as Hideo Gosha's _Tenchu_ , but if you can't easily see them I've decided not to extensively review them. ", "There are few things I find more frustrating than buying a book about a genre, and discovering that most of the films reviewed have not been available for many years. ", "At the time of writing, all but four of the films reviewed in this book are available on DVD from Amazon.com. ", "These four films – _Three Outlaw Samurai, Bandits vs. Samurai Squadron, Hunter in the Dark_ and _Samurai Saga_ – can be purchased from importers, and are not at all hard to find.", "\n\nSo, happy viewing... Many excellent films await you.", "\n\n## A NOTE ON JAPANESE NAMES\n\nIn Japanese, it is the family name that comes first when an individual's name is included in any form of text. ", "This is the opposite of the convention in English, where the family name comes second. ", "For example, in English my name is written Roland Thorne, but in traditional Japanese I might be referred to as Thorne Roland. ", "To avoid confusion for those with only a limited knowledge of the Japanese language (a category I certainly fall into) I have chosen to follow the English convention in this book. ", "As you explore the samurai film genre, you will probably notice that some books, articles and sub-titles on some of the films follow the Japanese convention. ", "\n\n# WHO WERE THE SAMURAI?", "\n\nPut simply, the samurai were a warrior class, forming the armies of feudal leaders during Japan's many civil wars between the 10th and 15th centuries, and during the relatively peaceful Tokugawa period (1603-1868). ", "They wore distinctive armour and fought with weapons and styles unique to Japan.", "\n\nThere are many aspects of the samurai's life which constantly crop up in samurai films, and these may confuse those unfamiliar with them. ", "What follows is a summary of the main issues of samurai life, which are commonly referenced in the films, as well as a brief summary of the historical periods in which the films are usually set.", "\n\n## CULTURED WARRIORS\n\nThe importance of the samurai in Japan's early civil wars gradually led to them becoming an important social class, the more powerful samurai becoming daimyo, feudal lords ruling a clan, and the warriors and peasants beneath him. ", "Many of these daimyo began to study the fine arts, in what has been described by many scholars as an attempt to legitimise their rule over the uneducated peasants. ", "Most of these daimyo insisted their samurai do the same, so the samurai became a highly educated warrior class, not only skilled at warfare, but also at arts such as painting, sculpture, calligraphy, poetry, and traditional dance and theatre. ", "This created in the samurai an interesting contradiction: a man who could write a beautiful haiku one day, and strike his enemy down the next. ", "Of course, to the samurai, there was no contradiction; both poetry and swordsmanship were considered arts, and there was beauty to be found in both.", "\n\n## THE DAISHO\n\nThe daisho were the two swords carried by the samurai, usually a katana (long sword) and a wakazashi (short sword). ", "In the Tokugawa period there was actually a law which stated only samurai were allowed to carry both a short and long blade. ", "These swords were immensely important to the samurai; they symbolised his position in the warrior class, and were described by many as the very soul of the warrior. ", "Even a samurai in the most desperate of situations would be loath to give up his swords.", "\n\n## BUSHIDO\n\nFocused on honour and obedience, the code of bushido has done much to colour how we view the samurai, specifically giving rise to the myth of all samurai being morally outstanding individuals obsessed with honour. ", "The underlying principles of the bushido code are loyalty and obedience; the ideal samurai puts the wishes of his daimyo and clan above his own, and is prepared to die for them. ", "Also important to bushido is a sense of honour, something which was tied closely to each samurai's reputation.", "\n\nHowever, the historical reality is far from the ideal. ", "Any close examination of how the samurai conducted themselves in times of war reveals that the vast majority followed the bushido code only when it suited them. ", "In truth, the samurai were much like many other warrior classes which have arisen throughout history. ", "They strove to be the best at warfare they possibly could, and placed more importance on victory than on honour.", "\n\nBoth the mythical bushido samurai and his more brutal historical counterpart, have been the subject of many Japanese films. ", "Regardless of his mythic status, the samurai always makes a compelling protagonist.", "\n\n## SEPPUKU AND HARA-KIRI\n\nPart of the bushido code focused on ritual suicide, known as seppuku, or, more crudely, as hara-kiri. ", "A samurai could be ordered by his daimyo to commit seppuku in punishment for some wrongdoing, or may have chosen to do so in the hope of absolving himself of some personal shame. ", "Seppuku could also be used as a form of protest, a signed letter outlining the samurai's grievance. ", "A death through seppuku was considered much more honourable than being killed by enemies, so if a battle was completely hopeless, a samurai might consider seppuku. ", "The actual ritual involved making a long deep cut across the stomach. ", "When this was done an assistant would complete the process by swiftly beheading the samurai, putting an end to his suffering.", "\n\n## RONIN\n\nThe term _ronin_ literally means _wave man_ , suggesting an individual adrift on the ocean, his future decided by the uncaring waves and currents. ", "Ronin were masterless samurai, and there were many ways a samurai could end up unemployed. ", "He may have displeased his daimyo, and been dismissed from his service. ", "When daimyo were defeated in battle, and their lands taken by another, their samurai were usually left unemployed. ", "It was also possible to be born a ronin. ", "The strict class system of feudal Japan made it difficult for the ronin to fit into society; no longer able to fulfil the role he was born to, the ronin was also often too proud to give up his swords and become a farmer or merchant. ", "Some lucky ronin were able to find employment with other daimyo. ", "Others became bandits, or bodyguards and teachers to wealthy members of the lower classes. ", "Many suffered dire poverty, unable to afford food and lodgings. ", "The Tokugawa period produced many ronin. ", "With the Tokugawa government regularly dissolving clans which displeased them, many samurai were left homeless and unemployed, forced to wander the roads.", "\n\nRonin in samurai films are typically portrayed as much more effective individuals than samurai in service. ", "In many ways the two are polar opposites of each other: the employed samurai well dressed and cultured, the ronin unkempt and rude. ", "However, the ronin's tougher lifestyle has often equipped him with a much more cunning and creative mind. ", "A common plot in samurai films is that of a ronin using his abilities to help employed samurai overcome difficulties they aren't equipped to handle themselves (see _Sanjuro_ and _Kill_ _!_ ). ", "The ronin, with his much freer lifestyle, is often used to show the shortcomings of the employed samurai's life of mindless obedience. ", "Sometimes ronin characters are even used to illustrate the moral deficiencies in this code. ", "The best examples of this are the films of Masaki Kobayashi, in which there is a stark contrast between compassionate ronin and uncaring samurai.", "\n\n## HISTORICAL CONTEXT\n\nMost samurai films take place in either the Sengoku or Tokugawa periods of Japanese history. ", "The Sengoku period (1478–1603) was a time of chaos for Japan; rival daimyo (lords in charge of a clan and an army) battled to control the nation, and these constant wars meant that nobody's safety was guaranteed. ", "Samurai films set in this era often focus on actual historical events, as is the case with _Samurai Banners_ and _Kagemusha_ , and as a result tend to feature large-scale battles in all their splendour.", "\n\nIn stark contrast to this is the Tokugawa period (1603–1868). ", "A daimyo named Ieyasu Tokugawa emerged from the Sengoku period victorious, and through various means was able to control the daimyo, preventing any challenges to his position as Shogun (military dictator in charge of Japan). ", "This time of stability and peace became known as the Tokugawa period, and would last for the next 267 years, as Ieyasu's descendants continued his rule. ", "Ieyasu's methods for maintaining peace in Japan involved establishing a regime of strict laws, with harsh penalties for disobedience. ", "Japan's already stringent class system became law, and travel was restricted through the use of passes and carefully guarded checkpoints. ", "The daimyo were kept in line through the very clever tactic of having them spend every second year in Edo (Ieyasu's new capital of Japan, later to become Tokyo), with their immediate families forced to live there permanently. ", "This prevented the daimyo from planning elaborate campaigns or mustering troops in their territory, and the fact that the Tokugawa had easy access to their families ensured their obedience. ", "Also, the Tokugawa showed no qualms about using their power to completely disband clans which failed to obey them, and this constant threat also served to ensure the loyalty of the daimyo.", "\n\nThe majority of samurai films are set in the Tokugawa period. ", "Some involve clans that try to avoid destruction at the hands of the oppressive Tokugawa, and others present the Tokugawa in a more positive way, as brave men doing whatever it takes to preserve the peace. ", "However, most of the films set in the Tokugawa period focus on the lives of individuals, in contrast to films set in the Sengoku period, which are often concerned with the epic histories of daimyo and their clans. ", "One common theme is the plight of the samurai in a time of peace; what does one skilled at warfare do, when there are no wars? ", "Many films set in the Tokugawa period describe the exploits of wandering ronin (masterless samurai), whose numbers were greatly increased during this time. ", "\n\n# WHAT MAKES A SAMURAI FILM?", "\n\nThe term 'samurai film' is an invention of American film critics, and is rarely used in Japan. ", "The Japanese prefer to group their films into two main genres, _jidaigeki_ (which very roughly translates as 'period drama') and _gendaigeki_ (films with a contemporary setting). ", "Within these two genres are a huge selection of sub-genres, creating what is perhaps the most detailed cinema genre classification system in the world.", "\n\nThe _jidaigeki_ films are often concerned with a very specific time in Japan's history, the Tokugawa era (1603-1868), which was a time of relative peace for Japan after centuries of civil war. ", "As period dramas, it is unsurprising that many (but not all) _jidaigeki_ are concerned with the samurai and other sword-wielding warriors of Tokugawa-era Japan. ", "Indeed, _jidaigeki_ , which are mainly concerned with swordplay, have their own sub-genre, _chambara_ or 'sword drama'. ", "Many of the films reviewed in this book could be correctly classified as _chambara_ , but I cannot help but feel that this description doesn't do them justice. ", "There is, after all, a lot more to these films than sword fights.", "\n\nThese considerations make the samurai film quite a difficult genre to define, and for the purposes of this book a definition separate to those such as _jidaigeki_ and _chambara_ is required. ", "Forming such a definition may seem easy at first; surely samurai films are simply films concerned with the samurai? ", "Unfortunately this definition is a bit _too_ simple. ", "It excludes a great many films generally assumed to be of the samurai genre, such as the _Zatoichi_ and _Lady Snowblood_ series, whose main protagonists are of peasant birth rather than the samurai class. ", "Perhaps it is easier to find a common theme or motif among the films. ", "Swordplay would seem to be a safe bet. ", "Surely all samurai films include swordplay? ", "Again, this is problematic. ", "The true samurai film deals with more than just swordplay. ", "Indeed, some samurai films contain very little action at all.", "\n\nIt is, more accurately, what goes on behind the swordplay that best defines the samurai film. ", "More specifically, samurai films are concerned with the problems and dilemmas (both internal and external) of the warrior, of the one who is skilled at performing violent acts. ", "The true samurai film forces its protagonist into situations where either they or the audience (or both) learn something new about the status of the individual as killer. ", "Whether it's Kambei from _Seven Samurai_ learning that he, and all other samurai, will eventually fade from history, or Sanjuro or Zatoichi, deciding that a life without killing would be better, but not knowing how to achieve that goal, the samurai film is concerned with the learning journey of the warrior.", "\n\nAdded to this is the iconography and setting of the samurai film. ", "Pre-industrial Japan, usually the Tokugawa period (1603-1868), forms the setting. ", "This allows for intrigue among the samurai in the larger cities and castles, or bloody battles between ronin (wandering masterless samurai) and yakuza (criminal gangs) in the smaller towns and villages. ", "The iconography consists of a variety of things, but perhaps most important is the sword: the essential instrument of the warrior. ", "The distinctive appearance of the Japanese sword or _katana_ will forever be associated with the samurai film and, together with the pre-industrial Japanese setting and warrior's learning journey, goes a long way towards defining it. ", "\n\n# OTHER RECURRING THEMES AND PLOT ELEMENTS\n\n## DEPICTIONS OF NATURE\n\nLike many cultures, the Japanese have a rich tradition of the depiction of nature in their art. ", "However, unlike most cultures, this tradition made the transition into the cinema, and is a dominant aspect of many Japanese films. ", "As such, many samurai films contain long, beautiful scenes of the distinctive Japanese landscape, something most noticeable in the breathtaking work of Akira Kurosawa and Hiroshi Inagaki. ", "As Patrick Galloway* has pointed out, these depictions of nature are often symbolic, and tap into an artistic language which is familiar to Japanese audiences, but not to international viewers. ", "For example, falling cherry blossoms are often symbolic of the way death can strike suddenly and unexpectedly. ", "These symbols are not crucial to enjoying the films, but, if understood, will enrich the viewer's experience. ", "As such, a little research on Japanese artistic traditions can be immensely rewarding.", "\n\n* Patrick Galloway's _Stray_ _Dogs_ _and Lone Wolves_ is a detailed guide to samurai films, and highly recommended as further reading.", "\n\n## THE GIRI/NINJO CONFLICT\n\nThe word _ninjo_ refers to the more emotional feelings of human beings, sentiments such as sympathy, love and the emotional decisions we make governing what is right and wrong. _", "Giri_ means duty to your superiors. ", "For the samurai, who was supposed to be unquestionably obedient, the giri/ninjo conflict is particularly important. ", "What if he is ordered to do something which goes against his conscience, or threatens someone he has an emotional attachment to? ", "He is supposed to obey without question, but this is much easier said than done... The giri/ninjo conflict is a constant theme in the samurai film, and one which makes for some very dramatic and compelling plots. ", "I haven't included the giri/ninjo conflict as part of my definition of the genre, simply because it isn't present in all of the films; there are a great many samurai films where the protagonist is no longer (or never has been) governed by giri, thus preventing any conflict with their emotional impulses. ", "\n\n# THE DIRECTORS\n\n## AKIRA KUROSAWA\n\nThe most internationally famous and acclaimed Japanese director, Akira Kurosawa is the master filmmaker responsible for some of the finest films ever made. ", "He started his film career for Toho as a writer and assistant director in 1936, and worked his way up to the position of director. ", "Beginning with the excellent _Rashomon_ , Kurosawa made one classic film after the other, throughout the 1950s and 60s. ", "These films were immensely appealing to international audiences, and this led to Kurosawa being criticised in his own country for making 'un-Japanese' films, designed to appeal to foreigners eager for orientalism. ", "Kurosawa vigorously protested these criticisms, and rightly so. ", "While he was more influenced by sources outside of Japan (such as Shakespeare and John Ford) than other Japanese directors, his films were also carefully constructed around Japanese artistic conventions. ", "It is perhaps this combination of influences that makes Kurosawa's work so entertaining and accessible to world audiences.", "\n\nKurosawa's films are often moving stories about the individual, told with beautiful cinematography. ", "In his long career, the Emperor, as he was nicknamed, proved he could make high-quality films in any genre. ", "Whether it was romantic dramas like _Scandal,_ medical dramas like _Red_ _Beard_ or cop films such as _Stray_ _Dog_ , Kurosawa always excelled, creating instant classics.", "\n\nKurosawa's influence on samurai films cannot be overstated. ", "His wonderful _Seven Samurai_ signified a new type of film for the genre, and the immensely successful _Yojimbo_ and _Sanjuro_ were such influential films that they completely transformed the genre in the 1960s.", "\n\n## HIROSHI INAGAKI\n\nAnother major Toho Studios director, Hiroshi Inagaki's work is also quite well known internationally. ", "Inagaki specialised in historical epics, telling the stories of famous samurai and daimyo from times past. ", "He excelled in the epic filmmaking that such projects required, as evidenced by films including _Samurai Trilogy_ , _The 47 Ronin_ and _Samurai Banners_. ", "Inagaki was also very adept at filming large-scale battles, utilising great numbers of extras. ", "His films are impressive for their epic scale, but also have a simple elegance about them.", "\n\n## MASAKI KOBAYASHI\n\nA director famous for his distinctly anti-authoritarian films, Masaki Kobayashi made some of the most harrowingly honest samurai films; unlike many of his contemporaries, Kobayashi was much less sentimental about bushido, and was unafraid to show the potential for cruelty in the samurai's code of unquestioning loyalty and obedience. ", "His films are usually concerned with the individual's struggle against corrupt authority, and never fail to be compelling viewing.", "\n\nDrafted into the Japanese army during World War Two, Kobayashi served in Manchuria. ", "He disapproved strongly of the war, and constantly refused promotion in the military. ", "As the war came to an end, Kobayashi spent a year as a P.O.W. When back in Japan he returned to work for Shochiku Studios, utilising his wartime experiences to make _The Human_ _Condition_ trilogy, which told the harrowing story of a pacifist drafted into the Japanese army during World War Two. ", "These films made Tatsuya Nakadai famous, and Kobayashi and Nakadai would continue to work together in a very successful partnership.", "\n\nUnfortunately, Kobayashi's anti-authoritarian themes were not popular with Shochiku Studios, a very conservative company. ", "Although a very talented director, Kobayashi made only 22 films.", "\n\nAlthough not as influential as the work of Akira Kurosawa, Kobayashi's samurai films are distinct for their honesty and lack of sentimentalism; _Hara-kiri_ especially shows the cruel realities of the bushido code. ", "They are not only distinct in thematic content, but also for their extremely high quality. ", "His direction is always sublime, and his choice of subject matter compelling and moving. ", "His _Hara-kiri_ and _Samurai_ _Rebellion_ rank alongside the work of Kurosawa as two of the finest samurai films ever made.", "\n\n## HIDEO GOSHA\n\nHideo Gosha originally worked in television, starting as a reporter with Nippon Television in 1953. ", "He eventually secured a position as a director and producer with Fuji Television, where he created a series of successful action TV shows during the 1950s. ", "One of these shows, _Three Outlaw Samurai_ , impressed Shochiku Studios so much that they hired Gosha to make a feature-length version. ", "Gosha continued to work with Shochiku Studios, directing many films throughout the 1960s and 70s, mainly of the samurai and yakuza (gangster) genres.", "\n\nAs Patrick Galloway has noted, Gosha blended elements of Kurosawa and Kobayashi's films with his fast-paced TV-style direction, to create a unique style of his own. ", "This results in highly entertaining films, distinct from those of other master directors. ", "Gosha's films are tremendous, and a wonderful addition to the samurai film genre.", "\n\nUnfortunately, although famous and much loved in Japan, Gosha's films are yet to be widely available elsewhere, unlike the other directors profiled here. ", "At the time of writing the Criterion release of _Sword of the_ _Beast_ on DVD is the only example of a large distributor with a Gosha film in their catalogue. ", "This is a terrible shame, as Gosha's films are of a very high quality, and would be thoroughly enjoyed by international audiences. _", "Three Outlaw Samurai_ , _Hunter in the Dark_ and _Bandits vs_. _", "Samurai Squadron_ are all available (with English subtitles) from importers, who source their stock from Asian distributors. ", "Unfortunately, the quality of these DVDs is often inferior to those of the larger distributors (such as the Criterion Collection in the USA or Eastern Eye in Australia), but on the plus side they are a lot cheaper. ", "It is definitely worth tracking these films down.", "\n\n## KIHACHI OKAMOTO\n\nLike Masaki Kobayashi, Kihachi Okamoto was drafted into the Japanese army during World War Two, an experience which undoubtedly had an effect on his films in later years.", "\n\nBeginning work for Toho Studios in 1947, Okamoto slowly worked his way up the ladder, directing his first film in 1958. ", "Although he showed skill in directing films of various genres, Okamoto began to specialise in action films. ", "He had a special talent for action scenes, which he was able to inject with a wonderful sense of rhythm and pacing, without over-stylising the violence.", "\n\nLike Kobayashi, Okamoto was sceptical of the bushido code in his samurai films, but not in Kobayashi's anti-authoritarian way. ", "Okamoto's films focus more on the individual, rather than the individual vs. authority. ", "His samurai films often resemble cautionary tales, showing the ultimately negative and self-destructive results of leading a violent lifestyle. ", "The best examples of this are the very gritty _Samurai Assassin_ and _Sword of Doom_ and the black comedy, _Kill_ _!_. ", "Okamoto's films combine his well-paced direction with moving subject matter, creating a result which clearly places him among the best samurai film directors. ", "\n\n# THE STARS\n\n## TOSHIRO MIFUNE\n\nToshiro Mifune is not only the most well-known performer to appear in a samurai film, but also the most famous actor to emerge from Japanese cinema.", "\n\nMifune's acting career began with an audition for Toho Studios in 1946. ", "Having served in the Japanese army during World War Two, Mifune found himself in need of work, and decided to use his military experience as an aerial photographer to attempt to secure work as a camera operator at one of the major studios in Tokyo. ", "There are a number of different accounts as to how Mifune ended up auditioning as an actor; one claims he did so in the hope of later transferring to become a camera operator, another that he was to be interviewed for a position as a cameraman, but auditioned as an actor by mistake (which certainly makes a better story). ", "Whatever the case, the audition process angered Mifune. ", "He felt demeaned by requests to show different emotions and flew into a wild rage, the expressive nature of which impressed Kajiro Yamamoto, one of Toho's leading directors at the time, and an upcoming talent, Akira Kurosawa.", "\n\nMifune's angry audition secured him work as an actor, beginning with roles in comedies and action films. ", "His long association with Akira Kurosawa began with _Drunken Angel_ , in which his originally small part was expanded into a co-starring role. ", "Mifune's relationship with Kurosawa continued throughout the 1940s, with leading roles in classic films such as _Stray_ _Dog_ and _Rashomon_. ", "His explosive entry to the samurai film genre came with Kurosawa's masterpiece, _Seven Samurai_. ", "Mifune brought a level of energy and expressiveness to all of these films, which Kurosawa was able to exploit to maximum effect. ", "Between 1948 and 1965 Mifune had lead roles in 16 of Kurosawa's films, each one an instant classic.", "\n\nMifune also worked with many other Japanese directors, and as his films were successfully distributed internationally he secured roles in productions from other countries, most notably _Hell_ _in the Pacific_ and the hugely popular American samurai TV series _Shogun_ , in 1980. ", "He also started his own production company in the 1960s.", "\n\nToshiro Mifune had an enormous influence on the samurai film genre. ", "Most of his characters, in particular Sanjuro ( _Yojimbo_ ) and Kikuchiyo ( _Seven Samurai_ ), were instant icons, and Mifune's unique portrayal was quickly copied by other actors. ", "Only Shintaro Katsu and Tatsuya Nakadai come close to having the same level of influence.", "\n\n## TATSUYA NAKADAI\n\nTatsuya Nakadai is best known among fans of samurai films for his appearances in some of the genre's best films, such as _Yojimbo_ , _Sanjuro_ , _Hara-kiri_ , _Kill_ _!_ ", "and, perhaps his greatest of all, _Sword of Doom_.", "\n\nBorn in Tokyo in 1932, Nakadai worked in theatre before making the transition to film in 1953. ", "His work with the Shingeki movement, a modern (rather than traditional) theatre group, rendered Nakadai with considerable acting experience before he was discovered by film director Masaki Kobayashi. ", "Working for Shochiku Studios, Kobayashi used Nakadai in many of his films, most notably in _The Human_ _Condition_ , a challenging trilogy telling the story of a conscientious objector drafted into the Japanese army during World War Two.", "\n\nBy 1960 Nakadai had appeared in numerous Shochiku films, but his greatest samurai film roles were yet to come. ", "Interestingly, Nakadai makes a very brief appearance in the best-known samurai film of all, _Seven Samurai_. ", "In the early stages of the film, Nakadai is one of the samurai glimpsed striding through town.", "\n\nThroughout the 1960s, Nakadai gave many memorable performances in samurai films such as _Hara-kiri_ , _Yojimbo_ , _Sanjuro_ , _Sword of Doom_ , _Kill_ _!_ ", "and _Samurai Rebellion_. ", "These roles ranged from tortured anti-heroes to sadistic villains, and Nakadai's excellent performance in each is testament to his impressive range.", "\n\nNakadai continues to work. ", "He runs his own actors studio, _Mumeijuko_ , and also appears in films, on television and on the stage.", "\n\n## SHINTARO KATSU\n\nMost famous for his role as Zatoichi the blind swordsman, Shintaro Katsu was a huge star in Japan throughout the 1960s and 70s. ", "Katsu was born into the acting profession, his family a successful kabuki (traditional Japanese theatre) troupe. ", "In the 1950s he made the transition to cinema, working for Daiei Studios. ", "His role as Zatoichi in the 1960s made him immensely popular, and the Zatoichi series continued into the 1970s and 80s. ", "Katsu's warm and charismatic performance as the blind swordsman endeared him to audiences, but he was also capable of many other roles, such as the cruel villain he played in _Incident at Blood_ _Pass_.", "\n\nKatsu formed his own production company, which produced the popular _Lone Wolf and Cub_ series, starring his older brother, Tomisaburo Wakayama. ", "\n\n# THE INFLUENCE OF SAMURAI FILMS ON WORLD CINEMA\n\nThe influence the samurai film has had on world cinema is unquestionable. ", "Themes from samurai films have been adopted both directly and indirectly by Hollywood; the never-ending _American Ninja_ series of films (1985–1993) and recent would-be blockbuster _The Last_ _Samurai_ (2003) are both good examples of this. ", "The relationship samurai films have with Hollywood's most famous genre, the western, is a bit more complicated. ", "Some classic westerns owe their origins to samurai films: Kurosawa's _Seven Samurai_ was remade as _The Magnificent Seven_ (1960), while _Yojimbo_ was remade by Sergio Leone in Italy as _A Fistful_ _of Dollars_ (1964), beginning the popular spaghetti western genre. ", "It should be noted, however, that Kurosawa, the man who invented the modern samurai film, lists John Ford, the master of the classic western, as one of his influences. ", "Kurosawa was able to create something unique, using Ford's films as one of his many inspirations. ", "His work would then have a similar effect on directors of westerns in the 1960s. ", "The samurai and western genres clearly share a very close relationship, but are distinct enough that they should remain separate.", "\n\nThe influence of samurai films in Hollywood was not limited to westerns. ", "Many contemporary directors have a great deal of admiration for samurai films, and this has influenced their work in a variety of other genres. ", "George Lucas's original _Star Wars_ film, _A New Hope_ (1977), was inspired in part by Kurosawa's _The Hidden Fortress_. ", "Similarly, Quentin Tarantino's _Kill Bill Volume_ _1_ (2003) and _Volume 2_ (2004) borrow heavily from samurai films, specifically _Lady_ _Snowblood_. ", "It is not only mainstream American films which have been influenced by the genre. ", "Jim Jarmusch, a highly acclaimed alternative director, made his own tribute to samurai films, titled _Ghost Dog: The Way of the Samurai_ (1999), an interesting film placing the samurai's unique moral code in the context of a modern American mob assassin. ", "\n\n# BEGINNINGS AND THE 1950s\n\nThe samurai film evolved from some of the earliest Japanese films, which were filmed kabuki theatre performances. ", "A traditional form of Japanese theatre, kabuki features carefully choreographed movements set to music and singing. ", "Although graceful and beautiful, kabuki choreography is highly stylised, and lacks the sense of realism that films are able to convey.", "\n\nIt was another form of theatre choreography which would lead to the birth of the samurai film. ", "The Shinkokugeki school of popular theatre, which had been around since 1912, distinguished itself with realistic and athletic swordplay, a stark contrast to the slow and graceful choreography of the filmed kabuki performances. ", "The more realistic and faster-paced stage fencing had proven popular with audiences, and Makino Shozo, a highly successful producer of filmed kabuki performances, saw the potential of the Shinkokugeki productions and began to make films using their choreography and actors. ", "Throughout the 1920s and 30s Japanese filmmakers began to explore the full potential of film as a medium, and the filmed kabuki performances were gradually replaced by narratives which were actually designed for the screen, rather than for the stage. ", "Among these films were the early samurai films, which were popular with Japanese audiences. ", "It would take another 20 years for the genre to be discovered by international audiences.", "\n\nSamurai films suffered greatly in the 1940s and early 50s. ", "Interestingly, they were suppressed by both the World War Two militaristic Japanese government, who considered them a useless form of entertainment, and the American post-war occupation censors, who maintained the often violent samurai films would inspire feudalistic sentiments among the Japanese. ", "This caused a large decline in the production of samurai films, which was only reversed when the Japanese production companies were completely released from American censorship in the early 1950s.", "\n\nOne company quick to take advantage of this was Toei, an already successful studio. ", "They began to mass produce samurai films, with great success, and were quickly copied by other studios. ", "Unfortunately the years of suppression and censorship had left their mark on the genre. ", "As Mitsuhiro Yoshimoto† has pointed out, many of the films made in the 1950s were extremely formulaic, and revolved around simplistic battles between good and evil. ", "Also, they had restored the kabuki choreography for the sword-fighting scenes, resulting in very slow, dance-like choreography.", "\n\nThere were, however, some excellent samurai films made during the 1950s. ", "Many directors tried to break the predictable formula which had such a tight grip on the genre. ", "Hiroshi Inagaki was one such director, who created his highly acclaimed _Samurai Trilogy_ during the 1950s. ", "Telling the exciting story of master swordsman Miyamoto Musashi (an historical figure), Inagaki's films utilised swift and realistic choreography.", "\n\nAkira Kurosawa was another innovator, and is the master filmmaker who would have the most influence on the genre. ", "His 1954 film, _Seven_ _Samurai_ , was the beginnings of the samurai film as we know it today. ", "As Yoshimoto has pointed out, in _Seven Samurai_ Kurosawa created a very different kind of samurai film. ", "Working for Toho, a company which had not made many samurai films, and didn't feel constrained by the existing formula, Kurosawa injected a level of realism and detail into his film which clearly set it apart. ", "Character motivations were carefully\n\n† Mitsuhiro Yoshimoto's highly informative work, _Kurosawa_ _: Film Studies and_ _Japanese Cinema_ , contains a fascinating, in-depth discussion of the evolution of the jidaigeki genre, and is the source of the information in this summary.", "\n\nthought out at the scripting stage, and every detail of the production design was researched to convey the sense of realism clearly lacking in many 1950s samurai films. ", "The battle scenes in the film were also brutally realistic, with characters battling feverishly for their survival, rather than engaging in symbolic dance. ", "Kurosawa continued to make high-quality samurai films throughout the 1950s, with _Throne of Blood_ and _The Hidden Fortress_.", "\n\nThe work of both Inagaki and Kurosawa was well received overseas, and with their films the samurai film genre found an international audience.", "\n\n### _Seven Samurai_ (1954)\n\n**Japanese Title:** _Shichinin no samurai_\n\n**Directed by:** Akira Kurosawa\n\n**Written by:** Shinobu Hashimoto, Hideo Oguni, Akira Kurosawa\n\n**Produced by:** Sojiro Motoki\n\n**Edited by:** Akira Kurosawa\n\n**Cinematography:** Asakazu Nakai\n\n**Cast:** Takashi Shimura (Kambei), Toshiro Mifune (Kikuchiyo), Yoshio Inaba (Gorobei), Seiji Miyaguchi (Kyuzo), Minoru Chiaki (Heihachi), Daisuke Kato (Shichiroji), Isao Kimura (Katsushiro), Keiko Tsushima (Shino), Yukiko Shimazaki (Rikichi's wife), Kamatari Fujiwara (Manzo), Yoshio Kosugi (Mosuke), Bokuzen Hidari (Yohei), Yoshio Tsuchiya (Rikichi), Kokuten Kodo (Gisaku)\n\n## PLOT SUMMARY\n\nDiscovering that bandits will return to their village next harvest, some peasants set about hiring unemployed samurai, in the hope that they will defend their village. ", "They find Kambei, an experienced and charismatic warrior, who not only takes on the assignment, but helps gather six other samurai. ", "Among these is Kikuchiyo, a particularly messy and unkempt individual, who is drawn to the group and accepted mainly out of pity. ", "Relations between the samurai and villagers are tense at best, neither group fully trusting the other. ", "More stress is placed on this relationship when Katsushiro, the youngest of the seven, and Shino, a young peasant girl, fall in love with each other. ", "Kikuchiyo turns out to be the key to maintaining the alliance of samurai and peasant, as it is discovered that he is of peasant origin himself. ", "In a series of violent exchanges the samurai are able to defeat the bandits, mainly through Kambei's intelligent use of tactics. ", "But this comes at a cost; at the end of the film only Kambei and two other samurai survive. ", "The love between Katsushiro and Shino must remain unfulfilled; the samurai are no longer needed and must move on.", "\n\n## ANALYSIS\n\n_Seven Samurai_ is the masterpiece by Akira Kurosawa that defined the samurai film as we know it today. ", "The film is an accomplished mix of superb characterisation, well-executed battle scenes and observations on the class structure of feudal Japan.", "\n\nThe characterisation in _Seven Samurai_ is exceptional, as we have come to expect from Kurosawa. ", "Each of the seven samurai is shown to have different motivations for joining the group, and they have widely varying character traits. ", "While all seven performances are of a very high standard, special mention must go to Takashi Shimura and Toshiro Mifune. ", "Shimura is well cast as Kambei, the wise samurai who brings the seven together. ", "Shimura's sensitive performance shows a balance of warmth, intelligence and martial prowess in Kambei, making it clear to the audience that he is ideally suited to hold the seven together. ", "Kikuchiyo, a wild, uncontrollable ronin, is played by Mifune, whose expressive features and blustering manner are perfect for the overblown character he plays. ", "Kurosawa and his writers allegedly worked out detailed past histories for each of the seven, which pays off in a script full of realistic dialogue and convincing motivations. ", "As we watch the seven prepare the village against the oncoming assault by the bandits, we grow attached to them, as we would to real people.", "\n\nThe seven enjoy a light-hearted moment. _", "Seven Samurai_ directed by Akira Kurosawa and produced by Sojiro Motoki for Toho Studios.", "\n\nKurosawa uses the samurai's interaction with the peasants as a device for examining class issues. ", "As with all of Kurosawa's films this is not executed in a heavy-handed way, but instead integrated seamlessly into the film. ", "There is a constant interplay of trust and mistrust between the samurai and the peasants, most of which arises from the class gulf between the two groups, which ultimately the characters in the film fail to bridge. ", "Not even the potential relationship between young samurai Katsushiro and peasant girl Shino is able to form a solid bond between the two classes. ", "This relationship fails the test set out by the film, just as the alliance between samurai and peasant does; when the unusual conditions that necessitated the two groups living and working together have passed, they both fall back into their old (separate) ways. ", "The film's ending, which highlights the inevitability of this revelation, is sad and moving to watch. ", "The final scenes of Kambei and the survivors, surveying the graves of their fallen comrades, while the peasants ignore them and continue to work as they have done for centuries, makes clear the ultimate fragility of the samurai class, stripping any sense of victory from Kambei and his men.", "\n\nPerhaps the greatest feature of _Seven Samurai_ is the lengthy battle scenes which take place towards its end. ", "After we have come to know Kurosawa's carefully drawn characters we watch them fight, and in some cases die, in some of the finest battle scenes of the era. ", "The action between the samurai and the bandits is choreographed carefully to give a realistic impression of combat. ", "The combatants strike wildly and as often as they can, doing whatever possible to fell their enemy and, more importantly, survive. ", "The screams of the dying are intercut with shots of their bodies in the muddy village, showing the true results of violence. ", "Kurosawa also makes good use of the bandits' guns. ", "The gun shots are always surprising, catching the audience off guard, and are sometimes, but not always, followed by death, creating an uneasy sense of uncertainty throughout the film.", "\n\n_Seven Samurai_ was remade as a western in 1960, _The Magnificent_ _Seven_ , directed by John Sturges and starring Yul Brynner, along with a cast of legends from the western genre such as Eli Wallach, Charles Bronson, Steve McQueen and James Coburn. ", "Kurosawa's plot translated well into the genre, and the film was immensely successful, spawning three sequels, all with basically the same story as the original.", "\n\n## THE VERDICT\n\nAn undisputed classic of the samurai genre, _Seven Samurai_ is compulsory viewing which satisfies on all levels.", "\n\n### _Samurai 1_ _:_ _Miyamoto Musashi_ (1954)\n\n**Japanese Title:** _Miyamoto Musashi_\n\n**Directed by:** Hiroshi Inagaki\n\n**Written by:** Adapted by Tokuhei Wakao and Hiroshi Inagaki from the novel by Eiji Yoshikawa\n\n**Produced by:** Kazuo Takimura\n\n**Edited by:** Hideshi Ohi\n\n**Cinematography:** Jun Yasumoto\n\n**Cast:** Toshiro Mifune (Takezo/Musashi), Rentaro Mikuni (Matahachi), Kuroemon Onoe (Takuan), Kaoru Yachigusa (Otsu), Mariko Okada (Akemi), Mitsuko Mito (Oko), Eiko Miyoshi (Osugi), Akihiko Hirata (Seijuro Yoshioka)\n\n## PLOT SUMMARY\n\nWhen they fight on the losing side at the Battle of Sekigahara, Takezo and Matahachi, two glory-hungry young men, are forced to hide from the enemy in a house occupied by two women: Oko and her daughter, Akemi. ", "A fierce warrior, Takezo protects them from some bandits, but is driven away by the unwanted advances of both women. ", "Oko lies to Matahachi, telling him that Musashi attempted to rape her, and convincing him to leave with her and Akemi. ", "Takezo, meanwhile, has become a wanted fugitive, after a dispute with some border guards. ", "Despite several attempts, including a trap set by Osugi, Matahachi's bitter mother, the authorities are unable to capture Takezo. ", "The wise priest, Takuan, and Otsu, the fiancée Matahachi left behind, are finally able to subdue him. ", "Takuan suspends Takezo from a tree, hoping to tame the wild young man with harsh discipline, but Otsu shows pity and releases him. ", "Takezo is touched that someone would actually help him and begins to see the selfish nature of his wild ways. ", "Otsu is captured by the authorities, and Takezo journeys to Himeji castle to rescue her. ", "There he is tricked by Takuan into beginning a rigorous moral education, and eventually becoming a samurai, renaming himself Musashi. ", "Musashi is ordered to travel and train himself. ", "He visits Otsu before he leaves, but decides he cannot take her with him, asking her to wait for him a little longer.", "\n\n## ANALYSIS\n\n_Miyamoto Musashi_ is a strong start to Hiroshi Inagaki's _Samurai Trilogy_ , a series of films that tell the famous story of the historical figure who many consider to be Japan's greatest swordsman. ", "A captivating story, told in a simple yet entertaining way, _Miyamoto Musashi_ was well deserving of the Academy Award for Best Foreign Film that it won in 1955.", "\n\n_Miyamoto Musashi_ is perhaps the best example of director Hiroshi Inagaki's unique style. ", "Along with cinematographer Jun Yasumoto, Inagaki uses a storytelling technique that is elegant in its simplicity. ", "Taking advantage of the film's magnificent landscapes, Inagaki utilises slow pans across muddy battlefields, daunting mountains and beautiful meadows. ", "Much more than pretty pictures (although, it must be noted, many of Inagaki and Yasumoto's shots would look fantastic framed on a wall), these shots also reveal important information. ", "The shot of Takezo, running through a picturesque meadow, wooden sword in hand, violently chopping flowers off their stalks, perfectly captures his wild nature. ", "Similarly, the priest Takuan, when attempting to capture Takezo, is clearly separated from the other would-be captors; in a shot taken from high in the mountains, he is in the foreground and the others in the background, far below him in a valley. ", "Similarly, the beginning of the Battle of Sekigahara is signified by an atmospheric shot of lightning striking, illuminating a skeletal tree. ", "Inagaki is a master of using simple images to convey information, one of the hallmarks of a great filmmaker.", "\n\nLike _Seven Samurai, Miyamoto Musashi_ not only contains some beautiful scenic shots, but also some very well-directed and atmospheric battle scenes. ", "Like Kurosawa, Inagaki was an innovator when it came to presenting violence, and the battle scenes have a greater sense of realism than many of the 1950s samurai films. ", "The Battle of Sekigahara scenes, although quite short, effectively convey the sense of confusion and brutality in warfare, through the use of a series of quick cuts, each shot filled with moving bodies, flailing wildly at each other. ", "We find it difficult to pick out Takezo and Matahachi in these frenetic images, and just as we locate them, Inagaki cuts to another shot. ", "The location – a muddy field with the occasional gnarled tree – complements the action.", "\n\nThe elegance and simplicity of Inagaki's direction is also present in the plot itself. ", "An uncomplicated story about a powerful young man who learns the error of his wild ways, _Miyamoto Musashi_ has a mythic and parabolic feel about it. ", "Contained within the story are a number of beautiful moments between the characters, played with just the right amount of emotion. ", "The scene when Takezo bandages Otsu's hands, injured when she freed him, is particularly touching, and shows him beginning to understand the needs of others. ", "Similarly, Otsu's sad realisation that Musashi has left her behind is handled very well, and Toshiro Mifune and Kaoru Yachigusa should be commended for their skilful performances.", "\n\n## THE VERDICT\n\nAn excellent film in its own right, _Miyamoto Musashi_ sets the tone of Hiroshi Inagaki's acclaimed _Samurai Trilogy_. ", "Inagaki's beautiful direction, along with an entertaining story and solid performances from a great cast, make this a must-see for anyone interested in samurai films.", "\n\n### _Samurai 2_ _: Duel at Ichijoji Temple_ (1955)\n\n**Japanese Title:** _Zoku Miyamoto Musashi: Ichijoji no ketto_\n\n**Directed by:** Hiroshi Inagaki\n\n**Written by:** Adapted by Tokuhei Wakao and Hiroshi Inagaki from the novel by Eiji Yoshikawa\n\n**Produced by:** Kazuo Takimura\n\n**Edited by:** Hideshi Ohi\n\n**Cinematography:** Jun Yasumoto\n\n**Cast:** Toshiro Mifune (Miyamoto/Takezo), Koji Tsuruta (Kojiro Sasaki), Kaoru Yachigusa (Otsu), Mariko Okada (Akemi), Michiyo Kogure (Lady Yoshino), Mitsuko Mito (Oku), Akihiko Hirata (Seijuro Yoshioka), Daisuke Kato (Toji), Kuroemon Onoe (Takuan), Sachio Sakai (Matahachi)\n\n## PLOT SUMMARY\n\nMusashi has been travelling for a few years now, improving his swordsmanship, but he is yet to master the psychological strengths of the samurai. ", "Arriving in Kyoto, Musashi begins a rivalry with the Yoshioka school of swordsmanship. ", "He wants to challenge the master of the school, Seijuro, but is continually betrayed by the Yoshioka, who make two attempts to kill him with their superior numbers. ", "Musashi visits a sword polisher, Koetsu, and begins to learn from him the benefits of emotional detachment when duelling. ", "He also sees Otsu for the first time in years, but now desires the perfection of his art more than her. ", "A sinister warrior, Kojiro Sasaki, witnesses Musashi's battle against the Yoshioka, and is impressed. ", "Otsu is heartbroken, and returns to Takuan's monastery, where she considers becoming a nun. ", "To avoid further confrontations with the Yoshioka, Musashi stays at a Geisha house, where Lady Yoshino teaches him the value of a gentle nature. ", "After Musashi defeats Denshichiro, Seijuro's brother, the Yoshioka finally agree to a duel with Seijuro, at Ichijoji temple. ", "The Yoshioka ambush him with 80 men, and Musashi fights bravely, killing many of his opponents before escaping. ", "He sees Seijuro, who he defeats easily, but decides to spare him, considering the teachings of Koetsu and Yoshino. ", "Wounded, Musashi is found by Otsu, who nurses him back to health. ", "Musashi violently embraces Otsu, but she rejects him. ", "Musashi continues on his lonely journey, watched by Kojiro, who hopes to have a match with him in the future...\n\n## ANALYSIS\n\n_Samurai 2_ _:_ _Duel at Ichijoji Temple_ is an enjoyable continuation of Hiroshi Inagaki's retelling of the life of Miyamoto Musashi, a famous swordsman from the pages of Japanese history. ", "The film continues Musashi's learning journey as he becomes a samurai as well as a skilled warrior.", "\n\nThe exact nature of this journey is one of the unique aspects of the samurai film, and may seem unusual to western audiences. ", "After all, it's hard to imagine the heroes of Hollywood films, such as the western or gangster genres, visiting a woman to learn etiquette and gentleness, as Musashi does. ", "And yet, this is one of the film's most captivating features. ", "The idea that a warrior can be cultured and skilled at killing at the same time is an interesting juxtaposition, which is explored very effectively here. ", "It's not enough for Musashi to be a skilled swordsman; he must have a detachment from the world that eclipses his fear and murderous desires, one of the hallmarks of the samurai.", "\n\nDirector Hiroshi Inagaki uses slightly different techniques in this film than he did in _Miyamoto Musashi_. ", "He again makes use of some spectacular scenery; the opening shots of Musashi walking along the road are particularly memorable. ", "However, while the focus of the first film was on introducing the characters, something Inagaki uses the landscape for very effectively, _Duel at Ichijoji Temple_ concerns the feud between Musashi and the Yoshioka school, and as such has a focus on battle scenes rather than picturesque landscapes. ", "Inagaki also brings Musashi's writings into the film in a couple of brief scenes in which we see the shaping of his philosophy. ", "These key moments contain the actual words of Musashi's works on screen, superimposed over the moment that Musashi chose that particular path. ", "The best example of this is the scene in which Musashi, preparing for a major duel, goes to pray for his success. ", "He stops himself and thinks carefully before deciding: 'I respect deities, but I do not rely on them'. ", "These small moments offer an insight into the formation of Musashi's philosophy, and form a strong link between Inagaki's films and the real Musashi.", "\n\nThe battle scenes in this film are very effective. ", "Interestingly, many of them appear to have been filmed in studio lots, rather than on location, as was the case for many scenes in _Miyamoto Musashi_. ", "However, Inagaki makes use of the studio setting to inject some mood into the scenes, through the use of wind machines and effective lighting. ", "A good example of this is the duel Musashi has at the beginning of the film, which takes place on a windy plain at night, an atmosphere created well in the studio environment; the battle itself is extremely tense and ends abruptly and unpredictably. ", "The choreography of the battle scenes is also of a high standard, both fast and unpredictable. ", "The film's climax – Musashi's battle with the 80 Yoshioka students – is also handled very well, and in a realistic manner. ", "It is believable that Musashi could have defeated the 80 men, particularly when we see him venture into a rice paddy, in which his enemies are slowed down by the marsh-like conditions and forced to attack him one at a time.", "\n\n## THE VERDICT\n\nAlthough very different to the first entry in the _Samurai Trilogy_ , _Duel at_ _Ichijoji_ _Temple_ is a very well-made film. ", "Inagaki uses simple but effective techniques to present an entertaining story, offering interesting insights into the world of the warrior and some very well-choreographed battle scenes.", "\n\n### _Samurai 3_ _: Duel on Ganryu Island_ (1956)\n\n**Japanese Title:** _Miyamoto Musashi_ _kanketsuhen ketto Ganryujima_\n\n**Directed by:** Hiroshi Inagaki\n\n**Written by:** Adapted by Tokuhei Wakao and Hiroshi Inagaki from the novel by Eiji Yoshikawa\n\n**Produced by:** Kazuo Takimura\n\n**Edited by:** Hirokazu Iwashita\n\n**Cinematography:** Kazuo Yamada\n\n**Cast:** Toshiro Mifune (Miyamoto Musashi), Koji Tsuruta (Kojiro Sasaki), Kaoru Yachigusa (Otsu), Michiko Saga (Omitsu), Mariko Okada (Akemi), Takashi Shimura (Court Official), Minoru Chiaki (Sasuke)\n\n## PLOT SUMMARY\n\nThe story of Miyamoto Musashi continues... Musashi's reputation as a formidable samurai has spread, and Lord Yagyu, fencing instructor to the Shogun, invites him to Edo. ", "Meanwhile Kojiro has also travelled to Edo and manages to secure a position with Hosokawa, a daimyo. ", "Finding Musashi, Kojiro challenges him to a duel which Musashi first agrees to, and then postpones, explaining that he needs first to take a journey. ", "Musashi, and his students, Jotaro and Kumagoro, journey to a small village which they help protect from bandits. ", "Musashi rediscovers village life and enjoys it, no longer craving fame and fortune. ", "The two women who love him, Otsu and Akemi, find Musashi at the village, and quickly renew their animosity. ", "In a struggle, they accidentally light a fire, which draws bandits to the village. ", "Akemi dies protecting Otsu, and Kumagoro is slain before the bandits are driven away. ", "Musashi receives word from Kojiro that he is growing impatient for their duel and he leaves the village, despite Otsu begging him not to. ", "The duel takes place at Ganryu island. ", "Kojiro fights bravely, but is ultimately defeated by Musashi's superior skill. ", "Realising Kojiro is the greatest swordsman he will ever face, Musashi weeps at the loss of such a man from the world.", "\n\n## ANALYSIS\n\n_Samurai 3_ _: Duel on Ganryu Island_ is a fitting end to Hiroshi Inagaki's _Samurai Trilogy_. ", "Inagaki combines his use of effective cinematography with a compelling story and well-choreographed battle scenes.", "\n\nThis film charts the final stages of Miyamoto Musashi's development; he is no longer obsessed with fame and instead has become the ultimate samurai, one who is more than simply strong and craves only to be the best he can at his chosen art. ", "Developing his persona further, Musashi now prefers to settle matters peacefully, avoiding unnecessary violence on a few occasions throughout the film, most notably when he placates some angry thugs by swiftly plucking flies from the air with a pair of chop-sticks, intimidating them with his speed and accuracy. ", "Musashi is contrasted to Kojiro, who is very ambitious, and seeks to make his reputation in the bloodiest way possible. ", "The progression of Musashi's character over the trilogy sets each film clearly apart, and avoids the repetition of themes present in other film series.", "\n\nWith _Duel on Ganryu Island_ , Hiroshi Inagaki again takes the opportunity to utilise some grand scenery, giving specific scenes an epic backdrop. ", "The opening scene of Kojiro standing in front of a waterfall, a rainbow clearly visible in the mist, is a spectacular image. ", "When we have finished admiring it, Inagaki quickly presents us with the sinister juxtaposition of Kojiro's cruelty (to Akemi and an unfortunate swallow). ", "Similarly, the tense and protracted duel between Musashi and Kojiro takes place on a beach at sunrise, and has as its backdrop a striking image of the sun over the water; even in its more brutal moments, Inagaki's film has a certain elegance and beauty.", "\n\nThe performances achieve the typically high standard of the entire _Samurai Trilogy_. ", "Koji Tsuruta is especially good as Kojiro, given many more opportunities to shine here than in the second film, where he appeared in only a few scenes. ", "Tsuruta skilfully captures the sinister edge to Kojiro's character, giving a convincing impression of a man who craves the recognition that defeating Musashi would bring.", "\n\nThe film's climactic moment, the duel between Musashi and Kojiro, is handled particularly well. ", "Mifune and Tsuruta both bring a level of intensity to this scene, which along with Inagaki's direction creates a tense atmosphere. ", "Inagaki cuts between shots of Musashi and then Kojiro, showing the determination on each man's face. ", "When the two actually clash, this is shown through quick cuts accompanied by the sound of the weapons meeting. ", "Words do not do this sequence justice. ", "It is one of the greatest duels in any samurai film, a befitting reconstruction of one of the most famous duels in Japanese history.", "\n\n## THE VERDICT\n\n_Samurai 3_ _: Duel on Ganryu Island_ is a highly satisfying conclusion to the _Samurai Trilogy_. ", "In the fulfilment of Musashi's learning journey, we glean a lot about the ideals of the samurai. ", "Inagaki's epic direction makes the entire trilogy essential viewing for any fan of samurai films.", "\n\n### _Throne of Blood_ (1957)\n\n**Japanese Title:** _Kumonosu jo_\n\n**Directed by:** Akira Kurosawa\n\n**Written by:** Adapted by Shinobu Hashimoto, Ryuzo Kikushima, Hideo Oguni and Akira Kurosawa from William Shakespeare's Macbeth\n\n**Produced by:** Sojiro Motoki, Akira Kurosawa\n\n**Edited by:** Akira Kurosawa\n\nCinematography: Asakazu Nakai\n\n**Cast:** Toshiro Mifune (Washizu), Isuzu Yamada (Asaji), Takashi Nomura (Noriyasu), Akira Kubo (Miki), Yoichi Tachikawa (Tsuzuki), Minoru Chiaki (Yoshiaki), Takamaru Sasaki (Kuniharo), Chieko Naniwa (spirit)\n\n## PLOT SUMMARY\n\nA daimyo's two finest samurai, Washizu and Miki, meet a spirit, which predicts they will both receive promotions and that Washizu will eventually become the new daimyo of the castle, succeeded by Miki's son. ", "To their amazement, the first prediction becomes true and both Washizu and Miki are promoted to higher positions, each put in charge of an important fort. ", "When Washizu's wife, Asaji, hears of the prediction, she urges him to fulfil the prophecy by murdering the daimyo. ", "Although reluctant at first, Washizu performs the murder, and is nearly driven mad by guilt. ", "Washizu and Asaji frame another samurai, Noriyasu, for the murder, who flees with the young prince. ", "Washizu appoints Miki's son as his successor, securing his support, but changes his mind when Asaji tells him she is pregnant. ", "Washizu orders some of his men to kill Miki and his son, and although Miki is slain, his son escapes. ", "As Washizu is gradually driven mad by his deeds, his enemies begin to move against him. ", "Noriyasu, the prince and Miki's son have allied themselves to Inui, a rival daimyo, and are marching on the castle. ", "Worried, Washizu visits the spirit again, who assures him that he will not be defeated unless Spider Web Wood, the thick forest surrounding the castle, marches on him. ", "Washizu is buoyed by confidence, and tells his men of the prophecy. ", "When they see the moving forest, which Noriyasu and his men have cut down and are using as camouflage, they kill Washizu, hoping to surrender him to his enemies.", "\n\n## ANALYSIS\n\n_Throne of Blood_ is an excellent adaptation of Shakespeare's _Macbeth,_ which benefits from superb direction by Akira Kurosawa. ", "Shakespeare's dark tale proves to be a perfect match for Kurosawa's atmospheric storytelling. ", "Kurosawa and his staff of writers make quite a few changes to Shakespeare's tale, but the same basic story of a man undone by his own ambition is present in the film, and the many inspired scenes in _Throne of Blood_ , particularly those at the end, would never have been filmed if Kurosawa had stuck strictly to the original story.", "\n\nThe most outstanding aspect of _Throne of Blood_ is Kurosawa's use of cinematic techniques to create atmosphere. ", "The film opens with a view of a fog-shrouded plain. ", "We hear the slow deliberate lyrics of a Japanese song, lamenting man's inability to escape ambition and violence. ", "Through the fog, a memorial comes into view, revealing that a castle once stood here. ", "The memorial is engulfed in thick fog, which slowly clears to reveal the castle, back in the time when it still stood. ", "This has to be one of the greatest beginnings to a samurai film, or, for that matter,\n\nany film. ", "Kurosawa captures the themes of Shakespeare's play in a few evocative images, and catapults us into his film; we already know the castle is doomed to be destroyed, a fate which, we later discover, will be shared by the film's tragic central character.", "\n\nSpider Web Castle. _", "Throne of Blood_ directed by Akira Kurosawa and produced by Sojiro Motoki and Akira Kurosawa for Toho Studios.", "\n\nKurosawa continues this highly evocative use of images and sound throughout his film. ", "The scene in which Washizu and Miki meet the spirit is particularly creepy; the spirit sits, completely pale, and doesn't move, except to continually weave silk on a Japanese spinning wheel. ", "The interior of the spirit's hovel is also completely white, and the whole scene is bathed in a white light which gives it a stark appearance, like the billowing fog or the bleached bones we see a moment later. ", "Similarly, the sounds of Washizu's wife, Asaji, as she moves are sinister, the impression intensified when it becomes clear just how ruthless she is. ", "The way her kimono makes a quiet shuffling sound as she moves across the bare boards of her home grows increasingly chilling throughout the early moments of the film. ", "When Asaji fetches some poisoned sake, we see her disappear into a darkened room, vanishing into the darkness. ", "The sounds of her kimono dragging on the floor grow quieter and then slowly louder as she returns, sake pot in hand, walking straight towards the camera.", "\n\nWashizu (Toshiro Mifune) under attack. _", "Throne of Blood_ directed by Akira Kurosawa and produced by Sojiro Motoki and Akira Kurosawa for Toho Studios.", "\n\nKurosawa's evocative direction is coupled with one of Toshiro Mifune's most memorable performances. ", "In his leading role as Washizu, Mifune presents a picture of a man slowly going mad; from his stunned, statue-like appearance after he has killed his lord, through his manic confidence, to his despair at the film's end, Mifune's performance is an unnerving portrayal of a man who loses everything to ambition. ", "Isuzu Yamada is also unnervingly convincing in her role as Asaji. ", "She is cold and inexpressive in many of her scenes, as she encourages her husband to murder first his lord, and then his closest friend. ", "Ultimately, she too succumbs to the horror of what she and her husband have done, and Yamada portrays this well, in the classic _Macbeth_ hand-washing scene.", "\n\n_Throne of Blood_ gains most of its dramatic mileage from atmospheric storytelling, rather than frenetic action, but this film contains one of the most distinct and memorable action scenes of any samurai film. ", "The scene in which Washizu's men turn on him, attempting to kill him with vast numbers of arrows, is particularly striking. ", "Washizu frantically runs from one side of a balcony to the other, arrows thudding into the wood around him. ", "His death scene, although bloodless, has to be one of the most shocking seen in any samurai film.", "\n\n## THE VERDICT\n\n_Throne of Blood_ is a classic fusion of an archetypical story with highly skilled direction and performances. ", "One of Kurosawa's finest films, and an example of the samurai film at its best.", "\n\n### _The Hidden Fortress_ (1958)\n\n**Japanese Title:** _Kakushi-toride no san-akunin_\n\n**Directed by:** Akira Kurosawa\n\n**Written by:** Adapted by Shinobu Hashimoto, Ryuzo Kikushima, Hideo Oguni and Akira Kurosawa from the novel by Shugoro Yamamoto\n\n**Produced by:** Akira Kurosawa, Masumi Fujimoto\n\n**Edited by:** Akira Kurosawa\n\n**Cinematography:** Ichio Yamazeki\n\n**Cast:** Toshiro Mifune (General Rokurota Makabe), Misa Uehara (Princess Yuki of the Akizuki clan), Minoru Chiaki (Tahei), Kamatari Fujiwara (Matashichi), Takashi Shimura (Izumi Nagakura), Susumu Fujita (General Hyoe Tadakoro), Toshiko Higuchi (girl bought from brothel owner)\n\n## PLOT SUMMARY\n\nTwo peasant prisoners of war, Matashichi and Tahei, escape the Yamana clan and discover the hidden fortune of the defeated Akizuki clan. ", "The two peasants are found by General Rokurota, who, along with Princess Yuki and the gold, is staying in the Akizuki hidden fortress, a building carefully concealed in the mountains. ", "Princess Yuki and the gold are both wanted badly by the Yamana, and Rokurota needs to get them safely to the friendly Hayakawa clan. ", "Hearing Matashichi and Tahei's bold plan to actually travel through Yamana territory to get to Hayakawa, Rokurota decides to go with them. ", "He ensures the peasants' help by promising them a share of the gold. ", "The high-spirited Princess Yuki pretends to be a mute peasant girl, as the unusual group sets out on their journey, carrying a cargo of gold, hidden in pieces of firewood. ", "Narrowly avoiding capture many times, Rokurota and Yuki are eventually caught by their enemies. ", "They escape execution with the help of Hyoe Tadakoro, a Yamana general who is impressed by Yuki's spirit and leadership. ", "Safely in Hayakawa territory, Yuki rewards the peasants with a small trinket. ", "Grateful to have escaped with their lives, the two friends head home.", "\n\n## ANALYSIS\n\nBy far the most commercial of Akira Kurosawa's films, _The Hidden_ _Fortress_ is nonetheless an exciting adventure, featuring impressive and well-realised scenes, on a much larger scale than any of his previous films.", "\n\nKurosawa makes good use of the widescreen format (this is his first widescreen film) and a large budget to tell an epic story. ", "Legions of extras are utilised to create convincing armies on the march, army encampments and a huge peasant procession. ", "Among these scenes is a frenetic sequence depicting a riot, as prisoners of war attempt to escape. ", "Kurosawa fills a darkened screen with writhing bodies as the prisoners swarm over their guards, suggesting the horror and confusion of violence on a large scale.", "\n\nThe scenes in which Princess Yuki and General Rokurota are pursued by large numbers of enemy troops are also worthy of mention, helped along by sombre music as the Yamana troops march through the forest. ", "The action scenes throughout _The Hidden Fortress_ are also of a high quality, particularly the spear fight between Rokurota and Hyoe. ", "The two battle all over a Yamana camp in a fast-paced and exciting scene.", "\n\nThe cast of this film all perform admirably. ", "The beautiful Misa Uehara brings a nice level of haughtiness to the high-spirited Princess Yuki, while Toshiro Mifune is flawless as the stern Rokurota, giving a slight promise of his future, influential performance in _Yojimbo_. ", "Susumu Fujita and Toshiko Higuchi also perform very well in their respective roles.", "\n\nInterestingly, despite the large numbers of extras used for lavish staging, the most influential element of _The Hidden Fortress_ is the way much of the story is told from the perspective of the two peasants, Matashichi and Tahei. ", "The constant bickering between these two characters is always amusing, particularly in the way they always seem to forget all their petty arguments the moment trouble looms. ", "Minoru Chiaki and Kamatari Fujiwara are to be commended for the energy they bring to their roles; despite their obvious greed the peasants come across as likeable characters. ", "Much of the humour in the film comes from the way these two interact with both each other and the remaining characters. ", "The scene in which Matashichi and Tahei attempt to convince Princess Yuki, who they believe is deaf and mute, that they want to take her gold-laden horse for a drink, is particularly amusing as the two engage in increasingly stupid sign language, all the while bickering over who is doing a better job.", "\n\nHowever, the two peasant characters do not only provide comic relief. ", "They also allow the audience a way into the film. _", "The Hidden_ _Fortress_ tells a story of royalty and generals, of big events involving important people. ", "While exciting, such stories are often difficult for audiences to relate to, as they have little in common with the central characters. ", "In Matashichi and Tahei, writers Shinobu Hashimoto and Ryuzo Kikushima give the audience two regular guys, just trying to get along in life, something most of us can easily relate to.", "\n\nIt was this element of _The Hidden Fortress_ that had a large influence on world cinema. ", "George Lucas has stated that the film was one of his main inspirations when writing the script for _Star Wars:_ _A New Hope_. ", "In particular, the characters of Matashichi and Tahei inspired him to tell his story largely from the perspective of two seemingly unimportant characters caught up in big events, the two droids, R2-D2 and C3P0. ", "The characters of Leia and Obi Wan Kenobi also bear a slight resemblance to Yuki and Rokurota. ", "Lucas has stated that earlier versions of the script of _Star Wars:_ _A New Hope_ actually contained scenes in which Leia and Obi Wan were making their way through enemy territory, as Yuki and Rokurota do in _The Hidden Fortress_.", "\n\n## THE VERDICT\n\n_The Hidden Fortress_ is a very enjoyable adventure film, utilising widescreen photography and large, well-staged scenes to tell an epic story. ", "Worth seeing alone for the amusing characterisation of Matashichi and Tahei.", "\n\n### _Samurai Saga_ (1959)\n\n**Japanese Title:** _Aru kengo no shogai_\n\n**Directed by:** Hiroshi Inagaki\n\n**Written by:** Adapted by Hiroshi Inagaki from Edmond Rostand's, _Cyrano de Bergerac_\n\n**Produced by:** Tomoyuki Tanaka\n\n**Edited by:** Kazuji Taira\n\n**Cinematography:** Kazuo Yamada\n\n**Cast:** Toshiro Mifune (Heihachiro Komaki), Yoko Tsukasa (Lady Ochii), Akira Takarada (Jurota Karibe), Seizaburo Kawazu (Lord Nagashima), Kamatari Fujiwara (Rakuzo, owner of the sake house), Akihiko Hirata (Akaboshi), Keiko Awaji (Nanae), Eiko Miyoshi (Okuni)\n\n## PLOT SUMMARY\n\nKomaki, a boisterous warrior with a large nose, is in love with Lady Ochii, his childhood friend, but she loves a handsome young samurai named Jurota. ", "Putting aside his own wishes, Komaki helps Jurota woo Ochii by writing him romantic poems to recite. ", "This works for a while, and culminates in Komaki making an impassioned speech to Ochii, declaring his love for her, from the cover of darkness outside her window. ", "Ochii believes Jurota to have made this speech and embraces him, but before their relationship can develop any further war breaks out. ", "At the Battle of Sekigahara Komaki and Jurota fight on the losing side and they narrowly escape the battlefield. ", "Realising Komaki's words are what Ochii really loves, Jurota urges him to make it back to her safely, committing suicide so as not to slow him down. ", "Ten years pass and Ochii has become a nun. ", "Komaki continues to visit her, but he is found by the Tokugawa, who still hunt him. ", "Tricked into a cowardly ambush, Komaki receives a fatal blow to his head. ", "He manages to visit Ochii one last time as he dies, and as she hears him read to her, she realises it was Komaki who made that speech at her window. ", "Komaki faces death bravely, regretful that he was killed in such a dishonourable fashion, but determined not to lose his indomitable spirit.", "\n\n## ANALYSIS\n\nAn adaptation of Edmond Rostand's play _Cyrano de Bergerac,_ _Samurai_ _Saga_ makes use of some interesting subject matter. ", "The material works very well in the context of a samurai film, and director Hiroshi Inagaki should be commended for utilising such unusual material.", "\n\nInagaki is able to capture both the pathos and humour present in Rostand's play. ", "Toshiro Mifune's energetic performance as Komaki adds humour to the scenes where he and others make fun of his unusually large nose. ", "Worthy of mention is a scene early in the film when Komaki disrupts a kabuki performance. ", "Angered, Lord Nagashima's samurai attempt to insult Komaki, but he beats them to it, making fun of his own nose in an exaggerated performance, which is very amusing. ", "Komaki then goes on to defeat Nagashima's men on the stage, composing a song as he does so. ", "Inagaki and his actors are able to bring just the right amount of pathos to the more dramatic scenes of _Samurai Saga_ , without descending into melodrama. ", "The final scenes of the film are handled very well by Toshiro Mifune and Yoko Tsukasa, whose convincing performances make Kamaki and Ochii's fate all the more tragic.", "\n\nThe cinematography in _Samurai Saga_ is up to the usual high standards of Inagaki's films, containing many memorable images. ", "Inagaki and Mifune handle Komaki's death scene especially well; he challenges death among the falling petals of a cherry tree, creating a beautiful image, evocatively capturing the sadness and inevitability of the act.", "\n\nThe action scenes in _Samurai Saga_ are quite unusual, and accompany a tonal shift in the film itself. ", "The action that takes place in the first half of the film is largely comedic and bloodless, such as Komaki's amusing humiliation of Nagashima's samurai on the kabuki stage, and Jurota's battle with a large group of samurai, watched gleefully by Komaki. ", "No one is hurt in these scenes; fallen samurai simply get to their feet and run away. ", "This all changes after the Battle of Sekigahara sequence, which utilises some of the gritty battle scenes shot for _Miyamoto Musashi_. ", "The scenes where Komaki, Jurota and other survivors of the losing side are gunned down by Nagashima's troops are brutal by comparison. ", "The choreography of Komaki's last battle is also a contrast to the earlier scenes; he dodges among alleys, using the close quarters to dispatch his multiple opponents one at a time, and, in these scenes, they actually stay dead.", "\n\nThis shift in tone is very effective. ", "Inagaki creates a gentler, whimsical mood in the first half of his film, which is shattered by the war and its subsequent violence. ", "The earlier comedic violence causes the audience to let their guard down, which makes the real violence all the more effective.", "\n\n## THE VERDICT\n\n_Cyrano de_ _Bergerac_ , samurai style. ", "In the hands of a skilled director like Hiroshi Inagaki this works very well, and proves the flexibility of the genre. ", "\n\n# THE 1960s\n\nThe 1960s saw an explosion of excellent samurai films, which forever changed the genre. ", "This trend was brought about by Akira Kurosawa and two of his early 1960s films, _Yojimbo_ and _Sanjuro_. ", "Both starred Toshiro Mifune as Sanjuro, a ronin with a wry sense of humour and a quick draw. ", "They featured graphic violence as it had never before been seen in samurai films; arms were cut off and shown falling to the ground, and in one particularly notable scene, blood spurts in a fine mist from the chest of one of Sanjuro's fallen opponents. ", "Furthermore, Kurosawa's films had a wonderfully dark sense of humour, with Sanjuro fashioned as a callous but immensely likeable anti-hero. ", "The moments of violence were used sparingly and to great effect in Kurosawa's films, and clearly audiences approved. _", "Yojimbo_ and _Sanjuro_ were both very successful commercially, so much so that Toei and the other companies were forced to take notice.", "\n\nThe commercial success of Kurosawa's work meant that the 1960s samurai films were free of the formulaic plots and slow choreography that had plagued many throughout the 1950s. ", "This shift in focus ensured their popularity throughout the 1960s, with many released each year. ", "This gave directors such as Kenji Misumi, Kihachi Okamoto, Masaki Kobayashi and Hideo Gosha a great deal more freedom, and resulted in consistently high-quality films throughout the 1960s. ", "These samurai films were characterised by Sanjuro-style anti-heroism and graphic violence, but many also told moving stories, and were far more than the simple genre films they appeared to be.", "\n\nThe 1960s also gave birth to Daiei studio's famous Zatoichi series. ", "Featuring a highly skilled blind swordsman, these films benefited from a novel concept, a variety of good directors and writers, and leading man Shintaro Katsu's very likeable portrayal of Zatoichi. ", "The original Zatoichi series would last into the 1980s (Katsu starring in every film), and was highly influential, spawning many imitators.", "\n\n### _Yojimbo_ (1961)\n\n**Japanese Title:** _Yojimbo_\n\n**Directed by:** Akira Kurosawa\n\n**Written by:** Ryuzo Kikushima, Akira Kurosawa\n\n**Produced by:** Ryuzo Kikushima, Tomoyuki Tanaka, Akira Kurosawa\n\n**Edited by:** Akira Kurosawa\n\n**Cinematography:** Kazuo Miyagawa\n\n**Cast:** Toshiro Mifune (Sanjuro), Tatsuya Nakadai (Unosuke), Yoko Tsukasa (Nui), Isuzu Yamada (Orin), Daisuke Kato (Inokichi), Seizaburo Kawazu (Seibei), Takashi Shimura (Tokuemon), Eijiro Tono (Gonji), Atsushi Watanabe (coffin-maker)\n\n## PLOT SUMMARY\n\nSanjuro, a ronin, arrives at a small town, and begins to provoke conflict between two criminal gangs, hoping they'll wipe each other out, cleaning up the town. ", "One of the gangs is led by Seibei and his cruel wife, Orin. ", "The other is led by Ushi-Tora and his two brothers, Inokichi, a fool, and Unosuke, a sadistic man who uses a modern revolver instead of a sword. ", "Sanjuro pretends to work as a bodyguard for both gangs, making them compete for his services. ", "When Sanjuro frees a captive woman, Nui, who's important to Ushi-Tora's gang, his machinations are undone. ", "Unosuke discovers Sanjuro's treachery, and has him badly beaten by his thugs. ", "Meanwhile, Ushi-Tora and his brothers eliminate Seibei and his gang in a surprise attack. ", "Using his cunning to escape his captors, Sanjuro is taken to a temple to recover by Gonji, a grizzled old tavern owner who despises the gangs and what they've done to his town. ", "When Gonji is taken captive and tortured by Ushi-Tora, Sanjuro returns to the town, and challenges Ushi-Tora and his gang. ", "In the bloody battle that ensues, Sanjuro defeats the entire gang. ", "Satisfied his work is done, the ronin moves on.", "\n\n## ANALYSIS\n\n1961 audiences must have known they were in for something different when they settled down to the opening scenes of _Yojimbo_. ", "The film has a feel and tone which are almost the complete opposite of the far gentler samurai films of the 1950s. ", "In the first reel of _Yojimbo_ we see a stray dog running through a dirty street, a decaying human hand in its mouth, and Sanjuro severing the arm of a thug, which we see fall to the ground. ", "Used to the gentle, gore-free choreography of the 1950s films, Japanese audiences would have been unaccustomed to such images.", "\n\nAlso, the potent tone director Akira Kurosawa brings to _Yojimbo_ would have been largely new and fresh to Japanese audiences. ", "The town Sanjuro wanders into is desolate and barren, free from any life except the aforementioned dog and the nasty thugs of two rival criminal gangs. ", "The only person enjoying himself is the coffin-maker, whose business has never been better. ", "Kurosawa matches the desolate appearance of the town with swift and graphic violence throughout _Yojimbo_ ; aside from the severed arm, we see gang members murder their enemies as they flee a burning house, and the film's climactic ending is far bloodier than any samurai film before it.", "\n\nDespite _Yojimbo_ 's reputation for violence, scenes of brutality are actually used quite sparingly in the film, with relatively few such moments appearing in comparison to other 1960s samurai films, or even Kurosawa's earlier work, _Seven Samurai_. ", "The graphic scenes, spread throughout, are used to punctuate key moments, often sudden and unexpected, so the audience doesn't become desensitised to their effect.", "\n\nSanjuro (Toshiro Mifune) in action. _", "Yojimbo_ directed by Akira Kurosawa and produced by Ryuzo Kikushima, Tomoyuki Tanaka and Akira Kurosawa for Toho Studios.", "\n\nAmazingly, Kurosawa is able to blend this sombre, violent tone with humour to create a very effective black comedy. ", "Sanjuro himself has an unusual wit, and his callousness makes much of the film darkly funny; after killing three thugs he casually remarks to the coffin-maker that he should make three more coffins. ", "Worthy of mention is Inokichi (Daisuke Kato), brother of Ushi-Tora, the leader of one of the rival gangs. ", "Inokichi is very stupid, and the scene in which he is tricked into helping carry a badly beaten Sanjuro (who is hidden in a coffin) to safety is made hilarious by the exuberance Daisuke Kato brings to the role. ", "Perhaps the moment which best epitomises the thread of humour running through _Yojimbo_ is when Sanjuro, badly beaten and scarred around his face, attempts to reassure Gonji that he is alright by smiling. ", "The image of Toshiro Mifune's face, made up with open wounds and dark bruises, with a huge smile, is disturbing yet funny, particularly when Gonji, horrified, remarks: 'You make it worse when you smile!'", "\n\nThe tonal shifts in _Yojimbo_ are facilitated and accentuated by changes in Masaru Sato's excellent score. ", "The theme accompanying Sanjuro's march into town is skilfully written, and perfectly conveys the energy and menace of his character.", "\n\n'You make it worse when you smile!' ", "Sanjuro (Toshiro Mifune) tries his best to look healthy. _", "Yojimbo_ directed by Akira Kurosawa and produced by Ryuzo Kikushima, Tomoyuki Tanaka and Akira Kurosawa for Toho Studios.", "\n\nThe entire cast of _Yojimbo_ performs admirably but, as usual, special mention must go to Toshiro Mifune. ", "Here he plays a character very different to his usual role of the loud, unkempt individual (for example, see his performances in _Seven Samurai_ , _Red Lion and Daredevil in the_ _Castle_ ), instead playing a stern ronin with a streak of dark humour. ", "Also worthy of mention is Tatsuya Nakadai, who performs admirably as the sadistic Unosuke, foreshadowing his classic portrayal of Ryunosuke in _Sword of Doom_.", "\n\nJapanese audiences appreciated the innovations in Kurosawa's film, and both _Yojimbo_ and its sequel, _Sanjuro_ , were hugely successful. ", "This success was so widespread that many other samurai film directors adopted their sombre tone and graphic portrayal of violence, which led to huge changes in the genre.", "\n\n_Yojimbo_ also had a considerable effect on how the anti-hero was represented, both in samurai films and genres outside of Japanese cinema. ", "Sanjuro is clearly an individual of high morals. ", "He cleans up the town because he finds corruption there; he doesn't profit from this course of action, and, in fact, nearly dies. ", "Coupled with Sanjuro's morality, however, is a callous disregard for the lives of those he judges to be evil, which clearly places him in the category of anti-hero. ", "While Kurosawa is not the first to use the anti-hero in a genre film, in _Yojimbo_ he creates his own unique brand of anti-heroism.", "\n\n_Yojimbo_ was remade by an Italian, Sergio Leone, as _A Fistful of Dollars,_ a hugely successful film which was the first of the spaghetti western genre. ", "Leone's adaptation of _Yojimbo_ was completely unauthorised, something which understandably frustrated Kurosawa. ", "He took legal action against Leone, in which he was successful, and was awarded a percentage of the takings of _A Fistful of Dollars_.", "\n\nLeone's central character, played by Clint Eastwood, also displayed a black comedy in his callousness, and was even more of an anti-hero than Sanjuro; Leone's gunslinger takes on the gangs for no reason other than profit, and at the end of the film walks away with hundreds of dollars, unlike Sanjuro, who leaves only with his life and his sword. ", "This cool form of anti-heroism would persist through the entire spaghetti western genre, which in turn would have a large effect on genre films worldwide.", "\n\n## THE VERDICT\n\nEvery aspect of _Yojimbo_ shines; Kurosawa creates a highly evocative tone, at times both deliciously sombre and hilariously funny. ", "This combined with vigorous performances from Toshiro Mifune and Tatsuya Nakadai creates what is not only one of the greatest samurai films of all time, but also one of the most entertaining films of any genre. ", "This is the perfect place to start if you haven't seen any samurai films.", "\n\n### _Sanjuro_ (1962)\n\n**Japanese Title:** _Tsubaki_ _Sanjuro_\n\n**Directed by:** Akira Kurosawa\n\n**Written by:** Adapted by Ryuzo Kikushima, Hideo Oguni and Akira Kurosawa from the novel by Shugoro Yamamoto\n\n**Produced by:** Ryuzo Kikushima, Tomoyuki Tanaka\n\n**Edited by:** Akira Kurosawa\n\n**Cinematography:** Fukuzo Koizumi, Takao Saito\n\n**Cast:** Toshiro Mifune (Sanjuro), Tatsuya Nakadai (Hanbei), Yuzo Kayama (Iori), Reiko Dan (Chidori), Takashi Shimura (Kurofuji), Kamatari Fujiwara (Takebayashi), Takako Irie (Mutsuta's wife), Masao Shimizu (Kikui), Yunosuke Ito (Mutsuta)\n\n## PLOT SUMMARY\n\nOverhearing a group of young samurai plotting to find and remove corrupt officials in their clan, Sanjuro, the ronin we met in _Yojimbo_ , reluctantly offers them his advice and help. ", "Sanjuro deduces that Chamberlain Mutsuta, the man the youths suspect, is, in fact, a good man, and that Superintendent Kikui, the man the youths thought was their ally, is actually the leader of the conspiracy. ", "Sanjuro saves the youths from the conspirator's men, then sets about helping them free the Chamberlain, who has been captured by Kikui and his men, who are attempting to make him sign a false confession. ", "Sanjuro gains the trust of Hanbei, one of the leading samurai amongst the conspirators, and infiltrates their group. ", "Although exposed as a traitor by Hanbei, Sanjuro is able to send his troops on a false errand, creating an opportunity for the youths to capture the ringleaders and rescue the Chamberlain, which they do. ", "Sanjuro turns down a place in the clan, a reward offered for his efforts, and finds Hanbei waiting for him. ", "In a final duel Sanjuro is victorious, but counsels the youths against becoming killers.", "\n\n## ANALYSIS\n\n_Sanjuro_ is Kurosawa's sequel to _Yojimbo_ , and was just as much a commercial success. ", "Toshiro Mifune reprises his role as Sanjuro, thewandering ronin, and brings the same cynicism and harsh sense of humour to the character as he did in _Yojimbo_. ", "This time Sanjuro becomes embroiled in an internal dispute taking place in a large samurai clan.", "\n\nLike _Yojimbo_ , _Sanjuro_ manages to be both brutal and humorous. ", "Much of the humour comes from Sanjuro's interaction with the young samurai, who for all their righteous zeal are woefully ineffective in the cunning game of wits Sanjuro must undertake against the corrupt officials. ", "The youths' constant blundering, and Sanjuro's reaction, creates the opportunity for several comic set pieces, all of which work extremely well thanks to a clever script and perfect comic timing from the well-picked cast. ", "In one scene, Sanjuro is finally able to convince the young samurai that the best course of action is to wait and see what move their enemy makes. ", "The youths rush around excitedly (and ineffectually), while the poor, exhausted ronin tries to get some sleep. ", "This soon becomes impossible, as the youths constantly slam the door, waking Sanjuro each time he nods off.", "\n\nThe battle scenes in _Sanjuro_ actually manage to exceed the violence of _Yojimbo_ , quite an achievement in early 1960s Japan. ", "Sanjuro's altercation with a large group of armed warriors at the film's beginning is greatly enhanced by the added sound effect of his sword cutting through fabric and flesh. ", "The duel at _Sanjuro_ 's conclusion is a true milestone for the samurai film, being the first to use the spraying-blood special effect which has become a staple of the genre. ", "To achieve the effect fake blood is held under pressure and then released at the appropriate moment, creating a vibrant spray of blood as a character is cut down. ", "It is surely here that it is used to its greatest effect. ", "As in _Yojimbo_ , the violence in _Sanjuro_ is often surprising, and used with great economy to punctuate key moments of the film.", "\n\nKurosawa flawlessly balances the humorous and violent aspects of his film, creating a highly entertaining product. ", "However, _Sanjuro_ is also thought-provoking, and for all its graphic fight sequences, ultimately delivers a condemnation of violence. ", "Unlike _Yojimbo_ , in _Sanjuro_ , the callous ronin actually meets someone who he can learn from. ", "After rescuing the Chamberlain's wife, Sanjuro is forced to consider his actions more carefully when she admonishes him for killing too readily. ", "She likens Sanjuro to a sword, saying he is too sharp. ", "Sanjuro is forced to yield to her wisdom, later becoming enraged when the blundering of the young samurai forces him to kill some of the conspirator's men. ", "Sanjuro is presented at the end of the film as a slightly tragic character; he doesn't want to kill but frequently finds it necessary for his survival. ", "He is offered a place in the clan, but cannot accept because he's accustomed to the freedom of his ronin lifestyle; he has no place in civilised society. ", "Kurosawa presents the anti-violent message in his film through a series of clever lines and Sanjuro's predicament. ", "This message is integrated seamlessly into the film, and loses none of its integrity.", "\n\n## THE VERDICT\n\nLike _Yojimbo_ , _Sanjuro_ is an absolute classic, and a must-see for anyone interested in samurai films, featuring swift battle scenes, humorous and well-crafted characters and a thought-provoking plot.", "\n\n### _The Tale of Zatoichi_ (1962)\n\n**Japanese Title:** _Zatoichi_ _monogatari_\n\n**Directed by:** Kenji Misumi\n\n**Written by:** Adapted by Minoru Inuzuka from a story by Kan Shimozawa\n\n**Produced by:** Ikuo Kubodera\n\n**Edited by:** Kanji Suganuma\n\n**Cinematography:** Chishi Makiura\n\n**Cast:** Shintaro Katsu (Zatoichi), Masayo Banri (Tane), Michio Minami (Tate), Shigeru Amachi (Hirate), Eijiro Yanagi (Sukegoro), Ryuzo Shimada (Shigezo), Hajime Mitamura (Hanji), Manabu Morita (Seisuke)\n\n## PLOT SUMMARY\n\nZatoichi, the blind masseur and deadly swordsman, arrives in the town of Iioka. ", "He decides to stay with Sukegoro, a yakuza boss he knows. ", "Sukegoro is preparing for a war with his rival, Shigezo. ", "He hopes to use Zatoichi's skill on his side, and does all he can to keep the blind man happy, assigning Tate, one of his nastier thugs, to look after him. ", "Zatoichi spends his time in Iioka relaxing, fishing at a nearby lake, where he meets Hirate, a disgraced samurai hired by Shigezo. ", "The two form a strong friendship, realising they may face each other on the battlefield. ", "Zatoichi rescues Tane, Tate's sister, from Seisuke, a yakuza thug who desires her, and she falls in love with him. ", "The tensions between the two gangs escalate and result in a war. ", "It seems as though both Zatoichi and Hirate won't participate, but Hirate is manipulated into fighting by Shigezo, which also draws Zatoichi into the fray. ", "Hirate insists they fight, as he wants to die at the hands of a master, rather than thugs. ", "Zatoichi wins the duel, but is sad to have lost his friend. ", "Sukegoro's men win the battle, and Zatoichi yells at him for the pointless waste of so many men, before seeing to Hirate's burial. ", "Tate attempts to kill him, but only ends up killing himself. ", "Tane waits on the road for Zatoichi but he avoids her by taking a longer route through the mountains.", "\n\n## ANALYSIS\n\n_The Tale of Zatoichi_ is the first film in the immensely popular Zatoichi series, which tells the story of the highly skilled blind swordsman. ", "This first entry is atypical of the series, which is most famous for frequent and well-executed battle scenes in which Zatoichi cuts down large groups of his enemies. _", "The Tale of Zatoichi_ takes a more gentle and thoughtful approach to deliver its character-driven story.", "\n\nInterestingly, the Zatoichi series begins with a film that's much closer to the work of Akira Kurosawa and Hiroshi Inagaki. ", "Director Kenji Misumi delivers some poignant scenes, both beautiful and revealing. ", "In the best of these Zatoichi and Hirate sit at the riverbank fishing; Misumi creates a sense of tranquillity with shots of the two warriors sitting in the sun, intermixed with shots of the still water, disturbed only by their fishing lines. ", "Misumi reveals much about the two characters during this scene. ", "Special mention must be made of the way he handles Zatoichi's amazing abilities, which require more than a little suspension of disbelief. ", "As Hirate approaches Zatoichi, who sits fishing, Misumi uses a simple technique to show how the blind swordsman's other senses compensate for his lack of sight. ", "Close-ups of Hirate's feet falling on the grass are intermixed with close-ups of Zatoichi's ear, the sound of Hirate's feet playing across both these shots. ", "This technique is repeated with a shot of Hirate's sword, which Zatoichi can hear moving in his belt. ", "This sequence makes later scenes, such as the moment when Zatoichi cuts a lit candle perfectly in half, all the more believable.", "\n\nMinoru Inuzuka creates some beautifully poetic moments in his script, which revolve around Zatoichi's blindness. ", "When he rescues Tane from the lustful Seisuke, Zatoichi pretends he doesn't know Seisuke is present. ", "Then, as he leads Tane away, Zatoichi dares Seisuke to attack him, asking if anyone is indeed there. ", "Seisuke is afraid and cowers away, and Zatoichi laughs, seeming to chide himself for the mistake, when in reality he knows exactly what has happened. ", "A similar moment occurs at the end of the film, achieved through Inuzuka's clever dialogue – but to say more would ruin the moment for anyone who hasn't seen it.", "\n\nAs always, Shintaro Katsu puts in a great performance as Zatoichi. ", "He's more restrained here than in later films, but still presents a very likeable, affable hero. ", "The kindness and warmth of Katsu's Zatoichi has endeared him to fans all over the world.", "\n\nThough there are fewer of them, _The_ _Tale of Zatoichi_ still mounts some very well-choreographed battle scenes. ", "When Zatoichi slices a lit candle clean in half, his blade moves so fast it's barely visible. ", "During the sequences in which yakuza gangs fight, a slow pan effectively captures a mass of writhing bodies and flashing blades. ", "A few wonderfully gory moments are scattered throughout the film, most notably when Hirate vomits blood all over his feet. ", "The duel between Zatoichi and Hirate towards the end of the film is particularly adept at conveying the dramatic weight of what has happened. ", "Katsu convincingly portrays Zatoichi's sadness for having killed his friend, provoking a profound sense of loss.", "\n\nShintaro Katsu as Zatoichi. _", "The Tale of Zatoichi_ directed by Kenji Misumi and produced by Ikuo Kubodera for Daiei Studios.", "\n\n## THE VERDICT\n\nAtypical of the popular series it spawned, _The Tale of Zatoichi_ is still a solid film, and a must-see for anyone interested in Zatoichi's humble beginnings.", "\n\n### _The Tale of Zatoichi Continues_ (1962)\n\n**Japanese Title:** _Zoku Zatoichi monogatari_\n\n**Directed by:** Kazuo Mori\n\n**Written by:** Adapted by Minoru Inuzuka from a story by Kan Shimozawa\n\n**Produced by:** Ikuo Kubodera\n\n**Edited by:** Koji Taniguchi\n\n**Cinematography:** Shozo Honda\n\n**Cast:** Shintaro Katsu (Zatoichi), Yoshie Mizutani (Setsu), Masayo Banri (Tane), Tomisaburo Wakayama – credited as Kenzaburo Jo – (Yoshiro), Yutaka Nakamura (Sanzo), Sonosuke Sawamura (Kanbei), Eijiro Yanagi (Sukegoro)\n\n## PLOT SUMMARY\n\nZatoichi makes an enemy of the Kuroda clan, but Setsu, a woman who reminds him of his first love, Chiyo, helps him to escape them. ", "Unable to find Zatoichi, the Kuroda samurai hire Kanbei, the local yakuza boss, to track him down. ", "Zatoichi escapes Kanbei's men, and returns to Sasagawa, where he plans to pay his respects to Hirate (see _Tale of_ _Zatoichi_ ). ", "Kanbei and his men pursue Zatoichi, and meet with Sukegoro, who agrees to help them. ", "Sukegoro has also been harbouring Yoshiro, a wanted criminal. ", "Sukegoro tells him to leave immediately, but has him followed, planning to betray Yoshiro to the authorities and collect a large reward. ", "Kanbei and his men confront Zatoichi and a violent battle ensues. ", "In an impressive display of swordsmanship, Zatoichi kills all the men, leaving only Kanbei alive. ", "Yoshiro appears and challenges Zatoichi. ", "It turns out that the two are brothers; Chiyo left Zatoichi when she discovered he was blind and married Yoshiro. ", "In his rage, Zatoichi cut Yoshiro's arm off. ", "Yoshiro now wants to settle the score and nearly succeeds, but Zatoichi is able to deal him a serious wound. ", "Sukegoro and his men arrive, intent on capturing Yoshiro. ", "Zatoichi helps Yoshiro escape, but he dies from his wounds. ", "Zatoichi is enraged. ", "Finding Sukegoro, Zatoichi kills him for betraying his brother.", "\n\n## ANALYSIS\n\nA satisfying sequel to _Tale of Zatoichi_ , this pushed the series forward with the kind of film that would come to dominate the series. ", "Around 20 minutes shorter than the first, _The Tale of Zatoichi Continues_ packs in a lot more of the frenetic fight scenes that would become a hallmark of the Zatoichi films.", "\n\nAnd what magnificent fight scenes they are. ", "The sight of Shintaro Katsu cleaving his way through a large number of yakuza thugs is a delight to behold. ", "Although it may seem hard to believe that a man could fight so effectively without being able to see, Katsu's astonishingly convincing movements make it easy to suspend disbelief. ", "He fights with his head bowed low, clearly concentrating on every sound around him, and strikes only when his opponents move.", "\n\nKatsu's performance as Zatoichi is as likeable as ever, but in this film his affable persona is offset by his creepy brother Yoshiro, played by Katsu's real brother, Tomisaburo Wakayama. ", "As Yoshiro, Wakayama plays a grim and inexpressive man of few words, who murders only for the sake of money. ", "Wakayama's cold stare is every bit as frightening as Katsu's chuckle is friendly, and his performance pre-dates his later role as Ogami Itto in the _Lone Wolf and Cub_ series.", "\n\nDirector Kazuo Mori handles the highly charged fight scenes very well. ", "Yet, there are some touching moments between the bloody scenes, which hark back to _Tale of Zatoichi_. ", "Zatoichi's brief experience of domesticity with the beautiful Setsu is tender, and made all the more fleeting by the arrival of Kanbei's thugs. ", "The moment when Zatoichi returns to the lake where he and Hirate used to go fishing, and considers his life thus far, is suitably calm. ", "The moment when Yoshiro dies, just after the two brothers have ended their long feud, is emotionally charged and sensitively handled.", "\n\n## THE VERDICT\n\nWith this film, the Zatoichi series found the voice it would use for the next 24 films. ", "Some Zatoichi films contain even more action, but _The_ _Tale of Zatoichi Continues_ founded its reputation for well-executed, and bloody, battle scenes. ", "Essential for Zatoichi fans, this film is worth seeing alone for Katsu and Wakayama's performances.", "\n\n### _The 47 Ronin_ (1962)\n\n**Japanese Title:** _Chushingura_ _–_ _Hana_ _no maki yuki_ _no_ _maki_\n\n**Directed by:** Hiroshi Inagaki\n\n**Written by:** Adapted by Toshio Yasumi from the play by Shoraku Miyoshi, Senryu Namiki, Izumo Takeda\n\n**Produced by:** Sanezumi Fujimoto, Tomoyuki Tanaka, Hiroshi Inagaki\n\n**Edited by:** Hirokazu Iwashita\n\n**Cinematography:** Kazuo Yamada\n\n**Cast:** Koshiro Matsumoto (Chamberlain Kuranosuke Oishi), Yuzo Kayama (Lord Naganori Asano), Chusha Ichikawa (Lord Yoshinaga Kira), Tatsuya Mihashi (Yasubei Horibe), Akira Takarada (Gunpei Takada), Yosuke Natsuki (Kinemon Okano), Makoto Sato (Kazuemon Fuwa), Tadao Takashima (Jyujiro Kan), Takashi Shimura (Hyuobu Chishaka), Toshiro Mifune (Genba Tawaraboshi), Setsuko Hara (Riku Oishi), Yuriko Hoshi (Otsuya)\n\n## PLOT SUMMARY\n\nWhen Lord Asano is appointed Head of Reception for an important ceremony, he refuses to bribe Kira, the Grand Master of Ceremonies, a particularly nasty, greedy old man. ", "Despite Kira's bullying, Asano won't break from his principles. ", "The strain grows too much for Asano when Kira refuses to tell him how to conduct the ceremony, and he draws his sword, trying to cut down his tormentor. ", "Having drawn his sword in the Shogun's palace, Asano is sentenced to commit seppuku. ", "Asano's samurai are displeased, and wish to remain in Asano's castle and fight the troops sent to claim it. ", "Oishi, the Chamberlain of the Asano samurai, convinces them to leave peacefully, hoping to reinstate the clan with Daigaku, Asano's brother, as the new lord. ", "When the Shogun banishes Daigaku, Oishi is forced to reconsider his position. ", "He decides on a course of justice, seeking to punish Kira for his crimes. ", "Oishi lives a false life, as a decadent drunk, hoping to fool Kira and his allies. ", "Many of the other ronin make similar sacrifices. ", "They are successful in fooling the authorities, and when the time comes, they assemble in Edo. ", "In a brave assault on Kira's mansion, the 47 ronin find and behead him. ", "The ronin are then ordered to commit seppuku, a punishment they accept, now that they've found justice for their dead lord.", "\n\n## ANALYSIS\n\n_The 47 Ronin_ is a true classic of the samurai film genre, and captures the very essence of the samurai ideal. ", "Based on historical events, which have become legendary through numerous retellings, _The 47 Ronin_ is a story of total loyalty and dedication.", "\n\nThe story of the 47 loyal ronin is a traditional tale in Japan, and one which Japanese audiences in 1962 would have been very familiar with, in much the same way that archetypical stories such as _Romeo and Juliet_ are immediately recognisable to western audiences. ", "As such, _The_ _47 Ronin_ can be a bit confusing to those unfamiliar with the traditional stories. ", "There are lots of characters and subplots, all variously linked to the central story of the ronin. ", "Don't be at all surprised if you find it difficult to remember who certain characters are; many are only introduced very briefly. ", "This is not a fault in the film; Japanese audiences would have no problem following the story, simply because they already know it. ", "Don't be too concerned about following the various subplots first time round; the central story is the most important, and is a rewarding viewing experience all of its own. ", "With subsequent viewings, the subplots become easier to follow, and make _The 47 Ronin_ an even more enriching film.", "\n\nHaving said this, the film's basic plot is a moving experience, and shows the best side of the samurai's dedication and loyalty. ", "The hardships the ronin suffer, and the sacrifices they are prepared to make, all for the sake of their dead lord, are truly amazing, and make for compelling viewing. ", "Chamberlain Oishi makes the biggest sacrifice of all: in order to fool his enemies, Oishi divorces his wife and adopts the life of a lazy playboy, much to the scorn and ridicule of many other ronin. ", "It's particularly moving when Oishi hears of the death of one of the ronin; struggling to contain his emotions he continues to party in a brothel, sad that his friend has died, but unable to show it. ", "Another of the ronin, Okano, makes a similarly difficult sacrifice: he courts Otsuya, the sister of a carpenter, in order to get the plans to Kira's new house. ", "When Okano realises he actually loves the girl, he grows to despise himself for using her, but does so anyway, and secures the plans. ", "The manner in which these men put aside all their personal concerns to pursue their just cause is a perfect representation of the unwavering loyalty of the ideal samurai.", "\n\nDirector Hiroshi Inagaki gives this story the epic treatment it deserves, taking us inside lush mansions and palaces, and, as always, making use of beautiful Japanese landscapes. ", "Having already told the epic story of master swordsman Miyamoto Musashi, Inagaki has the right experience to make the best of such larger-than-life material. ", "The battle at the end of the film is magnificent; the 47 ronin fight their way through Kira's mansion in a series of beautifully choreographed fight scenes, which not only look fantastic, but are also extremely convincing.", "\n\n## THE VERDICT\n\nA classic film, although potentially confusing to non-Japanese audiences. ", "Don't make this your first samurai film; Inagaki's _Samurai Trilogy_ or Kurosawa's _Yojimbo_ are much better places to start. ", "However, if you like the genre, and want to see what bushido really meant, then make sure to watch _The 47 Ronin_.", "\n\n### _Hara-kiri_ (1962)\n\n**Japanese Title:** _Seppuku_\n\n**Directed by:** Masaki Kobayashi\n\n**Written by:** Story by Yasuhiko Takiguchi, screenplay by Shinobu Hashimoto\n\n**Produced by:** Tatsuo Hosoya\n\n**Edited by:** Hisashi Sagara\n\n**Cinematography:** Yoshio Miyajima\n\n**Cast:** Tatsuya Nakadai (Hanshiro), Rentaro Mikuni (Kageyu), Shima Iwashita (Miho), Akira Ishihama (Motome), Tetsuro Tamba (Hikokuro), Yoshio Aoki (Umenosuke), Ichiro Nakaya (Hayato), Yoshio Inaba (Jinnai)\n\n## PLOT SUMMARY\n\nIn recent times many impoverished ronin have arrived at clan mansions, and requested to commit ritual suicide in their grounds, claiming that they can no longer endure their impoverished lifestyles. ", "Yet most have no desire to kill themselves, knowing full well that the clans will give them money simply to be rid of them. ", "This presents a problem for the clans, who see this as a form of extortion. ", "When Motome, a young ronin, requests to commit suicide in the Iyi mansion, rather than simply deny the request or give him money, Kageyu, the clan counsellor, has his samurai force the young man to commit hara-kiri, even refusing his request for a two-day postponement. ", "As if this isn't bad enough, they make him use the bamboo sword he carries; he is so poor he has sold his blades. ", "This is all done to preserve the honour of the Iyi clan and deter other ronin. ", "Motome had a sick child, and needed money for medicine – he was only driven to performing the hara-kiri scam by the most extreme circumstances.", "\n\nThe film revolves around Hanshiro, father-in-law of Motome. ", "Himself a ronin, Hanshiro realises he is most happy when he has no superiors and is with his family. ", "He praises his son-in-law for his brave actions, and curses his own stupidity for not selling his swords. ", "Hanshiro exposes the hypocrisy of the Iyi by also requesting to commit hari-kiri within their castle grounds. ", "He has previously removed the top knots of the three retainers most involved in Motome's enforced suicide. ", "According to the samurai code this is a grave dishonour, and can only be atoned by hara-kiri. ", "Hanshiro requests that these men assist with his suicide, but two of them hide in their homes, waiting for their hair to re-grow, demonstrating the same cowardice they accused Motome of. ", "Kageyu has his men attack Hanshiro, and he fights bravely, eventually succumbing to the Iyi's guns. ", "With Hanshiro dead, Kageyu sets about concealing the entire incident, something he does so well that the Iyi clan is praised for its handling of the ronin.", "\n\n## ANALYSIS\n\n_Hara-kiri_ is a tremendous film, and among the most moving and honest of the samurai genre. ", "Director Masaki Kobayashi, famous for films which explored the downtrodden, makes clear here the potential for the inhumane cruelty inherent in the samurai code. ", "This is in stark contrast to many other samurai films, which portray the harsh lifestyle of the samurai in a positive light.", "\n\nKobayashi shows the propensity of the samurai for senseless cruelty through the actions of the Iyi clan. ", "Their inhuman treatment of Motome is done entirely to preserve the good name of their clan, and this, in essence, is the fault in the samurai philosophy that Kobayashi is drawing our attention to; reputation should never be a justification for cruelty, and is far less important than the ethical treatment of human beings. ", "This is also highlighted through the character of Hanshiro, who comes to realise that those he loves are far more important than the social standing he has lost.", "\n\nThe story of Hanshiro and Motome is moving, and the audience cannot help but feel for their plight. ", "Yet, Kageyu and the Iyi learn nothing from these sad events; the hiding retainers are also forced to commit hara-kiri, and the entire incident is concealed in the clan records. ", "The Iyi are even praised for the way they dealt with the situation. ", "This shows the stubborn and unbending nature of the samurai code, which ultimately only history was able to defeat.", "\n\nThis frank and unyielding plot is effectively rendered by Kobayashi's skilled direction, and some robust performances. ", "The film abounds with memorable scenes and images. ", "The scene in which Motome is forced to cut his stomach open with a bamboo blade is harrowing in its brutality; we see Motome trying to force the blunt object into his chest many times, finally succeeding when he puts his full weight on it. ", "Akira Ishihama convincingly conveys the agony and desperation, which in its gory explicitness conveys the cruelty of the Iyi samurai. ", "The battle between Hanshiro and the Iyi samurai is very well realised, and more realistically than in many other samurai films. ", "It is clear that Hanshiro won't survive against so many enemies, and he becomes progressively more injured and fatigued as the battle progresses. ", "His duel with Hikokuro is also of the highest quality, filmed in long grass on a windy day with the constantly shifting grass creating a moody backdrop. ", "Many highly evocative and symbolic single frames pepper _Hara-kiri_ , such as the large Iyi clan crest, splattered in blood during Hanshiro's battle with the Iyi samurai.", "\n\nHanshiro (Tatsuya Nakadai) battles the Iyi samurai. _", "Hara-kiri_ directed by Masaki Kobayashi and produced by Tatsuo Hosoya for Shochiku Studios.", "\n\nTatsuya Nakadai delivers one of his best performances as Hanshiro, and skilfully shows a wide range of emotions. ", "We see Hanshiro at several different stages of his life, and Nakadai presents them all with complete conviction. ", "The sensitivity of Nakadai's performance imbues the scenes where he happily plays with his grandson with a touching quality, and makes the events which befall his family all the more tragic. ", "In contrast, Nakadai's portrayal of the later Hanshiro, who, having lost everything, is disturbingly morose and inexpressive, creates a character that's both sympathetic and slightly disturbing. ", "Nakadai's performance in this film is rightly hailed by many as one of the greatest of the samurai film genre.", "\n\n## THE VERDICT\n\nThe stark honesty of _Hara-kiri_ exposes a side of the samurai code ignored by many other samurai films. ", "With a moving plot, a classic performance by Tatsuya Nakadai and assured direction by Masaki Kobayashi, it's a captivating film. ", "Not only for samurai film fans, _Hara-kiri_ is an example of cinema at its best.", "\n\n### _New Tale of Zatoichi_ (1963)\n\n**Japanese Title:** _Shin Zatoichi_ _monogatari_\n\n**Directed by:** Tokuzo Tanaka\n\n**Written by:** Adapted by Minoru Inozuka from a story by Kan Shimozawa\n\n**Produced by:** Masaichi Nagata\n\n**Edited by:** Hiroshi Yamada\n\n**Cinematography:** Chishi Makiura\n\nCast: Shintaro Katsu (Zatoichi), Mikiko Tsubouchi, Chitose Maki, Mieko Kondo, Seizaburo Kawazu\n\n## PLOT SUMMARY\n\nZatoichi, the blind master swordsman, grows tired of his violent lifestyle, and resolves to lead a peaceful life. ", "He meets with Banno, the ronin who taught him swordsmanship, and stays in his village for some time. ", "Banno is a respected teacher, but he is secretly involved with the Tengu group, a gang of fugitive ronin. ", "His main concern, however, is ensuring that his sister, Yoyoi, marries into a rich family so he can regain a little of his lost status. ", "Banno and the Tengu gang hatch a plot to kidnap one of his students, who has a wealthy father. ", "They are successful and arrange to collect the ransom. ", "Zatoichi and Yoyoi's relationship develops, and the two wish to marry. ", "They ask Banno's permission, but he flies into a rage, refusing to let Yoyoi marry someone of such low status. ", "Humiliated, Zatoichi leaves. ", "He also discovers Banno's plot. ", "The next morning, the Tengu group set out to collect their ransom. ", "They are intercepted by Zatoichi who kills them all. ", "Banno, meanwhile, kills the father of his pupil, stealing the ransom money, which he plans to use to buy a lavish wedding for Yoyoi. ", "Zatoichi confronts Banno and narrowly defeats him in a tense battle, witnessed by Yoyoi. ", "Realising that he will never escape violence, Zatoichi continues his nomadic lifestyle, leaving Yoyoi behind.", "\n\n## ANALYSIS\n\n_New Tale of Zatoichi_ , the third entry in the Zatoichi series, is an involving film that brings a new dimension to the blind swordsman. ", "In this sad tale, Zatoichi is forced to consider the morality of his lifestyle, a lifestyle he is ultimately unable to escape.", "\n\nThe film's production values are much higher than the first two. ", "Clearly Daiei were prepared to spend a lot more on this film, based on the success of previous Zatoichi episodes. _", "New Tale of Zatoichi_ benefits from vibrant colours and smooth pans, and, in many ways, heralded the quality production values, emotional stories and large helpings of yakuza carnage that the series would go on to deliver.", "\n\nThese improved production values bring to life a script of a high standard, which in turn is supported by Shintaro Katsu's emotive performance. ", "It is Zatoichi's attempt to change his violent lifestyle which is the most compelling and dramatic aspect of Kan Shimozawa and Minoru Inozuka's story. ", "Katsu has no trouble grasping these new elements of Zatoichi's character. ", "He portrays the blind swordsman's hopes for a nonviolent lifestyle, his joy when he thinks he has found it, and his anger and sadness when it is taken away from him, with such conviction and integrity that only the hardest of viewers could fail to be touched by his plight. ", "The scenes between Zatoichi and Yoyoi are played at just the right dramatic level to elicit audience sympathy.", "\n\nLike The _Tale of Zatoichi Continues_ , _New Tale of Zatoichi_ contains a plethora of terrific fight scenes. ", "Katsu is at his sword-swinging best, this time fighting not only yakuza, but a nasty group of itinerant ronin, the Tengu group. ", "The duel at the film's conclusion between Zatoichi and Banno is swift and unpredictable, creating an evocative atmosphere; for a few tense moments it's impossible to know who has won.", "\n\n## THE VERDICT\n\nThe Zatoichi series just gets better and better. ", "With the third film, the series was really getting into its stride, presenting a likeable, morally conflicted hero, and a host of wonderfully executed fight scenes. _", "New_ _Tale of Zatoichi_ is a great way to introduce yourself to the series (there's no need to have seen the first two films) and it's a good representation of the series as a whole. ", "A real treat for those interested in Zatoichi and samurai films in general.", "\n\n### _Three Outlaw Samurai_ (1964)\n\n**Japanese Title:** _Sanbiki_ _no samurai_\n\n**Directed by:** Hideo Gosha\n\n**Written by:** Keiichi Abe, Eizaburo Shiba, Hideo Gosha\n\n**Produced by:** Ginichi Kishimoto, Tetsuro Tamba\n\n**Edited by:** Kazuo Ota\n\n**Cinematography by:** Tadashi Sakai\n\n**Cast:** Tetsuro Tamba (Shiba), Mikijiro Hira (Kikyo), Isamu Nagato (Sakura), Miyuki Kuwano (Aya), Kamatari Fujiwara (Jinbei), Yoko Mihara (Maki), Toshie Kimura (Ine), Tatsuya Ishiguro (Matsushita), Yoshiko Kayama (Oyasu), Jun Tatara (Yasugoro), Kyoko Aoi (Mitsu)\n\n## PLOT SUMMARY\n\nShiba, a wandering ronin, helps some peasants who are being overtaxed by their cruel magistrate. ", "Jinbei, the leader of the peasants, has captured Aya, the magistrate's daughter, and hopes to exchange her for a reduction in taxes. ", "Shiba helps the peasants against the magistrate and his men, who attack the old mill where Aya is held. ", "Sakura, a ronin sent by the magistrate, decides to join the peasant side. ", "The hostage situation is finally broken when some ronin hired by the magistrate kidnap Yasu, the daughter of Gasaku, one of the peasants in the mill. ", "Although Yasu kills herself, hoping that her father won't give in, Shiba and the others are drawn out of the mill, and Aya is returned to her father. ", "Shiba strikes a bargain with the magistrate, accepting punishment for the peasants' crimes: 100 lashes, on the condition that there are no other retributions. ", "The magistrate does not keep his word: he tortures Shiba and has three of the peasants killed by his ronin. ", "Kikyo, one of the magistrate's samurai, disapproves of his treachery and helps Sakura and Aya, who has grown to love Shiba, free him. ", "The magistrate sends some of his samurai after Kikyo, and this forces him to join Shiba's side. ", "Shiba and Kikyo have a showdown with the most skilled swordsmen in the magistrate's clan. ", "Although bribed to leave by the magistrate, Sakura arrives to help his friends, and they are victorious. ", "Despite his best efforts, Shiba cannot convince the terrified peasants to take their complaints to the magistrate's daimyo. ", "Enraged, he goes to kill the magistrate, but is stopped by Aya's pleading for his life. ", "The three outlaws leave, travelling the road together.", "\n\n## ANALYSIS\n\n_Three Outlaw Samurai_ is the first film of Hideo Gosha, a talented director who would go on to make many memorable samurai films. ", "It's actually adapted from a TV series that Gosha directed, and he shows his considerable talent for cinema in his first feature-length project.", "\n\nGosha's primary concern here is telling an exciting and entertaining story, and he draws on his earlier experience as a director for television to well and truly deliver. ", "As Patrick Galloway has pointed out, Gosha's TV-style direction imbues his films with a fast, rhythmic pace and a sense of immediacy that clearly sets him apart from other samurai film directors. ", "Gosha tends not to use static scenic shots, like Kurosawa and Inagaki did to great effect throughout their careers, but instead relies on a rapid progression of lively scenes. ", "This pacing and rhythm imbues Gosha's films with a life of their own, giving the impression of a story that's constantly in motion.", "\n\nThe plot of the film is one of its finest strengths. ", "A fairly simple tale about three ronin helping peasants against a cruel magistrate, the plot has clearly defined good guys and bad guys, yet pits them against each other in interesting ways. ", "The hostage situation at the beginning of the film, and the horrible way it's ultimately resolved, makes for compelling viewing, as do the scenes in which the ronin and the peasants are confronted by the magistrate's brutal, hired thugs.", "\n\n_Three Outlaw Samurai_ shares some similarities in both tone and plot with Kurosawa's immensely successful _Yojimbo_ and _Sanjuro_. ", "Indeed, as both Alain Silver and Patrick Galloway have pointed out, Gosha likes to quote these and other films in his work. ", "However, rather than try to copy the darkly comedic tone of these films, Gosha creates a different, though no less satisfying, feeling. ", "His characters are not such extreme anti-heroes as Sanjuro, because they are not as callous about the loss of human life. ", "Shiba helps the peasants out of a desire to prevent bloodshed, rather than a wish to inflict it on evil men, which is one of Sanjuro's motivations in _Yojimbo_. ", "Similarly, it is hard to imagine Sanjuro showing the mercy Shiba does at the end of the film, or being as guilty about a single death as Sakura is. ", "In many respects, this makes Gosha's heroes much easier to relate to than Kurosawa's anti-heroes. ", "Rather than the dark comedy that's employed by Kurosawa, Gosha creates a tone of camaraderie between his three, very likeable central characters, which extends to the audience.", "\n\nThese three central heroes are very well cast. ", "Tetsuro Tamba, with his chiselled jaw and stern delivery, is perfect as the morally heroic Shiba, a man who sticks to his principles no matter what. ", "Isamu Nagato plays the slightly more flawed, and thus comic, Sakura, who not only provides occasional humour but also drama. ", "Mikijiro Hira is the slightly ambiguous Kikyo; with just the right amount of inscrutability, we're unsure which side he will ultimately take right up to the point he actually makes his decision. ", "These three central characters, the three outlaws of the title, are the driving force behind Gosha's film and the end result is a credit both to the script and their talent.", "\n\nThe three outlaws: Shiba (Tetsuro Tamba), Kikyo (Mikijiro Hira) and Sakura (Isamu Nagato). _", "Three Outlaw Samurai_ directed by Hideo Gosha and produced by Ginichi Kishimoto and Tetsuro Tamba for Shochiku Studios.", "\n\nGosha shows right from the beginning that he has a great aptitude for directing battle scenes. ", "Like the rest of the film, these fights have a wonderful sense of rhythm and pacing, yet never seem overly stylised. ", "The film's finale, in which the three heroes do battle with skilled warriors from the magistrate's clan, is beautifully constructed, and Tamba, Nagato and Hira prove to be every bit as fun to watch cleaving through their enemies as Shintaro Katsu or Toshiro Mifune. ", "Nagato is particularly entertaining as Sakura, enthusiastically swinging a spear rather than a sword.", "\n\n## THE VERDICT\n\nWith this terrific first film, Gosha earned himself a place alongside the other masters of the samurai film. ", "Essential viewing.", "\n\n### _Samurai Assassin_ (1965)\n\n**Japanese Title:** _Samurai_\n\n**Directed by:** Kihachi Okamoto\n\n**Written by:** Adapted by Shinobu Hashimoto from the novel by Jiromasa Gunji\n\n**Produced by:** Tomoyuki Tanaka, Reiji Miwa, Toshiro Mifune\n\n**Edited by:** Yoshitami Kuroiwa\n\n**Cinematography:** Hiroshi Murai\n\n**Cast:** Toshiro Mifune (Niiro), Keiju Kobayashi (Kurihara), Michiyo Aratama (Okiku), Yunosuke Ito (Kenmotsu), Eijiro Tono (Kisoya), Koshiro Matsumoto (Li Naosuke), Tatsuyoshi Ehara (Hayama)\n\n## PLOT SUMMARY\n\nA group of samurai plan to assassinate Li Naosuke, a daimyo and Elder of the Shogunate. ", "Known as the Mito Tengu group, these conspirators are made up of samurai from clans which came off badly in a power struggle against Li, which led to many of their comrades being executed. ", "Thus far, Li has been able to avoid the Tengu group, who believe there's a traitor in their ranks and begin to observe two ronin in their group, Niiro and Kurihara. ", "Niiro doesn't know who his parents are; his mother, a concubine, told him he was of samurai blood, but refused to name his father. ", "Looked after by Kisoya, a wealthy merchant, Niiro was trained as a samurai, but became a ronin when his request to marry a princess was denied by her daimyo father. ", "Enraged, Niiro abandoned his studies and began life as a ruffian, all the while dreaming of becoming a samurai. ", "He joins the Mito Tengu in the hope that if he kills Li he will be employed by one of the clans that hates him. ", "Kurihara turns out to have a connection to Li through his wife, and Niiro is ordered to kill him. ", "Despite being good friends with Kurihara, Niiro kills him, and is then angered to discover that Kurihara was not the traitor at all. ", "The Tengu group discover that Niiro's father is in fact Li, and they attempt to have him killed. ", "Niiro survives and arrives the next morning to attack Li. ", "In a violent battle, most of the Tengu group and Li's entourage are killed, but Niiro succeeds in beheading Li, unaware that he has killed his father.", "\n\n## ANALYSIS\n\n_Samurai Assassin_ is a film rich with irony, suspense and violence. ", "Directed by Kihachi Okamoto, who also made the thoroughly entertaining _Sword of Doom_ and _Kill_ _!_ , _", "Samurai Assassin_ is without doubt a standout samurai film.", "\n\nThe rich vein of irony that runs through _Samurai Assassin_ is by far the film's most distinguishing feature. ", "If you've skipped the above plot summary hoping not to spoil the film, then I suggest you stop reading this analysis, and see _Samurai Assassin_ as soon as you can. ", "Unfortunately, it is impossible to discuss this film without referring to some of the revelations contained within the plot.", "\n\nNiiro Tsuruchiyo is so desperate to become an employed samurai that he joins a group of conspirators, who seek to kill Li Naosuke, a daimyo who has earned the ire of several clans. ", "Li turns out to be Niiro's father, who could potentially make him a samurai, but Niiro, ignorant of this and desperate to impress the other clans, brutally kills Li. ", "Furthermore, Li is the only man holding the Shogunate government together; without him, it will collapse, taking with it the samurai class. ", "Niiro is completely unaware of the self-destructive nature of his actions, and there is a delicious sense of irony to this plot, which stays with the viewer for some time after the film. ", "The scene of Niiro triumphantly staggering along, with Li's head on the end of his sword, is not only disturbing, but also strangely satisfying, as it serves to cement the ironic tone of _Samurai_ _Assassin_. ", "Like all good tragedies, we know how this film is going to end, and like many samurai films, _Samurai Assassin_ doesn't take the easy road with a happy ending. ", "As we are left with the image of Niiro with his father's head on the end of his sword, we can only wonder at what will happen to him when he discovers the truth of what he has done.", "\n\nOkamoto's direction in _Samurai Assassin_ is of the high standard that fans have come to expect of him, especially in the battle scenes. ", "The epic and extremely gory battle at the end of the film has got to be one of the finest in the genre. ", "It begins with rapidly cut shots of the conspirators preparing themselves for the arrival of Li's entourage. ", "They perform fast actions, checking swords, shutting umbrellas and kicking their sandals off – creating an impression of tension and anticipation. ", "Once the battle actually starts, Okamoto spares no blood. ", "The screen is filled with flailing bodies, striking at each other any way they can, covered in their own blood and that of their enemies. ", "This all takes place on a thick cover of snow, which is quickly stained a dark colour. ", "Snow falling from the sky also obscures the audience's view, creating a sense of chaotic confusion, which is suitable for the frenetic scenes taking place. ", "Niiro's beheading of Li is particularly gory, with blood literally filling the entire screen.", "\n\n## THE VERDICT\n\n_Samurai Assassin_ combines a richly ironic plot with one of the most well-constructed battle scenes in the entire genre. ", "This and _Sword of_ _Doom_ are Okamoto at his best.", "\n\n### _Sword of Doom_ (1966)\n\n**Japanese Title:** _Dai-bosatsu toge_\n\n**Directed by:** Kihachi Okamoto\n\n**Written by:** Adapted by Shinobu Hashimoto from the novel by Kaizan Nakazato\n\n**Produced by:** Sanezumi Fujimoto, Kaneharu Minamizato, Masayuki Sato\n\n**Edited by:** Yoshitami Kuroiwa\n\n**Cinematography:** Hiroshi Murai\n\n**Cast:** Tatsuya Nakadai (Ryunosuke), Yuzo Kayama (Hyoma), Michio Aratama (Ohama), Toshiro Mifune (Toranosuke), Yoko Naito (Omatsu), Tadao Nakamaru (Isamu), Ichiro Nakaya (Bunnojo)\n\n## PLOT SUMMARY\n\nRyunosuke, a swordsman renowned for his skill, is begged to let his opponent win in an upcoming fencing match by the man's wife, Ohama. ", "Ohama secures Ryunosuke's promise to spare her husband by sleeping with him. ", "Ryunosuke, however, wins the match, and kills his opponent in doing so. ", "Forced to leave the school, Ryunosuke takes Ohama with him for now her family have rejected her. ", "Ryunosuke falls in with a group of treacherous samurai and commits more murders in his thirst for power. ", "But he cannot escape the consequences of his actions; some relatives of his victims are stalking him: a skilled young samurai and a thief armed with a revolver. ", "Driven mad by visions of people he has murdered, Ryunosuke goes on a rampage through an inn, and the film ends suddenly with him badly wounded and surrounded by hostile samurai.", "\n\n## ANALYSIS\n\n_Sword of Doom_ is hailed by many samurai film fans as one of the greatest examples of the genre, and with outstanding direction by Kihachi Okamoto, and a classic performance by Tatsuya Nakadai, this praise is well earned.", "\n\nViolent and sombre in tone, Ryunosuke kills often, and usually only to indulge his sadistic personality. ", "He's a largely unsympathetic central character, which sets the film apart from most others in the samurai genre.", "\n\nIn arguably his greatest role, Tatsuya Nakadai's performance is highly evocative; his mixture of cold, uncaring stares and the occasional manic expression perfectly conveys Ryunosuke's sociopath tendencies. ", "During his fight scenes, Ryunosuke is methodical, coldly cutting down his enemies, on occasion showing joy as he does so. ", "Nakadai conveys this well and to disturbing effect.", "\n\nTatsuya Nakadai as Ryunosuke. _", "Sword of Doom_ directed by Kihachi Okamoto and produced by Sanezumi Fujimoto, Kaneharu Minamizato and Masayuki Sato for Toho Studios.", "\n\nOkamoto's direction surpasses even his own high standards. ", "The battles are swiftly paced, and Okamoto holds nothing back in his depiction of graphic violence. ", "Ryunosuke's battle on a forest path with some disgruntled samurai is a good example of Okamoto's skill at action scenes. ", "Shots from a variety of different angles show Ryunosuke methodically working through his enemies, cutting them down one at a time. ", "When there are no more enemies left, he stops moving and we see a close-up of his profile, a sadistic smile creeping onto his lips. ", "A classic shot of the forest path, strewn with bodies, follows and we see Ryunosuke, standing motionless in the distance. ", "In a later scene, Okamoto again makes use of snow, as he did in _Samurai Assassin_. ", "When Toranosuke, a skilled samurai sternly played by Toshiro Mifune, is confronted by a violent group of samurai conspirators, he is forced to fight them on a snow-covered road. ", "In a particularly violent moment, he cuts one of his enemies' hands off, which we see fall to the ground, and stain the snow.", "\n\nRyunosuke (Tatsuya Nakadai) follows the path of cruelty. _", "Sword of Doom_ directed by Kihachi Okamoto and produced by Sanezumi Fujimoto, Kaneharu Minamizato and Masayuki Sato for Toho Studios.", "\n\nThe scenes in which Ryunosuke goes on a rampage through an inn are among the best ever shot in a samurai film. ", "Believing the ghosts of those he has harmed are haunting him, he sees their looming, shadowy forms on the paper walls surrounding him, and hears them mocking him. ", "Striking at these phantoms, Ryunosuke completely destroys the room. ", "As he slashes through each wall, there is a sharp cry of pain, as if Ryunosuke believes he is really harming these imagined enemies, but they continue to taunt him. ", "These scenes offer a disturbing insight into Ryunosuke's twisted mind, and lead to an incredibly violent battle scene, in which he's confronted by the samurai conspirators he is supposed to be a member of.", "\n\nWhile Ryunosuke himself is an unsympathetic character, the victims of his violent actions form an emotional connection with the audience. ", "We follow the fortunes of several such characters. ", "Particularly tragic is Ohama, who, having been tricked into sleeping with Ryunosuke, then widowed by him, has to follow him when no one else will accept her. ", "She is tied even closer to him when she bears his child. ", "Faced with Ryunosuke's cruelty, Michiyo Aratama is particularly good at eliciting our sympathy for Ohama.", "\n\nBased on the early chapters of a long, serialised novel, Shinobu Hashimoto's script contains several clever devices. ", "Skilful use of metaphor is woven into both the plot and the dialogue; Ryunosuke uses a cruel form of swordplay where he lures his victims in with a series of feints before delivering a single sudden and devastating blow. ", "His teacher warns him of the dangers of using such a nasty form; a cruel sword leads to a cruel heart. ", "This idea resonates throughout the plot, and forms the core message of Okamoto's film.", "\n\nThe final scenes of Sword of Doom are frighteningly violent, when Ryunosuke is ultimately driven mad by his cruel deeds, and goes on a violent rampage. ", "The film's ending is appropriately abrupt and unpredictable.", "\n\n## THE VERDICT\n\nQuite different to most samurai films, _Sword_ _of_ _Doom_ is an entertaining examination of the consequences of cruelty for both the monster and his victims. ", "With Kihachi Okamoto's talented direction, and a captivating performance by Tatsuya Nakadai, this is a prime example of the high quality of 1960s samurai cinema.", "\n\n### _Samurai Rebellion_ (1967)\n\n**Japanese Title:** _Joi-uchi: Hairyo tsuma shimatsu_\n\n**Written by:** Adapted by Shinobu Hashimoto from the novel by Yasuhiko Takiguchi\n\n**Directed by:** Masaki Kobayashi\n\n**Produced by:** Tomoyuki Tanaka, Toshiro Mifune\n\n**Edited by:** Hisashi Sagara\n\n**Cinematography:** Kazuo Yamada\n\n**Cast:** Toshiro Mifune (Isaburo), Tatsuya Nakadai (Tatewaki), Yoko Tsukasa (Ichi), Go Kato (Yogoro), Tatsuyoshi Ehara (Bunzo), Etsuko Ichihara (Kiku), Isao Yamagata (Shobei), Shigeru Koyama (Geki), Michiko Otsuka (Suga)\n\n## PLOT SUMMARY\n\nWhen one of his concubines displeases him, Masakata, daimyo of the Aizu clan, orders that she marry Yogoro, the son of Isaburo, one of his samurai. ", "Isaburo initially refuses, wanting Yogoro to avoid marrying for political convenience, as he did. ", "However, Yogoro convinces his father that the marriage is for the best, and, surprisingly, he and his new wife, Ichi, fall in love and have a child, Tomi. ", "This brings great delight to Isaburo, who till then had been miserable and constantly berated by his nasty wife, Suga. ", "When Masakata's immediate heir dies unexpectedly, his child with Ichi, Kikuchiyo, becomes the new heir, and Masakata demands that Ichi be returned to him. ", "Isaburo and Yogoro refuse, but Suga and Bunzo, Isaburo's other son, trick Ichi into returning to the castle, where she is held prisoner. ", "Isaburo is ready to give up, but his friend Tatewaki, a border guard, convinces him not to. ", "Masakata's chamberlain has Kiku, the wife of a low-ranking samurai, work for Isaburo as a wet nurse so that Tomi doesn't starve. ", "Yogoro presents a petition for the return of Ichi, threatening to reveal Masakata's shameful behaviour to the rest of Japan. ", "Masakata sends his steward, who arrives at Isaburo's house with Ichi, hoping to force them all to declare they are no longer related. ", "Both men refuse, and Ichi responds by seizing a spear and killing herself. ", "The steward's men attack, and kill Yogoro. ", "Isaburo kills both the steward and his men, and heads for Edo with Tomi, hoping to tell the Shogunate of Masakata's shameful actions. ", "Tatewaki blocks Isaburo's progress across the border, and the two agree to a duel, which Isaburo wins. ", "In a final stand, Isaburo is killed by a large group of Masakata's men. ", "Kiku rescues Tomi, adopting her as her own.", "\n\n## ANALYSIS\n\n_Samurai_ _Rebellion_ is another moving film directed by Masaki Kobayashi, the talented filmmaker responsible for _Hara-kiri_. ", "As in _Hara-kiri_ , Kobayashi chooses compelling subject matter which elicits an emotional response from his audience.", "\n\nLike _Hara-kiri_ , _Samurai Rebellion_ tells a story of a man who refuses to adhere to the samurai code of unquestioning obedience, when he and his family are treated in an unjust and disgraceful way by his supposedly honourable superiors. ", "Isaburo's grievances are utterly justified, having had a beloved daughter-in-law snatched away for purely political reasons. ", "Though not as damning of the samurai code as _Hara-kiri_ , this film does suggest that family is far more important than any code. ", "Like Hanshiro in _Hara-kiri_ , Isaburo is ready to sacrifice all for his family.", "\n\nIsaburo makes for a very likeable, convincing character. ", "Toshiro Mifune offers another great performance as a man who has given way on so many other matters, but refuses to jeopardise the happiness of the people who are most important in his life. ", "Isaburo takes great delight in the happiness his son has found in married life (something he was never able to achieve), which Mifune conveys most movingly. ", "He convincingly portrays Isaburo's transition from the unhappy man we meet at the beginning of the film into a much warmer character. ", "His conviction adds weight to later scenes, when the family is in peril.", "\n\n_Samurai Rebellion_ also contains a memorable performance from the great Tatsuya Nakadai who is both likeable and disturbing as Tatewaki. ", "Carefully limiting his expressions, vocally and facially, Nakadai is a man who carefully considers his actions. ", "He only lets emotion creep into his performance in a few scenes, which consequently have great impact. ", "In many ways Tatewaki is the opposite of Isaburo; where Mifune's character is emotional and expressive, Nakadai's isn't. ", "It's a juxtaposition that works well, and results in some entertaining scenes between the two.", "\n\nAs in _Hara-kiri_ , Kobayashi stages some frantic battle scenes. ", "The duel between Isaburo and Tatewaki is a tense and unpredictable exchange of blows; by this point in their careers Mifune and Nakadai were both very experienced at swordplay. ", "The scenes in which Isaburo battles the Aizu clan samurai are also very well constructed; Isaburo grows progressively more fatigued and wounded as he battles on; each time we think he has defeated his enemies, more appear from the thick undergrowth surrounding him, accompanied by the sound of gunshots.", "\n\n## THE VERDICT\n\nContaining a compelling and moving story and perhaps the best ever pairing of stars Mifune and Nakadai, _Samurai Rebellion_ is an indisputable classic of the samurai film genre.", "\n\n### _Kill_ _!_ (", "1968)\n\n**Japanese Title:** _Kiru_\n\n**Directed by:** Kihachi Okamoto\n\n**Written by:** Adapted by Akira Murao and Kihachi Okamoto from the novel by Shugoro Yamamoto\n\n**Produced by:** Tomoyuki Tanaka\n\n**Edited by:** Yoshitami Kuroiwa\n\n**Cinematography:** Rokuro Nishigaki\n\n**Cast:** Tatsuya Nakadai (Genta), Etsushi Takahashi (Hanji), Naoko Kubo (Tetsutaro), Shigeru Koyama (Ayuzama), Akira Kubo (Monnosuke), Seishiro Kuno (Daijiro), Tadao Nakamaru (Shoda), Eijiro Tono (Hyogo), Isao Hashimoto (Konosuke), Yoshio Tsuchiya (Matsuo)\n\n## PLOT SUMMARY\n\nA ronin, Hanji, and a yakuza, Genta, meet in an all but deserted town. ", "There they become embroiled in the efforts of a group of seven samurai to wipe out the corruption from their clan. ", "As it turns out, Hanji is in fact a peasant who hopes to become a samurai, and Genta is a ronin, having rejected samurai life by choice, and now travelling in disguise. ", "The seven samurai become trapped in a small building, surrounded by their enemies. ", "Hanji falls in with a group of ronin working for the conspirators, promised samurai status if they succeed in dislodging the seven honest samurai. ", "The clan figure behind the corruption actually plans to kill them all, hoping to remove all evidence of his deeds. ", "Genta reveals this plot to Hanji, who is forced to reconsider his aspirations to join the world of the samurai. ", "Through Genta's machinations the conspirators are defeated, and Hanji decides that the samurai life is not for him after all.", "\n\n## ANALYSIS\n\n_Kill_ _!_ ", "is an interesting example of the samurai film, one that ventures much further into comedy than other films in the genre. ", "However, combined with the comedy is an effective criticism of the unquestioning obedience of the samurai code. ", "The plot of _Kill_ _!_ ", "is derived from the same novel that inspired Kurosawa's _Sanjuro_ , but the two films are structured quite differently. ", "Although both concern a ronin assisting a group of samurai against their corrupt superiors, the actual mechanics of the two plots are quite different. _", "Kill_ _!_ ", "revolves around two swordsmen, Genta and Hanji, and their differing experiences of the samurai lifestyle, rather than focusing on one protagonist, as Kurosawa does in _Sanjuro_.", "\n\nThe tone of _Kill!_ ", "is very different to director Kihachi Okamoto's sombre masterpiece, _Sword of Doom_. ", "Here Okamoto proves his versatility, and despite its darkness, the humour in _Kill!_ ", "is always amusing. ", "The scenes involving the simple and unruly Hanji (Etsushi Takahashi) and his visit to a brothel are hilarious, due to Takahashi's exuberant performance and Okamoto's clever use of simple gags. ", "The flamboyant soundtrack also adds much to the overall comedic tone, punctuating humorous scenes with quick beats of music, reminiscent of the great Ennio Morricone.", "\n\nSimilarly, Tatsuya Nakadai is highly entertaining as Genta, the vagabond who is never without a wry response. ", "It's evidence of his considerable range as an actor: the immensely likeable character he plays here is polar opposite to the cruelty he plays in films such as _Yojimbo_ , _Sanjuro_ and _Sword of Doom_.", "\n\nHanji (Etsushi Takahashi) and Genta (Tatsuya Nakadai); both very hungry. _", "Kill_! ", "directed by Kihachi Okamoto and produced by Tomoyuki Tanaka for Toho Studios.", "\n\nOkamoto's film is far more than a series of gags. ", "There is a clever interplay throughout, regarding truth and appearance. ", "Right from the beginning of the film, people are not as they seem. ", "Playing with typical samurai film archetypes, many characters are actually disguised, so the character we think we recognise is someone different. ", "This notion of deception is also woven more directly into the film's plot with the main villain constantly using subterfuge and untruths to his advantage.", "\n\nOkamoto also criticises the unquestioning obedience of the samurai, but in a far gentler manner than Masaki Kobayashi does in _Hara-kiri_. ", "Genta's life has been badly affected by the samurai code, and as he and Hanji become involved in events reminiscent of his past, Genta slowly educates Hanji on the shortcomings of being a samurai. ", "The revelation of Genta's past acts as a final denouncement of unquestioning obedience, and, in this respect, _Kill_ _!_ ", "is much less sentimental than many samurai films.", "\n\nThe dire results of this compliance, mainly needless violence, are handled well within _Kill!_ ", "As you might expect from such a title, there is plenty of action. ", "The sword fighting is fast and frantic, with plenty of grizzly special effects.", "\n\n## THE VERDICT\n\n_Kill_ _!_ ", "is similar to _Sanjuro_ in its combination of brutal violence and amusing set pieces. ", "However, _Kill_ _!_ ", "exaggerates both these features to new levels, which clearly distinguishes it from Kurosawa's film. _", "Kill!_ ", "is thoroughly entertaining, for both those familiar with samurai films and those new to the genre.", "\n\n### _Red Lion_ (1969)\n\n**Japanese Title:** _Akage_\n\n**Directed by:** Kihachi Okamoto\n\n**Written by:** Sakae Hirosawa, Kihachi Okamoto\n\n**Produced by:** Toshiro Mifune, Yoshio Nishikawa\n\n**Edited by:** Yoshihiro Araki\n\n**Cinematography:** Takao Saito\n\n**Cast:** Toshiro Mifune (Gonzo), Shiwa Iwashita (Tomi), Etsushi Takahashi (Hanzo), Minori Terada (Sanji), Nobuko Otowa (Oharu), Yuko Mochizuki (Ume), Jitsuko Yoshimura (Oyoo), Kawai Okada (Osode), Shigeru Koyama (Aragaki), Hideo Amamoto (Dr. Gensai), Tokue Hanazawa (Komotora)\n\n## PLOT SUMMARY\n\nGonzo, a peasant, has recently joined the Imperial Force, an army raised by the Emperor to oppose the Shogunate. ", "Promising lower taxes and cancellation of debts, the Imperial Force is having no trouble winning over village after village as they move though Japan. ", "Gonzo, a rather simple but very tough warrior, is bored by all these peaceful conquests, and asks to go on ahead to his home village, which he believes he can easily win over to the Imperial cause. ", "His commander allows this, and even lends Gonzo his red lion headdress, a mane of bright red, to give him authority in his efforts. ", "Arriving in Sawado, Gonzo uses his new authority to release the villagers from a variety of different debts, and free his wife from prostitution, but makes enemies of the local magistrate and yakuza in doing so. ", "There is also a mysterious group of samurai, hoping to protect the interests of the Shogunate. ", "The Imperial Force turns out to be a farce; the promises of lower taxes are false, used to secure the support of the peasants. ", "Gonzo and his wife are both killed by the Imperial troops, which spurs the peasants into action, as they refuse the Imperial Force entry into Sawado.", "\n\n## ANALYSIS\n\nBased loosely on real events in Japanese history, Kihachi Okamoto's _Red Lion_ is a moving film about the lower classes (in this case, peasants) and their manipulation by those in power. ", "This is among the most anti-authoritarian of Okamoto's films, which usually focus on flaws within an individual, rather than an institution. ", "While it may sound like heavy viewing, _Red Lion_ is a well-balanced combination of comedy and heart-wrenching tragedy.", "\n\nToshiro Mifune's performance as Gonzo is the key to the success of _Red Lion_. ", "This is Mifune at his blustering best; in Gonzo, Mifune creates a character who is charming in his energetic enthusiasm and naivety, and the audience cannot help but like him. ", "Arriving in his village of Sawado, Gonzo sets about making trouble for the local authorities, mainly the local samurai policeman (a coward at heart), his deputies and the local extortionists and moneylenders. ", "In a series of highly comedic scenes, Gonzo frees women who have been sold into prostitution by their indebted families and destroys ten years' worth of recorded peasant debts. ", "However, Gonzo is far more than just a comedic character. ", "Mifune adds extra depth to his performance, in particular when Gonzo is touchingly reunited with his wife and mother after a ten-year absence. ", "Gonzo's motivations are clearly quite pure; he truly believes in the 'world renewal' propaganda spouted by the Imperial Force and wants to make a better life for the peasants and his family.", "\n\nThe emotional investment Mifune forces us to put into his character makes the last quarter of the film all the more tragic. ", "Events take a turn for the worse in Sawado. ", "Hanzo, a ronin staying in Sawado, is proved correct in his cynical attitude to the Imperial Force. ", "As such, the entire film could be seen as cynical, an opinion that's reinforced by its enthusiastic, comedic beginning and violent, tragic end. ", "The Imperial Force isn't at all what it promised to be, and some of the film's most endearing characters die as a result of this betrayal. ", "However, the final moments of the film, sad as they are, are ultimately uplifting because they show what Gonzo was able to inspire in his hometown.", "\n\n## THE VERDICT\n\n_Red Lion_ is an entertaining blend of tragedy and humour, well worth seeing for Mifune's amusing performance and Okamoto's moving direction.", "\n\n### _Samurai Banners_ (1969)\n\n**Japanese Title:** _Furin kazan_\n\n**Directed by:** Hiroshi Inagaki\n\n**Written by:** Adapted by Shinobu Hashimoto and Takeo Kunihiro from the novel by Yasushi Inoue\n\n**Produced by:** Hiroshi Inagaki, Toshiro Mifune, Yoshio Nishikawa, Tomoyuki Tanaka\n\n**Edited by:** Yoshihiro Araki\n\n**Cinematography:** Kazuo Yamada\n\n**Cast:** Toshiro Mifune (Kansuke Yamamoto), Yoshiko Sakuma (Princess Yu), Kinnosuke Nakamura (Shingen Takeda), Yujiro Ishihara (Kenshin Uesugi), Katsuo Nakamura (Nobusato Itagaki), Kanemon Nakamura (Nobukato Itagaki), Kankuro Nakamura (Katsuyori Takeda)\n\n## PLOT SUMMARY\n\nA ronin named Kansuke Yamamoto uses considerable guile and cunning to secure a position with Shingen Takeda, a powerful daimyo. ", "Kansuke helps Shingen defeat one of his rivals, Suwa, by making overtures of peace, then having the man killed when he visits Shingen's castle. ", "When Shingen marches on Suwa's lands, Kansuke finds Yu, Suwa's daughter, who he takes into his own home. ", "Shingen takes Yu as his concubine, much to his wife Sanjo's distaste. ", "Yu resents being a concubine, but Kansuke convinces her she must, so that she can bear a son to Shingen, and the Suwa and Takeda blood can be combined. ", "Yu does have a son by Takeda, named Shiro. ", "Kansuke grows very close to them both, and manipulates matters so that Shiro becomes Takeda's heir. ", "With his ingenious use of tactics, Kansuke helps Shingen defeat many of his rivals. ", "As more battles take place, a showdown with Kenshin Uesugi, Shingen's most powerful rival, becomes more and more inevitable. ", "Kansuke prepares a castle where he believes the battle will take place, hoping that Shiro will be old enough to command when it does. ", "Kenshin arrives with a large army, and Kansuke wants to stay in the castle, luring Kenshin into a trap. ", "However, Shingen insists on a direct attack, which Kansuke plans. ", "For the first time, his tactics are ineffective, and Kenshin very nearly kills Shingen. ", "Kansuke dies in the battle, and Shingen mocks him, saying he was blinded by his love for Yu and Shiro.", "\n\n## ANALYSIS\n\nThe last of Hiroshi Inagaki's historical films, _Samurai Banners_ was filmed on a suitably grand scale. ", "A great example of an epic historical film, it tells the story of Takeda Shingen, a daimyo who actually lived and is famous for his many conquests during feudal Japan's long succession of civil wars. ", "Interestingly, this film fits together quite well with Kurosawa's Kagemusha, which details Takeda's death and the fate of the Shingen clan. _", "Samurai Banners_ is concerned with some of Takeda's most famous battles, and the ruthless samurai who helped him win them, Kansuke Yamamoto.", "\n\nWhat stands out most about this film are the lavish battle scenes, achieved through the use of large numbers of extras, all immaculately costumed and armed. ", "Inagaki is no stranger to directing large-scale battle scenes, and doesn't fail to deliver in this film. ", "The battles are well edited, and seem realistic, an admirable quality in an historical film. ", "Inagaki creates a sense of the confusion of warfare, filling the frame with extras, all flailing wildly at each other, desperately trying to stay alive. ", "We see some magnificent sights – rousing cavalry charges, and huge infantry clashes – and, as usual, Inagaki should be commended for his grasp of epic subject matter. ", "Some of the battle scenes are more reminiscent of the over-the-top style of combat seen in the _Lone Wolf_ _and Cub_ series: the scene in which three soldiers carry a huge blade, and run in a circle, creating something like an enormous blender, is highly entertaining. ", "Fortunately, such scenes do not detract from the epic feel of the entire film.", "\n\nThe lives of Shingen and Kansuke make for interesting viewing, whether you're familiar with the history or not. ", "Both men demonstrate the level of ruthlessness which must have been necessary for a samurai to succeed in such uncertain times. ", "While this is refreshingly realistic, it also makes it difficult for the audience to actually like them. ", "Kansuke, who is clearly supposed to be a sympathetic character, in particular suffers from this. ", "Despite a skilled performance by Toshiro Mifune, it is difficult to feel sorry for Kansuke at the film's conclusion, when he has shown so little regard for human life. ", "As such, _Samurai Banners_ is not as moving as other Inagaki's _Samurai Trilogy_ and _The 47 Ronin_.", "\n\n## THE VERDICT\n\nNot as touching as Inagaki's other work, _Samurai Banners_ contains some epic battle scenes and a compelling story lifted from the pages of Japan's turbulent history. ", "If you're in the mood for a larger-than-life tale, then this is the film for you. ", "\n\n# THE 1970s\n\nThe popularity of samurai films lasted into the 1970s, although the genre started to lose ground to the increasingly popular yakuza (gangster) films.", "\n\nDuring the 1970s, the genre was heavily influenced by Japanese comics (manga), many of which were adapted into live-action films. ", "These films shared the over-the-top action and characters of their source material, and took the graphic violence of the 1960s films even further. ", "The manga-inspired films were wonderfully overblown, and didn't take themselves too seriously, resulting in simple entertainment that was beautiful to look at. ", "The most famous of these films are the _Lone Wolf_ _and Cub_ series, featuring Itto Ogami, his baby son Daigoro and a baby cart concealing an arsenal of deadly weapons. ", "Others include the _Lady_ _Snowblood_ and _Hanzo_ _the Razor_ series. ", "There is more to these films than just the action; the _Lady Snowblood_ films in particular have a definite point to make.", "\n\nThe _Zatoichi_ series continued into the 1970s, also influenced in part by the style of manga-inspired films. ", "This is not surprising, considering that Shintaro Katsu's (the star of the _Zatoichi_ films) production company was responsible for both _Lone Wolf and Cub_ and the _Zatoichi_ films of the 1970s.", "\n\n### _Incident at Blood Pass_ (1970)\n\n**Japanese Title:** _Machibuse_\n\n**Directed by:** Hiroshi Inagaki\n\n**Written by:** Yumi Fujiki, Hideo Oguni, Hajime Takaiwa, Ichiro Miyagawa\n\n**Produced by:** Toshiro Mifune, Yoshio Nishikawa\n\n**Edited by:** Yoshihiro Araki\n\n**Cinematography:** Kazuo Yamada\n\n**Cast:** Toshiro Mifune (the Ronin), Yujiro Ishihara (Yataro), Ruriko Asaoka (Okuni), Shintaro Katsu (Gentetsu), Kinnosuke Nakamura (Heima), Chusha Ichikawa (samurai leader), Ichiro Arishima (Tokubei), Mika Kitagawa (Oyuki), Yoshio Tsuchiya (Itahachi), Jotaro Togami (Gonji)\n\n## PLOT SUMMARY\n\nA nameless ronin receives a strange assignment from his new employer. ", "He is to proceed to a desolate mountain pass and wait for something to happen. ", "His employer, a mysterious samurai, tells him he will know when the time is right to act. ", "Arriving at the pass the ronin stays at a small inn and meets a series of interesting characters. ", "Among them are a young gambler, a criminal, an inspector, a young woman the ronin saves from her abusive husband, and a mysterious physician, hiding away from the world. ", "Through a series of events it becomes clear what is really happening at the pass: Gentetsu, the physician, is in fact a samurai also hired by the ronin's employer, his mission being to ambush a caravan carrying Shogunate gold. ", "Gentetsu takes control of the inn with a gang of thugs and the ronin's real mission is delivered to him; his employer wants Gentetsu dead and the ronin is to kill him. ", "The caravan is completely fake, all to lure Gentetsu into a trap. ", "Enraged by the betrayal of his mysterious employer, the ronin attempts to save Gentetsu, who throws himself down a gorge, preferring to die than be captured. ", "The ronin leaves the pass alone and kills his employer, in vengeance for all the bloodshed he has caused.", "\n\n## ANALYSIS\n\n_Incident at Blood Pass_ is a character-driven film, set amid majestic snow- capped mountains. ", "The way these characters interact makes up much of the first half of the film, and their exchanges are both well written and acted. ", "The film's writing team have created an interesting blend of characters, whose differing perspectives often act as an examination of justice, one of the central themes of _Incident at Blood Pass_. ", "Mifune's ronin is a compassionate man, taking great pains to avoid killing his adversaries in combat. ", "He has his own sense of justice, choosing to viciously strike down those he believes deserve death. ", "Yujiro Ishihara plays Yataro, a tough young gambler, who despises the law and thieves alike. ", "Shintaro Katsu, famous for his long-running role as Zatochi the blind swordsman, here plays Gentetsu, a seemingly uncouth ex-physician, hiding away from the world for his own reasons. ", "The two women at the inn, Okuni and Oyuki, are both merciful and tolerant, and prefer not to see harm come to anyone. ", "This is particularly poignant for Okuni who, badly beaten by her husband, still begs the ronin not to kill him, and shows concern when he is injured later in the film.", "\n\nWhen an inspector and the criminal he was chasing arrive at the inn, both nearly dead from their wounds, the theme of justice is examined more thoroughly. ", "Gentetsu shows great apathy in refusing to treat them but is spurred into action by the ronin and Oyuki. ", "When he regains consciousness the inspector treats his prisoner with great brutality, beating him and making him eat like a dog, all the while refusing him water. ", "He claims to do this in the name of justice. ", "It's hard not to take a strange sense of enjoyment from a later scene, where the thief is freed and savagely beats the inspector, which seems far more just than the earlier tortures.", "\n\nThe second half of the film contains some unpredictable twists, which ultimately lead to violence. ", "The fight scenes are well choreographed, both frenetic and chaotic, which adds a sense of realism, even though there is very little blood and gore on display.", "\n\nAlthough the content of this film is different to the historical epics he usually directed, Hiroshi Inagaki created an entertaining film from this compelling material. ", "In particular, he makes good use of the scenic backdrop of the snowy mountain pass, in many ways reminiscent of the grand landscapes of his other films.", "\n\n## THE VERDICT\n\nAll in all, _Incident at Blood Pass_ is a great samurai film, containing clever characterisation, thought-provoking themes and skilled direction.", "\n\n### _Zatoichi Meets Yojimbo_ (1970)\n\n**Japanese Title:** _Zatoichi to Yojimbo_\n\n**Directed by:** Kihachi Okamoto\n\n**Written by:** Adapted by Kihachi Okamoto and Tetsuro Yoshida from a story by Kan Shimozawa\n\n**Produced by:** Shintaro Katsu, Hiroyoshi Nishioka\n\n**Edited by:** Toshio Taniguchi\n\n**Cinematography:** Kazuo Miyagawa\n\n**Cast:** Shintaro Katsu (Zatoichi), Toshiro Mifune (Sasa the yojimbo), Ayako Wakao (Umeno), Osamu Takizawa (Eboshiya), Masakane Sakatoshi (Masagoro), Shin Kishida (Kuzuryu), Kanjuro Arashi (Hyoroku), Toshiyuki Hosokawa (Sanyemon)\n\n## PLOT SUMMARY\n\nNeeding a break from his violent lifestyle, Zatoichi returns to a village he has fond memories of. ", "He finds the village a much more sombre place now, with a yakuza boss, Masagoro, and his father, Eboshiya, fighting over a hidden stash of gold stolen from the Shogunate. ", "Masagoro has hired Sasa, a samurai, as his yojimbo (bodyguard). ", "After Zatoichi roughs up some of his men, Masagoro sends Sasa after him, but the two end up having a drink instead. ", "Sasa is in love with Umeno, the young woman who runs the sake house. ", "Attacks by Sasa and Masagoro's men on Eboshiya's house and warehouse both fail to reveal the location of the gold. ", "Kuzuryu, a skilled warrior, arrives to protect Eboshiya, sent by Sanyemon, his other son, who originally sent the stolen gold from Edo. ", "It becomes clear that both Sasa and Kuzuryu are agents of the Shogun, attempting to recover the gold. ", "Meanwhile, Zatoichi discovers that the gold is hidden inside the 130 small Buddha statues that Eboshiya had made for the village shrine. ", "A large battle between Eboshiya and Masagoro's gangs erupts, and Zatoichi takes advantage of the confusion to gather all the gold dust in a large pile outside the village gates. ", "Sasa attempts to arrest Eboshiya, but Sanyemon, trying to kill him, wounds his father. ", "The battle subsides as Eboshiya, Masagoro and Sanyemon all make for the gold. ", "Kuzuryu kills them all with a pistol, wanting the gold for himself. ", "Sasa kills him, but not before Umeno is shot. ", "Sasa attempts to save Umeno, but believing it's hopeless, he and Zatoichi begin to fight. ", "Umeno regains consciousness, and the two stop fighting. ", "Both Zatoichi and Sasa attempt to get the gold, which all blows away in the wind. ", "Zatoichi leaves Sasa to take care of Umeno.", "\n\n## ANALYSIS\n\n_Zatoichi Meets Yojimbo_ combines two of the most enduring characters in samurai films: Shintaro Katsu's affable Zatoichi and Toshiro Mifune's gruff but likeable yojimbo. ", "The two meet in a village which hides a fortune in stolen gold. ", "Not only do they have greedy yakuza to contend with, but also each other.", "\n\nA co-production between Toho and Shintaro Katsu's production company, the greatest feature of _Zatoichi Meets Yojimbo_ is its two leading men. ", "As in _Incident at Blood Pass_ , they make a wonderful combination, and are even more entertaining here. ", "Mifune and Katsu play up the rivalry between their characters very well; their interplay is always entertaining, whether they're insulting, threatening or trying to fool each other. ", "The often sly humour of Katsu's Zatoichi and the blustering, sometimes drunken, outbursts of Mifune's yojimbo are a delicious mix, which writer and director Kihachi Okamoto never misses an opportunity to exploit.", "\n\nIndeed, this film contains much more comedy than most Zatoichi films; the scenes with Sasa (the yojimbo) and the bumbling yakuza he associates with are always amusing, particularly the way Sasa continually imitates them. ", "Similarly, Zatoichi himself is funnier, accidentally knocking himself out when trying to escape the local lawman and trying to fake death spasms with amusing results.", "\n\nAt no point does this tone detract from the more serious scenes, yet _Zatoichi Meets Yojimbo_ is not without its faults. ", "The plot has so many twists and turns that it could potentially confuse and irritate viewers, rather than surprise them. ", "This is unusual coming from Kihachi Okamoto, the talented director responsible for classic samurai films such as _Samurai Assassin_ , _Sword of Doom_ and _Kill_ _!_ ", "It looks as though Okamoto tried to put a little too much into the plot; with a shorter running time and fewer twists, _Zatoichi Meets Yojimbo_ could have been every bit as entertaining as his other work.", "\n\nThe battle scenes are also slightly disappointing. ", "While Katsu and Mifune draw on their unique styles, they have both done much better work in other films. ", "Similarly, the large-scale battle between the two yakuza factions towards the end is not up to Okamoto's usual standards. ", "The battles between Zatoichi and Sasa are not without merit, but seem somewhat anti-climactic.", "\n\n## THE VERDICT\n\nDespite disappointing on some levels, _Zatoichi Meets Yojimbo_ is interesting viewing for samurai film fans simply because it combines two of the genre's most popular characters, and is worth seeing alone for Katsu and Mifune's entertaining interaction.", "\n\n### _Zatoichi: The Festival of Fire_ (1970)\n\n**Japanese Title:** _Zatoichi abare-himatsuri_\n\n**Directed by:** Kenji Misumi\n\n**Written by:** Adapted by Takayuki Yamada and Shintaro Katsu from a story by Kan Shimozawa\n\n**Produced by:** Shintaro Katsu\n\n**Edited by:** Toshio Taniguchi\n\n**Cinematography:** Kazuo Miyagawa\n\n**Cast:** Shintaro Katsu (Zatoichi), Tatsuya Nakadai (ronin), Reiko Ohara (Okiyo), Masayuki Mori (Yamikubo), Peter (Umeji)\n\n## PLOT SUMMARY\n\nZatoichi, the famed blind swordsman, rescues a beautiful woman from a mistress auction. ", "She doesn't get far; a mysterious ronin finds and kills her. ", "Attending the promotion ceremony for a local yakuza boss, Kuroko, Zatoichi is disrespectful, but the angry men are stopped by their supreme leader, Yamikubo, another blind man referred to as the shogun of the underworld. ", "Yamikubo holds a vote among the yakuza bosses, and it is decided that Zatoichi must be killed. ", "Several attempts fail, and the yakuza send Okiyo, a pretty young girl, to lure Zatoichi into their trap. ", "Zatoichi meets the ronin, who accuses him of sleeping with his wife. ", "The ronin has killed everyone else she slept with, and mistakenly believes Zatoichi did after he rescued her. ", "The ronin promises they will duel soon. ", "Okiyo and Zatoichi form a bond, and she tries to convince him not to attend the festival to which Yamikubo has invited him. ", "Umeji, a young pimp Zatoichi befriends, unsuccessfully attempts to seduce and kill him. ", "Arriving at the festival, Zatoichi is lured into a cunning trap. ", "He escapes and succeeds in killing Yamikubo, but not before Okiyo's family are murdered by the yakuza boss. ", "The ronin arrives and saves Zatoichi from Yamikubo's many henchmen. ", "Zatoichi and the ronin duel, and Zatoichi emerges victorious. ", "Seeing the way love ruined the ronin's life, Zatoichi chooses not to have Okiyo accompany him, even though she wants to.", "\n\n## ANALYSIS\n\n_Zatoichi_ : _The Festival of Fire_ is an entertaining film and high point in the series. ", "With the usual amiable performance from Katsu, the assured direction of Kenji Misumi and a great performance from the immensely talented genre veteran Tatsuya Nakadai, it's one of Zatoichi's best adventures.", "\n\nKenji Misumi, the director responsible for the early Zatoichi films, who would go on to direct the best of the _Lone Wolf and Cub_ series, handles the material with the skill and assurance that samurai film fans have come to expect. ", "Misumi creates some wonderful scenes in this film. ", "The amusing opening sequence in which Zatoichi tries to get rid of a pesky dog, the scene where Zatoichi pulls Okiyo along in a cart and the blind swordsman's rude arrival at a yakuza gathering are all classic Zatoichi, that entirely utilise Katsu's charismatic performance.", "\n\nMisumi also makes sure he doesn't waste the talents of Tatsuya Nakadai, who puts in a tour-de-force performance as a ronin driven mad by his cheating wife; the kind of character he is famous for – an unnerving and inexpressive individual completely fixated on his violent goals. ", "Similar to the characters he played in films such as _Sanjuro_ and _Sword of Doom_ , Nakadai's cold stare, conveyed through his large eyes, is no less chilling here. ", "Particularly memorable is the sequence in which the ronin, having drunk a lot of sake, finds himself reliving the events which changed his life forever. ", "Shot against a stark white background, these scenes consist of very quick cuts of the ronin discovering his wife with another man, who he kills, before commencing the vengeful pursuit of his wife, for which he sacrifices his position as a Shogunate samurai. ", "The sight of Nakadai, a look of horror and anger stretched across his face, made mesmerising by the blank background, is an image the viewer will not soon forget. ", "Such highly stylised images show a talent that would become evident in Misumi's later work on the _Lone_ _Wolf and Cub_ films.", "\n\nAnother strength is the film's intriguing villain, Yamikubo, the blind lord of the yakuza. ", "Zatoichi and Yamikubo share a variety of interesting and amusing lines on the subject of their blindness, but Yamikubo turns out to be every bit as ruthless (perhaps more so) as any other yakuza boss. ", "Masayuki Mori plays this character very well, fashioning a credible rival for Zatoichi, and deserving of his rage.", "\n\nLike all Zatoichi films, _The Festival of Fire_ contains the requisite battle scenes. ", "The incident when Zatoichi is attacked by a large group of naked yakuza in a bathhouse is as brutal as it is bizarre, and the climactic scene, in which he's trapped by his enemies on a platform in the middle of a pool, makes for a tense spectacle, particularly when oil in the pool is set alight, trapping Zatoichi in a ring of fire.", "\n\n## THE VERDICT\n\nThis is a great film to watch if you've never seen any Zatoichi films; everything that made the series such a success is present. ", "Highly recommended.", "\n\n### _Lone Wolf and Cub: Sword of Vengeance_ (1972)\n\n**Japanese Title:** _Kozure Okami: Kowokashi udekashi tsukamatsuru_\n\n**Directed by:** Kenji Misumi\n\n**Written by:** Adapted by Kazuo Koike from the manga he created with Goseki Kojima\n\n**Produced by:** Shintaro Katsu, Hisaharu Matsubara\n\n**Edited by:** Toshio Taniguchi\n\n**Cinematography:** Chishi Makiura\n\n**Cast:** Tomisaburo Wakayama (Itto Ogami), Fumio Watanabe (Sugito), Tomoko Mayama (Osen), Shigeru Tsuyuguchi (Matsuki), Reiko Kasahara (Azami), Akihiro Tomikawa (Daigoro), Tokio Oki (Retsudo Yagyu)\n\n## PLOT SUMMARY\n\nItto Ogami was once the Shogun's second, his job to assist daimyos who have offended the Shogun in committing seppuku. ", "The Yagyu clan, jealous of his position, murder his wife and attempt to frame him for disrespectful behaviour towards the Shogunate. ", "Itto and his infant son survive, and both embark on the path of the assassin, hoping to eventually inflict their revenge on the Yagyu. ", "Itto meets with Ichige Gyobu, a chamberlain of the Oyamada clan, who wants to hire him as an assassin. ", "He wants Itto to kill Sugito, a chamberlain who is attempting to gain control of the Oyamada clan by assassinating the current lord. ", "Itto reaches the village where Sugito waits to ambush the Oyamada daimyo. ", "Itto is confronted by some of Sugito's ronin. ", "He does not resist them as they take his sword, beat him and force him to pleasure Osen, a prostitute. ", "Ready to leave to perform their duties for Sugito, the ronin plan to kill all the travellers in the village, but Itto intervenes, using weapons cleverly concealed in the baby cart in which he pushes Daigoro around. ", "Kanbei, the leader of the ronin, realises who Itto is, but it's too late. ", "Itto kills Kanbei, Sugito and all their men, before quietly leaving the village. ", "Osen attempts to follow him, but Itto threatens to cut the bridge she stands on, and she lets him go on his way.", "\n\n## ANALYSIS\n\nThere is something undeniably cool about an assassin pushing his child around in a deadly baby cart. ", "Welcome to the wonderfully overblown world of _Lone Wolf and Cub_ , where the action is fast, graphic and violent.", "\n\nThe first film in the popular _Lone Wolf and Cub_ series, _Sword of_ _Vengeance_ , is a good beginning, but doesn't reach the giddy heights of _Baby Cart on the River Styx_ , the second and best film in the series. _", "Sword of Vengeance_ is primarily concerned with how Itto and Daigoro came to be the wandering assassins known as Lone Wolf and Cub, and as such is more concerned with the backstory than the simple and violent tales the series excels in.", "\n\nA co-production between Toho and Shintaro 'Zatoichi' Katsu's production company, _Sword of Vengeance_ stars Katsu's brother, Tomisaburo Wakayama, as Ogami Itto, a role in which he excels. ", "Like the Zatoichi films, the _Lone Wolf and Cub_ series derives much of its appeal from its solid central character and one actor's unforgettable portrayal of him. ", "Wakayama's Itto is a stern, inexpressive man, whose features rarely change. ", "He's unemotional, having chosen a path of death and vengeance which he sticks to with the same inexpressive stoicism he uses to follow the code of bushido. ", "It is Wakayama's inexpressiveness that makes him so memorable; his cold, emotionless stare through narrowed eyes drills through the toughest of opponents, and never fails to impress, no matter how many times you watch the film. ", "There is one scene which is a classic example of Wakayama's Itto: the scene in which Itto places his sword and a colourful ball on the floor and tells Daigoro, his infant son, to choose his destiny by crawling towards one; the sword means he embarks on the assassin's life with his father, the ball means he joins his dead mother. ", "Wakayama plays this scene with such conviction that you really believe Itto has no qualms about killing his child, as he wishes to spare his son the harsh life of vengeance he is about to undertake. ", "When Itto occasionally does show emotion, such as the slight hint of amusement he gives when he defeats Gyubo's men, it's a mere glimmer through Wakayama's stone-like features. ", "Young Akihiro Tomikawa also offers an assured performance as Daigoro, Itto's little son, but is used to much greater effect in the next film, _Baby Cart_ _on the River Styx_.", "\n\nInterestingly, _Sword of Vengeance_ is directed by Kenji Misumi, who helmed the first Zatoichi film, there at the beginning of two of samurai films' most enduring characters. ", "Misumi is true to the popular manga which inspired the _Lone Wolf and Cub_ films, carefully creating a series of beautifully composed shots. ", "The image of water coursing over Itto's sword as it is cleaned in preparation for an execution and the bloodied fingers of Azami touching Daigoro's cheek as she dies are just two examples of the violent yet graceful shots that Misumi offers his audience.", "\n\nOf course, the cornerstone of the _Lone Wolf and Cub_ series is flamboyant manga-styled battle scenes, and _Sword of Vengeance_ well and truly delivers. ", "Wakayama proves to be just as competent as his brother at hacking his way through hordes of enemies, and the scenes in which he does are highly entertaining. ", "The gory effects, such as frequent blood sprays and severed limbs, make them gloriously grotesque. ", "Particularly good is the final battle in which Itto takes on Kanbei and his ronin. ", "Misumi builds a great sense of anticipation, and when the battle occurs it's full of gory surprises.", "\n\n## THE VERDICT\n\nNot as good as its sequel, _Sword of Vengeance_ is nevertheless a worthy film. ", "If you intend to watch the entire _Lone Wolf and Cub_ series then this is the place to start.", "\n\n### _Lone Wolf and Cub: Baby Cart on the River Styx_ (1972)\n\n**Japanese Title:** _Kozure Okami: Sanzu no kawa no ubaguruma_\n\n**Directed by:** Kenji Misumi\n\n**Written by:** Adapted by Kazuo Koike from the manga he created with Goseki Kojima\n\n**Produced by:** Shintaro Katsu, Hisaharu Matsubara\n\n**Edited by:** Toshio Taniguchi\n\n**Cinematography:** Chishi Makiura\n\n**Cast:** Tomisaburo Wakayama (Itto Ogami), Kayo Matsuo (Sayaka), Akiji Kobayashi (Benma Hidari), Minoru Ohki (Tenma Hidari), Shin Kishida (Kuruma Hidari), Akihiro Tomikawa (Daigoro)\n\n## PLOT SUMMARY\n\nOgami Itto's deadly enemies from the previous film, the Yagyu clan, are still after him. ", "This time utilising two skilled teams of shinobi (ninja) from their ranks, one all male, the other all female, the Yagyu hope to eliminate Itto once and for all. ", "Itto has continued on the path of the assassin that he chose in the first film, and still takes his little son Daigoro with him everywhere. ", "This time, Itto accepts a contract to kill a dye-maker who threatens to ruin a lucrative monopoly held by a small clan. ", "His target is protected by the three Hidari brothers, the highly skilled, official escorts of the Shogunate. ", "Itto nearly fails in his mission, and is almost killed by the shinobi. ", "Daigoro nurses him back to health but is then captured by the surviving shinobi, and is almost drowned before Itto rescues him. ", "Following the Hidari brothers onto a boat, Itto and Daigoro must escape from a fire lit by thugs trying to kill the Hidari, and survive the cold night by sharing body warmth with Sayaka, the only survivor of the female shinobi. ", "Sayaka finds it increasingly hard to harm Itto, mainly because of Daigoro. ", "Catching up with the Hidari brothers, Itto kills them in a bloody battle and completes his mission by killing the dye-maker. ", "Sayaka confronts him one last time, but cannot bring herself to fight him.", "\n\n## ANALYSIS\n\n_Baby Cart on the River Styx_ is considered by many to be the best of the _Lone Wolf and Cub_ series, and for good reason. ", "With the backstory told in _Sword of Vengeance_ (1972), this film is free to tell its bloody tale. ", "Itto and Daigoro must contend with two teams of deadly shinobi (ninja), one male, one female, and the highly skilled Hidari brothers, otherwise known as the Masters of Death.", "\n\nThe simple plot is one of the film's best assets. ", "Presenting a series of causes and effects, the plot never feels as if it's crudely assembled around the violence, which is sometimes the case with _zankoku_ __ eiga (cruel films). ", "The characters all have sufficient motivation to carry out their violent acts. ", "The Yagyu clan, for example, feel it is vital to eliminate Ogami because he's humiliated them; this is expressed simply through their anger as they discuss events. ", "The Hidari brothers, for their part, are charged to protect by the Shogun, a duty they take very seriously.", "\n\nLike the other _Lone Wolf and Cub_ films, the most obvious feature of _Baby Cart on the River Styx_ is its graphic violence. ", "This film is not for the squeamish. ", "Buckets of blood, along with a multitude of body parts, are flung all over the screen. ", "But with its manga origins, it is only natural that the _Lone Wolf and Cub_ series should inherit this gory, heightened violence. ", "Director Kenji Misumi uses quick cuts, never lingering too long on any individual violent act, creating rapid montages of bloody combat which have an incredibly appealing visceral nature. ", "During the battle scenes a variety of exotic weapons are on display, not least the baby cart itself, which conceals Ogami's considerable arsenal. ", "The choreography creates smooth-flowing exchanges; the scene in which Itto dispatches most of the male shinobi is one such example; he reacts quickly to the attacks of his multiple opponents, moving rapidly from one to the next, fighting them on different levels (from above, below, and so on).", "\n\nAs much attention is paid to characterisation as action. ", "Though low on dialogue, the film's central characters are cleverly designed, and prove to be intriguing in their own right. ", "This is assisted greatly by performances from a talented cast. ", "Ogami Itto (Tomisaburo Wakayama) continues to be an interesting protagonist. ", "His face seems permanently frozen, a sign of the horrors he has faced. ", "Largely unexpressive, he's able to convey a great deal with a simple glance or slight movement of his brows. ", "This is a far cry from the highly expressive heroes that usually feature in samurai films, portrayed by actors such as Toshiro Mifune, Shintaro Katsu and Tatsuya Nakadai.", "\n\nThe villains in this film, Sayaka and her female shinobi in particular, are wonderfully exaggerated, presenting comic-book evil at its best, a pleasing contrast with Itto's constant stern expression.", "\n\nSpecial mention must be made of Akihiro Tomikawa, the child actor who plays Daigoro, Itto's little son. ", "Only five or six years old, he gives an amazing performance, and matches his father's cold stare. ", "Yet he also retains childlike qualities, which makes for an interesting juxtaposition; in one scene he helps his father deal with some shinobi, then in the next he points and laughs at a scarecrow. ", "The scenes in which Daigoro helps nurse his father back to health are touching, and contrast well with the visceral violence that has just taken place.", "\n\n## THE VERDICT\n\nIf you only see one film from the _Lone Wolf and Cub_ series, make sure it's _Baby Cart on the River Styx_. ", "This film combines all the best elements of the series, including gory fight scenes, entertaining scripting and skilled performances from Wakayama and Tomikawa.", "\n\n### _Lone Wolf and Cub: Baby Cart to Hades_ (1972)\n\n**Japanese Title:** _Kozure Okami: Shinikazeni mukau ubaguruma_\n\n**Directed by:** Kenji Misumi\n\n**Written by:** Adapted by Kazuo Koike from the manga he created with Goseki Kojima\n\n**Produced by:** Shintaro Katsu, Hisaharu Matsubara\n\n**Edited by:** Toshio Taniguchi\n\n**Cinematography:** Chishi Makiura\n\n**Cast:** Tomisaburo Wakayama (Itto Ogami), Go Kato (Kanbei), Yuko Hamada (Torizo), Isao Yamagata (Genba), Akihiro Tomikawa (Daigoro)\n\n## PLOT SUMMARY\n\nItto Ogami and his son Daigoro continue to travel the path of the assassin. ", "They encounter Ometsu, a young girl who has been sold to the yakuza as a sex slave and is trying to escape. ", "Itto refuses to hand her over to Torizo, a tough female yakuza boss, when he sees the girl carries a memorial tablet, which reminds him of the tablet which ruined his own life. ", "Eventually Itto agrees to undergo the torturous process that Ometsu must complete to be free of the yakuza, in her place. ", "Surviving the tortures, although badly beaten, Itto then accepts an assignment from Torizo's father, Miura, who is in fact a ronin. ", "Miura wants Itto to kill Genba, the man who betrayed his clan, causing it to be dissolved. ", "Itto agrees and sets off to complete this mission. ", "Genba also attempts to hire Itto to kill his superior, who he fears is plotting against him, but Itto refuses. ", "He kills Genba's two most skilled samurai. ", "Genba raises a small army to hunt the assassin. ", "Itto confronts the army, and through a combination of heavy firepower, concealed in the baby cart, and his great skill, defeats them, killing Genba himself. ", "A ronin named Kanbei then steps forward to challenge Itto, having been hired by Genba. ", "Itto defeats him, and Kanbei recounts his tale, where he was shunned by his clan for leaving his lord's side to protect him. ", "Itto applauds his actions and acts as his second as he commits seppuku. ", "Torizo, who has watched the entire battle, tries to follow Itto, but is restrained by her men, who fear for her safety.", "\n\n## ANALYSIS\n\nNot as enjoyable as _Baby Cart on the River Styx_ , _Baby Cart to Hades_ is nevertheless a strong entry in the series. ", "Featuring more exaggerated comic-book violence, this is the first film in which Itto takes on an entire army.", "\n\nThis film puts Itto into a number of new situations, the most interesting of which takes place when he and Daigoro help Ometsu, a girl who is to be sold to a brothel. ", "The plight of the innocent is not usually something Itto concerns himself with, not part of the assassin's path he has chosen. ", "This predicament leads to some interesting negotiations between Torizo, a yakuza who wants the girl back, and Itto, who refuses to hand her over. ", "The solution is typical of Itto; he agrees to undertake a series of tortures so that the girl can be set free, as described in a yakuza custom. ", "It's a perfect opportunity to show just how tough Itto is; the entire time he is beaten, Itto doesn't make a sound, something which terrifies his torturers, and reinforces his stoic fortitude. ", "Similarly, the supporting characters of _Baby Cart to Hades_ add depth to the film, making it more than just an exercise in bloody action sequences. ", "Kanbei, the conflicted ronin, and Genba, the treacherous and paranoid samurai, drive the more thought-provoking material in the film, providing an intriguing backdrop to the action.", "\n\nThe best aspect of _Baby Cart to Hades_ is, of course, the epic battle scene, which takes place towards the end, in which Itto destroys Genba and his army singlehandedly. ", "Despite the overblown manga style of the series, it must surely have been a challenge to choreograph such a scene convincingly. ", "First Itto kills some enemies with guns and bombs, then he wades in, moving quickly among them, his blade flashing. ", "Wakayama is at his bodycount best in these scenes, and moves with such fluidity and precision you simply enjoy the scene, never questioning its preposterous nature.", "\n\n## THE VERDICT\n\nThe _Lone Wolf and Cub_ series was still going strong with its third film, featuring top-notch performances from Wakayama and Tomikawa, and plenty of the requisite, fiercely paced battle scenes.", "\n\n### _Lady Snowblood_ (1972)\n\n**Japanese Title:** _Shurayukihime_\n\n**Directed by:** Toshiya Fujita\n\n**Written by:** Adapted by Norio Osada from the manga by Kazuo Koike and Kazuo Kamimura\n\n**Produced by:** Kikumaru Okuda\n\n**Edited by:** Osamu Inoue\n\n**Cinematography:** Masaki Tamura\n\n**Cast:** Meiko Kaji (Yuki AKA Lady Snowblood), Toshio Kurosawa (Ryurei), Masaaki Daimon (Go), Miyoko Akaza (Sayo), Shinichi Uchida (Shiro), Takeo Chii (Tokuichi), Noburo Nakaya (Banzo), Yoshiko Nakada (Kobue), Akemi Negishi (Tajire), Kaoru Kusuda (Otora)\n\n## PLOT SUMMARY\n\nYuki Kashima is born into a life of vengeance. ", "Her mother is unable to avenge the murders of her husband and child, so she conceives and gives birth to Yuki, in the hope that her daughter can finish what she started. ", "Yuki is trained by a harsh samurai turned priest, and honed into a lethal assassin. ", "Ready to begin her quest, Yuki employs the help of a clan of beggars to track down the gang of criminals who murdered her father and older brother 20 years earlier. ", "First she finds Banzo, who has become a truly pathetic old man, reduced to cheating at gambling and living off the prostitution of his daughter, Kobue. ", "He puts up no resistance as Yuki cuts him down. ", "Yuki is disappointed to discover her next victim has seemingly already died, and angrily strikes at his tombstone. ", "Yuki's mentor tells her story to a young journalist, Ryurei, in the hope that publicising her story will draw out Otora, the last survivor of the murderers. ", "Yuki's attempts at revenge are frustrated yet again when, after a bloody exchange, Otora appears to hang herself. ", "It turns out that Yuki's earlier target is not dead at all, and is in fact Ryurei's father, and a corrupt and wealthy weapons dealer. ", "Yuki confronts and kills him, and Ryurei also dies in the process. ", "Wounded, Yuki staggers into the snow, where she is stabbed by Kobue, intent on avenging her father.", "\n\n## ANALYSIS\n\n_Lady Snowblood_ is a compelling study of revenge, and a welcome counterpoint to the many genre films which glorify 'getting even'. ", "The film also looks fantastic, with highly stylised direction from Toshiya Fujita.", "\n\n_Lady Snowblood_ is primarily concerned with showing the ultimate futility of revenge. ", "This is illustrated through the experiences of Yuki, herself a living instrument of revenge. ", "Yuki is a sympathetic protagonist rather than a heroic one; she has been trained to avenge the murders of her family her whole life, deprived of a normal existence and life's simple pleasures. ", "The beautiful Meiko Kaji is perfectly cast in the role, convincingly portraying Yuki's pain as she is forced to make difficult decisions about her revenge and showing frightening rage when she confronts the real villain of the film.", "\n\nThe first victim of Yuki's revenge, Banzo, is a weak old man who offers no resistance to Yuki's blade. ", "Hardly a satisfying victory. ", "Worse still, she meets Kobue, his loving daughter, and must face the thought of depriving this girl of her father. ", "Yuki's actions set Kobue on the same course she has been following; Kobue too must give up a normal life as she focuses on vengeance. _", "Lady Snowblood_ thus reveals the futility of revenge; it is simply an endless cycle of violence which brings nothing but pain to all those involved.", "\n\nTrue to the manga origins of _Lady Snowblood_ , the story is told in a distinctive style. ", "Director Fujita makes use of a number of interesting techniques. ", "Yuki's murder of a gang leader at the film's beginning is extremely stylised; there is a slow-motion shot of Yuki as she somersaults over her opponents then a series of rapid shots as she dispatches them. ", "There is no shortage of blood, and Fujita makes constant use of the red-on-white motif, either blood on snow or on the white portions of the Japanese flag. ", "The montage in which a portion of novelist Ryurei's work on Yuki is read aloud is also very striking, and makes use of dynamic, manga-style art imposed over shots of people feverishly buying the book.", "\n\nInterestingly, _Lady Snowblood_ is listed as one of the inspirations for Quentin Tarantino's _Kill Bill_ films. ", "Although both feature a tortured female protagonist seeking revenge, Tarantino takes the much more predictable route of glorifying revenge, rather than condemning it.", "\n\n## THE VERDICT\n\n_Lady Snowblood_ is a prime example of the samurai film's ability to interrogate notions of violence and revenge, and a must-see for fans of the genre.", "\n\n### _Lone Wolf and Cub: Baby Cart in the Land of Demons_ (1973)\n\n**Japanese Title:** _Kozure Okami: Meifumando_\n\n**Directed by:** Kenji Misumi\n\n**Written by:** Adapted by Kazuo Koike and Tsutomo Nakamura from the manga by Kazuo Koike and Goseki Kojima\n\n**Produced by:** Masanori Sanada, Tomisaburo Wakayama\n\n**Edited by:** Toshio Taniguchi\n\n**Cinematography:** Fujio Morita\n\n**Cast:** Tomisaburo Wakayama (Itto Ogami), Michiyo Yasuda (Shiranui), Akihiro Tomikawa (Daigoro), Shingo Yamashiro (Lord Naritaka), Tomomi Sato ('Quick Change' Oyoo), Satoshi Amatsu (Inspector Senzo), Minoru Ohki (Retsudo Yagyu)\n\n## PLOT SUMMARY\n\nItto is hired by Kuroda clan samurai, after they test his skill as a warrior. ", "His assignment is to recover a document, which reveals that the young heir of the clan is in fact a girl, born to Naritaka (the current lord) and his favourite concubine. ", "Naritaka's son, Matsumaru, the true heir, is being hidden in a tower. ", "The document is in the possession of Jikei, a powerful Abbot, who intends to deliver it to the Yagyu, who will expose the scandal and ruin the clan. ", "Finding Jikei at a temple, Itto finds he cannot bring himself to strike him, as Jikei has reached a state of perfect enlightenment. ", " Meanwhile Daigoro has run into some trouble of his own. ", "A pickpocket, 'Quick Change' Oyoo, leaves him holding her loot as she flees from Senzo, an inspector. ", "Daigoro refuses to identify Oyoo, even when Senzo beats him. ", "Oyoo is so touched by his loyalty she promises never to steal again. ", "A Kuroda woman named Shiranui hires Itto to kill Naritaka, his mistress and the false heir, so that the true Matsumaru can become lord of the Kuroda, an assignment which Itto accepts. ", "As Jikei sails across a river, Itto cuts the bottom of the boat out from under him, killing him swiftly underwater and taking the document. ", "Shiranui intentionally wets the document, making it blank, but Ogami delivers it to the Kuroda anyway. ", "In the castle of the Kuroda, Itto challenges Naritaka about his deception, and the lord orders his men to kill him. ", "Itto defeats them, fighting his way to Naritaka and fulfilling his assignment. ", "The young Lord Matsumaru is now able to take his rightful place.", "\n\n## ANALYSIS\n\n_Baby Cart in the Land of Demons_ is a return to form for the _Lone Wolf and_ _Cub_ series, after the slight disappointment of _Baby Cart in Peril_. ", "This film is almost as good as _Baby Cart on the River Styx_ , the best of the series.", "\n\n_Baby Cart in the Land of Demons_ is supported by a driving plot, which not only keeps the film moving at a nice pace, but also provides the excuse for compelling scenarios and visceral fight scenes. ", "The idea that Itto must defeat a succession of samurai to begin his assignment, each one giving him a portion of his instructions and fee, is magnificent, and works very well on screen. ", "Other plot elements, such as the Kuroda secret document which everyone wants and will kill to get, ensure that _Baby Cart in the Land of Demons_ is always exciting in its twists and turns.", "\n\nThis film also contains some of the most violent and well-choreographed battle scenes in the _Lone Wolf and Cub_ series. ", "As usual, Tomisaburo Wakayama is magnificent. ", "He moves with perfect precision in his fight scenes, and _Baby Cart in the Land of Demons_ is full of classics. ", "The duels towards the beginning, against the men sent to test him, are especially worthy of mention. ", "The scenes of Itto fighting his way through the Kuroda palace are also particularly well realised, with plenty of rapid cuts and pans. ", "The gore level is high; watch for the messenger giving Itto his assignment as he burns alive, or the brutal shot in which Itto literally cuts a man in half.", "\n\nAlso worthy of mention is the scene in which Daigoro stoically covers for a pickpocket, even when he's beaten by an inspector. ", "Itto looks on, proud that his son has honourably kept his promise.", "\n\n## THE VERDICT\n\nDirector Kenji Misumi restores the _Lone Wolf and Cub_ series to the former levels of excitement he reached with the second film in the series. ", "Not only a welcome entry to the series, but a fine samurai film in its own right.", "\n\n### _Lady Snowblood: Love Song of Vengeance_ (1974)\n\n**Japanese Title:** _Shuri-yuki-hime: Urami Renga_\n\n**Directed by:** Toshiya Fujita\n\n**Written by:** Adapted by Kiyohide Ohara and Norio Osada from the manga by Kazuo Koike and Kazuo Kamimura\n\n**Produced by:** Kikumaru Okuda\n\n**Edited by:** Osamu Inoue\n\n**Cinematography:** Tatsuo Suzuki\n\n**Cast:** Meiko Kaji (Yuki AKA Lady Snowblood), Yoshio Harada (Shusuke), Kazuko Yoshiyuki (Aya), Shin Kishida (Kikui), Juzo Itami (Ransui)\n\n## PLOT SUMMARY\n\nYuki has survived the seemingly fatal wound she received at the end of the first film, but has been sentenced to death for her crimes. ", "She is rescued by members of Japan's secret police, headed by Kikui, who wants Yuki to assassinate Ransui, an anarchist who poses a real threat to Kikui and Terauchi, the minister of justice. ", "Yuki accepts the assignment and poses as Ransui's maid, but finds herself bonding with him and his wife, Aya. ", "Ransui figures out that Yuki is Lady Snowblood, and explains to her that Kikui and Terauchi unlawfully executed a large group of his anarchist friends, and that he has a document which proves it. ", "Should the document be made public, Kikui and Terauchi will be ruined. ", "Yuki becomes Ransui's protector, but he is arrested. ", "Yuki takes the document to Shusuke, Ransui's brother. ", "Shusuke runs a clinic in a slum, but his motivations are different to his brother's. ", "He plans to blackmail Kikui and Terauchi to give the people of the slums food and money. ", "Ransui is beaten and tortured by the police, who eventually release him, but they have injected him with plague. ", "He soon dies, and Aya, distraught with grief, attacks the police, who kill her. ", "Shusuke reveals that Aya was once his wife, and left him for his brother. ", "He continues with his blackmail plot, even though he too is now suffering from the plague. ", "Yuki delivers Shusuke's terms to Kikui, who responds by setting fire to the slums, hoping to kill Shusuke and burn the document. ", "Yuki finds Shusuke still alive among the wreckage, and together they attack Kikui and Terauchi, killing them. ", "Shusuke himself dies in the fighting and Yuki is left alone again.", "\n\n## ANALYSIS\n\nThe second and final film of the Lady Snowblood series, _Love Song of_ _Vengeance_ is much more political than _Lady Snowblood_. ", "Although the first had some political overtones, it was in the main a revenge-oriented tale. ", "Rather than repeat this formula, the filmmakers chose to tell a very different and distinct story.", "\n\nUnlike most samurai films, _Love Song of Vengeance_ takes place in the Meiji era of Japanese history, just after the Russo-Japanese war of 1904–1905. ", "This is after the abolition of the Shogunate and the dissolution of the samurai class, and the beginnings of a more industrialised Japan. ", "The political themes in the film focus around a pair of activist brothers and their struggle against some corrupt government officials. ", "This makes for a compelling story, as Yuki, Ransui and Shusuke struggle against their powerful enemies, who go to great lengths to conceal their murderous pasts, even setting fire to a large slum, which is home to many people. ", "The central theme of resistance against corrupt authority works very well in this film, reminiscent of the work of Masaki Kobayashi.", "\n\nDespite its setting and preoccupations, the elements of the samurai film are still clearly present. ", "Meiko Kaji as Yuki continues to slash her way through large groups of enemies, proving to be just as adept as other stars of the genre, such as Shintaro Katsu and Tomisaburo Wakayama. ", "Toshiya Fujita continues his carefully styled direction, creating a variety of visually satisfying shots. ", "Worthy of mention is the sequence towards the beginning of the film, where Yuki, cornered on a beach, surrenders herself to the police. ", "Yuki throws her sword away, then there's a shot from above, as the police encircle Yuki, obscuring her from our view. ", "Next we see a beautiful image of Yuki's sword, lodged in the ground, surrounded by the ocean, both the metal and water reflecting the sun and each other.", "\n\nUnlike many sequels, _Love Song of Vengeance_ allows Yuki's character to develop. ", "It is disturbing to see her at the beginning of the film; she moves like a ghost, clearly tired of the fugitive's life she leads, and shows very little expression. ", "For those who followed Yuki's painful journey in the first film, it is a pleasure to see her finally smile.", "\n\n## THE VERDICT\n\nA very fitting sequel and a great film in its own right, _Love Song of_ _Vengeance_ builds on themes touched upon in _Lady Snowblood_ as well as adding new elements. ", "A standout example of the samurai film genre, not only because of its unusual heroine and setting, but also its superior quality.", "\n\n### _Bandits vs. Samurai Squadron_ (1978)\n\n**Japanese Title:** _Kumokiri Nizaemon_\n\n**Directed by:** Hideo Gosha\n\n**Written by:** Adapted by Kaneo Ikegami from the novel by ShotaroIkenami\n\n**Produced by:** Masahiro Sato, Ginichi Iwamoto, Shigemi Sugisaki\n\n**Edited by:** Michio Suwa\n\n**Cinematography:** Masao Kosugi\n\n**Cast:** Tatsuya Nakadai (Nizaemon), Shima Iwashita (Ochiyo), Shogoro Ichikawa (Shikibu), Takashi Yamaguchi (Owari), Koshiro Matsumoto (Kuranosuke), Tetsuro Tamba (Kichibei), Keiko Matsuzaka (Oshino), Teruhiko Aoi (Rokunosuke), Mitsuko Baisho (Omatsu), Hiroyuki Nagato (Kichigoro)\n\n## PLOT SUMMARY\n\nThe Kumokiri, a gang of skilled thieves, continually avoid Shikibu, a samurai inspector.", "\n\nTheir latest plan is to rob the vault of a wealthy merchant, Matsuya. ", "Nizaemon Kurokiri, the leader of the Kumokiri, sends Ochiyo, a seductive woman, to make Matsuya fall in love with her. ", "Matsuya proposes to her, and Ochiyo, along with some of her accomplices, is able to infiltrate his household. ", "Shikibu discovers that Nizaemon is really Iori Tsuji, a samurai whose brother was accused of embezzlement by the Owari clan. ", "The Owari clan killed their family, while the two brothers were able to escape. ", "Nizaemon's brother, Kuranosuke, urges him to seek revenge on the Owari by helping him kill their daimyo, but he refuses, no longer caring about their old life. ", "Ochiyo discovers the location of Matsuya's vault and his keys, but Shikibu is waiting for them on the night of the heist. ", "In a long brutal battle, only Nizaemon, Ochiyo and two other members of the gang escape. ", "Kuranosuke gives himself up, pretending to be his brother. ", "He is executed, along with the other captured members of the gang. ", "When Nizaemon hears of his brother's sacrifice, he realises he must take his place in the assault on Lord Owari. ", "Sneaking into the Owari castle, Nizaemon battles his way through Owari's retainers, but stops when he discovers that a child born to his ex-lover Oshino and heir to the Owari, is actually his, and not Lord Owari's. ", "Nizaemon tries to escape with Oshino, but she is killed by their pursuers. ", "Shikibu resigns his post, as he has discovered corruption in the Owari, and is sympathetic to the Tsuji brothers. ", "When visiting Kuranosuke's grave, he and Nizaemon pass each other on the road.", "\n\n## ANALYSIS\n\nAnother film by Hideo Gosha, _Bandits vs_ _. ", "Samurai Squadron_ combines elements from the two genres he was most familiar with: yakuza and samurai. ", "The result is an epic tale of gangster heists and samurai-style revenge, a pleasing combination which benefits from Gosha's skilled direction.", "\n\n_Bandits vs_ _. ", "Samurai Squadron_ tells the story of the Kumokiri gang, a group which specialises in infiltrating the households of wealthy individuals, such as merchants and sake brewers, in order to rob them. ", "The film's plot works very effectively to keep viewer attention; the devious ways in which the Kumokiri gang rob their targets, and the constant efforts of the valiant Inspector Shikibu to apprehend them, make for some entertaining scenes, in the tradition of classic heist films. ", "The slowly unfolding plot gradually reveals the relationship between Nizaemon and Kuranosuke, and keeps the viewer wondering what this will mean for the two characters and the gang. ", "There are also plenty of twists and changes in the plot, which keeps the story moving at a nice pace. ", "The only criticism is that some of the twists come too late in the film, which means their implications do not have sufficient time to be explored.", "\n\nAt 2 hours 40 minutes, with a large cast of characters, and complex plot, there's always the potential for the viewer to become lost or confused. ", "But the pace is perfect: not so slow that it becomes boring, and not so fast that we lose track of what's happening. ", "Many of the characters assume false identities, and Gosha employs the simple technique of text on screen to show their name and true allegiance.", "\n\nGosha lends his distinctive sense of rhythm to the battle sequences. ", "The fight between the samurai police and the Akatsuki gang at the beginning of the film is particularly good, complete with ingeniously paced squirts of blood that shoot out as the camera pans across the scene.", "\n\nTatsuya Nakadai as Nizaemon, is the strong, inexpressive boss of the Kumokiri gang, who loses everything, and then embarks on a selfless quest for revenge. ", "As always, he excels at portraying both an inscrutable strength and a profound sense of loss. ", "Shogoro Ichikawa is equally effective as Inspector Shikibu, lending credibility to this noble character who must change when he discovers corruption in the clan he works for. ", "Also worthy of mention is Shima Iwashita, the beautiful yet harsh Ochiyo, master infiltrator of the Kumokiri gang.", "\n\n## THE VERDICT\n\nA pleasing fusion of the yakuza and samurai genres, _Bandits vs_ _._ _", "Samurai_ _Squadron_ is a solid film, although not quite as good as some of Gosha's earlier works. ", "But like all his films, it's definitely worth seeing.", "\n\n### _Hunter in the Dark_ (1979)\n\n**Japanese Title:** _Yami no karyudo_\n\n**Directed by:** Hideo Gosha\n\n**Written by:** Adapted by Hideo Gosha from the novel by Shotaro Ikenami\n\n**Produced by:** Masayuki Sato, Ginichi Kishimoto, Shigemi Sugisaki\n\n**Edited by:** Michio Suwa\n\n**Cinematography:** Tadashi Sakai\n\n**Cast:** Tatsuya Nakadai (Gomyo), Yoshio Harada (Yataro), Sonny Chiba (Shimoguni), Ayumi Ishida (Oriwa), Keiko Kishi (Omon), Ai Kanzaki (Osaki), Kayo Matsuo (Oren), Tetsuro Tamba (Tanuma)\n\n## PLOT SUMMARY\n\nGomyo, a yakuza boss, hires Yataro, a ronin who has lost all memories of his past. ", "He helps his new boss escape an attempt on his life by Omon, a woman jilted by Gomyo, and also manages to kill Jihei, Gomyo's rival. ", "Omon escapes Gomyo's men, and is taken in by Kasuke, a poor fisherman. ", "Meanwhile, Shimoguni, an ambitious samurai, is charged with the task of wiping out the Kitamae ronin, a group attempting to restore their clan. ", "Shimoguni hires Gomyo to perform this task and sends Yataro after them. ", "In a vicious battle he kills most of them, but a few escape. ", "Recovering from his wounds in Gomyo's house, Yataro is recognised by Oriwa, who used to be his wife. ", "Unable to bring his memory back, she sends him to a temple, where he will learn all the secrets of his past. ", "Gomyo overhears all of this, and Shimoguni demands he hand over Yataro. ", "At the temple, Yataro regains his memory; he is the last hope of the Kitamae clan, entrusted with a document proving the clan's ownership of the wealthy Ezo province. ", "The remaining Kitamae ronin burst in and attack him, eager for revenge. ", "In the confusion the temple catches fire, and Yataro is rescued both from the fire and his madness by Gomyo, who has him hidden in an old warehouse. ", "Gomyo sends Oriwa to be with him, even though he loves her himself. ", "Shimoguni destroys Gomyo's house, but discovers Yataro's whereabouts from Omon. ", "Orei, a woman wanting to avenge Jihei, also finds Yataro, killing him in his weakened state, although he manages also to kill her. ", "Shimoguni arrives in time to see Oriwa commit suicide, and leaves, confident he has been successful. ", "Gomyo has recovered the Kitamae document, and confronts Shimoguni with it. ", "In a final duel, the two kill each other.", "\n\n## ANALYSIS\n\nConsidered by many to be Hideo Gosha's best film of the 1970s, _Hunter_ _in the Dark_ is a gripping samurai film, combining Gosha's trademark direction with a compelling plot.", "\n\nThe film revolves around Yataro, a ronin with no memory whatsoever of his past. ", "Throughout, small details about his identity are revealed, and the audience is left to piece them together. ", "A number of other characters, each with their own bloody aims, most of which are closely intertwined with Yataro's past, ensure there's a constant sense of conflict and opposition in the film. ", "Also, the character who actually ends up fulfilling the heroic role of _Hunter in the Dark_ is very surprising, which lends great momentum to the later scenes.", "\n\nThe moment where Yataro finally regains his memory is hard to forget. ", "Having just escaped a burning temple, weak from his wounds, Yataro cries out as he recalls the horrors of his past. ", "With his clothes still smouldering, he swings his sword wildly, desperately attempting to kill the ghosts of his old life. ", "Poetic moments are peppered throughout: when Yataro stares at a burning lantern, for instance, an image that plays an important part in his tragic past; or when Omon, a tough yakuza woman, kills Kasuke, one of her admirers, with the same hairpin which caused them to meet earlier in the film.", "\n\nThe battle scenes are of a very high standard. ", "Yataro's battle with the Kitamae ronin is particularly impressive, and includes one of the most surprising severed arms ever shown in a samurai film. ", "After defeating the ronin, Yataro is confronted by a group of vengeful yakuza women, who, in an intensely frenetic scene, almost succeed in killing him. ", "The battle between Gomyo and Shimoguni is also realised with Gosha's usual skill, and takes place in the unique location of a large chicken coop. ", "Tatsuya Nakadai and martial arts superstar Sonny Chiba bring a necessary energy to this scene, both swift and unpredictable.", "\n\nTatsuya Nakadai again demonstrates his considerable range in his performance as Gomyo, the tough yakuza boss who proves to be more than just a criminal. ", "Yoshio Harada is also very engaging in his role, convincingly conveying anguish and pain when Yataro finally regains his memory. ", "Keiko Kishi offers a frightening performance as Omon, a treacherous woman prepared to do anything to survive. ", "Sonny Chiba is similarly well cast as the ruthlessly ambitious Shimoguni.", "\n\n## THE VERDICT\n\nYet another swiftly paced Gosha film, with a compelling plot and absorbing performances. ", "A definite highlight of 1970s samurai films. ", "\n\n# THE 1980s, 90s AND CURRENT CINEMA\n\nBy the 1980s, samurai films had lost much of their popularity, with audiences' attention turning instead to the yakuza (gangster) genre; and studios followed the money. ", "Even Akira Kurosawa struggled to make his two samurai epics of the 1980s, _Kagemusha_ and _Ran_ , which were saved from cancellation by international funding. ", "George Lucas and Francis Ford Coppola, both admirers of Kurosawa's films, provided him with the funds to finish _Kagemusha_ , a haunting film telling the story of Takeda Shingen (a famous daimyo) and his body double.", "\n\nThroughout the 1980s and 90s few samurai films were made, compared to the voluminous output of the 1960s. ", "Recently, however, the samurai film has been enjoying somewhat of a revival. ", "Popular directors in Japan are returning to the genre, creating films that are finding acclaim overseas. ", "Yoji Yamada's trilogy of samurai films ( _The Twilight Samurai, The Hidden Blade and Love and Honour_ ) were all popular among judges and audiences on the film festival circuit, and rightly so. ", "Takeshi Kitano, a popular director of crime films, made his own version of _Zatoichi_ , putting himself in the lead role, with great success: the film was not only popular with audiences, but also won a variety of awards both in Japan and abroad. ", "The inflated style of the 1970s samurai films is still alive and well with films such as _Aragami_. ", "Directed by Ryuhei Kitamura, famous for his flamboyant action films, _Aragami_ is every bit as wonderfully overblown as the _Lone Wolf and Cub_ series.", "\n\n### _Kagemusha_ (1980)\n\n**Japanese Title:** _Kagemusha_\n\n**Directed by:** Akira Kurosawa\n\n**Written by:** Masato Ide, Akira Kurosawa\n\n**Produced by:** Akira Kurosawa, Tomoyuki Tanaka, Francis Ford Coppola (international release), George Lucas (international release)\n\n**Edited by:** Yoshihiro Iwatani (assistant editor), Tome Minami (negative cutter)\n\n**Cinematography:** Takao Saito, Shoji Ueda\n\n**Cast:** Tatsuya Nakadai (Shingen Takeda/Shingen's double), Tsutomo Yamazaki (Nobukado Takeda), Kenichi Hagiwara (Katsuyori Takeda), Jinpachi Nezu (Sohachiro Tsuchiya), Hideji Otaki (Masakage Yamagata), Daisuke Ryu (Nobunaga Oda), Masayuki Yui (Ieyasu Tokugawa)\n\n## PLOT SUMMARY\n\nA common thief is the exact likeness of Shingen Takeda, a powerful daimyo vying for control of Japan. ", "The thief is trained as Shingen's double, so as to trick his enemies. ", "When Shingen dies from a gunshot, the thief must take his place full time, so Shingen's enemies do not attempt to take advantage of his death. ", "The thief is reluctant to accept this role, even trying to escape, but is moved by Shingen's secret funeral to change his mind. ", "He grows bold in the role, becoming close to Shingen's grandson, Takemaru. ", "Shingen's son, Katsuyori, becomes tired of pretending this thief is his father. ", "Nobunaga and Ieyasu, rival daimyos, also try to gain control of Japan, first using spies and then an attack on Shingen's territory to discover whether or not he is still alive. ", "But the double fools them, and they hold off on any further attacks. ", "The illusion is shattered when the double attempts to ride Shingen's horse, which realises the thief isn't his master and throws him off. ", "Exposed in front of a large crowd, the double is forced to leave. ", "He finds himself unable to detach from the Takeda family, and watches Shingen's official funeral from behind a barrier with the other peasants. ", "Katsuyori is now in charge of the Takeda, and he takes the army to attack Nobunaga. ", "Nobunaga defeats the Takeda army with brilliant use of firearms. ", "The double witnesses this and, heartbroken, charges Nobunaga's troops. ", "He is shot, and dies lying in the water, the abandoned Takeda banner just out of his reach.", "\n\n## ANALYSIS\n\n_Kagemusha_ is another compelling film from master director Akira Kurosawa. ", "Using real historical events as his inspiration, he crafts an emotive tale about the perils of adopting another's identity. ", "What happens to someone who loses their own identity by assuming someone else's? ", "This is the question Kurosawa explores.", "\n\nShingen's double finds he is unable to distance himself from the Takeda clan, even though he is no longer wanted by them. ", "He has become so involved in Shingen's life that he cannot return to his own. ", "Kurosawa predicts this through some interesting dialogue from Nobukado, Shingen's brother who also performed as his double on occasion, and with some skilful uses of cinematic techniques. ", "Among the most memorable is when the double, dressed in Shingen's full armour, leaves a dimly lit room. ", "His huge shadow looms menacingly above him, showing that he is only a shadow of the real Shingen and will suffer for letting another's identity obscure his own.", "\n\nAs usual, Kurosawa's direction creates many memorable images. ", "In some battle scenes, the sky is lit a very dark red and the sight of the samurai commanders silhouetted atop a mountain reflects the bloody fighting going on below them. ", "The film's final battle, in which Katsuyori completely ruins Shingen's army, contains a long sequence of the Takeda troops lying dead and wounded in the dirt, victims of Nobunaga's riflemen. ", "Kurosawa never shies away from showing the true results of warfare, this time in vivid colour.", "\n\nTatusuya Nakadai gives a consummate performance as Shingen's double, switching seamlessly from playing a stern, forthright man, to the timid, more jovial figure. ", "He shows us a man who has lost everything and is denied the one thing he has come to want. ", "Nakadai's performance is unnerving in its conviction and his ability to elicit sympathy.", "\n\n## THE VERDICT\n\nA rich, well-directed film that explores a fascinating theme. ", "Highly recommended.", "\n\n### _Ran_ (1985)\n\n**Japanese Title:** _Ran_\n\n**Directed by:** Akira Kurosawa\n\n**Written by:** Adapted by Akira Kurosawa, Hideo Oguni and Masato Ide from William Shakespeare's King Lear\n\n**Produced by:** Katsumi Furukawa, Masato Hara, Hisao Kurosawa, Serge Silberman\n\n**Edited by:** Akira Kurosawa, Hideto Aga, Hajime Ishihara, Ryusuke Otsubo\n\n**Cinematography:** Asakazu Nakai, Takao Saito, Masaharu Ueda\n\n**Cast:** Tatsuya Nakadai (Hidetora), Akira Terao (Taro), Jinpachi Nezu (Jiro), Daisuke Ryu (Saburo), Mieko Harada (Kaede), Yoshiko Miyazaki (Sue), Hisashi Igawa (Kurogane), Peter (Kyoami), Masayuki Yui (Tango), Takeshi Nomura (Tsurumaru)\n\n## PLOT SUMMARY\n\nHidetora, a daimyo who has conquered a large area, wants to retire and announces his intention to abdicate to Taro, his eldest son. ", "His other two sons, Jiro and Saburo, will get a castle each, and are expected to help their brother. ", "Saburo sees the foolishness of this situation; he explains to his father that they will simply end up fighting each other, but Hidetora banishes him for his troubles. ", "Fujimaki, another daimyo, is impressed with Saburo's honesty and courage and asks him to marry his daughter, an offer which he accepts. ", "Taro's wife, Kaede, convinces him to assert more authority over Hidetora; this angers Hidetora and he leaves to stay with Jiro, who turns him away on orders from Taro. ", "With nowhere to go, Hidetora and his escort capture a castle held by one of Taro's generals. ", "Betrayed by two of his samurai, Hidetora is attacked by his two sons and flees into a storm, where he finally succumbs to madness. ", "Jiro has Taro killed, and becomes the new daimyo. ", "Hidetora is found by Tango and Kyoami, his fool, but he has suffered a complete emotional breakdown. ", "Saburo hears of his father's plight, and arrives with a small force, making it clear that he only wants to take Hidetora away with him. ", "Saburo finds his father and they share a painful reunion. ", "Hidetora finally emerges from his madness, and is content. ", "Jiro betrays Saburo, sending riflemen, who kill him. ", "Upon seeing this, Hidetora dies from grief. ", "Jiro finds himself trapped in his castle, surrounded by rival daimyos, who take advantage of his weakness.", "\n\n## ANALYSIS\n\nIn many ways, _Ran_ is a dream come true for fans of samurai films: the most influential director of the genre, Akira Kurosawa, bringing to the screen an epic saga, on a Hollywood-scale budget.", "\n\n_Ran_ is a big film. ", "It features big performances from a superb cast, large battles, extensive sets and an epic plot. ", "It is difficult not to get caught up in its grand scale. ", "There are scenes that involve hundreds of extras, all dressed for battle; a castle, built specially for the film, is burned to the ground; and Kurosawa makes use of grand locations, such as the beautiful mountainous terrain at the film's beginning and the huge empty plain at its end. ", "Such scale comes at a price and it's easy to see why Kurosawa ran into trouble finishing this film. ", "Fortunately, he persevered. ", "The tone and imagery of _Ran_ is luxurious, a feast for the senses. ", "Nonetheless, for those familiar with Kurosawa's earlier work, _Ran_ seems to lack a little of the simplistic brilliance which characterises films such as _Seven Samurai_ _,_ _Yojimbo_ and _Throne of Blood_.", "\n\nIt is hard to think of any scenes in _Ran_ that are as purely entertaining and evocative as the opening scene of _Throne of Blood_ but Kurosawa does create some wonderful images: the billowing clouds forming over Hidetora as he makes his fateful decision to abdicate in favour of his sons foreshadow the storm that will come when they betray him; the battle for the castle, accompanied by sombre music, playing over the shots of carnage; Tsurumaru, the blind man, standing completely alone in the battlements of his ruined castle, waiting for his sister, who will never come. ", "Lacking something of the poetry of Kurosawa's earlier work, such images are beautifully composed, presented in vibrant, arresting colours.", "\n\nAn adaptation of Shakespeare's _King_ _Lear_ , Kurosawa uses this rich material to its full potential. _", "Ran_ is a compelling examination of a man, Hidetora, who, through his own folly, loses everything he has gained throughout his life. ", "As in _Kagemusha_ , Tatsuya Nakadai plays a man descending into madness. ", "Particularly memorable is the scene in which Hidetora, having lost a battle against his two treacherous sons and cornered in a burning castle, walks quietly down the castle stairs, an unchanging look of shock on his face. ", "Fires rage around him, and he is surrounded by his enemies, but Hidetora walks quietly down the stairs and out the gates. ", "Nakadai performs what must have been a difficult scene with complete conviction, and the result is unforgettable. ", "Mieko Harada also offers an unnerving performance as Kaede, a woman seething with hatred. ", "The single-named Peter does very well as Kyoami, Hidetora's fool, who cannot help but love his master, despite his decisions.", "\n\n## THE VERDICT\n\nAlthough lacking some of the poetry of Kurosawa's earlier films, _Ran_ is still a worthy entry to the genre, with a rich plot and some captivating performances. ", "But if you haven't seen any of Kurosawa's samurai films, you might do better to start with his earlier work.", "\n\n### _The Twilight Samurai_ (2002)\n\n**Japanese Title:** _Tasogare Seibei_\n\n**Directed by:** Yoji Yamada\n\n**Written by:** Adapted by Yoji Yamada and Yoshitaka Asama from the novels by Shuuhei Fujisawa\n\n**Produced by:** Hiroshi Fukazawa, Shigehiro Nakagawa, Ichiro Yamamoto\n\n**Edited by:** Iwao Ishii\n\n**Cinematography:** Mutsuo Naganuma\n\n**Cast:** Hiroyuki Sanada (Seibei), Rie Miyazawa (Tomoe), Nenji Kobayashi (Choubei), Ren Osugi (Toyotarou), Mitsuru Fukikoshi (Michinojo), Hiroshi Kanbe (Naota), Min Tanaka (Zenemon), Tetsuro Tamba (Tozaemon)\n\n## PLOT SUMMARY\n\nSeibei Iguchi is a poor samurai, forced to care for his two daughters and senile old mother alone after his wife dies. ", "Without the proper money for bathing and grooming, Seibei is criticised by his fellow samurai, and given the nickname 'Twilight' because he has to hurry home each evening to look after his children. ", "After helping his childhood friend Tomoe escape her abusive husband, the two grow close, but Seibei decides not to marry her because he fears she won't like his frugal lifestyle. ", "Political turmoil wracks Japan, and many in Seibei's clan are ordered to commit suicide as the power balance shifts. ", "One such samurai, Zenemon, refuses to do so, and Seibei is ordered to kill him. ", "About to carry out his mission, Seibei realises that he wants Tomoe as his wife, but she tells him she has accepted another proposal. ", "After a bloody duel, Seibei kills Zenemon, and finds Tomoe waiting for him. ", "The two wed, but Seibei dies in a war three years later. ", "Seibei is remembered fondly by his youngest daughter, who knows he lived a full, albeit short, life.", "\n\n## ANALYSIS\n\n_The Twilight Samurai_ is a standout samurai film and proof that the genre is alive and well in modern cinema. ", "The film is a simple story told beautifully. _", "The Twilight Samurai_ centres around Seibei, a samurai, and his family, and despite the fact that they're desperately poor and barely surviving, the scenes of them all together create a warm atmosphere. ", "The scenes' strength comes from the convincing relationship between Seibei and his daughters, and director Yoji Yamada works hard to emphasise their closeness, showing the family in a variety of simple, day-to-day moments. ", "Seibei appears to be a man before his times; he is a caring single father, encouraging his daughters to learn to read and treating them with kindness and good humour, despite the understandable stress of his domestic situation.", "\n\nThe love story that plays out between Seibei and Tomoe is subtle and touching rather than melodramatic and clichéd, conveying true affection with very little dialogue, through glances and expressions.", "\n\n_The Twilight Samurai_ presents one of the most realistic visions of samurai life in the Tokugawa era. ", "Yamada's preoccupation with the routine life of the samurai adds a level of realism to his film, as we see characters engaged in rather unremarkable activities. ", "Seibei works with several other samurai as a public servant in the food stores of his clan's castle, keeping track of the supplies. ", "Shots of samurai working at their desks, rather than at war, show the administrative duties that were a large part of most samurai's lives in the Tokugawa era. ", "Yet when Yamada is required to show violence he does so with startling realism, and Seibei's battle with the insane Zenemon has to be one of the most convincing in any samurai film. ", "The two flail wildly at each other with their blades, beginning to slow down and limp as wounds and exhaustion take their toll. ", "This plays in stark contrast to the assured duels of so many samurai films, which are over in a few swift strikes.", "\n\nThis marriage of realism and in-depth characterisation is the greatest triumph of Yamada's film.", "\n\n## THE VERDICT\n\n_The Twilight Samurai_ is a touching story bolstered by impressive realism and rounded characterisation. ", "Essential viewing.", "\n\n### _Zatoichi_ (2003)\n\n**Japanese Title:** _Zatoichi_\n\n**Directed by:** Takeshi Kitano\n\n**Written by:** Adapted by Takeshi Kitano from a story by Kan Shimozawa\n\n**Produced by:** Masayuki Mori, Tsunehisa Saito\n\n**Edited by:** Takeshi Kitano, Yoshinori Oota\n\n**Cinematography:** Katsumi Yanagishima\n\n**Cast:** Takeshi Kitano (Zatoichi), Tadanobu Asano (Hattori), Michiyo Ookusu (Oume), Daigoro Tachibana (Seitaro/Osei), Yuuko Daike (Okinu), Yui Natsukawa (O-Shino), Ittoku Kishibe (Ginzo), Saburo Ishikura (Ogi), Akira Emoto (Torakichi), Ben Hiura ('Gramps')\n\n## PLOT SUMMARY\n\nZatoichi, the blind swordsman, arrives at a small town, where residents are troubled by the powerful alliance of two yakuza bosses, Ginzo and Ogi. ", "Zatoichi stays with Oume, a woman who manages a small farm on her own. ", "A ronin named Hattori arrives in town. ", "His wife is ill, and he needs money to treat her, so he takes a job as a yojimbo (bodyguard) for Ginzo. ", "Zatoichi and Shinkichi meet two geishas, Okinu and Osei (actually a man), who have been seeking the men who murdered their parents ten years ago. ", "When Ginzo's yakuza attempt to cheat him at gambling, Zatoichi attacks them, killing many. ", "Hattori arrives to stop him, but is too late. ", "Meanwhile Okinu and Osei discover that Ogi was one of the men responsible for the murder of their family. ", "A strange figure gives orders to Ginzo and Ogi, telling them he suspects he knows the truth about the two geishas. ", "When the tavern owner discovers where Zatoichi and the geishas are staying, he sends some men, who burn down Oume's house. ", "Ginzo and Ogi attempt to trap Okinu and Osei, but Zatoichi saves them, killing Ogi in the process. ", "Following Ginzo to the beach, Zatoichi finds Hattori and defeats him in a tense duel. ", "Ginzo flees and is found the next morning drowned in the river. ", "Zatoichi finds the real bosses, Tarakichi the tavern owner, and his waiter, 'Gramps'. ", "Zatoichi kills Tarakichi and blinds 'Gramps', who was Ginzo and Ogi's boss all along, as punishment for his crimes. ", "With their town finally free of criminals, Oume and the other townsfolk enjoy the festival.", "\n\n## ANALYSIS\n\nZatoichi is back, and you've never seen him like this before. ", "Director Takeshi Kitano, famous for his popular Japanese crime films, tried his hand at the character in 2003, and created a refreshingly different film, clearly distinct from the original series.", "\n\nKitano's Zatoichi is very different to the series produced throughout the 1960s, 70s and 80s, which may prove unsettling to fans of those films. ", "Kitano, who not only directs but also stars as the blind swordsman, presents a Zatoichi that is in many ways the opposite of Shintaro Katsu's. ", "Zatoichi has very few lines in this film, and often communicates with grunts and mumbled words, a far cry from Katsu's very vocal hero.", "\n\nKatsu's Zatoichi was a product of his unique talent, and anyone trying to imitate his performance would only end up the victim of unfavourable comparisons. ", "Kitano's Zatoichi makes a very interesting hero; he's utterly inscrutable, which leaves the audience constantly wondering what his plans are.", "\n\nThere is a very amusing thread of comedy running through _Zatoichi_. ", "Shinkichi, a clumsy gambler, features in some highly comedic scenes, in particular when he tries to teach some farmers how to wield a sword, and then attempts to master Zatoichi's gambling technique.", "\n\nKitano uses rhythm very effectively in _Zatoichi_ : the sounds of farmers working in a field, carpenters building a house and rain drops falling into a bucket create catchy tunes which synthesise with the images they accompany. ", "The extended festival dance towards the end of the film is bizarre and unexpected, but visually lush and thrilling.", "\n\n_Zatoichi_ contains a great deal of graphic violence, even for a samurai film. ", "Hattori, Zatoichi's strongest enemy in the film, is a highly effective ronin character, as sinister as he is skilled, and both he and the blind swordsman feature in some highly creative fight sequences. ", "Kitano uses digital effects to take the violence to a new level, showing severed body parts and blood sprays with more realism than ever before. ", "The fight scenes are well executed; Kitano clearly has a talent for frenetic, visceral battles. ", "Particularly worthy of mention is the scene where Hattori hacks his way through the entire Funamachi gang, and the scene where Zatoichi fights a large group of yakuza in the heavy rain. ", "Thanks to Kitano's modern style of directing and use of digital effects, all the battles in _Zatoichi_ are extremely slick.", "\n\n## THE VERDICT\n\nRather than follow the pattern established by Shintaro Katsu, Takeshi Kitano creates his own version of the Zatoichi character, different yet no less entertaining. ", "Taking a fresh approach, Kitano's _Zatoichi_ shows that the samurai film genre is still ripe for exploitation in the current cinema landscape.", "\n\n### _Aragami_ (2003)\n\n**Japanese Title:** _Aragami_\n\n**Directed by:** Ryuhei Kitamura\n\n**Written by:** Ryuhei Kitamura, Ryuichi Takatsu\n\n**Produced by:** Yuuji Ishida, Shinya Kawai, Haruo Umekawa\n\n**Edited by:** Shuichi Kakesu\n\n**Cinematography:** Takumi Furuya\n\n**Cast:** Takao Osawa (the samurai), Masaya Kato (the master of the temple), Kanae Uotani (the woman of the temple), Tak Sakaguchi (new challenger), Hideo Sakai (the samurai's friend)\n\n## PLOT SUMMARY\n\nTwo wounded samurai fleeing a battle arrive at an old temple in the mountains, where they both collapse in exhaustion. ", "One of the samurai awakens and begins to talk to the master of the temple, a strange man who has travelled far and wide, collecting a variety of objects from around the world. ", "A woman sits and watches them talk, never speaking herself. ", "Through conversation, the samurai discovers he was fed the specially prepared liver of his companion, which is why he was able to survive his fatal wounds. ", "Enraged, he attacks his host, who stabs him through the chest. ", "The samurai isn't even wounded; as the temple master explains, only a sword through his heart or head can kill him now. ", "The temple master goes on to explain that he is in fact Miyamoto Musashi, and has never been defeated in battle. ", "He is a near immortal super human, and can only be killed in the same way as the samurai. ", "Musashi is tired of living, and wants to die in a duel. ", "The samurai agrees to fight him, and chooses an unusual sword. ", "In the battle that follows, the samurai seems to lose, but discovers a hidden power within himself. ", "The samurai is victorious, and Musashi can finally rest and dream as he has been craving. ", "The samurai discovers that the woman is Aragami, a goddess of war, and he agrees to stay with her in the temple, continuing to fight challengers just as Musashi did.", "\n\n## ANALYSIS\n\n_Aragami_ is another fine example of a recent samurai film, the work of action/horror director Ryuehi Kitamura. ", "Kitamura is famous for fast-paced and stylistic fight scenes, and _Aragami_ is no exception, featuring beautiful battles that are a feast for the senses.", "\n\nThe overall style of _Aragami_ is even more overblown than that of the manga-inspired samurai films of the 1970s, such as the _Lone Wolf and_ _Cub_ series. _", "Aragami_ seems to have a lot in common with the loud, over-the-top style of Japanese anime and video games, and this is especially true in the highly stylised fight sequences. ", "Kitamura has a good understanding of tone, and uses it to craft some highly atmospheric moments. ", "While action is the main focus of _Aragami_ , Kitamura and co-writer Ryuichi Takatsu create an intriguing, though not overly complex, plot.", "\n\nTaking place entirely in the confines of a creepy temple, _Aragami_ gradually builds to a climactic duel between the film's two main characters. ", "These scenes are composed mainly of the samurai and his host talking, and slowly reveal the disturbing situation the samurai finds himself in. ", "Despite its simple structure, the viewer's interest is constantly piqued by mysteries and revelations.", "\n\nKitamura creates an unsettling atmosphere; inside the temple are rusty chains, weathered rafters and a large, solemn, stone statue (whose expression changes throughout the film), all lit to cast long shadows. ", "The setting matches some of the more horrific revelations in the film, and creates the right level of menace when the fierce battle rages at the conclusion.", "\n\nThe battles present some of the most stylised violence ever shown in a samurai film. ", "The scene where the samurai and his host fight in complete darkness, with only the sparks coming off their swords for illumination, is utterly stunning. ", "The thrash rock soundtrack by Nobuhiko Morino exhilarates, complementing the modern anime feel of the film.", "\n\n## THE VERDICT\n\nAn atmospheric film with an intriguing plot and a grand duel at its conclusion, _Aragami_ is a worthy addition to the samurai film genre. ", "While Yoji Yamada continues the work of the more reflective filmmakers, such as Kurosawa, we can rest assured the action-oriented samurai film is still alive and well in _Aragami_.", "\n\n### _The Hidden Blade_ (2004)\n\n**Japanese Title:** _Kakushi ken oni no tsume_\n\n**Written by:** Adapted by Yoshitaka Asama and Yoji Yamada from the novel by Shuuhei Fujisawa\n\n**Directed by:** Yoji Yamada\n\n**Produced by:** Hiroshi Fukazawa\n\n**Edited by:** Iwao Ishii\n\n**Cinematography:** Mutsuo Naganuma\n\n**Cast:** Masatoshi Nagase (Munezo), Takako Matsu (Kie), Yukiyoshi Ozawa (Yaichiro), Hidetaka Yoshioka (Samon), Min Tanaka (Kansai Toda), Tomoko Tabata (Shino), Ken Ogata (Hori), Nenji Kobayashi (Ogata), Reiko Takashima (Yaichiro's wife)\n\n## PLOT SUMMARY\n\nMunezo is a samurai of the Unesaka clan, learning to use new European rifles and artillery. ", "Kie, a peasant girl who used to work at Munezo's house, has married into the Iseya family, who badly mistreat her. ", "Weak from disease and exhaustion, Kie nearly dies, but Munezo takes her away from the Iseya, saving her life with medical treatment from a doctor. ", "Meanwhile, Munezo's friend, Yoichiro, has been found guilty of ploting against the Shogun in Edo. ", "He is brought back to the Unesaka lands where he is held prisoner. ", "Untrue rumours begin to spread that Kie is Munezo's mistress, and when she is recovered, despite loving her, Munezo sends her back to her father. ", "Yoichiro escapes from his prison and holds a peasant family hostage. ", "Hori, the senior retainer of the clan, orders Munezo to kill him. ", "Munezo visits his old teacher, Toda, who teaches him a new technique to defeat Yoichiro, who is considered one of the finest swordsmen in the Unesaka clan. ", "Yoichiro's wife attempts to convince Munezo to spare him, even offering to sleep with him, but Munezo refuses. ", "She also visits Hori. ", "Munezo and Yoichiro fight, and Munezo wins, but is disappointed to see Yoichiro gunned down by Unesaka riflemen. ", "He discovers that Hori slept with Yoichiro's wife, promising to spare Yoichiro, a promise he never had any intention of keeping. ", "Enraged, Munezo uses his hidden blade technique to kill Hori, hoping this will allow Yoichiro and his wife, who has committed suicide, to rest in peace. ", "Munezo renounces his samurai status to become a merchant, and marries Kie.", "\n\n## ANALYSIS\n\nAlong with _The Twilight Samurai_ _,_ _The Hidden Blade_ cements Yoji Yamada's reputation as one of the finest directors of samurai films working in the current cinema landscape. ", "Both films skilfully combine touching and humorous moments with moving personal drama and conflict.", "\n\nThere are certain thematic similarities between this film and _The Twilight Samurai_. ", "Both feature a main character whose compassion alienates him from his peers, who is forced by his superiors to kill a man he respects and admires. ", "However, _The Hidden Blade_ is clearly distinct from Yamada's previous film, and is not simply a re-working of previous thematic content. ", "Unlike Seibei in _The Twilight Samurai_ , Munezo, the protagonist in _The Hidden Blade_ , has the respect of his peers, and actually makes an effort to keep it, causing considerable dramatic tension. ", "The film begins with Munezo saving Kie, a young peasant girl who used to be a servant at his mother's house, from the cruel merchant family she has married into. ", "People begin to gossip that she is Munezo's mistress, and although he loves her, he sends her away, for the sake of both their reputations. ", "Seibei, by comparison, puts the happiness of his loved ones before his reputation. _", "The Hidden Blade_ also has added drama in Munezo's struggle against Hori, his corrupt superior. ", "Hori is a cruel man, and makes an interesting counterpoint to Munezo's compassion. ", "Unseen for much of the film, he drives the plot, his corruption forcing Munezo and Yoichiro into conflict, and ultimately leading Munezo in a completely new direction.", "\n\nLike _The Twilight Samurai_ the major strength of this film is Yamada's grasp of characterisation. ", "Through a series of candid domestic scenes, he brings us into the midst of Munezo and Kie's lives, and this closeness adds weight to later scenes. ", "We cannot help but feel empathy with these characters, something helped greatly by the strong performances of Masatoshi Nagase and Takako Matsu. ", "As in Yamada's earlier work, there's a warm feeling in aspects of the film, generated mainly by the tender family moments shared by the characters.", "\n\nOne of the most interesting aspects of _The Hidden Blade_ is its exploration of the modernisation of the samurai armies. ", "Munezo's clan, the Unesaka, are in the process of training their men in the use of modern European rifles and artillery. ", "Rather than take the predictable route and show these weapons in action on the battlefield, Yamada shows us the problems encountered by the samurai as they learn how to use them. ", "Humorous scenes have the instructor from Edo, wearing his European suit, collar and neck-tie, growing increasingly frustrated with the Unesaka samurai, who do not understand the relevance of European traditions such as drills and synchronised marching. ", "Yamada does briefly show the devastating effects of the new cartridge-loading rifles – they completely destroy a human arm in one scene – but for the most part uses much more subtle means to convey the effects of modern weapons on the samurai traditions. ", "This theme is handled much more intelligently and effectively than in the rather obvious ending of Hollywood's attempt at the samurai film, _The_ _Last Samurai_.", "\n\n## THE VERDICT\n\nAnother great film by Yamada, born from his firm grasp of characterisation, realism and compelling material.", "\n\n### _Love and Honour_ (2006)\n\n**Japanese Title:** _Bushi no ichibun_\n\n**Directed by:** Yoji Yamada\n\n**Written by:** Adapted by Yoji Yamada, Emiko Hiramatsu and Ichiro Yamamoto from the novel by Shuuhei Fujisawa.", "\n\n**Produced by:** Hiroshi Fukazawa, Ichiro Yamamoto\n\n**Edited by:** Iwao Ishii\n\n**Cinematography:** Mutsuo Naganuma\n\n**Cast:** Takuya Kimura (Shinnojo Mimura), Rei Dan (Kayo Mimura), Mitsugoro Bando (Toya Shimada), Takashi Sasano (Tokuhei), Kaori Momoi (Ine Hatano), Nenji Kobayashi (Sakunasuke Higuchi), Ken Ogata (Shinnojo's teacher)\n\n## PLOT SUMMARY\n\nShinnojo works as a food taster for his daimyo, ensuring that none of his meals are poisoned. ", "Not enjoying this boring work, he hopes to one day open his own fencing school. ", "While performing his duty, Shinnojo eats shellfish that wasn't prepared properly, making it toxic. ", "He prevents his daimyo from eating the same food but grows ill from its effects and loses his sight completely. ", "His loving wife, Kayo, does her best to care for him, but Shinnojo becomes increasingly depressed. ", "His family insist that Kayo visit Shimada, a high-ranking samurai she knows, to ask him to make sure that they'll continue to be supported by the clan. ", "This seems to work, and Shinnojo is happy for a time, no longer needing to worry about his livelihood. ", "But he begins to suspect Kayo of having an affair and sends his servant, Tokuhei, to follow her. ", "Kayo has been sleeping with Shimada, in exchange for his help. ", "When Shinnojo discovers this, he divorces Kayo. ", "He later realises Shimada tricked her; he actually had nothing to do with the daimyo's decision to continue supporting Shinnojo. ", "He is enraged, and determines to kill Shimada. ", "Adapting his swordsmanship to his blindness, Shinnojo challenges Shimada, and defeats him. ", "Tokuhei brings Kayo back to him, and Shinnojo realises he treated her badly, but she still loves him.", "\n\n## ANALYSIS\n\n_Love and Honour_ is the third in Yoji Yamada's recent trilogy of samurai films, and, like the two previous entries, benefits from his expert use of characterisation and exceptional attention to detail.", "\n\nLike _The Twilight Samurai_ and _The Hidden Blade_ , _Love and Honour_ focuses on one samurai, learning an important lesson through adversity. ", "In many ways Shinnojo is reminiscent of Seibei and Munezo; he has Seibei's modern attitudes to education (he plans to start a fencing school catering to people of all classes) and Munezo's firm sense of samurai pride. ", "Shinnojo, however, is far less attuned to the feelings of others around him than Yamada's previous heroes, and this, in many ways, is the flaw he must overcome in the film. ", "The Shinnojo we meet at the beginning of the film shows a lack of appreciation of those who care for him; he mocks both his loving wife Kayo and his loyal old servant, Tokuhei, failing to understand that these are the two most important people in his life. ", "This makes Shinnojo considerably more flawed than both Seibei and Munezo, and thus his journey is a much harder one.", "\n\nThe simple plot of _Love and Honour_ is both captivating and moving; only the hardest of audiences would fail to be moved by Shinnojo's painful journey. ", "When he loses his sight, he loses his reason to live; he believes he can no longer function as an effective member of society, and this is a huge blow to his pride. ", "We watch Shinnojo give in to anger and then despair, before he is finally able to find a purpose in his life again. ", "Also touching is the plight of Kayo, who makes huge sacrifices to help her husband, but only suffers herself as a result, as a distraught Shinnojo badly mistreats her. ", "The counterpoint to both Shinnojo and Kayo is Toya Shimada, an evil man whose actions drive the plot forward to its violent climax.", "\n\nThis moving plot is greatly assisted by performances from a well-chosen cast. ", "Takuya Kimura is utterly convincing in his role, and flawlessly ranges the gamut of emotions that Shinnojo goes through during his painful journey. ", "Rei Dan is charming as Kayo, presenting a touching impression of a woman who cares deeply for her husband. ", "The two share some beautiful scenes together, for example when Kayo lovingly nurses Shinnojo out of a fever. ", "Takashi Sasano puts in a fine performance as Tokuhei, who functions as a source of gentle comedy throughout the film. ", "Sasano perfectly captures the humorous aspects of Tokuhei's character, when he practises fencing with a samurai child for instance, and skilfully conveys his dedication to Shinnojo and Kayo.", "\n\nAs in his other samurai films, Yamada creates an extremely realistic impression of Tokugawa-era Japan, showing us the daily routines of his characters. ", "Shinnojo's job as a food taster for his daimyo, a seemingly exciting role, is portrayed instead as a mundane job; the food tasters sit in a row, eat a single mouthful of a dish, and then the food is rushed away to the daimyo's luxurious chambers. ", "The domestic scenes involving Kayo and Tokuhei are similarly realistic, not only giving an interesting insight into times past, but also helping us to grow closer to Yamada's characters.", "\n\nThe duel between Shinnojo and Shimada is particularly well handled. ", "Yamada treats the idea of a blind swordsman more practically than the Zatoichi films; Shinnojo's movements are entirely consistent with someone who has lost his sight; each time he attempts to strike his opponent he swings his sword multiple times, hoping to reach his mark. ", "The duel's conclusion is sudden and surprising.", "\n\n## THE VERDICT\n\nAnother strong film from Yamada, who should be applauded for making samurai films of such a consistently high quality. ", "The genre will survive long into the future if more films of this calibre are made. ", "\n\n# BIBLIOGRAPHY\n\nGalloway, Patrick, _Stray Dogs and Lone Wolves: The Samurai Film Handbook,_ Berkeley: Stone Bridge Press, 2005.", "\n\nKure, Mitsuo, _Samurai: An Illustrated History,_ Massachusetts: Tuttle Publishing, 2002.", "\n\nRatti, Oscar and Westbrook, Adele, _Secrets of the Samurai: The Martial Arts of Feudal Japan,_ Massachusetts: Tuttle Publishing, 1973.", "\n\nSilver, Alain, _The Samurai Film_ , Woodstock: The Overlook Press, Peter Mayer Publishers, Inc., 2005.", "\n\nWilson, William Scott, _The Lone Samurai: The Life of Miyamoto Musashi,_ Tokyo: Kodansha International, 2004.", "\n\nYoshimoto, Mitsuhiro, _Kurosawa: Film Studies and Japanese Cinema,_ North Carolina: Duke University Press, 2000. ", "\n\n# kamera BOOKS\n\nESSENTIAL READING FOR ANYONE INTERESTED IN FILM AND POPULAR CULTURE\n\nTackling a wide range of subjects from prominent directors, popular genres and current trends through to cult films, national cinemas and film concepts and theories. ", "Kamera Books come complete with complementary DVDs packed with additional material, including feature lms, shorts, documentaries and interviews.", "\n\n# Copyright\n\nFirst published in 2008 by Kamera Books, \nan imprint of Oldcastle Books Ltd, \nP O Box 394, Harpenden, AL5 1XJ\n\nThis ebook edition first published in 2010\n\nAll rights reserved \n© ROLAND THORNE, 2008\n\nThe right of ROLAND THORNE to be identified as author of this work has been asserted in accordance with Section 77 of the Copyright, Designs and Patents Act 1988\n\nThis ebook is copyright material and must not be copied, reproduced, transferred, distributed, leased, licensed or publicly performed or used in any way except as specifically permitted in writing by the publishers, as allowed under the terms and conditions under which it was purchased or as strictly permitted by applicable copyright law. ", "Any unauthorised distribution or use of this text may be a direct infringement of the author's and publisher's rights, and those responsible may be liable in law accordingly\n\nISBN 978–1–84243-400-0\n\nA promotional poster for _Seven Samurai. ", "Seven Samurai_ directed by Akira Kurosawa and produced by Sojiro Motoki for Toho Studios. ", "Image provided by Toho Company Ltd. and Photofest. ", "© Toho Company Ltd.\n\nTakezo (Toshiro Mifune) is only interested in perfecting his swordsmanship. _", "Miyamoto Musashi_ directed by Hiroshi Inagaki and produced by Kazuo Takimura for Toho Studios.", "\n\nMusashi (Toshiro Mifune) and Kojiro (Koji Tsuruta) during their epic duel. _", "Duel on Ganryu Island_ directed by Hiroshi Inagaki and produced by Kazuo Takimura for Toho Studios.", "\n\nTwo icons of the samurai film finally meet in combat: the Yojimbo (Toshiro Mifune) and Zatoichi (Shintaro Katsu). _", "Zatoichi Meets Yojimbo_ directed by Kihachi Okamoto and produced by Shintaro Katsu and Hiroyoshi Nishioka for Toho Studios.", "\n\nItto Ogami (Tomisaburo Wakayama), Daigoro (Akihiro Tomikawa) and their deadly baby cart. _", "Lone Wolf and Cub: Baby Cart on the River Styx_ directed by Kenji Misumi and produced by Shintaro Katsu and Hisaharu Matsubara for Toho Studios.", "\n\nYuki (Meiko Kaji) is an instrument of vengeance. _", "Lady Snowblood_ directed by Toshiya Fujita and produced by Kikumaru Okuda for Toho Studios.", "\n\nA promotional poster for _Kagemusha. ", "Kagemusha_ directed by Akira Kurosawa and produced by Akira Kurosawa, Tomoyuki Tanaka, Francis Ford Coppola and George Lucas for Kurosawa Production Co., Toho Studios and 20th Century Fox. ", "Image provided by 20th Century Fox and Photofest. ", "© 20th Century Fox.", "\n\nTatsuya Nakadai as Hidetora. _", "Ran_ directed by Akira Kurosawa and produced by Katsumi Furukawa, Masato Hara, Hisao Kurosawa and Serge Silberman for Greenwich Film Productions, Herald Ace Inc. and Nippon Herald Films.", "\n\nJiro's army on the move. ", "This beautiful image from _Ran_ gives a good impression of the film's large-scale battle scenes. _", "Ran_ directed by Akira Kurosawa and produced by Katsumi Furukawa, Masato Hara, Hisao Kurosawa and Serge Silberman for Greenwich Film Productions, Herald Ace Inc. and Nippon Herald Films. ", "Image provided by Orion Classics and Photofest. ", "© Orion Classics.", "\n\nSeibei (Hiroyuki Sanada) is both a caring father... _The Twilight Samurai_ directed by Yoji Yamada and produced by Hiroshi Fukazawa, Shigehiro Nakagawa and Ichiro Yamamoto for Hakuhodo, Nippon Television Network Corporation and the Sumitomo Corporation.", "\n\n...and a skilled warrior. _", "The Twilight Samurai_ directed by Yoji Yamada and produced by Hiroshi Fukazawa, Shigehiro Nakagawa, and Ichiro Yamamoto for Hakuhodo, Nippon Television Network Corporation and the Sumitomo Corporation.", "\n\nTakeshi Kitano as Zatoichi. _", "Zatoichi_ (2003) directed by Takeshi Kitano and produced by Masayuki Mori and Tsunehisa Saito for Bandai Visual Co., Saito Entertainment and Office Kitano Productions.", "\n\nTadanobu Asano as Hattori and Takeshi Kitano as Zatoichi. _", "Zatoichi_ (2003) directed by Takeshi Kitano and produced by Masayuki Mori and Tsunehisa Saito for Bandai Visual Co., Saito Entertainment and Office Kitano Productions. ", "Image provided by Miramax and Photofest. ", "© Miramax.", "\n\nAn unusual duel in an unusual temple. _", "Aragami_ directed by Ryuhei Kitamura and produced by Yuuji Ishida, Shinya Kawai and Haruo Umekawa for Napalm Films, Amuse, Micott and DUEL film partners.", "\n\nYukiyoshi Ozawa as Yaichiro and Masatoshi Nagase as Munezo. _", "The Hidden Blade_ directed by Yoji Yamada and produced by Hiroshi Fukazawa for Shochiku Co. Image provided by Shochiku, Tartan and Photofest. ", "© Shochiku.", "\n\nMasatoshi Nagase as Munezo and Takako Matsu as Kie. _", "The Hidden Blade_ directed by Yoji Yamada and produced by Hiroshi Fukazawa for Shochiku Co. Image provided by Shochiku, Tartan and Photofest. ", "© Shochiku. ", "\n" ]

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[ "Q:\n\nNeed help trying to read Sharepoint folder from a standalone windows application (c# based)\n\nI have a standalone windows app written in c#, that needs to connect to a sharepoint folder and list/read all the files in that directory. ", "I have not been able to find a solution, some people suggest getting Microsoft.", "Sharepoint.", "DLL which lets you read files and folders easily, but when i try to install sharepoint web services it tells me it can only be installed on windows server. ", "Is there any possible (and preferably simple) way to just connect to a sharepoint folder and just get the contents???", "\n\nA:\n\nUse the Managed Client Object Model:\nhttp://msdn.microsoft.com/en-us/library/ee857094(v=office.14).aspx\n...or connect to the folder via SharePoint's web services:\nhttp://sarangasl.blogspot.com/2009/12/sharepoint-list-web-service.html\n\n" ]

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[ "\n'It's crazy': Chase forgiving all debt owed by its Canada credit card customers - electriclove\nhttps://www.cbc.ca/news/business/chase-bank-amazon-visa-marriott-credit-card-debt-1.5239411\n======\nal2o3cr\nMy guess: when Chase says \"we felt it was a better decision for all parties\"\nthey mean \"we realized we broke some kind of law without anybody noticing, and\nselling the debts to collections could turn up evidence of that in future\nlitigation\"\n\n~~~\npaxys\nA more likely scenario is that the total outstanding debt was small enough\nthat the positive PR + tax write-offs were bigger than getting pennies from a\ncollections agency.", "\n\n~~~\ngruez\nTax write-offs are profits that were never made in the first place. ", "It's not\nsome sort of a tax credit. ", "The reason you pay less taxes is because you didn't\nmake a (or made less) profit.", "\n\n~~~\npaxys\nYou are talking about losses. ", "Unpaid debts/invoices is its own category, and\ncan definitely be deducted (see\n[https://www.irs.gov/publications/p535#idm140359415938416](https://www.irs.gov/publications/p535#idm140359415938416)).", "\n\n~~~\nkgwgk\nBecause they are losses.", "\n\n------\nfreedomben\nI don't know how Canada does it, but a lot of those smiles would change at\nleast a little bit in the US when they get a 1099-C in February and realize\nthe IRS counts debt forgiveness as taxable lump-sum income.", "\n\n~~~\nnrdgrl\nYikes. ", "Nope, I live in Canada and I had a few tens of thousands in debt\nforgiven. ", "Definitely didn't have to pay taxes on it. ", "That would be absolutely\ncrazy and would have driven me to bankruptcy!", "\n\n~~~\niscrewyou\nNot judging you at all, I promise. ", "I found it ironically funny that forgiving\ndebt could lead someone into bankruptcy. ", "Talk about a win-win situation.", "\n\n~~~\nfreedomben\nYep. ", "In my case we were overjoyed having finally worked out a deal with the\nbank, only to discover that now I was in debt to the IRS instead of the bank\n:'(\n\nIt sure feels like your government is shitting on you during an already tough\nsituation.", "\n\n~~~\ndmix\nSo the idea is the bank gave you a loan then forgave it, so it’s now income?", "\nThat’s a big leap in logic and sounds evil considering you never consider that\nwhen getting a loan, you only expect the internet to accrue.", "\n\n~~~\nbriandear\nIt is income. ", "Someone gave you money. ", "Otherwise, why wouldn’t a company “loan”\nyou a higher salary and then just “forgive” the debt? ", "Or, you could set up a\ncompany to loan yourself money — the company deducts the “loss” and you don’t\npay taxes on the gain.", "\n\n~~~\nRetric\nThe principal is presumably income, however the interest or fees should not\nbe. ", "The IRS will even occasionally cancel debt that’s mostly fines and\ninterest without considering it income.", "\n\n------\nsetgree\nIf you wanted to design a system to reward addictive spending, it would look\nlike this -- random intermittent reinforcement of problematic behaviors.", "\n\n~~~\nhurrdurr2\nCame here to post this exact sentiment... I mean that one long haul trucker\nwas so ecstatic his almost 7k debt was forgiven and said something to the\neffect of \"I'm glad the number was up there.\" ", "Really?", "\n\n~~~\ngrenoire\nHe's honest. ", "If he had accumulated just _1k_ , then he would be annoyed that\nhe hadn't taken on more. ", "To him it's just free money.", "\n\n------\ndxf\nI didn't see it in the article, but I wonder how much debt that was forgiven\nwas actual credit extended for purchases (which is money that Chase has \"lost\"\nas they won't recover it) and how much debt was interest+fees on the credit\nthey extended.", "\n\n------\ndata_spy\nWow! ", "That's one way to get out of the Canadian market. ", "Wonder what the number\none cost was the get out of the market the normal way, legal fees?", "\n\n~~~\nhermitdev\nAssuming people are only making minimum payments, they could have had to\nmaintain operations for 20 years or so, even if they otherwise closed the\naccounts and only accepted credits (to them) and no debits on the accounts.", "\n\nI dont know what infrastructure amd employment levels they would have had to\nmaintain to service the accounts. ", "I'm sure they probably ran the numbers,\ncompared what they'd receive to cost of operations and probably realized itd\neither be a wash or a money losing proposition and decided to take the\ncheaper/expedient way out.", "\n\nPersonally, I'd love this deal. ", "My CC is closed, but still paying down a very\nlarge sum. ", "Got married, assumed my wife's debts and struggling to get our\nheads above water. ", "Should be clear in another 4 years _sigh_ , maybe sooner if\nI can get a few good bonuses in the next few years.", "\n\n~~~\nyurishimo\nYou got this! ", "My wife and I have been married just over 5 years now and still\nhave $50k~ of debt left, most of it is her student loans.", "\n\nDon't be afraid to shop around for jobs too. ", "I'm about to transition to a new\ncompany making 50% more after putting 5 years in at my current job. ", "Luckily, I\nliked the job so I had time to really search for another one that would be a\ngood fit culturally as well and that paid more.", "\n\nNow we're going to be debt free hopefully by Christmas 2020 and making\n$110k/yr and 26 y/o at that time. ", "Not to mention bonuses and raises for both\nof us in the next 18 months. ", "My wife has only been out of school and working\nfor 2 years as an engineer, so she has plenty of room left to move up and I\ncan keep working for software companies with great work/life balance and\npeople that I like.", "\n\nWin win! ", "Rooting for you :)\n\n~~~\nhermitdev\nI'm not worried. ", "We have the savings to cover the debt, problem is I have a\nhard time touching it, since I work in Back office finance IT. ", "I have access\nto the entirety of the firms positions and trades. ", "Id like to cash out,\nbecause earning 3-4% interest, while paying out 20% interest on around 50k in\ndebt makes far less sense than paying no interesting and paying into a\nmatching 401k...\n\nTo be honest, this has probably been my single biggest stressor since getting\nmarried, and my wife's apparent mental block that finances are tight (when\nthey shouldn't be) and she keeps buying non essential items.", "\n\nA lot of this is self inflicted, then complicated with medical issues on\nshitty insurance. ", "I mean, the year before I got married, I was debt free, even\nafter been unemployed for 6 months (and I didnt file for benefits, stupidly).", "\n\nWe spent too much on our rings, but not on the wedding (we did a JOP wedding\nand a nice dinner afterward with just my wife, 2 step kids and myself). ", "But,\nwe had to move out of my 1 bed + den apartment into a 3 bed, 3.5 bath\ntownhouse. ", "More than doubled rent, but was necessary.", "\n\nI mean, I make good money, but on my salary, we're struggling, living paycheck\nto paycheck, in large part of debt I assumed from marriage and medical issues.", "\nKicker is I _have_ the savings to cover it, but cannot get to due to\ncompliance issues.", "\n\n------\nhprotagonist\nJubilee is pretty fun.", "\n\n------\nScoundreller\nI wonder how this gets reported to the credit bureaus.", "\n\n------\nbreakingcups\nOh man, I'm predicting a new wave of scam emails in the coming months.", "\n\nLegitimate news articles like this are irresistible to the 419 scammers.", "\n\n------\nfaissaloo\nBetter not to own a credit card in the first place, with so many people in so\nmuch debt you really should be questioning the notion that there's a\n'responsible' way to use a credit card.", "\n\n~~~\nmruts\nLiquidity and debt help societies and people. ", "It’s just important that you pay\noff the card before the 18% rates kick in. ", "But there are smart ways of\navoiding these rates for a long time. ", "For example you can roll over your debt\ninto new cards before the interest rates kick. ", "This could allow you to keep\ndebt for months without paying any interest at all.", "\n\nThe problem with debt is when you use it purely for consumption instead of\ninvestment or increased efficiency of your consumption. ", "But in general, debt\nand leverage are a very powerful thing and essential to an efficient market.", "\n\n~~~\nfaissaloo\n>Liquidity and debt help societies and people\n\nInterest helps a small portion of people, while harming the majority.", "\n\n>It’s just important that you pay off the card before the 18% rates kick in.", "\n\nIf enough people did that banks wouldn't bother.", "\n\n>The problem with debt is when you use it purely for consumption instead of\ninvestment or increased efficiency of your consumption\n\nNo, it merely mitigates the risks, if your business venture goes sour you will\nnot be in a good place. ", "There's also the question of 'what counts as an\ninvestment' although this is a minute issue compared to the aforementioned.", "\n\n~~~\nmruts\n> Interest helps a small portion of people, while harming the majority.", "\n\nWould you rather that no one could get access loans? ", "If you truly believe that\nposition, it would very much undermines the autonomy and choice of the people\nwithout capital: businesses, individuals, start-ups, whatever.", "\n\nIf you think that interest is a bad thing, what is the alternative? ", "Sharia\nfinance? ", "You wanna go back to times of usury laws? ", "Or that Christians can't\nloan to other Christians?", "\n\nWhat about government? ", "You think there should only be negative interest rate\nbonds? ", "What about the federal funds rate, LIBOR, T-note yields, etc? ", "Do you\nhave a coherent system that could replace these financial instruments?", "\n\n~~~\nfaissaloo\n>Would you rather that no one could get access loans?", "\n\nIf they had interest then yes.", "\n\n>If you truly believe that position, it would very much undermines the\nautonomy and choice of the people without capital: businesses, individuals,\nstart-ups, whatever.", "\n\nWithout interest the amount of capital those groups would need would\nsignificantly decrease. ", "I'm willing to sacrifice a reasonable amount of\nautonomy in order to stop people burning themselves and devaluing the earnings\nof others.", "\n\n>If you think that interest is a bad thing, what is the alternative? ", "Sharia\nfinance?", "\n\nThe alternative is a number of things working together, sharia finance yes,\nthe end of fiat currency, guaranteed minimum income to get those without\ncapital to a point where they can contribute to society and a restoration of\ntrust based society so that those with close bonds will be more likely to loan\nto each other interest free and out of good will (this is probably the most\ndifficult of the three but I have some ideas).", "\n\n~~~\nmruts\nOkay, how about you give me $1000 and I'll pay you back when I die. ", "I'm good\nfor it, I promise.", "\n\nIf so, I'll give you my bitcoin address.", "\n\nThe time value of money is so fundamental, and so obvious, that you must be\nbeing deliberately obtuse to not understand it. ", "Money today is worth more than\nmoney tomorrow.", "\n\n~~~\nfaissaloo\n>Okay, how about you give me $1000 and I'll pay you back when I die. ", "I'm good\nfor it, I promise.", "\n\nI have no reason to trust you.", "\n\n>The time value of money is so fundamental, and so obvious, that you must be\nbeing deliberately obtuse to not understand it\n\nNo one's saying time doesn't have monetary value, it's a variable many\nbusinesses depend on, but that shouldn't mean you simply get to do the direct\nconversion and sidestep creating meaningful longterm value and make it more\ndifficult for those without money to get anywhere without being under your\nthumb.", "\n\n------\nalgaeontoast\nAre we sure this actually occurred? ", "If anything this is going to make it\neasier for american banks to exploit students and side-step legislation that\nwould actually fix the root of the student debt bubble in America.", "\n\nBy this I mean people will now just point to Canada and demand a bailout\nwithout really committing effort to passing laws that will prevent\nexploitative interest rates and pricing schemes by private universities.", "\n\n~~~\nlstamour\nYes, I can confirm it happened. ", "A relative of mine was quite happy when this\nhappened. ", "Myself, I migrated off their cards years ago.", "\n\nThat said, I don’t think it will lead to bailout. ", "Debt forgiveness is a rare\nbut standard practice in trying to rebuild credit scores, is my understanding,\nand a way of getting some return rather than the zilch you’d get from a\npersonal bankruptcy. ", "It’s just that bankruptcy doesn’t affect student loans in\nthe US, so folks are absolutely stuck there...\n\n~~~\nderefr\n> It’s just that bankruptcy doesn’t affect student loans in the US, so folks\n> are absolutely stuck there...\n\nI mean, _in theory_ (wink), you could always pay off your student loan debt\nusing other forms of debt, and _then_ go bankrupt.", "\n\n~~~\nflaviu1\nCourts aren't stupid, I don't think they'd look kindly upon you if they see\nyou've done this.", "\n\n~~~\nlonelappde\nWhy would courts care? ", "Student loans are not dischargable, because the student\nloan creditor lobbied to make sure they get laid. ", "The replacement creditor has\nnot.", "\n\nOf course, there is no lender who is going to give a an unsecured loan the\nsize of your substantial student debt to someone with said loans and no other\nassets, for obvious reasons.", "\n\n~~~\nceejayoz\n> Why would courts care?", "\n\nBecause it's fraud. ", "Taking on big debts you never intend to pay right before a\nbankruptcy will get you in a lot of trouble.", "\n\n" ]

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[ "\\(2019\\) Issue Information. ", "Respirology Case Reports, 7(2), e00338. ", "doi: 10.1002/rcr2.338.", "\n" ]

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[ "Senate Democrats are investigating accusations by former Yale University student Deborah Ramirez who claims to have had her own “drunken party” incident with Supreme Court nominee Brett Kavanaugh.", "\n\nAccording to New Yorker reporter Ronan Farrow, Kavanaugh’s freshman year at Yale is now being investigated by at least two Democratic senators. ", "Meanwhile, Republican legislators are pressing for Kavanaugh to be quickly confirmed.", "\n\nADVERTISEMENT\n\nRamirez was resistant to speak publicly because she was drinking at the same time and she has gaps in her memory similar to the ones Kavanaugh buddy Mark Judge describes. ", "After talking it through and describing the incident, she knows with certainty that Kavanaugh exposed himself during a dormitory party. ", "She said that he “thrust his penis” into her face, and “caused her to touch it without her consent as she pushed him away.”", "\n\nRamirez studied sociology and psychology while at Yale and later worked for an organization that helps survivors of domestic violence.", "\n\n“I would think an F.B.I. investigation would be warranted,” she told Farrow.", "\n\n“This is another serious, credible, and disturbing allegation against Brett Kavanagh. ", "It should be fully investigated,” said Sen. Mazie Hirono (D-HI).", "\n\n“These allegations seem credible, and we’re taking them very seriously. ", "If established, they’re clearly disqualifying,” said an aide of another Senate office.", "\n\nADVERTISEMENT\n\nKavanaugh continues to refute all incidents being reported.", "\n\n“This alleged event from 35 years ago did not happen,” he said in a statement. “", "The people who knew me then know that this did not happen, and have said so. ", "This is a smear, plain and simple. ", "I look forward to testifying on Thursday about the truth, and defending my good name–and the reputation for character and integrity I have spent a lifetime building–against these last-minute allegations.”", "\n\nRamirez said that it happened at a party in Lawrence Hall with a small group of students playing a drinking game.", "\n\nADVERTISEMENT\n\n“We were sitting in a circle,” she said. “", "People would pick who drank.” ", "Ramirez was chosen repeatedly, she said, and quickly became inebriated. ", "At one point, she said, a male student pointed a gag plastic penis in her direction. ", "Later, she said, she was on the floor, foggy and slurring her words as that male student and another stood nearby.”", "\n\nShe also identified the other male students watching the game. ", "She said that a third student exposed himself to her.", "\n\nADVERTISEMENT\n\n“I remember a penis being in front of my face,” she said. “", "I knew that’s not what I wanted, even in that state of mind.”", "\n\nShe said she remembers responding “That’s not a real penis,” which caused the other students to laugh at her confusion and taunt her. ", "She was told she should kiss it.", "\n\n“I wasn’t going to touch a penis until I was married,” she told Farrow. “", "I was embarrassed and ashamed and humiliated.”", "\n\nADVERTISEMENT\n\nKavanaugh was standing next to her laughing, she said she watched him pull up his pants.", "\n\n“Brett was laughing,” she said. “", "I can still see his face, and his hips coming forward, like when you pull up your pants.”", "\n\nShe remembered another student shouting down the hall “Brett Kavanaugh just put his penis in Debbie’s face!”", "\n\nShe recalled it was his full name and how mortified she felt that people knew." ]

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[ "Masaya Ozaki is a well-rounded scriptwriter. ", "His first writing credit dates back to 1995. ", "However, it is in 2010 that he added director to his skillset. ", "His first work as a writer/director was “Randebû!”. “", "Her Sketchbook” is his second feature. ", "His impressive background is perhaps why the film is well-written and has a nice pace.", "\n\n“Her Sketchbook” is screening as part of The Japan Foundation Touring Film Programme\n\nMami Konuma, twenty-something, works in a factory, is clumsy, seems to live in her own world, and – greatest sign of social inadequacy- she really likes mangas. ", "After leaving her job at the factory, her worried father finds her a job as a video game tester. ", "One day, as she is eating in the staircase, she overhears Yabe, who is part of the production team and needs a drawing to be revised. ", "Without thinking too much, she becomes a Secret Revision Savior (basically, her and Batman are the same when it comes to saving people) for the young man. ", "Her stepping out of her comfort zone will broaden her horizons, soothe some old wounds and help her to be more assertive.", "\n\nMami is an attaching character, well-supported by actress Mugi Kadowaki. ", "She is seen by others as a ‘shut-in who reintegrates society’. ", "But the story shows up a slightly more complex person. ", "She is shy, doesn’t really know how to bond but does try, and she doesn’t have a lot of self-confidence (which finds a rough explanation in the absent mother). ", "Mami does think of herself as a ’shut-in and a loser’ (her words, not mine). ", "And it is when she meets people who stop treating her as such and embrace her creative mind that her life can evolve for a seemingly better.", "\n\n“Her Sketchbook” is interesting in that it blends indie vibes (natural lighting, very few close-ups), but also fairytale aspects (with the ending, for example) and mangas’ influence (with the almost-interactive way to display her drawing). ", "This last point allows a really smart and fun way to introduce her drawings, flashbacks, etc. ", "However, the downside of the manga-esque aspect of the film is an acting sometimes over the top from the supporting characters.", "\n\n“Her Sketchbook” is visually appealing, entertaining, and although a bit cliché, it leaves you with a reassuring feeling, or what I would call a hot-chocolate-and-cosy-blanket-feeling." ]

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[ "Yves Feys\n\nYves Feys (born 16 January 1969 in Torhout) is a retired Belgian professional football goalkeeper. ", "He has played most of his career for Cercle Brugge.", "\n\nClub career\nFeys started playing football at age 9 with top level team Cercle Brugge. ", "He stayed with the green and black side until they relegated to the second division. ", "He went to Excelsior Mouscron. ", "In the last season with the Hainaut side, Feys wasn't given much play time. ", "As a result, Feys returned to his roots. ", "Feys became back-up goalie for Björn Sengier.", "\n\nAfter this quite disappointing season for Feys, he decided to try his luck with Jupiler League side FC Antwerp. ", "Feys ended his career with Deinze.", "\n\nYves Feys won the Cercle Brugge Pop Poll three consecutive times.", "\n\nRetirement\nDuring and after his career, Feys was active in the building industry.", "\n\nExternal links\nCerclemuseum.be \nProfile - FC Antwerp\n\nCategory:1969 births\nCategory:Living people\nCategory:People from Torhout\nCategory:Association football goalkeepers\nCategory:Belgian footballers\nCategory:Cercle Brugge K.S.V. players\nCategory:Royal Excel Mouscron players\nCategory:Royal Antwerp F.C. players\nCategory:Belgian First Division A players\nCategory:K.M.S.K. Deinze players" ]

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[ "The chromosome 9p21 region and myocardial infarction in a European population.", "\nSequence variation at Ch9p21 is a predisposing genetic factor for a number of diseases, including myocardial infarction (MI) and diabetes. ", "We determined the risk of MI associated with various alleles and haplotypes, established and compared the predictive values of risk alleles, tested for the independence of associations between different risk alleles and MI, and sought to provide evidence for dual association of alleles with MI and diabetes. ", "With the use of 35 single nucleotide polymorphisms, together capturing common variation seen in the associated interval, we genotyped 3657 MI cases and 1211 controls prospectively sampled in a European population. ", "Polymorphisms rs10757278 and rs1333049 both exhibited the strongest individual risk signal (OR, 1.45; 95% CI, 1.32-1.59). ", "Two haplotype blocks were established, each of which was mainly represented by a pair of a risk-conferring and a protective haplotype, but none of the risk-associated haplotypes exhibited stronger effects than rs10757278 or rs1333049 alone. ", "Specific polymorphisms (rs7865618, rs1537378, rs7857345, rs1333049) were identified as independent predictors of MI in multivariable models adjusted for conventional cardiovascular risk factors. ", "In specific instances, the presence of two or three polymorphisms in a model, instead of only one, improved the discriminating power. ", "Finally, evidence was provided to suggest dual association of rs7865618 with MI and diabetes. ", "In keeping with published results, this work was consistent with the association of alleles and haplotypes at Ch9p21 with MI and extended prior knowledge by also showing independence of associations among different risk alleles and an association of a specific polymorphism with both MI and diabetes." ]

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[ "Search This Blog\n\nThe Way Forward for The PC(USA): A Modest Proposal\n\nI would be remiss if I didn't include--along with my assessment of the recent \"Open Letter to the PC(USA)\"--a proposal for a way forward that might serve as a compromise from the band-aid removal method the Open Letter seems to espouse.", "\n\nBut first, I need to say a few things about why the change is needed. ", "Our denomination (in it's previous forms) did not used to be so bogged down with bureaucracy and bureaucrats. ", "I've written elsewhere that the Book of Order used to fit in a shirt pocket.", "\n\nSo what happened? ", "Here's my Readers Digest version: The bureaucrats in the church created larger and larger sets of rules and regulations each and every year. ", "They then fashioned departments, divisions and branches of government to \"support\" what they created. ", "As a result, they became the de facto experts on all things Presbyterian. ", "Now they spend an inordinate amount of money and energy convincing the rest of us that we can't possibly do without both them and the unwieldy bodies they represent. ", "Keep in mind that these are for the most part good people with good intentions who are trying to serve the Church as best they can. ", "Nevertheless, the legacy we are creating is unsustainable.", "\n\nNow, the recent move to reduce and transform our Form of Government was a move in the right direction, but it wasn't radical enough for my taste. ", "It also doesn't address the real problems most of our churches are facing as they struggle to stay alive.", "\n\nThe local church in the PC(USA) has become little more than a caretaker of the vision the General Assembly establishes---a kind of necessary evil for the ivory tower crowd to manipulate and mystify in order to accomplish their own goals. ", "And almost none of these goals address the fact that the vast majority of our churches are on life support.", "\n\nI see the local church a bit differently. ", "I see the local church as the only way out of the mess that we've created and the best and surest tool to fix our leaky ship. ", "I see the local church as it was meant to be.", "\n\nA few months ago, I blogged about the 219th General Assembly of the PC(USA) and expressed my concern over the way the bureaucrats in our denomination have their head in the sand about our future. ", "I asserted that growing, vibrant churches (regardless of denominational affiliation) have at least 10 things in common. ", "I'll list them here once again:\n\n1. ", "Effective, Engaging and Relevant PreachingThe preacher most likely does not read his/her sermon. ", "The sermon is not an academic exercise, it's a proclamation of the Gospel that relates to real life. ", "People have a way to respond to it. ", "The preacher works hard to not be self-indulgent, but to deliver messages that the community needs to hear in order to more fully follow Jesus. ", "The goal is to draw people in to a closer relationship with Christ. ", "If the \"senior pastor\" isn't the most effective communicator, then the leader or pastor who is... gets the job. ", "Far too many people are leaving Presbyterian seminaries with the knowledge on how to write a sermon, but without really learning how to be an effective preacher.", "\n\n2. ", "Evangelism is a PriorityEvangelism is taught from the pulpit, emphasized in the church's culture and is part of the DNA. ", "People want to invite, to share their faith and they are given the tools to do it. ", "The big secret here is: When people are excited about their church and about worship, they invite. ", "When they have a real, true, vibrant and transformational relationship with Jesus, they want to share it.", "\n\n3. ", "Prayer is an Integral Part of Community LifeThe extent of the prayer life of the community of faith is not formal read prayers on Sunday morning or perfunctory prayers before a committee or Session meeting. ", "There are prayer meetings, opportunities to learn about prayer, to go deeper and to bear burdens. ", "And there are prayer warriors who take on the \"heavy lifting\" in the prayer ministry.", "\n\n4. ", "Joyful, Authentic WorshipThe worship services in all of their variety are celebrations. ", "People are not afraid to express joy, to laugh, to applaud to respond in some way. ", "They leave feeling that they have experienced God and given their best in worship. ", "Nothing should be forced, but should be done authentically, and in Spirit and in Truth.", "\n\n5. ", "Bible Studies/Small GroupsThere are plenty of opportunities for the community to engage in Bible study in small groups. ", "There is a clear structure and plenty of opportunities to be trained for leaders. ", "Small groups that meet regularly to pray and study help to develop community and nurture members in their faith.", "\n\n6. ", "Clear Vision/OrganizationThe core values and noble goal of the church are clear and communicated to the congregation. ", "There is a clear vision that the church leadership owns and keeps in front of the people. ", "The church is organized well and has systems in place to generate trust, involvement and commitment from members.", "\n\n7. ", "Stewardship as a Way of LifeBiblical Stewardship is preached, taught, espoused lifted up and communicated in a variety of ways and not just once a year. ", "There is a dedicated group that devotes itself to the stewardship ministries of the church on a year-round basis. ", "There are opportunities for members to take classes, learn, study about Biblical financial planning, stewardship.", "\n\n8. ", "Mission/Outreach There is a vibrant and growing hands-on mission to the church's surrounding community. ", "The church seeks to answer the question, \"If we ceased to exist tomorrow, who would miss us?\" ", "Members have multiple ways to do mission and volunteer their time talent and treasure to support it. ", "The church also places a priority on supporting global missions, and is actively seeking ways to get members involved in hands-on global missions.", "\n\n9. ", "Ministry to Families--Youth and ChildrenThe church dedicates resources to ministries to children, youth and their families. ", "There are dedicated staff for these key areas. ", "The church welcomes children in worship, there is space for youth and efforts made to engage youth and children in the life of the church. ", "Families are considered when scheduling events, providing support, resources, etc. ", "The church understands that in order to live it must work on engaging multiple generations.", "\n\n10. ", "Focus on Outsiders as well as InsidersThe church doesn't live in the Past. ", "It is aware that it may have wonderful traditions and practices that might not \"outsider-friendly\" and does a good job to make them more so, without losing it's denominational or particular identity. ", "The church listens to Outsiders and tries to adjust to become the kind of community that welcomes and engages them. ", "The church also ministers, nurtures and cares for Insiders even while it encourages them toward flexibility and openness.", "\n\nThey distilled it down to four aspects:\n1. ", "Small Groups\n2. ", "Worship Services that are diverse (traditional and contemporary) with relevant sermons\n3. ", "Pastors who mentor and cultivate laity\n4. ", "Effective lay leadership\n\nHonestly, I think my ten assessments could be drawn out of their four, but I digress.", "\n\nI think the only way that we are going to survive as a denomination is if we become less concerned with property than with people. ", "We need to become more nimble and get a lot more honest about what is and isn’t working in our churches. ", "Our middle bodies (Presbyteries and Synods) need to become \"equipping\" bodies rather than \"governing\" bodies (The GA must also, for that matter), and we need to begin focusing on ministry and mission that will result in new converts, church growth and an expanded impact on our communities and the world. ", "Here's how this might look:\n\n1. ", "Lead By Example In Areas of Property\nI think that our \"governing\" (including the GA) bodies need to divulge themselves of their property and use the funds that they would receive for skilled staff and materials to support churches in the 4 (or 10) key areas of church growth. ", "There are many churches in the area with space that could be used for Presbytery, Synod or GA offices. ", "I remember when I worked for Best Buy we had to do the same thing for our District Office in order to save $$ to be used for staffing and other areas. ", "And release the property to the control of the Sessions. ", "It was a mistake to hold them in trust because it's now created an environment of distrust and stagnation. ", "When you have to hold the issue of property over a congregation's head in order to force them to remain in the denomination, you've lost anyway. ", "Who knows? ", "Maybe if the denomination extended this act of trust, it would lead to further dialogue and at least some form of connection with congregations on both sides of the liberal/conservative dichotomy who feel unrepresented.", "\n\n2. ", "Get Real About Non-Viable Churches\nI think the governing bodies need to get more involved and become more aggressive in working with churches that are declining. ", "We need to either find ways to revitalize them, re-imagine the use of their space or merge them with churches in their area that are thriving. ", "There’s nothing wrong with having satellite locations that are resourced, equipped, etc by larger, growing churches in spaces that used to be small, dying congregations. ", "This can be done in collaborative ways that are not heavy-handed, bringing partner churches together to solve the issues. ", "I have seen presbytery committees act in heavy handed ways when dealing with congregational issues, disputes and dying churches (again, the \"expert\" mentality shines through in those moments) and essentially throw gasoline on the fire when partner churches and collaborative efforts could have resolved the issue far more easily.", "\n\n3. ", "Find Out What Is Working And Do That\nI would also like to see us do more “best practice” kind of brain storming. ", "Get the pastors and leaders of churches that are growing together to talk about what they are doing to grow-- and then get that information in the hands of churches that aren’t. ", "This isn't about providing \"templates\" for transformation that are sold by some \"expert.\" ", "Every church is different and their contexts are unique. ", "What might work in one church would fail in another. ", "We've got to get away from the template approach and provide space for conversations, opportunities for conferences, workshops, etc. ", "In this kind of space, church leaders won't feel like they've failed if some experts template doesn't work at their church. ", "They get the tools to find their own template, and for the most part it won't cost churches any money.", "\n\n4. ", "Staff For Growth\nThe things that we see in strong, vibrant churches are fairly common: Energetic, creative, relevant and engaging preaching; Commitment to evangelism; Strong ministries to youth, children and families; Clear mission and focus on growth both “deep and wide;” Outward, rather than inward, focus.", "\nHonestly, I think we need to staff our middle bodies--an our churches--with these things in mind--focusing on youth, college, children and family ministry, etc. ", "Our governing bodies halfheartedly staffed these positions because the majority of their budget is going to things that---honestly---are not contributing to local church growth and strength AT ALL. ", "Until our denomination starts seriously staffing for church development, evangelism, family ministries and pastoral development---with people who are actually qualified and skilled at these tasks---we will probably not make it another 40 years. ", "Some people might hammer me for this, but things like creation care and global missions tend to suck up a lot of resources in our governing bodies, while their impact on the local church is barely felt. ", "I'm not saying that we don't devote resources to them, but we should empower those local churches who feel the call to those ministries to pursue them, and focus the energies of our middle bodies on growth issues.", "\n\n5. ", "From Governing to Equipping\nIf middle bodies began focusing on equipping churches for growth, it wouldn't mean the end of their \"governing\" responsibilities. ", "However, it should mean the end of governing as their main focus. ", "For example, governing bodies need to lead the way to look outside of our denomination to discover new ways to Evangelize, and to start putting money and resources into helping our churches develop vibrant youth ministry, children’s ministry and family ministry. ", "For example, what if instead of wasting resources on a Presbytery-wide youth \"facilitator\" we were able to fund a youth director for a cluster of small churches in the same area or town, who couldn't afford one on their own? ", "Why aren't we spending more resources to fund college ministries or strengthen churches who have them? ", "Why aren't we finding more ways to do mass-marketing and outreach to benefit churches who can't afford to do their own? ", "Maybe instead of prescribing ministries where resources will go, middle bodies might find what is working well for outreach, missions, evangelism, ministry, etc. ", "in the churches and find ways to support them and equip them?", "\n\n6. ", "Development of Leadership\nWhile it is true that many middle bodies provide workshops and leadership training, the events are typically poorly attended, held when most active members and church leaders can't attend, not focused on growth issues, etc., ", "etc. ", "For the most part, the \"best practices\" church leaders don't attend these--at least in my experience. ", "I think that the governing bodies should provide amply opportunities and/or resources for the following:\n\n1. ", "Support Continuing Education for Pastors in these areas: Preaching, Leadership, Stewardship, Evangelism, Visioning, Mission(al) Issues. ", "Provide scholarships to pastors who wish to receive training in these areas (especially preaching!).", "\n\n2. ", "Support Continuing Education for Youth Workers and Children's Ministry leaders. ", "Provide scholarships to those who wish to attend conferences and workshops.", "\n\n3. ", "Hold Continuing Education events where the training and workshops are focused solely on growth issues, and hold the events in locations and on dates that will attract the most people.", "\n\n4. ", "Organize and facilitate cluster groups for Elder training, Peer-to-Peer development of pastors, and much more. ", "We are currently using them for Missions, why not for lots of other stuff?", "\n\n7. ", "Reduce Number of Issues that Middle Bodies and GA Currently Handle\nI believe that the \"governing\" responsibilities of the middle bodies (and even the GA) can be reduced by empowering middle body committees to handle more of the issues referred to them by local Sessions (including ordination, installation of pastors). ", "Additionally, we suffer too much from \"paralysis by analysis.\" ", "Our governing bodies spend an inordinate amount of time studying, writing white papers on controversial issues, voting on the same issues over and over again. ", "I think this needs to end. ", "No more position papers, no more studies, no more... trust local churches to take up prophetic challenges as they are called to them. ", "In addition, I believe that we can give local churches more authority to govern themselves in their own context without giving up our Presbyterian identity. ", "And in so doing we can free up our governing bodies to equip and resource the local churches in the aforementioned growth areas. ", "Right now, the tail is wagging the dog.", "\n\nI realize that this is incomplete and probably will get even more shot full of holes. ", "And I don't see any way to achieve the things that I have outlined here other than by radically transforming the way our denomination works. ", "Honestly, in order to truly retain our Presbyterian identity, we mustreform. ", "So it is in this spirit that I affirm many of the ideas that were lifted up in the \"Open Letter To The Presbyterian Church (USA).\" ", "Perhaps we might find new ways to relate, new bodies and new structures that can be combined with tried and true \"Presbyterian\" or \"Reformed\" ways of being the Church. ", "And then we might begin to find our way once again.", "\n\nComments\n\nI can't claim to be very familiar with the work at the Synod level and above, but it feels like it has gotten bloated through the years. ", "I'd love to see the denominational bodies move away from provider of content and programs to providing resources and support for local churches directly.", "\n\nBut part of me wonders what the big fuss is about reforming the denomination. ", "I don't feel that the denominational entities or governing bodies are hindering my church in any way, shape or form. ", "And the resources and connections they do provide can be helpful.", "\n\nI think if each local church focused on being the kind of church it needs to be, then the denomination would reform on its own.", "\n\nPopular posts from this blog\n\nIt's also one of those Sundays when you can't ignore the church calendar and just preach whatever you want. ", "I am sure that some people do just that, but they probably aren't Presbyterian, and I am sure that the liturgical rhythm of the Church is not first and foremost in their mind.", "\n\nAnd they probably have had no trouble at all working on their sermon this week.", "\n\nI'm not one to blindly follow tradition, but there are some things that you just don't do---and you can't just ignore the story of Jesus' Triumphal Entry into Jerusalem on Palm Sunday.", "\n\nBut this leads to a bit of a quandary... In the short time I have been doing this whole preaching thing I have gone through the Palm Sunday story a few times. ", "After a while you sort of wonder if your congregation has heard your Palm Sunday riff a few too many times.", "\n\nThat sermon needs to get preached, though. ", "While we celebrate the cheers and palm waving …\n\nThere's something about this night that brings us together---even those of us for whom church is not part of or regularly scheduled programming.", "\n\nI have a soft spot in my heart for the non-Church-y people who find their way to church on Christmas Eve. ", "There were a lot of years when I wasn't really the church going type, you see. ", "In fact, not only was church not part of my regularly scheduled programming, I had pretty much cancelled it from my life altogether. ", "But when Christmas Eve would come around again, as it seems to do each year, I'd discover myself sitting in a pew, showered, shaved and wearing somewhat respectable church clothes.", "\n\nI think the reason why I showed up was because there was part of me that wanted to believe everything that everyone around me was singing and praying. ", "I wanted to believe in the story of Hope that the various pastors I …\n\nThis week we're launching a brand new sermon series--a study in the New Testament book of James entitled \"Different\"---a series exploring what it truly means to live like a Christian.", "\n\nThere are all kinds of people who claim to have a corner on the market when it comes to the marks of what it means to be Christian, and typically the people who feel this way are not shy about telling you all the ways you aren't living like a Christain.", "\n\nThe point of this series is not to leave all of us feeling less-than because we aren't living the kinds of lives we ought to live. ", "The fact of the matter is, none of us live the lives we ought to live---we're all in the same boat here.", "\n\nThe point of this series is to lift up the ways that we can step into the kind of abundant life that Jesus declared he wanted for all of us, and for us to truly live like Christians, people who belong to Jesus.", "\n\nToday we're going to be learning that one of the marks of the well-led Christian…\n\nLeon Bloder is a preacher, a poet, a would-be writer, a husband, a\nfather, a son, a dreamer, a sinner, a former fundamentalist, a pastor, a\nfellow-traveller and a failed artist. ", "He is talentless, but\nwell-connected. ", "He stumbles after Jesus, but hopes beyond hope that he\nis stumbling in the right direction" ]

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[ "Osteoporosis and pathologic fractures in anorexia nervosa.", "\nOsteoporosis with pathologic fractures occurred in three patients with chronic anorexia nervosa. ", "The authors discuss the pathophysiology of this rarely reported complication and advise clinicians to thoroughly investigate complaints of bone or back pain from this high-risk population." ]

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[ "Adenosine induces a calcium-dependent glomerular contraction.", "\nGlomeruli isolated from rat kidney cortex were incubated with adenosine in the presence or absence of verapamil and calcium and their change in cross-sectional area was recorded. ", "Adenosine induced a 10% decrease in glomerular cross-sectional area. ", "This decrease was blocked by verapamil or a calcium-free medium. ", "The results suggest that the effect of adenosine in the kidney could be due to glomerular constriction, and that this constriction depends on the entry of calcium into glomerular cells." ]

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[ "Q:\n\nReading part of a file in S3 using Boto\n\nI am trying to read 700MB file stored in S3. ", "How ever I only require bytes from locations 73 to 1024. ", "\nI tried to find a usable solution but failed to. ", "Would be a great help if someone could help me out.", "\n\nA:\n\nS3 supports GET requests using the 'Range' HTTP header which is what you're after.", "\nTo specify a Range request in boto, just add a header dictionary specifying the 'Range' key for the bytes you are interested in. ", "Adapted from Mitchell Garnaat's response:\nimport boto\ns3 = boto.connect_s3()\nbucket = s3.lookup('mybucket')\nkey = bucket.lookup('mykey')\nyour_bytes = key.get_contents_as_string(headers={'Range' : 'bytes=73-1024'})\n\n" ]

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[ "Physicochemical background for ambiguity of clinical recommendations in treating phosphate nephrolithiasis.", "\nEfficiency of clinical recommendations for curing and prevention of phosphate nephrolithiasis founded on physicochemical investigations is unexpectedly low and apparently did not exceed 50%. ", "We tried to consider possible physicochemical causes of this fact. ", "For this purpose the influence of changes of urine pH and of calcium, phosphate and complexon concentrations on the probability of different precipitation phases of solid calcium phosphate has been reviewed. ", "The importance of tendencies of changing the urine dynamic physicochemical parameters such as the precipitation induction period and the amplitude of urine pH variations in time has been shown. ", "It was established that the probability of the existence of Ca3(PO4)2, Ca8H2(PO4)6.5H2O, CaHPO4.2 H2O and MgNH4PO4.6 H2O in urine depends on the time of its transition from the supersoluble state and is determined in the final analysis by the relationship of formation rates and solid phase dissolution rates. ", "This was verified by experiments and by data obtained in the clinical laboratory." ]

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[ "Treatment of complex perineal trauma. ", "A review of the literature.", "\nPerineal injuries are uncommon, but not rare. ", "They may present a wide variety of injury patterns which demand an accurate diagnostic assessment and treatment. ", "Perineal injuries may occur as isolated injuries to the soft tissues or may be associated with pelvic organ, abdominal or even lower extremity injury. ", "Hence the importance to know in depth not only the anatomy of the perineum and its organs, but also the implications of the patient's hemodynamic stability on the decision making process when treating these injuries using established trauma guidelines. ", "The purpose of this review is to describe the current epidemiology and clinical presentation of perineal injuries in order to provide specific guidelines for the diagnosis and treatment of both stable and unstable patients." ]

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[ "Q:\n\nAccess linux paths in windows git powershell\n\nI am running a Windows Powershell provided through the git for windows installation. ", " This shell provides many unix style commands (i.e. \"ls\", \"mv\", etc.).", "\nMy question is: How do I access Unix style paths from the powershell cmd line on Windows?", "\nConsider this example: the \"ls\" program is installed and works in the powershell. ", " The path is shown as \"/usr/bin/ls\" if I type \"which ls\" as the cmd prompt. ", " But if I try to change my current directory using \"cd /usr/bin/\", the shell complains that the path is not found.", "\n\nI can't see any mounted volumes or anything like that using \"mount\" (perhaps in PowerShell it is a different command?). ", " \nI'm asking this question because I have other files that I need to get to which are listed under unix-style paths, and right now I can't get to anything. ", " I figure if I can get to /usr/bin, then I can figure out how to get where I really need to go.", "\n\nA:\n\nPowershell is not Unix. ", "It may have a few familiar commands like \"ls\" and \"ps\", but that's where the similarity ends.", "\nWhen you installed Git For Windows, you likely installed the Git Bash shell as well. ", " Run that instead to get a more Unix like atmosphere. (", "Re-install Git For Windows if you didn't select this option on install).", "\nBut even with Git Bash, there's still no such folder as /usr/bin. ", " That folder doesn't exist on Windows. ", " If you want a Unix emulation on Windows that includes the traditional folder structure, use Cygwin. ", " And you can run Git on that environment too and access an emulated /usr/bin folder.", "\n\n" ]

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[ "Jul 10, 2017 – Sep 10, 2017 |\n\nDemand is growing for evidence-based policy making, but there is also growing recognition in the social science community that limited transparency and openness in research have contributed to widespread problems. ", "With this 3-week, self-paced Massive Open Online Course (MOOC), you can explore the causes of limited transparency in social science research, as well as tools to make your own work more open and reproducible.", "\n\nTransparent and Open Social Science Research is based on Professor Ted Miguel‘s UC Berkeley course on methods for transparent research. ", "He and Project Scientist Garret Christensen lead the online version. ", "They will be online to answer your questions and facilitate discussions.", "\n\nIn addition to providing a solid theoretical foundation and extensive reading list for researchers looking to make their research more transparent, the course also gives opportunities for hands-on practice with tools like p-curve and the Open Science Framework (OSF). ", "The topics we cover include:\n\nAn overview of the Reproducibility Crisis and the Open Science movement\n\nPublication Bias\n\nPre-registration and Pre-analysis Plans\n\nReplication\n\nMeta-Analysis\n\nOpen Data\n\nData Visualization\n\nThe future of Open Science\n\nThis course is hosted by FutureLearn, a platform that uses a social learning model to better engage online learners. ", "This means that, rather than having discussions in forums, learners can start a discussion at any point in the course, just like in a physical classroom.", "\n\nLearners are expected to spend about 5 hours per week on course videos, readings, and exercises.", "\n\nThe course is open to anyone, anywhere, but learners with some statistical background will likely get more out of it. ", "The first course run formally ends on August 31, but extended enrollment means you can take the course anytime until September 8, 2017!", "\n\nRead more about the MOOC on our blog!", "\n\nEnroll now!" ]

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[ "What to Know Saturday, Dec. 29; doors open at 10 a.m.\n\nLos Angeles Equestrian Center in Burbank\n\n$15 via Sharp Seating Company; $10 parking\n\nWe'd never dare paint all ponies with a giant brush, but we can say one thing, about most horses, that is fairly true.", "\n\nThey're on the move. ", "They've got places to be. ", "They're going to put one hoof down, and then another, all to get to some near or far destination, and they're going to do so in prompt pony fashion.", "\n\nAnd, when they're in a parade? ", "You can definitely count on every horse you spy to be laying tracks, creating distance, and heading for the end of the route in a stately but dedicated manner.", "\n\nSuch is the case with the Rose Parade, the iconic New Year's Day event that famously features a number of equine-amazing participants.", "\n\nBut those horses and their riders are fully \"trot-forward\" during the parade, all to make sure everyone watching along the route gets to enjoy these splendid and regal animals.", "\n\nThere is a way, however, to spend significantly more time enjoying these mane-rocking rock stars, and even see some of the horses from a pettable distance.", "\n\nIt all happens at Equestfest presented by Wells Fargo, an annual celebration that will again canter into the Los Angeles Equesterian Center for a few hours of equine-sublime showmanship on Saturday, Dec. 29.", "\n\nThe day's activities include the noontime show, as well as the way-cool chance to \"stroll through the stables,\" oh yeah.", "\n\nLearning about tack? ", "Watching some displays of trick riding? ", "Visiting the on-site food and drink vendors? ", "Meeting riders? ", "Savoring the live tunes?", "\n\nAll quite possible, and enjoyable, during one of our region's horse-iest happenings.", "\n\nA happening that, yes, takes place outside of Pasadena, a rarity for a Tournament of Roses event, but ultimately not too far beyond the Crown City's borders.", "\n\nFind your $15 ticket through Sharp Seating Company, then giddy up, for 480 W. Riverside Drive in Burbank, on the final Saturday of December 2018." ]

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[ "The overall goal of this project is to determine how sickle cell disease may alter the characteristics of the hematopoietic stem cell populations and the way how hematopoiesis responds to the chronic hemolysis. ", "Over the past year we completed the study on \"Circulating Cytokines Response and the level of Erythropoiesis in Sickle Cell Anemia\" (Am. ", "J of Hematology 60:105-115) and focused our attention on the behavior of circulating LTC-IC ( Long term culture -Initiating cells ) and clonogenic stem cells in SS disease. ", "Our results show that the SS anemia is characterized by the various degree of mobilization of stem and progenitor cells (on average ,approximately 10-fold) .The fact that all progenitors examined were found to be increased ( mainly in patients with elevated HbF) showed that the pathological effect of SS disease is not restricted to erythroid lineage only, but affects the entirety of stem cell compartment. ", "Correlation analysis of the circulating LTC-IC and CFC values for individual SS patients confirmed that the changes seen were not compartment specific Additional evidence of a common underlying mechanism was obtained from a horizontal studies performed on a subset of individual SS patients .These studies showed that the numbers of all progenitors fluctuated markedly over time but in correlated fashion . ", "The majority of circulating LTC-IC were found to be quiescent, but were recruited into the cycle more rapidly than thus of normal individuals. ", "The present findings provide evidence that SS anemia is not associated with any signs of exhaustion of circulating stem and progenitors cells. ", "On the contrary, that these cells, in sickle cell anemia circulate in increased numbers and may be particulary suited as a target for gene transfer. ", "These result are submitted for publication in Br. ", "J of Haematology." ]

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[ "3*u - 4. ", "Let y be i(3). ", "Let p = -1 + y. Calculate the lowest common multiple of f(-2) and p.\n220\nLet z = -466/5 + 95. ", "Let i be 2/(-7) + 1825/(-7). ", "What is the common denominator of z and (-16)/12*i/(-30)?", "\n5\nLet b = -6 - -10. ", "Find the common denominator of (-1645)/(-50) + b/(-10) and -99/10.", "\n10\nLet b = 11 + -8. ", "What is the common denominator of (b/20)/(24/670) and 27/14?", "\n112\nSuppose -30 = -5*f + 5*g, -5*f - 4*g = -1 + 7. ", "Suppose -3*r = -6*r + 120. ", "Suppose -z + r = z. Calculate the lowest common multiple of f and z.\n20\nLet h = 7827/530 - 258/53. ", "Let z(b) = 14229*b + 2. ", "Let m be z(1). ", "Let c = m + -284693/20. ", "What is the common denominator of h and c?", "\n20\nSuppose -4*f = -w, -5*w + 0*w + f = 0. ", "Suppose -15 = -3*a - w. What is the least common multiple of a and (-76)/(-6) + (-135)/81?", "\n55\nSuppose 18*s - 6*s = 228. ", "What is the least common multiple of 1 and s?", "\n19\nSuppose 2*m + 4*k = 2, 2*m + 1 - 19 = 4*k. ", "Suppose -m*j + 11 = -u, 2*j = -u - 3*j + 29. ", "Calculate the lowest common multiple of u and 4.", "\n36\nSuppose -2*p + 3 = -13. ", "What is the common denominator of ((-22)/p)/(45/(-50)) and -121/10?", "\n90\nWhat is the common denominator of (2/5)/((-24)/630) and 50?", "\n2\nSuppose 3*d - 16 = 8. ", "Suppose 3*z = -g + d + 8, -3*g - z + 8 = 0. ", "Calculate the least common multiple of ((-2)/(-6))/(2/6) and g.\n1\nLet l(q) be the third derivative of q**4/12 - 7*q**3/6 - 2*q**2. ", "Let s be l(8). ", "What is the lowest common multiple of 3 and 1 + (-3)/s*-3?", "\n6\nLet b(a) = 3*a + 35. ", "Suppose 2*r + 2*m - 20 = 0, 0 = -5*r - 0*m + 3*m + 34. ", "What is the lowest common multiple of b(-8) and r?", "\n88\nSuppose -5*p + 37 = 4*q, 0*p - 27 = -3*p - 4*q. ", "Suppose p*x - t - 4*t - 40 = 0, 38 = 3*x + 4*t. ", "Let f = 6 - -16. ", "What is the least common multiple of x and f?", "\n110\nLet u = -263007/73840 + -3/4615. ", "What is the common denominator of u and 79/36?", "\n144\nLet v(s) = -2*s**2 - 7*s + 1. ", "Let j be v(-5). ", "Let d = j - -24. ", "Calculate the least common multiple of d and 11.", "\n110\nSuppose l + 4 = -4. ", "What is the least common multiple of 18 and (-6)/((60/l)/5)?", "\n36\nLet o = -2 + 2. ", "Let m = 1 - o. Suppose -2*i = -3*i - m. Calculate the common denominator of i and -59/5.", "\n5\nLet i = -90/11 + 81/22. ", "What is the common denominator of 93/10 and i?", "\n10\nLet c = -17931 + 824889/46. ", "Find the common denominator of -55/14 and c.\n322\nLet x(c) = -c**3 + 2*c**2 + 2*c - 1. ", "Let u be x(3). ", "Let o be (-1 - 0)*(-7 - -4). ", "What is the lowest common multiple of -8*(27/u)/o and 2?", "\n18\nLet i be (9/(-165))/(6/395625). ", "Let v = i - -3598. ", "What is the common denominator of 101/16 and v?", "\n176\nSuppose -l = -3*m - 52 - 8, -m + 2*l = 15. ", "What is the common denominator of (-5)/(-18)*(-924)/60 and ((-58)/32)/(7/m)?", "\n144\nSuppose 2*t + 5*m = 30, 4*t - m - 53 = -15. ", "What is the smallest common multiple of t and 11?", "\n110\nLet v(f) = -11*f - 18. ", "Let c be v(6). ", "Calculate the common denominator of 1939/c - (-2)/(-3) and 39/8.", "\n8\nLet v(g) = g**2 + 8*g - 2. ", "Let x be v(-8). ", "Let y = 0 - x. What is the least common multiple of y and 10?", "\n10\nLet j = -91245 + 2007821/22. ", "Let x = 2104 + -23110/11. ", "Let r = x - j. What is the common denominator of -29/4 and r?", "\n4\nLet j be 5*((-6)/(-5))/(-3). ", "Let u(h) = 2*h**2 - 5*h + 4. ", "What is the smallest common multiple of u(2) and ((-2)/3)/(j/24)?", "\n8\nWhat is the common denominator of 79/10 and 2 + (-202)/12 - -1?", "\n30\nLet o = -3663/404 + -5/303. ", "Find the common denominator of o and -113/6.", "\n12\nLet w = 1 - -2. ", "Let b = w + -3. ", "What is the common denominator of -99/10 and (-3 - b) + 42/(-8)?", "\n20\nLet a = 83 + -33. ", "Let k = -424 + a. What is the common denominator of -1/20 and 1/(-3) - k/(-120)?", "\n20\nLet u(n) = -n**2 + 2*n. ", "Let s be u(2). ", "Suppose -t = 3*t + 20, s = 5*l + t - 30. ", "Calculate the least common multiple of l and 7.", "\n7\nCalculate the common denominator of (142/72)/(7/84*-9) and -68/15.", "\n135\nSuppose 0 = t + 47 - 65. ", "Calculate the smallest common multiple of 1 - -1 - (-5 - 1) and t.\n72\nLet c be 12/(5*2/(-5771)). ", "Let x = -6966 - c. Let u = x - -623/10. ", "Calculate the common denominator of u and -85/22.", "\n22\nSuppose -5*k + 4*s - 15387 = 0, 2*k - 2*s + 8807 = 2653. ", "Let y = k - -18587/6. ", "What is the common denominator of y and -79/8?", "\n24\nSuppose -138 = -i - 2*i. ", "Let k = i + -3/2. ", "Calculate the common denominator of k and 67/4.", "\n4\nSuppose -3*z - 54 = -4*z. ", "Suppose -2*s + 5*s = -z. ", "Let j = -8 - s. What is the lowest common multiple of j and 8?", "\n40\nLet x be 9635/(-3) - (-8)/12. ", "Let c = x + 19397/6. ", "What is the common denominator of c and -3/4?", "\n12\nLet y = 17 - 26. ", "What is the common denominator of (-13*1)/(y*1) and -67/4?", "\n36\nSuppose 0 = v + 1 - 7. ", "Let z = -1 - -2. ", "Calculate the lowest common multiple of v and (z - (-3 - -2)) + 2.", "\n12\nLet o be 2/7 + (-268050)/(-74704). ", "Let k = o + 3/2668. ", "Find the common denominator of k and 75/22.", "\n88\nLet z = -1174 - -5849/5. ", "Let b = 2340 - 18675/8. ", "What is the common denominator of b and z?", "\n40\nLet b = -6 + 42. ", "What is the smallest common multiple of 11 and 7*(b/(-14))/(-3)?", "\n66\nLet p = 856855/18828 + 794/523. ", "Let q = 19/36 - p. Calculate the common denominator of -151/18 and q.\n18\nLet u = -181237 - -59655. ", "Let f = u + 490535/4. ", "Let r = -1046 + f. What is the common denominator of -19/18 and r?", "\n36\nLet j = 3 - -11. ", "Let y = 43 + -29. ", "Calculate the lowest common multiple of j and y.\n14\nLet q(j) = j**3 + 10*j**2 + 8. ", "Calculate the lowest common multiple of q(-10) and 2.", "\n8\nLet f be (3 - -1) + 0 + -1. ", "Suppose 2*o - 35 = -f*o. ", "What is the common denominator of o and 20/(-4)*1/11?", "\n11\nSuppose -4*h = 12, 3*x = -5*h + 3 - 33. ", "Calculate the lowest common multiple of x*(0/(-4) + -1) and 5.", "\n5\nLet n(z) = z**2 - 5*z + 4. ", "Let m be n(5). ", "Calculate the common denominator of 2/8 - 183/m and -111/14.", "\n14\nSuppose -2*h - 6*k - 5 = -k, 4*h - 5*k - 35 = 0. ", "Let m = h + -3. ", "Suppose 23 = 4*r - 5. ", "Calculate the lowest common multiple of m and r.\n14\nLet y = 882209533 + -8426865435853/9552. ", "Let p = 5/597 - y. Calculate the common denominator of p and -13/8.", "\n16\nSuppose 5*m - 3*z = 2655, 4*m + 0*m + z = 2141. ", "Find the common denominator of ((-1)/22)/(2/(-148)) and m/(-36) - 2/3.", "\n22\nLet i be ((-1)/2)/((-2)/8). ", "Suppose 0 = l, 2*s = i*l + l + 36. ", "What is the smallest common multiple of s and 20?", "\n180\nLet z be (-3)/(-6) - (-26)/(-4). ", "Find the common denominator of -6/7 and z/(-6) + (-194)/(-4).", "\n14\nSuppose 22 = 4*c - 3*c. ", "Calculate the smallest common multiple of c and ((-13)/5 - 9/(-15))*-1.", "\n22\nLet s be (-1)/4 + 5811/(-14). ", "Let p = s - -415. ", "What is the common denominator of p and 81/2?", "\n28\nLet u = 2170 - 8587/4. ", "Calculate the common denominator of 0/(-2) - (-693)/(-36) and u.\n4\nLet b(q) = -q + 2. ", "Let p be b(-3). ", "Suppose 0 = -w - 2*f + 7, -p*w + f - 3*f + 11 = 0. ", "Calculate the common denominator of 1/10 and w + (1001/(-6))/(-7).", "\n30\nSuppose 0 = 3*k - 1 - 20. ", "Let l(d) = -d**2 + 7*d + 10. ", "Suppose -c + 0*y = 2*y - 18, -2*y - 4 = 0. ", "What is the lowest common multiple of l(k) and c?", "\n110\nLet c = -94/5 - -848/35. ", "Find the common denominator of -81/2 and c.\n14\nLet y be (-1323)/(-12) - 6/(-8). ", "What is the least common multiple of 2 and 15/25 + y/15?", "\n8\nLet i = 24 + -14. ", "Let k = 42 - 24. ", "Calculate the smallest common multiple of i and k.\n90\nLet w = -31038/13 - -142632/65. ", "Let v = w - -191. ", "What is the common denominator of v and -8?", "\n5\nLet v = -14 - -8. ", "Let o = v + 18. ", "Let l = -30 + 48. ", "Calculate the lowest common multiple of l and o.\n36\nLet c be (-2)/9 - 60367/2346. ", "Let b = 496/23 + c. Calculate the common denominator of b and -37/30.", "\n90\nSuppose -x = -3*w - 12, 6*x = 2*x + w + 15. ", "Calculate the least common multiple of x and 5.", "\n15\nWhat is the common denominator of 57/22 and 4/14 + -523*5/700?", "\n220\nSuppose 4*p = 65 + 95. ", "Let q be ((-2)/(-22))/(p/(-155)). ", "Let v = 3/8 - q. What is the common denominator of v and -27/2?", "\n22\nLet r be 2*(3556/8)/7. ", "Let n = r + -517/4. ", "What is the common denominator of n and -73/10?", "\n20\nLet g(j) = 3*j - 9. ", "Let u be 675/63 - 2/(-7). ", "What is the smallest common multiple of u/(-2)*-1*2 and g(6)?", "\n99\nLet r = -35333/1782 + -5/891. ", "Let q be (-5 - -462)/(2*6). ", "Let z = q + -171/4. ", "Find the common denominator of r and z.\n6\nLet q(j) be the third derivative of 5*j**4/12 + j**3/6 - 9*j**2. ", "Calculate the lowest common multiple of q(1) and 2.", "\n22\nLet q(i) = i**3 + 5*i**2 + 4*i + 4. ", "Let x = -4 + 6. ", "Suppose -12 = b + x*b. ", "What is the lowest common multiple of q(b) and 5?", "\n20\nLet n = 615 " ]

{ "pile_set_name": "DM Mathematics" }

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[ "package sempass\n\nimport (\n\t\"shanhu.io/smlvm/lexing\"\n\t\"shanhu.io/smlvm/pl/tast\"\n\t\"shanhu.io/smlvm/pl/types\"\n)\n\nfunc refAddress(b *builder, opTok *lexing.", "Token, B tast.", "Expr) tast.", "Expr {\n\top := opTok.", "Lit\n\topPos := opTok.", "Pos\n\n\tbref := B.R()\n\tif types.", "IsType(bref.", "T) || !", "bref.", "IsSingle() {\n\t\tb.CodeErrorf(opPos, \"pl.refAdrress.notSingle\",\n\t\t\t\"%q on %s\", op, bref)\n\t\treturn nil\n\t} else if !", "bref.", "Addressable {\n\t\tb.CodeErrorf(opPos, \"pl.refAddress.notAddressable\",\n\t\t\t\"reading address of non-addressable\")\n\t\treturn nil\n\t}\n\n\tr := tast.", "NewRef(&types.", "Pointer{T: bref.", "T})\n\treturn &tast.", "OpExpr{Op: opTok, B: B, Ref: r}\n}\n\nfunc binaryOpNil(b *builder, opTok *lexing.", "Token, A, B tast.", "Expr) tast.", "Expr {\n\top := opTok.", "Lit\n\tswitch op {\n\tcase \"==\", \"!", "=\":\n\t\tref := tast.", "NewRef(types.", "Bool)\n\t\treturn &tast.", "OpExpr{A: A, Op: opTok, B: B, Ref: ref}\n\t}\n\n\tb.CodeErrorf(opTok.", "Pos, \"pl.invalidExprStmt\", \"%q on nils\", op)\n\treturn nil\n}\n\nfunc binaryOpPtr(b *builder, opTok *lexing.", "Token, A, B tast.", "Expr) tast.", "Expr {\n\top := opTok.", "Lit\n\tatyp := A.R().T\n\tbtyp := B.R().T\n\n\tswitch op {\n\tcase \"==\", \"!", "=\":\n\t\tif types.", "IsNil(atyp) {\n\t\t\tA = tast.", "NewCast(A, btyp)\n\t\t} else if types.", "IsNil(btyp) {\n\t\t\tB = tast.", "NewCast(B, atyp)\n\t\t}\n\n\t\treturn &tast.", "OpExpr{A: A, Op: opTok, B: B, Ref: tast.", "NewRef(types.", "Bool)}\n\t}\n\n\tb.CodeErrorf(opTok.", "Pos, \"pl.invalidExprStmt\",\n\t\t\"%q on pointers\", op)\n\treturn nil\n}\n\nfunc binaryOpSlice(b *builder, opTok *lexing.", "Token, A, B tast.", "Expr) tast.", "Expr {\n\top := opTok.", "Lit\n\tswitch op {\n\tcase \"==\", \"!", "=\":\n\t\treturn &tast.", "OpExpr{A: A, Op: opTok, B: B, Ref: tast.", "NewRef(types.", "Bool)}\n\t}\n\tb.CodeErrorf(opTok.", "Pos, \"pl.invalidExprStmt\",\n\t\t\"%q on slices\", op)\n\treturn nil\n}\n" ]

{ "pile_set_name": "Github" }

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[ "Introduction {#Sec1}\n============\n\nThe neuroinflammatory process has been associated with most neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) \\[[@CR1]\\]. ", "Furthermore, emerging evidence indicates that neuroinflammation constitutes a critical process for the progression of neurodegeneration involved in neurodegenerative disorders \\[[@CR2]\\]. ", "Microglial activation plays a central role in neuroinflammation, with microglial cells being the main source of reactive oxygen species (ROS) and nitrogen species, glutamate and TNF-α, all of which are highly neurotoxic when released in high doses by activated microglia \\[[@CR2]--[@CR5]\\].", "\n\nSeveral studies have shown that microglial activation may be evoked by the stimulation of toll-like receptors (TLRs) through the aggregated proteins in the central nervous system (CNS) of individuals with neurodegenerative diseases, as well as in animal models \\[[@CR6]--[@CR9]\\]. ", "For instance, a pathological hallmark in the brain of AD patients includes extracellular deposition of the fibrillar form of β-amyloid peptide (Aβ) surrounded by dystrophic neurites, forming senile plaques and intracellular neurofibrillary tangles constituted of hyperphosphorylated forms of the microtubule-binding protein Tau \\[[@CR10]\\]. ", "Similarly to AD, PD is a proteinopathy that is characterised by the accumulation and aggregation of misfolded α-synuclein and ubiquitin in cytoplasmic inclusions called Lewy bodies and Lewy neurites. ", "These cytoplasmic inclusions are found in both sporadic and inherited forms of PD \\[[@CR11]\\]. ", "Similarly, ALS involves the aggregation of superoxide dismutase 1 (SOD1) in the CNS \\[[@CR12]\\]. ", "Other examples include associations of aggregated huntingtin in Huntington's disease, Prp-amyloid in prion disease and Reelin in aging brain \\[[@CR1]\\].", "\n\nSimilar to the functional behaviour of peripheral macrophages \\[[@CR2]\\], microglia can not only be activated with an inflammatory and neurotoxic phenotype (M1-like phenotype), but they can also acquire a neurosupportive functional phenotype (M2-like phenotype), characterised by the production of anti-inflammatory mediators and neurotrophic factors, including insulin-like growth factor 1 (IGF-1), brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), among others \\[[@CR13]--[@CR15]\\]. ", "Intercellular interactions between microglia and other cellular factors play a fundamental role in the outcome of the functional phenotype acquired by activated microglia and, therefore, in neurodegeneration. ", "Cellular factors influencing microglial fate include astrocytes, neurons, epithelial cells of the blood-brain barrier (BBB) and T-cells infiltrating the CNS \\[[@CR2]\\]. ", "Indeed, during the last decade, several studies have shown that CD4^+^ T-cells infiltrate the CNS in many neurodegenerative disorders, and that their participation has a critical influence on the outcome of microglial activation and consequent neuronal damage \\[[@CR1],[@CR2]\\].", "\n\nThe precise role of CD4^+^ T-cells infiltrating the CNS in the outcome of neuroinflammation strongly depends on the functional phenotype of these cells \\[[@CR2]\\]. ", "Naïve CD4^+^ T-cells may be activated by antigen-presenting cells (APCs) in the presence of diverse mediators and, depending on the precise composition of the mediators *milieu*, they can differentiate different functional phenotypes, each of them specialised in orchestrating an immune responses against a different kind of threat. ", "For instance, in the presence of IL-12, the differentiation of CD4^+^ T-cells toward the T-helper 1 (Th1) phenotype is favoured, representing a functional phenotype specialised in the elimination of intracellular pathogens. ", "Furthermore, this inflammatory phenotype has been associated with neuroinflammation and neuronal damage \\[[@CR16],[@CR17]\\]. ", "The acquisition of the inflammatory Th1 phenotype is controlled by the master transcription factor Tbet, and the main effector cytokine produced by these cells is IFN-γ \\[[@CR18]\\]. ", "Another important inflammatory functional phenotype associated with neuroinflammation and neurodegeneration is the Th17 phenotype, which is favoured by the presence of IL-23 during the activation of naïve CD4^+^ T-cells. ", "These cells normally play an important role in gut immunity, as their phenotype is controlled by the master transcription factor RORγt and their main effector cytokines are IL-17 and IL-22 \\[[@CR18]\\]. ", "On the other hand, differentiation of the functional phenotype Th2 is controlled by the master transcription factor GATA3, which is favoured by the action of IL-4, and their main effector cytokines are IL-13, IL-5 and IL-4. ", "This effector phenotype not only plays a fundamental role in the orchestration of immunity against helminths and in allergy \\[[@CR19]\\], but is also involved in the attenuation of neuroinflammatory processes and contributes to the consolidation of spatial memory under physiological conditions \\[[@CR20]--[@CR24]\\]. ", "CD4^+^ T-cells can also acquire an anti-inflammatory functional phenotype, the T-regulatory phenotype (Treg), which can suppress the inflammatory function of effector T-cells \\[[@CR13]\\]. ", "Tregs cells are normally involved in the maintenance of tolerance toward self-constituents, limiting inflammatory responses against foreign antigens and, importantly, they are also known to be involved in the attenuation of neuroinflammation and consequent neurodegeneration \\[[@CR25]--[@CR28]\\]. ", "During recent years, these functional phenotypes of CD4^+^ T-cells have been shown to participate in the physiopathology of neurodegenerative disorders. ", "In this study, we focus on the analysis of the interplay between the different sub-populations of CD4^+^ T-cells and how they participate in regulating the outcome of neuroinflammation and neurodegeneration in the context of PD, AD, ALS and MS. ", "Furthermore, in the last part of this review, we analyse the participation of peripheral monocytes/macrophages infiltrating the CNS, their interaction with T-cells and their contribution to the regulation of neuroinflammation.", "\n\nRole of T-cells infiltrating the CNS parenchyma in multiple sclerosis {#Sec2}\n---------------------------------------------------------------------\n\nMS represent a neurodegenerative disease in which a T-cell-mediated response has been known to be involved for more than a decade. ", "MS is a chronic demyelinating disease generated by an autoimmune response against constituents of the CNS. ", "This autoimmune disease affects approximately 2.4 million individuals worldwide \\[[@CR29]\\]. ", "MS is characterised by the progressive loss of neurological function caused by the destruction of the axonal myelin sheath in several areas of the brain and the spinal cord, which is mediated, mainly, by self-reactive CD4^+^ T-cells \\[[@CR30]\\]. ", "The loss of myelin is manifested in clinical symptoms such as paralysis, muscle spasms, optic neuritis and neuropathic pain \\[[@CR31]\\]. ", "The pathological features of MS lesions involve BBB permeability, myelin sheath destruction, axonal damage, glial scar formation and the presence of inflammatory cells, mostly lymphocytes, infiltrated into the CNS \\[[@CR32]\\]. ", "The most used and accepted animal model equivalent of MS is experimental autoimmune encephalomyelitis (EAE), which corresponds to an induced autoimmunity in mice. ", "EAE may be triggered in mice upon injection of peptides derived from myelin emulsified with adjuvant \\[[@CR33]\\]. ", "The administration of myelin-derived antigens in an immunogenic context induces the activation of self-reactive T-cells that are specific for myelin antigens, mediating myelin destruction. ", "This induced autoimmunity is characterised by focal areas of demyelination along the brain and spinal cord, with axonal loss that results in ascending paralysis, affecting first the tail and then the hind limbs. ", "Self-reactive CD4^+^ T-cells are activated by auto-antigen-presenting dendritic cells in peripheral lymph nodes and, then, the activated self-reactive CD4^+^ T-cells migrate into the CNS parenchyma. ", "Self-reactive Th17 cells are the first T-cell population to infiltrate the CNS, as they express C-C chemokine receptor 6 (CCR6), which recognises C-C chemokine ligand 20 (CCL20) that is constitutively expressed on epithelial cells from the choroid plexus \\[[@CR34]\\]. ", "Th17 cells infiltrating the CNS are re-stimulated once inside the CNS by resident APCs, which is followed by microglia activation and production of IL-1β, TNF-α and IL-6, which contribute to myelin sheath damage \\[[@CR35]\\]. ", "This initial neuroinflammatory process results in BBB disruption and the entrance of leukocytes into the CNS parenchyma. ", "Once T-cells enter the CNS, they are re-stimulated by resident APCs, such as astrocytes, microglia or infiltrated APCs such as dendritic cells and macrophages \\[[@CR36]\\]. ", "Thereby, APCs play an important role during the course of EAE, as they are involved in the peripheral activation of T-cells as well as in the re-stimulation of T-cells inside the CNS. ", "Infiltration of T-cell into the CNS and their local re-stimulation lead to the manifestation of clinical symptoms \\[[@CR37]\\]. ", "Although there are several studies indicating that Th17 and Th1 cells infiltrate the CNS during the course of EAE, recent studies have shown that none of their signature cytokines are essential for the development of this disease. ", "In contrast to the expression of IL-17 and IFN-γ, the production of granulocyte macrophage-colony-stimulating factor (GM-CSF) by autoreactive CD4^+^ T-cells has proven to be essential for the development of EAE \\[[@CR38],[@CR39]\\]. ", "The production of this cytokine is stimulated by IL-23 and by the expression of both transcription factors RORγt and Tbet, whereas it is inhibited by IL-12, IFN-γ and IL-27 \\[[@CR38],[@CR40]\\]. ", "On the other hand, Tregs progressively infiltrate the CNS, starting at disease onset. ", "However, the generation of Tregs and the suppressive activity of CNS-infiltrated Tregs is impaired by γδT-cells \\[[@CR27]\\]. ", "γδT-cells infiltrate the CNS during EAE, starting at the onset of disease, reaching the highest cell number at the peak of disease manifestation before progressively disappearing from the CNS, thus correlating with the time course of EAE manifestation \\[[@CR27]\\]. ", "γδT-cells inhibit the function of Tregs cells and produce large amounts of IL-17 in response to IL-23. ", "Once γδT-cells begin disappearing from the CNS, Tregs continue to progressively infiltrate the CNS and they can recover their suppressive activity, which correlates to the progressive attenuation of EAE manifestation \\[[@CR27]\\]. ", "Another kind of T-cell that is relevant for EAE is the CD8^+^ population. ", "In this regard, some studies involving cell transfer have suggested the participation of CD8^+^ T-cell sub-populations in a pathogenic role of EAE \\[[@CR41]\\]. ", "On the other hand, there is strong evidence to indicate the participation of a regulatory sub-population of CD8^+^ T-cells, which play a beneficial role in EAE \\[[@CR42],[@CR43]\\]. ", "Studies show that EAE is more severe in mice that are deficient in or depleted of CD8^+^ T-cells, and the disease severity has been inversely correlated with the frequency of CD8^+^ T-cells infiltrating the CNS \\[[@CR41]\\]. ", "In this regard, distinct sub-populations of CD8^+^ Tregs have been described, including CD8^+^CD28^−^, CD8^+^CD122^+^ and CD8^+^LAP^+^ \\[[@CR44]--[@CR46]\\]. ", "Importantly, the frequency of CD8^+^ T-cells is greater than that of CD4^+^ T-cells in inflamed plaques from MS patients, and CD8^+^ T-cells show oligoclonal expansion in plaque, cerebrospinal fluid and blood, suggesting an important role of this cell population in MS. ", "Taken together, these data indicate the complex role of several T-cell populations in MS, which finally regulate microglial activation and, therefore, the outcome of neuroinflammation. ", "An overview of the role of the different T-cell populations participating in neuroinflammation associated with MS is schematised in Figure [1](#Fig1){ref-type=\"fig\"}.Figure 1**T-cell-mediated regulation of neuroinflammation in neurodegenerative disorders.** ", "The scheme shows how the participation of inflammatory and anti-inflammatory subsets of encephalitogenic T-cells might regulate microglial fate and, consequently, the degeneration or survival of neurons. ", "Whereas Th1, Th17, GM-CSF-producer CD4^+^ T-cells and γδT-cells favour the acquisition of the neurotoxic M1-like phenotype by microglia (left side of the illustration), Th2, Tregs and some kinds of CD8^+^ T-cells can contribute to the promotion of neurosupportive M2-like phenotype in microglial cells (right side of the illustration). ", "The scheme in **(a)** shows the \\'natural\\' scenario during the progression of multiple sclerosis (MS), Parkinson\\'s disease (PD) and Alzheimer\\'s disease (AD), which involve the M1-like microglia and consequent neurodegeneration; however, upon disease remission or immunosuppressive interventions, it is possible to induce the M2-like phenotype of microglia and neuroprotection. ", "In the case of PD and AD, only Th1, Th17 and Tregs cells have been associated with the regulation of neuroinflammation. ", "The role of other T-cell subsets in the regulation of neuroinflammation associated to AD and PD remains unexplored. ", "The scheme in **(b)** illustrates the participation of T-cells in the regulation of neuroinflammation associated to amyotrophic lateral sclerosis (ALS). ", "The physiopathological scenario of this disorder \\'naturally\\' involves the participation of encephalitogenic or meningeal Tregs and Th2 cells, which strongly contribute to the induction of the anti-inflammatory M2-like phenotype on microglial cells, thus slowing the progression of the neurodegenerative process. ", "BDNF, brain-derived neurotrophic factor; GDNF, glial cell-derived neurotrophic factor; IGF-1, insulin-like growth factor 1; RNS, reactive nitrogen species; ROS, reactive oxygen species.", "\n\nInvolvement of T-cell-mediated immune response in Parkinson's disease {#Sec3}\n---------------------------------------------------------------------\n\nPD is the second most common neurodegenerative disease after AD. ", "PD is characterised by the loss of 50 to 70% of dopaminergic neurons located in the substantia nigra pars compacta (SN*pc*). ", "The progressive degeneration of dopaminergic fibres in the brain results in prominent motor symptoms, such as bradykinesia, tremors, rigidity and postural instability. ", "Although studied less in PD than in MS, the fundamental participation of T-cells has also been described in PD. ", "An altered frequency of peripheral CD4^+^ T-cells has been described in blood samples obtained from PD patients \\[[@CR47],[@CR48]\\]. ", "Moreover, CD4^+^ and CD8^+^ T-cells that infiltrated into the brain parenchyma have been found in *post-mortem* samples obtained from PD patients \\[[@CR49],[@CR50]\\], as well as in animal models using mice \\[[@CR50],[@CR51]\\] and rats \\[[@CR52]\\]. ", "Recent studies carried out with T-cell receptor (TCR)-β-chain-deficient mice, SCID mice and recombination-activating-gen-1 (RAG1) knockout (RAG1KO) mice demonstrated that T-cell deficiency results in a strong attenuation of dopaminergic neurodegeneration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD \\[[@CR50],[@CR53]\\]. ", "This reveals that T-cells are not only relevant, but are also required for neurodegeneration in PD. ", "Additional experiments have shown that although CD8^+^ T-cell deficiency is negligible, the participation of CD4^+^ T-cells is fundamental for promoting the neurodegeneration of dopaminergic neurons in the SN*pc* of mice with PD \\[[@CR50]\\]. ", "These studies support the involvement of pathogenic CD4^+^ T-cell populations, which would induce the acquisition of an M1-like pro-inflammatory phenotype by the microglia, which is characterised by the secretion of inflammatory factors such as TNF-α, IL-1β, glutamate and superoxide \\[[@CR14],[@CR54]\\]. ", "Supporting the pivotal role of CD4^+^ T-cells potentiating microglial activation and favouring neurodegeneration in PD, it has recently been reported that a deficiency of class II major histocompatibility complex (MHC) results in attenuation of both microgliosis and loss of dopaminergic neurons in a mouse model of PD \\[[@CR55]\\]. ", "Experiments addressing the phenotype of pathogenic CD4^+^ T-cells involved in PD have shown that both Th1 and Th17 autoreactive cells are important for the promotion of neuronal loss \\[[@CR26]\\]. ", "Addressing the molecular mechanisms involved in CD4^+^ T-cell-mediated loss of dopaminergic neurons in PD, a study has shown that the participation of Fas-FasL interactions seems to contribute to the neurodegenerative process \\[[@CR50]\\]. ", "Importantly, we have recently demonstrated that dopamine receptor D3 (D3R), expressed in CD4^+^ T-cells, is fundamental in inducing the loss of dopaminergic neurons in the SN*pc* of a PD mouse model \\[[@CR17]\\]. ", "In this regard, we and others have reported that D3R-deficient (D3RKO) mice are resistant to MPTP-induced PD \\[[@CR17],[@CR56]\\]. ", "Interestingly, when wild type (WT) CD4^+^ T-cells were transferred to D3RKO mice, the animals acquired the capability to respond to MPTP-induced neurodegeneration. ", "On the other hand, RAG1KO mice, which are devoid of T-cells and are resistant to MPTP-induced PD, acquire the capability to respond to MPTP-induced neurodegeneration when WT CD4^+^ T-cells were transferred, but not when D3RKO CD4^+^ T-cells were transferred \\[[@CR17]\\]. ", "Notably, our data indicate that the stimulation of D3R expressed on CD4^+^ T-cells favours the acquisition of Th1 inflammatory cells, thus indicating the crucial importance of this pathogenic phenotype in the CD4^+^ T-cells immune response that is involved in PD \\[[@CR17]\\]. ", "In this regard, we observed that WT, but not D3RKO, CD4^+^ T-cells infiltrating the SN*pc* during MPTP-induced PD produced high levels of IFN-γ and TNF-α, which are two cytokines that act synergistically in microglia, promoting the inflammatory M1-like phenotype \\[[@CR57]\\]. ", "Thus, these findings point towards the important role of CNS-derived dopamine in the regulation of T-cell-mediated immunity during neuroinflammation. ", "Conversely, other T-cell subsets, such as Tregs and Th2, could contribute to microglial acquisition of an M2-like anti-inflammatory phenotype, which release neurotrophic factors, including IGF-1, promoting neuronal protection \\[[@CR14],[@CR26]\\]. ", "Indeed, it has been demonstrated that Tregs elicit neuroprotection for dopaminergic neurons of SN*pc* in MPTP-induced PD in mice \\[[@CR26],[@CR58]\\]. ", "Further analyses have shown that these Tregs cells act directly on activated M1-like microglial cells, attenuating migration, phagocytosis and the production of neurotoxic factors \\[[@CR58],[@CR59]\\]. *", "In vitro* experiments have shown that Tregs-mediated inhibition of M1-like microglia functions occurred through the suppression of NF-κB activation and required not only soluble mediators from Tregs, but also cell-cell contacts with microglial cells \\[[@CR59]\\]. ", "Another group of studies have also shown evidence of the neuroprotective role of Tregs in PD. ", "In these studies, copolymer-1 was used as an immunogen, which is a potent inducer of encephalitogenic Tregs \\[[@CR60]\\]. ", "It has been shown that adoptive transference of CD4^+^ T-cells isolated from mice, immunised with copolymer-1, attenuates the neurodegeneration of dopaminergic neurons in SN*pc* of mice with MPTP-induced PD \\[[@CR61]\\]. ", "On the other hand, Reynolds *et al*. ", "found that Th2 cells, which are specific against CNS antigens involved in PD, do not play a relevant role, exacerbating or attenuating neurodegeneration in MPTP-induced PD \\[[@CR26]\\]. ", "Other encephalitogenic T-cell subsets described as playing important inflammatory or anti-inflammatory roles in MS have not yet been studied in PD. ", "Thus, future efforts are necessary to elucidate the participation of anti-inflammatory CD8^+^ T-cell subsets, inflammatory γδT-cells and GM-CSF-producer T-helper cells in the physiopathology of PD. ", "An integrative summary of the role of T-cells in the neurodegenerative process associated with PD is shown in Figure [1](#Fig1){ref-type=\"fig\"}.", "\n\nT-cell-mediated immune response associated with Alzheimer's disease {#Sec4}\n-------------------------------------------------------------------\n\nAD is the most common neurodegenerative disorder worldwide, and it leads to irreversible cognitive impairment and important behavioural alterations. ", "Similar to PD, T-cells have been detected as infiltrating the brain parenchyma in close proximity with Aβ deposits in *post-mortem* samples of AD patients and in mouse models of AD \\[[@CR62],[@CR63]\\]. ", "Consistent with this observation, Aβ-reactive T-cells have been found in peripheral blood obtained from AD patients \\[[@CR64]\\]. ", "Interestingly, Aβ-specific T-cell response was highly dependent on a particular epitope. ", "IFN-γ has been shown to play an important role in T-cell-mediated responses involved in AD. ", "Limited expression of IFN-γ in the brain favoured T-cell infiltration into the CNS parenchyma and the formation of immunosynapses with microglia in a mouse model of AD \\[[@CR62]\\]. ", "Moreover, recent data indicate that IFN-γ produced by T-cells infiltrating the brain in AD favour increased microglial activation, Aβ deposition and impaired cognitive functions \\[[@CR16]\\]. ", "Indeed, systemic administration of anti-IFN-γ antibody in mice with AD decreased microglial activation and Aβ deposition, and improve cognitive functions \\[[@CR16]\\]. ", "Interestingly, vaccination with Aβ peptide has proved efficacious in AD mouse models \\[[@CR65]\\]. ", "In this regard, transcutaneous immunisation with aggregated Aβ plus the adjuvant cholera toxin results in a high titre of anti-Aβ antibodies and a significant decrease in cerebral Aβ aggregated in mice with AD \\[[@CR24]\\]. ", "The fact that most anti-Aβ antibodies were of IgG1 isotype in this vaccine can be explained by the induction of a Th2-mediated immune response using this therapeutic approach; this represents a kind of immune response that promotes a switch-on microglial M2-like phenotype with consequent neuroprotection \\[[@CR14],[@CR21],[@CR25],[@CR66],[@CR67]\\]. ", "Notably, in the study carried out by Nikolic *et al*., ", "they did not detect T-cell infiltration in the brain parenchyma \\[[@CR24]\\]. ", "Thereby, it is possible that, when Th2 responses are induced against CNS antigens, CD4^+^ T-cells mainly act from meningeal space, affecting glial function without infiltrating the brain parenchyma, as seen in healthy animals \\[[@CR21],[@CR66]\\]. ", "The role of Tregs has also been addressed in AD. ", "The adoptive transference of Tregs significantly ameliorates impaired cognition and reduces the Aβ-deposits and microglial activation in a mouse model of AD \\[[@CR25]\\]. ", "Moreover, higher Tregs function has been associated with lower cognitive manifestation in AD patients \\[[@CR68]\\]. ", "Addressing the participation of different inflammatory phenotypes of CD4^+^ T-cells infiltrating the brain during AD, studies indicate an important role for both Th1 and Th17 cells. ", "In this regard, Browne *et al*. ", "examined the role of Aβ-specific CD4^+^ T-cells on Aβ accumulation in transgenic mice that overexpress amyloid precursor protein and presenilin-1. ", "The results revealed that Aβ-specific Th1 and Th17 cells infiltrate the brain in this AD model. ", "To address the relevance of the different CD4^+^ T-cell phenotypes in AD, the same authors generated Aβ-specific CD4^+^ T-cells by immunisation of WT mice with Aβ and a TLR agonist, and then polarised them *in vitro* towards Th1, Th2 or Th17, which were then adoptively transferred into mice with AD. ", "Their results showed that Th1 cells, but not Th2 or Th17 cells, increased microglial activation and Aβ deposition, and these changes were associated with impaired cognitive function \\[[@CR16]\\]. ", "Thus, this data indicates a leading role of inflammatory Th1 cells in the immune response associated with AD. ", "However, there is a group of studies supporting the relevance of the participation of Th17 cells in the immune response associated with AD. ", "In this regard, the phenotypic analysis of circulating T-cells obtained from AD patients has shown higher frequencies of the activation marker CD25 and of CCR6, which is characteristic of Th17 cells \\[[@CR69]\\], an inflammatory phenotype associated with neuronal damage in MS and PD \\[[@CR26],[@CR30]\\]. ", "Moreover, significant infiltration of Th17 cells has been detected in the hippocampus by the immunodetection of the master transcription factor RORγt and the expression of Th17 cytokines IL-17 and IL-22, which have been associated with neuron loss and gliosis in cornu ammonis area 1 (CA1) in a rat model of AD \\[[@CR70]\\]. ", "Furthermore, immunohistochemical analyses in brain sections of AD animals showed a high expression of Fas in the hippocampal neurons and a high expression of FasL in Th17 cells that were in close proximity with neurons. ", "Thus, these findings suggest that Th17 cells, which were infiltrated into the hippocampus parenchyma, participate in neuroinflammation and neurodegeneration of AD by releasing pro-inflammatory cytokines and by inducing neuron apoptosis mediated by Fas-FasL contacts \\[[@CR70]\\]. ", "Taken together, the current evidence indicates that inflammatory Th1 and Th17 CD4^+^ T-cells play an important role in the physiopathology of AD, favouring the disease progression (Figure [1](#Fig1){ref-type=\"fig\"}). ", "Nevertheless, other important encephalitogenic T-cell subsets that play important inflammatory or anti-inflammatory roles in MS have not yet been studied in AD. ", "Furthermore, studies implementing the genetic deletion of specific subsets of inflammatory or anti-inflammatory T-cells would be very helpful in order to clarify the specific roles and relevance of these different T-cell subsets in the development and progression of AD. ", "Therefore, similar to the case for PD, future efforts are required to evaluate the participation of important T-cell subsets, such as γδT-cells and GM-CSF-producer T-helper cells, in the physiopathology of AD.", "\n\nInvolvement of T-cell function in the pathogenesis of amyotrophic lateral sclerosis {#Sec5}\n-----------------------------------------------------------------------------------\n\nALS is a neurodegenerative disorder characterised by selective and progressive degeneration of upper and lower motor neurons, leading to dramatic muscle paralysis and death. ", "The initial cause of ALS remains unclear, but nearly 2% of patients have mutations in the *Cu/Zn SOD1* gene, which codes for a ubiquitous protein that acts in removing dangerous superoxide radicals from inside the cell. ", "It has recently been proposed that both loss of dismutase activity and protein aggregation of SOD1 are involved in triggering neuronal loss in ALS \\[[@CR12]\\]. ", "Transgenic mice that overexpress human mutant SOD1 (mSOD1) develop motor pathology resembling ALS \\[[@CR71]\\]. ", "Similar to that occurring in other neurodegenerative diseases such as PD, AD and MS, neuroinflammation is a prominent feature in the process of neuronal loss in ALS patients, as well as in animal models of ALS \\[[@CR1]\\]. ", "Accumulating evidence has emerged during recent years, indicating that the adaptive immune system plays an important role in regulating the progression of ALS \\[[@CR20],[@CR23],[@CR72]\\]. ", "Interestingly, T-cell infiltration in spinal cords of ALS mice has been described in close proximity with dying motor neurons and has been associated with glial activation \\[[@CR20],[@CR23],[@CR72]\\]. ", "Nevertheless, the exact role of the direct interaction of T-cells with motor neurons in ALS remains unclear. ", "Studies addressing the role of T-cells in ALS have shown that T-cell-deficient mice with ALS, generated by crossing mSOD1 transgenic mice with RAG2KO or with TCR β-chain knockout (TCRβKO) mice, develop an accelerated progression to the symptomatic stage of ALS \\[[@CR20],[@CR23]\\]. ", "Furthermore, T-cell deficiency in mice models of ALS is associated with accelerated neuronal loss and decreased glial activation. ", "Moreover, the reconstitution of mSOD1/RAG2KO mice with functional T-cells has shown to recover a prolonged survival of ALS mice, increased glial activation and delayed neuronal loss \\[[@CR20]\\]. ", "Further experiments have shown that mSOD1/CD4KO mice display a phenotype resembling that observed in mSOD1/RAG2KO mice, thus attributing the neuroprotective role to CD4^+^ T-cells, but not to CD8^+^ T-cells or B-cells \\[[@CR20]\\]. ", "Importantly, ALS mice show microgliosis and astrogliosis in the spinal cord, and T-cell deficiency does not significantly affect astrogliosis. ", "However, when lacking T-cells or, specifically, CD4^+^ T-cells, ALS mice display microglial cells with attenuated morphological microgliosis, decreased activation markers such as CD11b and CD68, increased levels of pro-inflammatory cytokines such as IL-6 and TNF-α, decreased levels of trophic factors such as IGF-1, GDNF and BDNF as well as elevated levels of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2, which is known to enhance microglial release of ROS \\[[@CR20],[@CR23]\\]. ", "All these data indicate that CD4^+^ T-cells play a regulatory role on microglial cells during ALS progression, providing supportive neuroprotection by favouring the acquisition of the M2-like phenotype by microglial cells. ", "Recent evidence suggests that both Tregs as well as Th2 cells actively contribute to the neuroprotective effect exerted by CD4^+^ T-cells over microglia. ", "In this regard, analysis of peripheral blood CD4^+^ T-cells obtained from ALS patients has shown decreased levels of Tregs and a decreased level of protein FoxP3 expression, both of which result in a lower suppressive activity \\[[@CR73]\\]. ", "Both parameters were reduced in rapidly progressing ALS patients, and inversely correlated with the progression rates \\[[@CR72],[@CR74],[@CR75]\\]. ", "In addition, both the Th2 cytokine IL-4 and the master transcription factor controlling Th2 phenotype, GATA3, also became reduced in rapidly progressing patients, inversely correlating with the progression of motor symptoms \\[[@CR74]\\]. ", "Furthermore, supporting the participation of Th2 cells during ALS progression, elevated IL-4 levels were found in spinal cords that were obtained from mSOD1 mice \\[[@CR23]\\]. ", "Moreover, stimulation of microglial cells from healthy or ALS mice with IL-4 induces a strong expression of IGF-1 and attenuates the production of inflammatory cytokine IL-6 \\[[@CR23]\\]. ", "Thus, current evidence collectively suggests that, by regulating the acquisition of the functional phenotype of microglia, Tregs as well as Th2 lymphocytes would play an important neuroprotective role during ALS progression. ", "See Figure [1](#Fig1){ref-type=\"fig\"} for an integrative overview of the role of T-cells in neuroinflammation in ALS.", "\n\nContribution of macrophages to the neuroinflammatory process associated with neurodegenerative diseases {#Sec6}\n-------------------------------------------------------------------------------------------------------\n\nCurrent evidence indicates that microglial cells play a key role in sensing protein aggregates in a TLR-dependent manner in the CNS of patients suffering neurodegenerative diseases \\[[@CR6],[@CR7]\\]. ", "This initial activation of microglia produces pro-inflammatory mediators, favouring BBB permeabilisation and, therefore, the infiltration of peripheral leukocytes into the CNS, including T-cells, macrophages and others \\[[@CR76]\\]. ", "Macrophages share several functional features with microglia, including: i) the expression of TLRs and, therefore, the capability of being activated by aggregated proteins or pathogen-associated molecular patterns \\[[@CR6],[@CR7]\\], ii) the expression of class II MHC and, therefore, the capability to present antigens to CD4^+^ T-cells and exert an influence on the functional phenotype of T-cells \\[[@CR77]\\], and iii) the ability to polarise their functional phenotype towards an inflammatory M1 phenotype versus an anti-inflammatory M2 phenotype, which can be influenced by inflammatory T-cells and Tregs \\[[@CR78]\\]. ", "Thus, when the BBB is already permeabilised, the possibility arises in which peripheral macrophages may acquire a relevant role in the outcome of neuroinflammation. ", "In fact, there is also evidence suggesting that a strong inflammatory response in the periphery, such as systemic lipopolysaccharide (LPS) \\[[@CR79]\\] or viral infections \\[[@CR80]\\], may result in subsequent infiltration of peripheral leukocytes into the CNS with consequent neuroinflammation and neurodegeneration. ", "Therefore, irrespective of where the inflammatory response is initiated (periphery versus CNS), macrophages infiltrating the CNS can acquire a relevant role in the outcome of neuroinflammation associated with neurodegenerative disorders. ", "According to this notion, there are a number of studies associating neurodegenerative disorders with alterations in molecular components, determining the M1/M2 behaviour of peripheral macrophages. ", "In this regard, the anti-inflammatory surface molecule CD200R is decreased in monocyte-derived macrophages obtained from the peripheral blood of PD patients in comparison with those from healthy donors \\[[@CR81]\\]. ", "Interestingly, the same authors found that inducible expression of CD200R in monocyte-derived macrophages correlated inversely with the onset age of PD and with the capability of these cells to produce TNF-α \\[[@CR81]\\]. ", "According to the important role of chemoattraction of monocytes in inflamed tissues, as well as their relevance in neurodegenerative disorders, the polymorphism of monocyte chemoattractant protein 1 (or CCL2) has been associated with the age of PD patients at onset \\[[@CR82]\\]. ", "Similarly, a study found that peripheral blood monocytes obtained from PD patients displayed a strong up-regulation of the surface CCR2, which is the receptor for the chemokine CCL2 \\[[@CR83]\\]. ", "Furthermore, according to the relevance of monocytes/macrophages in PD, a recent study has shown that the transference of GDNF-transfected macrophages into mice undergoing 6-hydroxydopamine-induced PD results in a potent neuroprotective effect \\[[@CR84]\\]. ", "Another study addressing the analysis of these alterations in gene-expression profiling of peripheral blood mononuclear cells obtained from patients undergoing sporadic ALS found an up-regulation of TLR4-signaling-associated genes \\[[@CR85]\\], thus suggesting a chronic activation of peripheral blood monocytes/macrophages in ALS. ", "According to this idea, Butovsky *et al*. ", "have found that monocytes obtained from an ALS mouse model present a polarised M1 phenotype and increased CCR2 expression \\[[@CR86]\\]. ", "The same authors have shown that the treatment of ALS mice with anti-Ly6C antibodies results in a partial depletion of monocytes, decreased infiltration of M1 macrophages in the spinal cord and attenuated neurodegeneration \\[[@CR86]\\], thus indicating a pivotal role of monocytes/macrophages in the physiopathology of ALS. ", "Similar to the inflammatory phenotype observed in monocytes/macrophages from PD and ALS patients, studies addressing the characterisation of peripheral blood monocytes/macrophages of AD patients have shown that these cells display an increased M1 phenotype, with increased expression of chemokine receptors CCR2 and CXCR1 \\[[@CR87],[@CR88]\\], and stronger production of inflammatory cytokines, including IL-1β, IL-6 and IL-23 \\[[@CR88],[@CR89]\\]. ", "Regarding MS, studies analysing the M1/M2 profile of monocytes/macrophages obtained from human blood samples are more difficult to interpret, as many studies are performed with relapsing-remitting patients and/or individuals treated with the immunomodulatory cytokine IFN-β. ", "However, the relevance of the M1/M2 profile of monocytes/macrophages has been addressed in EAE. ", "In this regard, M1 macrophages have been found in the early stage of acute EAE, whereas the frequency of M2 macrophages is increased during the peak of disease manifestation and throughout the recovery stage \\[[@CR90]\\]. ", "Indeed, a reduced M1/M2 ratio in the profile of monocytes/macrophages in the blood, as well as in the CNS, promotes an attenuated manifestation of the disease, whereas an increased M1/M2 ratio favours relapsing EAE \\[[@CR91]\\]. ", "Furthermore, the administration of *ex vivo*-activated M2 monocytes both reduces the severity of ongoing EAE and favours the expression of immunosuppressive molecular profile in CNS lesions \\[[@CR91]\\]. ", "In addition, experiments carried out in an animal model of focal demyelinisation have shown that M2 macrophages promote remyelinisation by inducing oligodendrocyte differentiation through a mechanism involving the secretion of activin-A \\[[@CR92]\\]. ", "Importantly, a study has shown that GM-CSF production by encephalitogenic CD4^+^ T-cells is absolutely necessary for EAE manifestation, and its cellular targets were myeloid cells expressing the GM-CSF receptor \\[[@CR38]\\]. ", "Furthermore, experiments performed with bone-marrow chimeras, generating animals with selective deletion of the GM-CSF receptor in microglia or in CNS-infiltrating myeloid cells, have demonstrated that the GM-CSF receptor was required to be expressed in myeloid cells from a peripheral origin, but not in microglia, in order to allow EAE manifestation \\[[@CR38]\\]. ", "Taken together, all of these data indicate that peripheral monocytes/macrophages display an inflammatory M1 phenotype in human individuals suffering neurodegenerative disorders. ", "Moreover, evidence obtained from animal models suggests that these cells may be relevant in neuroinflammation and in the progression of neurodegeneration, and their manipulation favouring the M2 phenotype has shown promising therapeutic potential.", "\n\nConclusions {#Sec7}\n===========\n\nNeuroinflammation constitutes a critical process in the physiopathology of several neurodegenerative disorders, which is required for the progression of neurodegeneration. ", "Differential activation of microglial cells constitutes a central point of regulation in neuroinflammation, which can result in neurotoxic or neuroprotective environments that are critical for the fate of neurons. ", "Growing evidence has indicated a fundamental role of CD4^+^ T-cells in the regulation of neuroinflammation and consequent neurodegeneration in a number of neurodegenerative diseases. ", "In this regard, encephalitogenic inflammatory CD4^+^ T-cells such as Th1, Th17, GM-CSF-producer CD4^+^ T-cells and γδT-cells strongly contribute to feed chronic neuroinflammation, thus perpetuating neurodegenerative processes. ", "In contrast, encephalitogenic or meningeal Tregs and Th2 cells decrease inflammatory functions in microglial cells and promote a neurosupportive microenvironment. ", "Interestingly, whereas some neurodegenerative disorders such as MS, PD and AD involve the participation of inflammatory CD4^+^ T-cells \\'naturally\\', the physiopathology of other neurodegenerative diseases, such as ALS, is associated with the participation of anti-inflammatory CD4^+^ T-cells that delay the neurodegenerative process. ", "Thus, current evidence supports the hypothesis that the involvement of a CD4^+^ T-cell-mediated response against CNS antigens constitutes a key component for the progression of the neurodegenerative process. ", "Furthermore, an increasing number of studies have shown the relevance of peripheral monocytes/macrophages in the progression of neuroinflammation and their therapeutic potential for neurodegenerative disorders. ", "According to this notion, immunoregulatory strategies to attenuate inflammatory CD4^+^ T-cells or M1 monocytes/macrophages and to strengthen the function of M2 monocytes/macrophages or Tregs specific for CNS antigens involved in neurodegenerative disorders should be considered in future therapies.", "\n\n**Competing interests**\n\nThe authors declare that they have no competing interests.", "\n\n**Authors' contributions**\n\nHG and RP have contributed equally to the conception of the main body of the manuscript, design of the structure, acquisition of data, analysis and interpretation of data. ", "In addition, HG made the illustration (Figure [1](#Fig1){ref-type=\"fig\"}) of this manuscript. ", "RP wrote the sections of introduction and conclusion as well as the abstract of this manuscript. ", "Both authors read and approved the final manuscript.", "\n\n**Authors' information**\n\nHG is PhD performing a postdoctoral training supervised by RP in the Laboratory of Neuroimmunology of the Fundación Ciencia & Vida. ", "RP is the Principal Investigator of the Laboratory of Neuroimmunology, Associate Investigator at Fundación Ciencia & Vida and Professor at Universidad Andrés Bello.", "\n\nThis work was supported by grants 1130271 from FONDECYT and PFB-16 from CONICYT. ", "Both grants contribute to HG and RP salaries and both grants funded publication costs.", "\n" ]

{ "pile_set_name": "PubMed Central" }

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[ "Q:\n\nFilter EntityType by owner/current user\n\nI have an EntityType field in a form:\n$builder->add('site')\n\nnow all the sites are shown in the dropdown, but I want to show only the ones that belong to the current user.", "\nThe app logic is that there are many users, each of them can manage only their own sites (Site::user is a @ORM\\ManyToOne(targetEntity=\"User\", inversedBy=\"sites\"))\nI know I can use the query_builder - but what is the best way to get the current user inside the form?", "\n\nA:\n\nTo get the current user object (or id) in the form there are actually multiple ways. ", "One would be to set it via the form's options\n$form = $this->createForm(MyFormType::class, $obj, [\n 'user' => $this->getUser(),\n]);\n\nAnd enable the option with default value null like so.", "\nclass MyFormType extends AbstractType\n{\n\n public function configureOptions(OptionsResolver $resolver)\n {\n $resolver->setDefaults([\n 'data_class' => '...',\n 'user' => null,\n ]);\n }\n\nNow you can use $options['user'] within the buildForm() (make sure to check if it is null or not before using).", "\n\nBut this way you have to always inject the user yourself - why not let Symfony take care of it? ", "First, register your form as a service in services.yml like so\napp.form.myform:\n class: AppBundle\\Form\\MyFormType\n arguments: [\"@security.token_storage\"]\n tags:\n - { name: form.type }\n\nYou see, I already added another thing: the @security.token_storage argument. ", "Now in your form, add a constructor\nuse Symfony\\Component\\Security\\Core\\Authentication\\Token\\Storage\\TokenStorageInterface;\n\nclass MyFormType extends AbstractType\n{\n\n protected $tokenStorage;\n\n public function __construct(TokenStorageInterface $tokenStorage)\n {\n $this->tokenStorage = $tokenStorage;\n }\n\nAnd retrieving the user within buildForm() will now be as easy as\n$user = $this->tokenStorage->getToken()->getUser();\n\n" ]

{ "pile_set_name": "StackExchange" }

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[ "Q:\n\nProblem will paginate ajax rails?", "\n\nMy problem is this:\nI have got a view/action called new. ", "In this action I can create product_packs. ", "Each pack have many products. ", "OK? ", "\nThen in new view I have a button which open a popup. ", "This popup allow add_products to pack.", "\nThis products is paginated with will_paginate plugin. ", "So products pagination code is on action new. ", "OK?", "\nBesides this popup is inside a partial. (", "The button is a <%= button_to_function \"add_product\", \"BasicModal(\"id_add_product_partial\")\"%> which open popup through Simplemodal plugin).", "\nOk, when I select a product from the list these are loaded in a list. ", "So when i click add products button in popup I don´t want to see this products again. ", "OK?", "\nadd_products button go to ajax request ajax where I reload products (I reject selected products).", "\nSO I want paginate products again but the will paginate products render to action new. ", "But must go to add_products ajax action. ", "OK?", "\nI need a solution for rewrite will_paginate links in view.", "\n(Example: when I load action new charge <% will_paginate @products%> but when I selected products and I add to my list replace these will_paginate links with <% will_paginate @products, #links go to add_products action in ajax request %>)\nOR \nI need load/initialize products when I open popup. ", "So popup code is not on new view. ", "Popup code load products collection in add_products action so will_paginate links always go to this action.", "\nThanks in advice and excuse me. ", "If you need the code of my application I post in other answer.", "\n\nA:\n\nI find a solution for this problem. ", "When I have a little time I am going to publish my code more explanatory.", "\nBroadly speaking, we can combine the ajax pagination described in oficcial gitHub documentation and use Simple modal.", "\nFirst I create a button_to_remote to remote action and a empty div with a ID attr, then here I could work the logic of my method such that we will use only once the will_paginate plugin with conditions.", "\nThen I could use a RJS or in the controller render :update. ", "There we could use a page.replace_html and fill the empty div with our remote_form (in a partial). ", "then I call Basicmodal function with the ID of empty div.", "\nthen I create n the route a map.connect relative_url, :controller \"foo\", :action :bar.", "\nSo we have got a popup with remote pagination in other controller different ,from what is called the current action.", "\nThanks\n\n" ]

{ "pile_set_name": "StackExchange" }

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[ "Phylogenetic analysis of nuclear and mitochondrial genes reveals evolutionary relationships and mitochondrial introgression in the sertifer species group of the genus Neodiprion (Hymenoptera: Diprionidae).", "\nNeodiprion Rohwer (Hymenoptera: Diprionidae) is a Holarctic genus of conifer-feeding sawflies with a remarkable amount of inter- and intraspecific diversity in host use, behavior, and development. ", "This variation is thought to play a central role in Neodiprion diversification, but speciation hypotheses remain untested due to a lack of a robust phylogenetic estimate. ", "Here, we utilize sequence data from three nuclear genes (CAD, ANL43, EF1alpha) to obtain a phylogenetic estimate for the genus. ", "These analyses suggest that: (1) North American and Eurasian Neodiprion are monophyletic sister clades, (2) the sertifer group is paraphyletic with respect to the monophyletic lecontei group, and (3) on at least two occasions, dispersal from eastern to western North America proceeded via southern host bridges. ", "Based on these results and host biogeography, we revise a previous scenario for the evolution of Neodiprion and suggest maximum ages for the genus and for the lecontei group (25 My and 14 My, respectively). ", "In addition, because a previous study reported rampant mitochondrial introgression in the lecontei group, we assess its prevalence in the sertifer group. ", "Analysis of three mitochondrial genes (COI, tRNA-leucine, and COII) reveals that mito-nuclear discordance is prevalent in the sertifer group, and patterns of species monophyly are consistent with those expected under frequent mitochondrial introgression. ", "As was the case for lecontei group species, we find that introgression appears to be most pronounced between species that occasionally share hosts, suggesting that divergent host use is an important barrier to gene flow in Neodiprion. ", "Finally, we suggest that the lack of phylogenetic resolution and prevalence of species non-monophyly in the non-Pinus feeding Neodiprion may result from the rapid divergence (possibly with gene flow) of these species following their entry into a novel adaptive zone." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "#!", "/usr/bin/env python\n\n#Copyright (C) 2012 P.J. Onori (pj@somerandomdude.com)\n\n#This program is free software: you can redistribute it and/or modify\n#it under the terms of the GNU General Public License as published by\n#the Free Software Foundation, either version 3 of the License, or\n#(at your option) any later version.", "\n\n#This program is distributed in the hope that it will be useful,\n#but WITHOUT ANY WARRANTY; without even the implied warranty of\n#MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. ", " See the\n#GNU General Public License for more details.", "\n\n#You should have received a copy of the GNU General Public License\n#along with this program. ", " If not, see <http://www.gnu.org/licenses/>.", "\n\n\nimport fontforge\nimport json\nfrom pprint import pprint\njson_data=open('iconic_uni.json')\n\ndata = json.load(json_data)\n\nfont = fontforge.open('blank_fill.sfd')\n\nfor file_name, char in data.iteritems():\n\tc = font.createChar(int(\"0x\" + char, 16))\n\t\n\tc.importOutlines('svg/' + file_name + '.svg')\n\tc.autoHint()\n\t\n\tc.left_side_bearing = 15\n\tc.right_side_bearing = 15\n\n#font files\n\nfont.generate('iconic_uni.svg')\nfont.generate('iconic_uni.ttf')\nfont.generate('iconic_uni.eot')\nfont.generate('iconic_uni.otf')\nfont.generate('iconic_uni.woff')\n\n#css file\n\ntheString=\"@font-face { font-family: 'IconicUni'; src: url('iconic_uni.eot'); src: url('iconic_uni.eot?#iefix') format('embedded-opentype'), url('iconic_uni.ttf') format('truetype'), url('iconic_uni.svg#iconic') format('svg'); font-weight: normal; font-style: normal; }\"\ntheString+=\".iconic { display:inline-block; font-family: 'IconicUni'; }\"\nfor file_name, char in data.iteritems():\n\ttheString += \".\" ", "+ file_name + \":before {content:'\\\\\" + char + \"';}\"\n\nf = open(\"iconic_uni.css\", 'w')\nf.write(theString)\nf.close()\n\n#html file\ntheString=\"<html><head><title>Iconic Font-embedding demo</title><link rel='stylesheet' href='iconic_uni.css' type='text/css' media='screen' /><style> body {font-family:'Helvetica', arial, sans-serif;} span { font-size:36px; }</style><body>\"\ntheString += \"<table><tr><th>Name</th><th>Iconic Icon</th><th>Unicode Icon</th><th>Hexidecimal Code</th>\"\nfor file_name, char in data.iteritems():\n\ttheString += \"<tr><td>\" + file_name + \"</td><td><span class='iconic \" + file_name + \"'></span></td><td><span class='\" + file_name + \"'></span></td><td>\" + char + \"</td></tr>\"\n\ntheString += \"</table></body></html>\"\n\nf = open(\"iconic_uni_demo.html\", 'w')\nf.write(theString)\nf.close()\n" ]

{ "pile_set_name": "Github" }

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[ "* Now files from different datasets could be loaded simultaneously, if they are mapped to the same reference genome\n\n\n\n* Build process is moved to SpringBoot framework. ", "Now to options are avaible for building NGB binaries. ", "See [Standalone installation instructions](../../installation/standalone.md) for details\n * `./build.sh --war #produces war file that should be deployed to a tomcat instance`\n * `./build.sh --jar #produces jar file that could be used standalone`\n* Now variations table columns set is stored for a user. ", "When a *custom* column is added to a variations table it would be shown always (if a VCF file contains that column) until a user will explicitly remove it\n* INFO tab of a variation details popup now shows annotation fields as a table (sorting and column reordering is allowed)\n\n\n\n* Main application toolbar is moved to the left to provide more space for the tracks data\n\n\n\n* Context menus items now shows assigned hotkeys, if they are set\n\n\n\n* \"Loading\" indicator is added to VCF/Genes/BED tracks. ", "Previously existed only for BAM tracks\n* URL format changed\n * It does not include dataset id. Instead of it - a reference genome name is used\n * Tracks list is now always included into URL, to be able to specify files from different datasets\n* VCF and GTF/GFF files registration increase ~2x times \n* Next/Previous variation buttons added to a VCF track header GUI. ", "Previously only hotkeys were available for navigation\n* Added **Close** button for each track\n* \"Show 3D structure\" for a gene now opens **Molecular viewer** pane automatically. ", "Previously it should be opened manually before selecting a gene\n* Added **unique** constraint for the file names at registration routine\n\n" ]

{ "pile_set_name": "Github" }

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[ "Gliederung\n\nObjective: Infections with neurotropic viruses [simian virus 40 (SV40), JC virus (JCV), BK virus (BKV), human papilloma virus (HPV), human cytomegalovirus (HCMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV)] are thought to play a role in the development of primary brain tumors, but the cellular source of positive PCR results in infected tumor tissues remains unclear. ", "In immunodeficient patients, EBV-carrying B-lymphocytes were proposed to be a possible source, but a direct infection of brain resident cells has not been excluded. ", "In this study, we tested different types of primary brain tumors for the appearance of neurotropic viruses and verified an EBV infection in one oligodendroglioma tissue. ", "Here we describe results obtained from our study sample and our attempt to analyze the source of EBV-positive cells to determine the role of EBV infection for tumorigenesis.", "\n\nMethods: Frozen tumor samples of 55 brain tumor patients (gliomas, meningiomas) were homogenized and genomic DNA was isolated. ", "DNA was tested by nested PCR analysis for the integration of viral sequences from the above mentioned neurotropic viruses. ", "In one patient with EBV-infected tumor tissue, DNA derived from the tumor tissue, the corresponding tumor cell culture and the patient’s blood was analyzed for an EBV sequence. ", "Immunohistochemical staining of frozen tumor tissues and, for positive control, of an EBV-immortalized lymphoblastoid cell line (GCi-LCL) was done using antibodies against the EBV-specific protein LMP1.", "\n\nResults: While HSV, HCMV, HPV, BKV, JCV and SV40 were not detected in any of the tumor samples, we amplified a viral DNA sequence of the EBV-specific protein EBNA-2 in the tumor tissue of a 53-year-old patient suffering from low-grade oligodendroglioma. ", "High IgG titers against EBV were detected in the patient’s serum and the EBNA-2 sequence was amplified from the tumor tissue and blood cells but not from the corresponding cell culture. ", "In line with these results, immunohistochemical staining of the tumor tissue did not reveal any LMP1 protein expression.", "\n\nConclusions: Our data suggest that the infection of brain tissue by neurotropic viruses is an extremely rare event and does not seem to play a significant role in the development of primary brain tumors. ", "For the only patient in our study sample with EBV-infected tumor tissue, we were the first to identify blood cells to be the real source of EBV infection while tumor cells were negative. ", "Therefore future studies should include an analysis of corresponding blood DNA in order to answer the question whether viral infections are involved in tumorigenesis." ]

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[ "At the River\n\n\"At the River\" is a song by British duo Groove Armada. ", "It was released as a single in 1997 on 7\" vinyl, limited to 500 copies. ", "The song appeared on the duo's debut album Northern Star and again on their second album, Vertigo, released in April 1999.", "\n\nProduction and content \nThe song was written and produced whilst the duo were staying in a cottage in Ambleside in the Lake District, writing material for their first album.", "\n\nA sample of Patti Page's \"Old Cape Cod\" forms the basis of the song: the lines \"If you're fond of sand dunes and salty air/Quaint little villages here and there\", sung in Page's multi-tracked close-harmony, is repeated throughout the song, with the addition of synthesizer bass and slowed-down drum programming. ", "The band found \"Old Cape Cod\" when they bought a 1950s compilation album from a bargain bin in a shop in Ambleside for 50p. ", "Tom Findlay suggested that the use of only one section of the song's lyric left the track open to interpretation, \"giving it a slightly eerie, melancholy quality\", although he admitted that this wasn't by design but because the sampler they were using could only record ten seconds of audio at a time. ", "A blues-style trombone solo inspired by the spiritual song \"At the River\" was performed by Andy Cato to produce a more chill-out track. ", "According to Cato the only reason he had taken his trombone to the Lake District was because he wanted to practice before an upcoming jazz concert: when he wanted to record the trombone melody, he had to improvise a microphone by swapping around the wires in a speaker from the cottage's Alba hi-fi as the duo didn't have a microphone with them and were staying in a remote location. ", "Cato credited this as giving the recording \"a real vintage character\".", "\n\nRelease \n\n\"At the River\" was originally released as a single on 7\" vinyl in 1997 in a limited pressing of 500 copies, and appeared on the duo's debut album Northern Star as well as its follow-up, Vertigo, in 1999. ", "Rob da Bank made it his single of the week in DJ Mag: he subsequently handed a copy to Zoe Ball, who started playing it on The Radio 1 Breakfast Show. ", "Although the BBC Radio 1 playlist committee initially believed the song was too slow for radio, support from radio producers and listeners meant that it forced its way into rotation. ", "On 26 July 1999, the single was re-released on 12\" and CD. ", "This re-release peaked at number 19 in the UK Singles Chart.", "\n\nIt was used in adverts for Marks & Spencer Food in 2006, and in the films About Time and The Low Down.", "\n\nTrack listing \n\nAll songs were written by Andy Cato, Tom Findlay, Allan Jeffrey, Claire Rothrock, and Milton Yakus, except where noted.", "\n\n 7\" vinyl\n\n 12\" vinyl\n\n CD\n\nCertifications\n\nReferences\n\nExternal links\n\n \n \n\nCategory:1997 debut singles\nCategory:1999 singles\nCategory:Groove Armada songs\nCategory:Songs written by Andy Cato\nCategory:1997 songs\nCategory:Songs written by Milton Yakus\nCategory:Downtempo songs" ]

{ "pile_set_name": "Wikipedia (en)" }

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[ "---\nauthor:\n- |\n Teng Zhang, Arnold Wiliem\\*, Siqi Yang and Brian C. Lovell\\\n The University of Queensland, School of ITEE, QLD 4072, Australia\\\n [@uq.edu.au, lovell@itee.uq.edu.au]{}\nbibliography:\n- 'egbib.bib'\ntitle: 'TV-GAN: Generative Adversarial Network Based Thermal to Visible Face Recognition'\n---\n\n\n" ]

{ "pile_set_name": "ArXiv" }

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[ "Product Details\n\nShipping: This item is also available for shipping to select countries outside the U.S.\n\nASIN: B005FKGNQA\n\nItem model number: EL-S4SM-CBL-BA\n\nPrice : $10.99You Save : $9.00 (45%)\n\nProduct Description\n\nKeep the iPhone four/4S secure protected in style with the S4 Slim Fit Case. ", "Exclusive style permits hassle-free access to all buttons, controls ports without having to eliminate the case. ", "Polyurethane coated to guard from scratches and for improved grip, Product developed by elago in California and Produced in Korea.", "\n\nCustomer Reviews\n\nI've only had the case for a week, but I enjoy it. ", "It is slim, so doesn't boost the size of my iPhone at all. ", "Actually cute color. ", "The only factor is it is exceptionally smooth, which I assumed it would be, hence why I did not take off in rating. ", "If you have it on a smooth surface it will slide like crazy. ", "Excellent case, so far. ", "Also, I was told by an individual though I was out that they dropped their telephone with this case and it broke immediately after a couple occasions. ", "To this, this case is not meant to safeguard it from crazy falls or something, which I am aware. ", "It really is meant to appear cute, but also shield it from everyday scratches from your purse or pocket. ", "If I wanted to be able to run it over by a automobile and it nonetheless be fine I would have purchased the case that doubles the size of the iPhone.", "\n\nI've been utilizing this case for a week now, and merely really like it! ", "It is slim, sleek, and fashionable. ", "The coral blue color matches my white iPhone 4S perfectly. ", "And it feels so superior in hand that I never ever wanted to take it off. ", "It is surely the lightest, least bulky, and prettiest case that I've ever utilised, and presents really good protection when my telephone slipped to the ground once out of my pocket. ", "No harm accomplished at all. ", "Thank you" ]

{ "pile_set_name": "Pile-CC" }

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[ "$icon-font-path: \"~bootstrap-sass/assets/fonts/bootstrap/\";\n\n@import \"~bootstrap-sass/assets/stylesheets/bootstrap\";\n@import \"~react-bootstrap-table/dist/react-bootstrap-table.min\";\n@import \"react-tagsinput/react-tagsinput.css\";\n@import \"react-bootstrap-timezone-picker/dist/react-bootstrap-timezone-picker.min.css\";\n\n@import \"../src/styles/main\";\n" ]

{ "pile_set_name": "Github" }

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[ "Q:\n\nwhat are hidden states in HMM based language model?", "\n\nThere are several ways to build language models, n-gram based models are straightforward, but for the language models built on HMMs, what are hidden states and what are observations?", "\n\nA:\n\nGenerally the hidden states are the parts of speech (eg, noun, verb) and the observations are the words. ", "\nSo we assume that each word (emission) depends only on the part of speech and each part of speech depends only on the part of speech preceding it in the sequence (this last one is \"markov\", or memoryless, assumption).", "\nThe part of speech is therefore \"hidden\" as it is not directly observed. ", "\n\n" ]

{ "pile_set_name": "StackExchange" }

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[ "[Postoperative treatment in the surgery of acute hand injuries].", "\nErrors happen most often in emergency cases because of insufficient theoretical and practical knowledge and disrespect of the basic principles for the hand management. ", "It is neglected in many surgical wards because of overworking of surgeons with other emergency cases. ", "The hand is usually managed by a junior physician, quickly and inadequately because he is insufficiently trained for such a complicated job. ", "To prevent the consequences of such work which more or less leads to disability, in each medical institution one surgeon should be educated in the modern care of the injured hand. ", "Nowadays, the centres for hand surgery are being established where the hand is reconstructed in team work. ", "It includes the plastic surgeon, orthopedic surgeon and physiatrist and the microsurgical methods are applied for ideal suturing of the nerve or the blood vessel. ", "After hemostasis, immobilization, elevation, pain relieving, protection against infection have been performed the general surgeon should refer complicated cases to the institution where the hand is managed by the team." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "RNAi targeting embryonic myosin heavy chain isoform inhibited bound thrombin-induced migration of vascular smooth muscle cells.", "\nTo investigate the effect of bound thrombin, a complex of alpha-thrombin with fibrin fragments derived from clots, on proliferation and migration of cultured rabbit vascular smooth muscle cells, cell proliferation was measured by WST-1 reagent and migration was evaluated by counting migrated cells through pores of cell culture insert (8 mum size) after 48-hour treatment with bound thrombin (10 U/ml). ", "To examine the role of an embryonic myosin heavy chain isoform (SMemb) in these effects by bound thrombin, the cells were subsequently treated for 48 h with an siRNA expression vector (ORF-2/pSilencer) directed against the open reading frame of SMemb mRNA. ", "SMemb and plasminogen activator inhibitor-1 mRNA expressions were measured by Northern blot analysis. ", "Bound thrombin significantly increased SMemb mRNA expression by 1.4 +/- 0.01-fold and significantly increased plasminogen activator inhibitor-1 mRNA expression by 2.65 +/- 0.69-fold (p < 0.01 vs. PBS treatment for each), which were abolished by treatment with ORF-2/pSilencer. ", "Although bound thrombin had no effect on cell proliferation, bound thrombin significantly increased migration by 1.93 +/- 0.20-fold (p < 0.05). ", "ORF-2/pSilencer treatment significantly reduced the bound thrombin-stimulated migration activity by 1.28 +/- 0.15-fold (p < 0.05). ", "Thus, SMemb plays an important role in bound thrombin-induced cell migration activity of cultured vascular smooth muscle cells." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "In New Zealand, Anzac Day Tours saw a surge in popularity immediately after World War II. ", "However this was short-lived, and by the 1950s many New Zealanders had become antagonistic or indifferent towards the day. ", "Much of this was linked to the legal ban on commerce on Anzac Day, and the banning by many local authorities of sports events and other entertainment on the day\n\nOn 31st of March the Gallipoli ballot was completed and many people missed out. ", "Because of this, we all met to organise alternatives places for those who wants to come to Turkey for Anzac Tours 2016 with Samyeli Travel.", "\n\nSamyeli Travel are Turkey travel specialists who can help you plan the perfect holiday in Turkey, whether it be Anzac Day Tours, Ephesus Tours, Istanbul City Tours, Hotels and Hostels, Airport Transfers or anything else you can think of, we can help.", "\n\nSamyeli Villas Villas For Sale in Kusadasi is a recently completed site of 28 co-joint villas. ", "The site is located in a quiet neighborhood with excellent access to local transport, shopping centres and bars and restaurants. ", "The villas are finished to an exceptionally high quality and are situated within a unique site with pine trees and established vegetation lining stone pathways and walls. ", "The swimming pool area is set in the centre of this site and provides an excellent location for its residents to meet, socialise and enjoy their time in Kusadasi." ]

{ "pile_set_name": "Pile-CC" }

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[ "Circular dichroic spectra of 6-thioguanosine nucleotides and their complexes with myosin subfragment 1.", "\nThe circular dichroic spectra of the thione form of 2-amino-6-mercapto-9 beta-ribofuranosylpurine 5'-triphosphate (thioGTP), thioGDP, thioGTP(gamma S), thioGMP-P(NH)P, and 6-mercapto-9 beta-ribofuranosylpurine 5'-diphosphate (thioIDP) and their complexes with myosin subfragment 1 and heavy meromyosin have been measured between 300 and 400 nm. ", "The free nucleotides have a weak negative circular dichroic spectral peak at their absorption maxima, with a longer wavelength shoulder. ", "On binding to the proteolytic fragments of myosin, the negative peak in enhanced approximately 10-fold and a longer wavelength positive peak appears. ", "These effects are attributed to a change in the stereochemical structure of the nucleotide and specific interactions within the nucleotide binding site. ", "All four thioguanosine nucleotides give these spectral changes although minor significant differences do occur. ", "The CD spectra of the subfragment 1 steady-state complexes with thioGTP and thioGTP(gamma S) are similar to each other but different from the complexes of subfragment 1 with thioGDP and thioGMP-P(NH)P. Interactions between nucleotides in the complexes are excluded by a study of their spectra in 2-propanol when base stacking occurs. ", "This is the first investigation where circular dichroism has been used to determine structural differences between different myosin--nucleotide states and provides evidence that the nucleotide in the gamma S bound state is similar to that of the triphosphate bound state." ]

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[ "Q:\n\nWhat are these stars in my microscopic image?", "\n\nI see this very curious patterns on the sun-facing side of a jasmine (probably) leaf - visible with a makeshift microscope (about 50x)\nWhat are them? ", "Pores? ", "Are there other plants with similar textures?", "\nThe microscope is made out of a webcam, as described here\n\nA:\n\nDespite low resolution, I'd say those are trichomes. ", "Jasminum is genera that produce essential oils, so it have glandular hairs and other trichomes wich help to rettain the oil layer.", "\n\nSource: http://cms.herbalgram.org/herbalgram/issue53/article2207.html?ts=1376643526&signature=b4349f7f3ca6f6a47823f4754237eaac\nThe image displayed above shows glandular and non-glandular trichomes in lavander shown by scanning electron microscopy. ", "I'm afraid I couldn't find anything about Jasminum in particular, but I think it must be the same kind of structure.", "\n\n" ]

{ "pile_set_name": "StackExchange" }

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