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[ "Ta•o Taido\n\nis a 1993 fighting arcade game developed and published by Video System. ", "It was Video System's only attempt in the fighting game genre, and it was created during the fighting game trend of the 1990s that was popularized by Capcom's 1991 arcade hit Street Fighter II.", "\n\nGameplay\nThe game takes place on Earth, where eight martial artists from around the planet compete against each other to fight and defeat the legendary master and reveal the secrets of Ta•o Taido. ", "The game appears to be similar to other 2D versus fighting games during its release, but has different gameplay. ", "The player's character fights against his or her opponent in single round matches in a single player tournament mode with the computer or against another human player, while using very simplistic commands that summon charging attacks. ", "Players press and hold two out of three buttons down to charge up, then move the joystick toward a direction to perform an attack. ", " The longer the players hold two buttons down, the more powerful and longer the attack gets and lasts; however, there are three levels of energy, and after the third and highest charge, it returns to the first and lowest charge. ", "Short charges create weak moves, medium charges create moderate moves, and long charges create strong attacks. ", "Both players have 3 levels of health in each round, instead of one like in most other fighting games. ", " Ta•o Taido also has a cooperative 2-player feature similar to the ones in SNK's Street Smart and Fatal Fury: King of Fighters. ", " The controls can be switched to what most other fighting games have.", "\n\nCharacters\nPlayers have a character roster of eight fighters to choose from, and one unplayable boss. ", "Each with their own unique fighting style and special techniques.", "\n - The protagonist of the game.", "\n\n - Later appeared in the 1995 Neo Geo title Aero Fighters 3.", "\n\nBoss\n - Teacher Chung's older twin.", "\n\nExternal links\nTa•o Taido at The Large Cult Fighting Game March \n\nTa•o Taido at arcade-history\n\nCategory:1993 video games\nCategory:Arcade games\nCategory:Arcade-only games\nCategory:Cooperative games\nCategory:Video System games\nCategory:Multiplayer video games\nCategory:Versus fighting games\nCategory:Video games developed in Japan" ]

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

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[ "Curtis-Wright Flow Control Wins 25k Grant for Energy Management Program\n\nCurtiss-Wright Flow Control Company''s EMD business unit, located in Cheswick, PA, was awarded a $25,000 grant from the Pennsylvania Technical Assistance Program, sponsored by the U.S. Department of Energy (DOE),\n\nCurtiss-Wright Flow Control Company”s EMD business unit, located in Cheswick, PA, was awarded a $25,000 grant from the Pennsylvania Technical Assistance Program, sponsored by the U.S. Department of Energy (DOE), to support its efforts to become ISO 50001 certified for excellence in energy management.", "\n\nEMD applied for a grant through a new DOE-sponsored program called the Pennsylvania Technical Assistance Program, which is administered through Pennsylvania State University. ", "In May, EMD was selected to participate in the Pennsylvania Superior Energy Performance Demonstration project.", "\n\nAs a participant, EMD will receive training and other support to implement an energy management program that conforms to ISO 50001. ", "Certification and assessment to the ISO standard will take approximately 18 months to achieve. ", "To date, only 35 companies in the nation have been selected to participate in the certification program.", "\n\n“We are honored to be selected as a member of this elite group and look forward to applying energy management best practices throughout all of our businesses,” said Greg Hempfling, senior VP & GM of the Electro-Mechanical Systems Division of Curtiss-Wright Flow Control Company." ]

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[ "Introduction {#sec1_1}\n============\n\nTumor markers may be defined as molecules which indicate the presence of cancer or provide information about the likely future behavior of a cancer (i.e., likelihood of progression or response to therapy) \\[[@B1],[@B2]\\]. ", "In asymptomatic subjects, tumor markers are potentially used in screening for early malignancy. ", "In symptomatic patients, markers may help in the differential diagnosis of benign and malignant disease. ", "Following diagnosis and surgical removal of a malignancy, markers may be used for assessing prognosis, postoperative surveillance, therapy prediction and monitoring response to systemic therapy \\[[@B1],[@B2]\\].", "\n\nIrrespective of its application, an ideal tumor marker should exhibit the following characteristics: possess a high positive and negative predictive value;have an inexpensive, simple, standardized and automated assay with clearly defined reference limits;be acceptable to subjects undergoing the test; andhave its clinical value validated in a large prospective trial.", "\n\nSuffice it to state, the ideal tumor marker does not currently exist. ", "Despite this, several markers are now indispensable in the management of patients with cancer. ", "The aims of this article are to review the most widely measured markers in clinical practice and summarize published guidelines for their use.", "\n\nUse of Markers in Screening for Cancer {#sec1_2}\n======================================\n\nScreening involves the detection of early disease or a preclinical state in subjects without signs or symptoms of disease. ", "Unlike disease diagnosis, screening is performed on individuals without any clinical sign of disease. ", "Compared to established screening tests such as mammography for breast cancer, the Papanicolaou test for cervical cancer and colonoscopy for colorectal cancer (CRC), the use of tumor markers might be expected to have practical advantages in cancer screening \\[[@B3]\\]. ", "These advantages include \\[[@B3]\\]: Markers can be measured in fluids such as blood and urine that can be obtained with minimal inconvenience to the individuals undergoing screening.", "For many markers, automated assays are available, allowing the processing of large numbers of samples in a relatively short period of time.", "Tests for markers provide quantitative results with objective endpoints.", "Assays for markers are relatively cheap compared to radiological, histological and endoscopy procedures.", "\n\nDespite these advantages, markers have several limitations as cancer screening tests. ", "In particular, lack of sensitivity for early invasive disease or premalignant lesions and lack of specificity for malignancy limit the use of existing markers in screening asymptomatic subjects for early malignancy \\[[@B1],[@B3]\\]. ", "The dual problem of limited sensitivity and specificity, especially when combined with the low prevalence of most cancers in the community, means that markers, if used alone, have low positive predictive values in screening asymptomatic populations. ", "Indeed, it is the low prevalence of cancer in the general population that prohibits most biomarkers from being used in screening for cancer \\[[@B1],[@B3]\\]. ", "Despite this, a number of markers have either undergone or are presently undergoing evaluation for cancer screening (table [1](#T1){ref-type=\"table\"}). ", "Some of the most widely investigated markers in cancer screening are now discussed.", "\n\nFecal Occult Blood Testing in Screening for CRC {#sec2_1}\n-----------------------------------------------\n\nOne of the best validated screening markers is the use of fecal occult blood testing (FOBT) in screening for CRC. ", "Indeed, 4 large randomized prospective trials carried out in Europe and North America have all shown that screening apparently healthy subjects over 50 years of age using FOBT significantly reduced mortality from CRC \\[[@B4]\\]. ", "Combined results from the 4 trials showed that the screening resulted in a 16% reduction in the relative risk of CRC mortality \\[[@B4]\\]. ", "Following adjustment for those subjects that failed to attend screening, mortality reduction increased to 25%.", "\n\nScreening healthy individuals aged ≥50 years using FOBT is now recommended, especially in Europe \\[[@B5],[@B6]\\]. ", "Although the 4 prospective randomized trials mentioned above all used a guaiac-based FOBT, both the European Group of Tumor Markers (EGTM) and a European Union expert panel currently recommend the use of a fecal immunochemical test in screening for CRC \\[[@B5],[@B6]\\]. ", "As previously reviewed, the use of fecal immunochemical tests have several advantages vis-à-vis FOBTs, including greater analytical sensitivity and specificity, improved clinical performance and potential for automation \\[[@B5]\\].", "\n\nProstate-Specific Antigen in Screening for Prostate Cancer {#sec2_2}\n----------------------------------------------------------\n\nIn contrast to FOBT in screening for CRC, the clinical value of prostate-specific antigen (PSA) in screening for prostate cancer is less clear \\[[@B7]\\]. ", "In 2009, results from 2 large randomized prospective trials evaluating the screening potential of this marker were published. ", "The first of these trials was carried out in the USA and involved 76,693 men that were randomized to either annual screening or regular care \\[[@B8]\\]. ", "Following analysis at 7--10 years of follow-up, death rates were similar in the 2 groups. ", "A limitation of this study was that approximately 50% of men in the control group underwent screening during the study. ", "This trial could thus be regarded as a comparison between a heavily screened group and a less heavily screened group rather than a true randomized trial \\[[@B8]\\]. ", "A further limitation was that approximately 40% of the men participating had a PSA test prior to the start of the trial. ", "These men were thus less likely to be diagnosed with prostate cancer during the trial proper.", "\n\nIn a somewhat similar but larger trial carried out in Europe, 162,243 men were randomly allocated to PSA screening or to a control group not subjected to screening \\[[@B9]\\]. ", "After a median follow-up of 9 years, death rates from prostate cancer were found to be 20% lower in the screened compared to the control group. ", "This apparent benefit, however, resulted in major overdetection and overtreatment. ", "Thus, according to the paper\\'s authors, 1,410 men would have to be screened and 48 additional cases of prostate cancer would have to undergo treatment to prevent 1 death from prostate cancer \\[[@B9]\\].", "\n\nWith these conflicting findings it is not surprising that guidelines published by expert panels vary with respect to PSA screening for prostate cancer, i.e., while some groups recommend screening, others are opposed to the practice \\[[@B7],[@B10]\\]. ", "Although expert panels disagree on whether or not to recommend PSA screening, most recommend that prior to undergoing screening for prostate cancer, men should be informed of the risks and benefits of early disease detection \\[[@B7]\\]. ", "Only after receiving such information should PSA screening be initiated.", "\n\nCA 125 in Screening for Ovarian Cancer {#sec2_3}\n--------------------------------------\n\nFor the past decade or so, 2 large prospective randomized trials have been evaluating the role of CA 125 and transvaginal ultrasound in screening for ovarian cancer \\[[@B11],[@B12]\\]. ", "One of these trials recently reported its findings \\[[@B13]\\]. ", "In this trial carried out in the USA, 78,216 women aged 55--74 years were randomized to undergo either annual screening with CA 125 for 6 years and transvaginal ultrasound for 4 years or standard care. ", "After 13 years of follow-up, death rates were similar in the screened and control groups. ", "Clearly, in this trial, screening with CA 125 and transvaginal ultrasound did not reduce ovarian cancer mortality \\[[@B13]\\]. ", "According to the EGTM guidelines, CA 125 either alone or in combination with other modalities cannot be recommended in screening for ovarian cancer in asymptomatic women outside the context of a randomized controlled trial \\[[@B14]\\].", "\n\nα-Fetoprotein in Hepatocellular Cancer {#sec2_4}\n--------------------------------------\n\nSubjects at increased risk of developing hepatocellular cancer (HCC) include those with cirrhosis due to infection with hepatitis B virus or hepatitis C virus, genetic hemochromatosis or biliary cirrhosis. ", "Guidelines published by expert panels differ in their recommendations regarding the use of α-fetoprotein (AFP) in screening for HCC. ", "Thus, the National Academy of Clinical Biochemistry USA (NACB) \\[[@B15]\\] state that, 'AFP should be measured and abdominal ultrasound performed at six-monthly intervals in patients at high risk of HCC, especially in those with hepatitis B and hepatitis C-related liver cirrhosis. ", "AFP concentrations that are \\>20 µg/l and showing consistent increases in concentration should prompt further investigation even if ultrasound is negative.' ", "On the other hand, the American Association for the Study of Liver Disease recommend that surveillance of high-risk subjects should be performed only with ultrasound. ", "According to this organization, AFP should only be used when ultrasound is not available. ", "This latter recommendation is based on the limited use of AFP in detecting early HCC.", "\n\nUse of Markers as Diagnostic Aids for Cancer {#sec1_3}\n============================================\n\nAs discussed above with screening, limited sensitivity for small or early cancers and lack of tumor specificity preclude the use of serum markers for the primary diagnosis of cancer. ", "In a limited number of situations, however, markers may aid in the differential of benign and malignant disease. ", "Thus, CA 125 is used as an adjunct in differentiating between benign and malignant pelvic masses in postmenopausal women \\[[@B14]\\]. ", "The EGTM recommend that CA 125 should be measured in postmenopausal women presenting with such masses. ", "According to this expert panel, patients with elevated levels (e.g. \\>35 U/l) should be considered for referral to a surgeon specialized in gynecological oncology surgery \\[[@B14]\\]. ", "This recommendation was based on studies showing superior outcome in patients with ovarian cancer if treated by a gynecological oncologist rather than by a general surgeon \\[[@B16]\\].", "\n\nAnother marker that may be helpful in cancer diagnosis is AFP in the detection of HCC. ", "According to the American Association for the Study of Liver Disease, finding a hepatic mass of \\>2 cm in diameter in a patient with a cirrhotic liver is highly suspicious of HCC. ", "If AFP is \\>200 µg/l and the radiological appearance is suggestive of HCC, the likelihood is that the lesion is HCC and biopsy is not essential \\[[@B17]\\]. ", "Similar recommendations have been published by the NACB \\[[@B15]\\]. ", "AFP, however, is of limited value in aiding the diagnosis of lesions \\<2 cm in diameter.", "\n\nUse of Markers in Assessing Prognosis {#sec1_4}\n=====================================\n\nPrognostic markers provide information on the likely outcome following diagnosis of a disease. ", "Such markers may help avoid undertreatment of patients with aggressive disease and overtreatment of those with indolent disease. ", "Prognostic markers are most important in cancers that vary widely in their outcome such as prostate and breast cancer. ", "In these cancers, prognostic markers may help identify those patients with aggressive disease that could benefit from additional therapies and simultaneously select those patients who may not require additional therapy.", "\n\nPrognostic markers are most widely used in breast cancer, especially in the subset with lymph node-negative disease. ", "In this subgroup of patients with breast cancer, prognostic markers help identify patients who may be spared the toxicity and side effects of adjuvant chemotherapy. ", "The 2 best validated prognostic markers for breast cancer are the Oncotype DX test and uPA/PAI1. ", "The Oncotype DX test measures the expression of 16 cancer-associated and 5 control genes by RT-PCR on RNA isolated from paraffin-embedded breast cancer tissue \\[[@B18]\\]. ", "This test is currently available from a commercial laboratory in the USA. ", "Although the Oncotype DX test is recommended by several expert panels including the American Society of Clinical Oncology (ASCO), NACB and EGTM \\[[@B10],[@B19],[@B20]\\], the test has not yet been validated in a large prospective randomized trial. ", "Such a study, however, is ongoing as part of the TAILORx trial.", "\n\nuPA and PAI-1 are the best validated prognostic markers in breast cancer, especially for patients with lymph node-negative disease \\[[@B21]\\]. ", "uPA is a protease that mediates invasion and metastasis. ", "Although PAI-1 normally functions as an endogenous inhibitor of uPA activity, at the high concentrations frequently present in tumors it appears, like uPA, to also play a role in cancer spread \\[[@B21]\\]. ", "Unlike any other marker in breast cancer, the prognostic impact of uPA and PAI-1 has been validated in both a multicenter randomized prospective trial and a pooled analysis of raw data from several small retrospective and a prospective study \\[[@B22],[@B23]\\], i.e., in 2 level I evidence studies.", "\n\nAs with Oncotype DX, measurement of uPA/PAI-1 is recommended by a number of expert panels \\[[@B10],[@B19],[@B20]\\]. ", "According to ASCO, 'uPA and PAI-1 may be used for the determination of prognosis in patients with newly diagnosed, node negative breast cancer. ", "Low levels of both markers are associated with a sufficiently low risk of recurrence, especially in hormone receptor-positive women who will receive adjuvant endocrine therapy, that chemotherapy will only contribute minimal additional benefit. ", "Furthermore, CMF-based adjuvant chemotherapy provides substantial benefit, compared with observation alone, in patients with high risk of recurrence as determined by high levels of uPA and PAI-1' \\[[@B19]\\]. ", "Other widely studied cancer prognostic markers are listed in table [2](#T2){ref-type=\"table\"}.", "\n\nTherapy-Predictive Markers in Cancer {#sec1_5}\n====================================\n\nAs mentioned above, therapy-predictive markers are factors that prospectively identify likely response or resistance to a specific treatment. ", "Predictive markers are important in cancer patient management as patients with the same histological type of malignancy respond very differently to a specific drug. ", "Thus, response rates for patients with different types of advanced cancer to currently available systemic treatments vary from about 10 to \\>90% \\[[@B24]\\]. ", "Many of the newer biological therapies, in particular, have efficacy in only a minority of patients. ", "This finding, when combined with the high costs of these drugs \\[[@B25]\\], illustrates the importance of having accurate predictive markers.", "\n\nAs well as assessing efficacy, predictive markers may also be able to identify optimum drug dose and predict toxicity. ", "Thus, measurement of predictive markers can increase drug efficacy and result in decreased toxicity. ", "This, in turn, should reduce overall health care costs and lead to an enhanced quality of life for patients \\[[@B26]\\].", "\n\nAs with prognostic markers, predictive markers are most developed for breast cancer. ", "Thus, in breast cancer, measurement of estrogen receptors and progesterone receptors is universally used to identify patients for treatment with hormone therapy (tamoxifen or aromatase inhibitor), while the assay of human epidermal growth factor receptor 2 is routinely used to select patients for treatment with trastuzumab (Herceptin) or lapatinib \\[[@B27]\\]. ", "Newly introduced predictive markers include mutant KRAS status for identifying responsiveness to anti-epidermal growth factor receptor antibodies (cetuximab and panitumumab) in advanced CRC and epidermal growth factor receptor mutation status for selecting patients with advanced non-small cell lung cancer for treatment with anti-epidermal growth factor receptor kinases (gefitinib and erlotinib) \\[[@B27]\\].", "\n\nUse of Markers in Surveillance following Initial Treatment for Cancer {#sec1_6}\n=====================================================================\n\nOne of the most frequent uses of tumor markers at present is in the postoperative follow-up of patients following a diagnosis of malignancy (table [3](#T3){ref-type=\"table\"}). ", "In several situations, serial levels of cancer markers can predict the presence of early recurrent/metastatic disease, i.e., provide a lead time over clinical or radiological findings. ", "It is assumed that the early detection of recurrent/metastatic disease followed by the initiation of treatment enhances the chance of cure or results in an improved survival \\[[@B2]\\]. ", "For some cancer types, however, the evidence currently available does not support this widely held assumption. ", "Indeed, the value of makers in postoperative surveillance may vary from cancer to cancer. ", "Below, I discuss the usefulness of markers in surveillance following the diagnosis of different cancers.", "\n\nCarcinoembryonic Antigen in CRC {#sec2_5}\n-------------------------------\n\nMultiple studies have shown that following curative surgery for CRC, patients undergoing an intensive surveillance regime that included regular carcinoembryonic antigen (CEA) measurements had a significantly better outcome than those undergoing surveillance without CEA testing \\[[@B28],[@B29]\\]. ", "Most expert panels in Europe and the USA therefore recommend serial measurements of CEA following curative surgery for CRC \\[[@B10],[@B30],[@B31],[@B32]\\]. ", "According to the EGTM, 'CRC patients with stage II and III (Dukes' B and C) CRC that may be candidates for either liver resection or systemic treatment in the event of recurrence in that organ, should have CEA measured every 2 to 3 months for at least 3 years after diagnosis' \\[[@B30],[@B31]\\]. ", "Although serial measurements of CEA are widely recommended as part of a surveillance regime, agreement is lacking as to the extent of concentration change that constitutes a clinically significant increase in marker levels. ", "According to the EGTM group \\[[@B30]\\], 'a significant increase in CEA levels occurs if the elevation is at least 30% over that of the previous concentration'. ", "This organization also states that prior to initiating therapy, any increase must be confirmed by a second sample taken within approximately 1 month. ", "If the second sample is also increased, the patient should undergo further investigations such as imaging \\[[@B30]\\].", "\n\nAFP and Human Chorionic Gonadotrophin in Patients with Germ Cell Tumors {#sec2_6}\n-----------------------------------------------------------------------\n\nTwo main histological types of germ cell tumors exist, seminoma and non-seminoma. ", "The use of AFP and human chorionic gonadotrophin (HCG) in monitoring patients with the non-seminomatous type germ cell tumors of the testis is often regarded as approximating the ideal use of tumor markers \\[[@B2]\\]. ", "This is because these 2 markers are sensitive indicators of germ cell disease status, i.e., whether disease is stable, progressing or regressing. ", "A further reason why these markers are particularly helpful in patients with germ cell tumors is that these malignancies are highly chemosensitive. ", "Indeed, it is now widely accepted that following orchidectomy for non-seminomatous testicular germ cell tumors, increasing AFP or HCG levels in the absence of radiological or clinical evidence of disease suggests active disease and may provide sufficient reassurance to initiate treatment, provided likely causes of false-positive marker levels can be eliminated \\[[@B2]\\].", "\n\nAccording to the ASCO guidelines, AFP and HCG should be assayed during surveillance following definite therapy for non-seminomatous germ cell tumors, regardless of stage \\[[@B33]\\]. ", "These measurements may be carried out every 1--2 months in the first year, every 2--4 months in the second year, every 3--6 months in the third and fourth years, every 6 months in the fifth year and annually thereafter. ", "Surveillance should be continued for at least 10 years after therapy is completed. ", "For monitoring patients with pure seminoma, HCG and/or LDH are generally recommended \\[[@B33]\\].", "\n\nCA 125 in Patients with Ovarian Cancer {#sec2_7}\n--------------------------------------\n\nThe clinical value of serial determination of CA 125 in post-therapy monitoring of patients with a history of ovarian cancer is unclear. ", "Although regular measurement of the marker may detect early recurrences with a median lead time of 4--5 months \\[[@B34]\\], a recently completed prospective randomized trial found no survival benefit from starting early treatment based on a rising serum CA 125 level \\[[@B35]\\]. ", "This trial involved 1,442 women previously diagnosed with ovarian cancer but in clinical remission. ", "CA 125 levels were measured every 3 months, but the results were not made available to patients or their doctors. ", "The women were randomized when their marker concentrations reached twice the upper limit of the normal range, to receive treatment immediately or to continue with blinded CA 125 determinations. ", "In this latter situation, women underwent treatment only when there was clinical evidence of recurrence. ", "Despite the earlier introduction of second-line chemotherapy, no significant difference in overall survival was found in the 2 groups. ", "This negative finding may relate, at least in part, to the lack of effective therapy for recurrent ovarian cancer.", "\n\nUncertainties therefore exist with respect to the value of CA 125 measurement and timing of treatment for relapsed ovarian cancer. ", "Although the NACB panel currently recommends serial measurement of CA 125 following surgery and initial systemic therapy for ovarian cancer \\[[@B10]\\], the EGTM panel is opposed to this practice \\[[@B14]\\]. ", "With such conflicting recommendations, a practical way forward may be to take the patients' wishes into consideration.", "\n\nPSA in Prostate Cancer {#sec2_8}\n----------------------\n\nIrrespective of whether men with diagnosed prostate cancer undergo active treatment (e.g. with radical prostatectomy, radiotherapy or brachytherapy) or active surveillance, regular monitoring with PSA is now commonly carried out \\[[@B36]\\]. ", "Following successful radical prostatectomy, PSA levels should decline to undetectable levels. ", "A subsequent increase to ≥0.2 µg/l is defined as biochemical recurrence \\[[@B37]\\]. ", "Generally, decreases in PSA levels following radiation therapy are less than those following radical prostatectomy. ", "A rise in PSA levels of ≥2 µg/l over and above the nadir value has been proposed as a definition of radiation therapy failure \\[[@B38]\\]. ", "It is still unclear whether the introduction of salvage therapy based on these definitions of PSA recurrence enhances patient outcome or quality of life.", "\n\nCA 15-3 in Breast Cancer {#sec2_9}\n------------------------\n\nThe most widely used marker in surveillance following a diagnosis of breast cancer is CA 15-3 \\[[@B39]\\]. ", "Although widely used in some countries for this purpose, it is unclear whether serial measurement improves patient outcome. ", "Consequently, guidelines vary with respect to their recommendations on the use of CA 15-3 in monitoring asymptomatic women following a diagnosis of breast cancer. ", "While expert panels such as ASCO recommend against routing use of CA 15-3 in surveillance in the surveillance of breast cancer patients \\[[@B19]\\], EGTM endorses its measurement in this setting \\[[@B20]\\]. ", "According to the NACB guidelines \\[[@B10]\\], 'CA 15-3 should not be routinely used for the early detection of recurrences/metastases in patients with diagnosed breast cancer. ", "However, as some patients, as well as some doctors, may wish to have these measurements, the ultimate decision on whether or not to use CA 15-3 must be taken by the doctor in consultation with the patient.'", "\n\nMonitoring Systemic Therapy {#sec1_7}\n===========================\n\nAnother frequent use of tumor markers is in monitoring patients with advanced cancer receiving systemic therapy (table [3](#T3){ref-type=\"table\"}) \\[[@B1],[@B2],[@B10]\\]. ", "The markers used in monitoring therapy in a specific malignancy are the same as those measured in postoperative surveillance (see above). ", "Generally, decreasing levels of markers following the initiation of therapy correlates with tumor regression and increasing levels predict progressive disease. ", "Tumor markers, however, should not be used alone in assessing response to therapy.", "\n\nA caveat in the use of markers in monitoring therapy in patients with advanced malignancy is the possible occurrence of transient increases or spikes within the first few weeks of administering therapy. ", "These transient increases appear to be due to tumor cell necrosis or apoptosis in response to the initial treatment with chemotherapy. ", "Such transient increases have not yet been reported with biological therapies such as therapeutic antibodies (e.g. Herceptin, cetuximab or panitumumab).", "\n\nConclusion {#sec1_8}\n==========\n\nFrom above, it is clear that certain tumor markers are mandatory in the management of patients with certain types of cancer. ", "Indeed, in some situations, markers can be used as the sole criterion for clinical decision making. ", "This applies particularly for therapy-predictive markers such as estrogen receptor and human epidermal growth factor receptor 2 in breast cancer. ", "Another good example is the use of HCG and AFP in therapy decision making in patients with diagnosed non-seminomatous germ cell tumors. ", "In other situations, however, the value of markers is less clear, for example, the role of PSA in screening for prostate cancer, assay of CA 125 following surgery and chemotherapy for ovarian cancer and assay of CA 15-3 in the surveillance of patients following the diagnosis of breast cancer. ", "Hopefully, future studies will provide definite answers on the use of these markers, in the near future. ", "New procedures for measuring tumor markers in the future are likely to focus on gene expression microarray, proteomics and detection of circulating tumor cells.", "\n\nThe authors wish to thank Science Foundation Ireland, Strategic Research Cluster Award (08/SRC/B1410) to Molecular Therapeutics for Cancer Ireland.", "\n\n###### \n\nBiomarkers that have undergone or are currently under-going evaluation in screening asymptomatic subjects for cancer\n\n Marker or test Malignancy\n ---------------- -------------------------------------------------\n FOBT colorectal\n PSA prostate\n CA 125 ovarian\n VMA/HVA neuroblastoma\n AFP hepatocellular[^1^](#T1F1){ref-type=\"table-fn\"}\n Pepsinogen gastric[^1^](#T1F1){ref-type=\"table-fn\"}\n HCG trophoblastic[^2^](#T1F2){ref-type=\"table-fn\"}\n\nVMA = Vanillylmandelic acid; HVA = homovanillic acid.", "\n\nOnly in high-risk areas/high-risk subjects.", "\n\nIn patients who have had a previous hydatidiform mole.", "\n\n###### \n\nMarkers that may be used for determining prognosis in different cancers\n\n Cancer Marker(s)\n ------------ ------------------------\n Breast Oncotype DX, uPA/PAI-1\n Germ cell AFP, HCG, LDH\n Colorectal CEA, MSI\n Prostate PSA\n Ovarian CA 125\n\nLDH = Lactate dehydrogenase; MSI = microsatellite instability.", "\n\n###### \n\nSerum markers that may be used in postoperative surveillance and monitoring therapy in different cancers\n\n Cancer Marker(s)\n -------------------------- -----------------\n Colorectal CEA\n Hepatocellular AFP\n Pancreatic CA 19-9\n Ovarian CA 125\n Breast CA 15-3\n Prostate PSA\n Germ cell AFP, HCG\n Lung (non-small cell) CYFRA 21-1, SCC\n Lung (small cell) NSE, proGRP\n Melanoma S100\n Trophoblastic HCG\n Thyroid (differentiated) thyroglobulin\n\nSCC = Squamous cell carcinoma; NSE = neuron-specific enolase.", "\n" ]

{ "pile_set_name": "PubMed Central" }

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[ "Jarl Öhman\n\nJarl (\"Lali\") Öhman (14 November 1891 in Helsinki – 20 January 1936 in Kokkola) was a Finnish amateur football player who competed in the 1912 Summer Olympics.", "\n\nHe was a part of the Finnish football team squad, which finished fourth in the football event. ", "He participated in all four matches in the main tournament and scored two goals.", "\n\nHe was also the first manager of the Finland national football team.", "\n\nCategory:1891 births\nCategory:1936 deaths\nCategory:Association football forwards\nCategory:Finnish footballers\nCategory:Finland international footballers\nCategory:Finland national football team managers\nCategory:Vaasan Palloseura players\nCategory:Footballers at the 1912 Summer Olympics\nCategory:Olympic footballers of Finland\nCategory:Sportspeople from Helsinki\nCategory:Finnish football managers" ]

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[ "India’s Q1 solar power production surges 103%\n\nMay 4 (Renewables Now) - Solar photovoltaic (PV) parks in India generated 8.54 billion kWh of electricity in the first quarter of 2018, registering a 103% year-on-year jump, Mercom Capital Group said on Friday.", "\n\nSolar power production was also 31% higher as compared to the fourth quarter of last year, which saw generation of over 6.5 billion kWh, the consultancy said, citing data from India’s Central Electricity Authority (CEA). ", "The growth was achieved on the back of rising solar capacity additions.", "\n\nAccording to Mercom’s India Solar Project Tracker, the cumulative installed solar power capacity in India at the end of January was 20 GW, while at the end of March it exceeded 22 GW. ", "First-quarter capacity deployments surged due to the commissioning of several large-scale PV parks that could not secure grid-connection last year.", "\n\nFor 2018, Mercom previously projected that India will put on stream 7 GW of fresh PV capacity, expecting the market to be affected by the rising prices of Chinese PV modules, certain infrastructure and power evacuation issues and the renegotiation of power purchase agreements (PPAs) terms in line with the record-low level of solar tariffs." ]

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[ "An experimental geneticist looks at catecholamine metabolism.", "\nThe contributions of genetic variation, including that at unstable and duplicated loci, interactions between alleles at different loci and genotype-environment interaction to observable phenotypic variation in experimental animals are discussed with particular reference to catecholamine metabolism. ", "The possibilities and complexities involved in extrapolating to human populations, and to behavioural consequences of biochemical variation, are outlined." ]

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[ "Q:\n\nargs4j: How to make an argument required if another argument is/isn't given?", "\n\n@Options(name=\"--in-file\")\nString fileName;\n\n@Option(name=\"--table\")\nString table;\n\nI would like to make the --table option be required if and only if no value is given for --in-file. ", "How might I go about doing this? ", "I know that there are some solutions (I think at least) where I can do this with multiple classes, but that seems like overkill for only two arguments in a simple program. ", "\nI know I can also manually check the values after the parsing is completed, but that seems to defeat the purpose of using args4j.", "\n\nA:\n\nI realized I can use the forbids annotation option to most of accomplish this. ", "You only need the tag on one or the other, but I put it on both for completeness.", "\nUsing forbids\n@Options(name=\"--in-file\", forbids{\"--table\"})\nString fileName;\n\n@Option(name=\"--table\", forbids={\"--in-file\"})\nString table;\n\nOne could use the depends annotation for reverse logic.", "\n\nWhy the above is not complete:\nThe above is only partially correct: the solution still fails if you want one of the options to be required if another isn't given. ", "The required part overrules the forbids, so doing\n@Options(name=\"--in-file\", forbids{\"--table\"})\nString fileName;\n\n@Option(name=\"--table\", required=true, forbids={\"--in-file\"})\nString table;\n\ncauses a logic error in that if I give --in-file it tries to forbid --table but it can't because --table is required.", "\nSo, the original solution fails because it allows the user to give neither option, even though I want --table' to be required, if and only if --in-file` is not given. ", "So, basically, my original question.", "\nSo\n\nA:\n\nYou can use forbids as you mentioned. ", "\n@Options(name=\"--in-file\", forbids{\"--table\"})\nString fileName;\n\n@Option(name=\"--table\", forbids={\"--in-file\"})\nString table;\n\nAnd you can add check-condition in your class.", "\nif (fileName == null && table == null) {\n throw new CmdLineException();\n}\n\nYou can set exception message same with message shown when required option set.", "\n\n" ]

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[ "Obsession with the customer drives Amazon success\n\nThis video is probably pretty old now judging by the look of Jeff Bezos, the founder of Amazon.com. ", "However, it does bring to light something that is fast becoming the most important criteria to success in the global economy today.", "\n\nLooking at Amazon’s rise to success seems rapid and overnight, but like any successful venture, there is significant amount of foundation that is unseen to make it happen. ", "My Amazon account dates back to 1995 when I was an undergraduate in the US and it seemed like a novel way to buy books. ", "No more driving twenty miles to Borders bookstore in sub-zero temperatures, snow and all just to get my favorite book. ", "Let the UPS or FedEx driver brave the elements instead! ", "Fast forward 25 years years since Amazon started, and the company is basically selling everything literally A to Z, but more importantly, it is also growing its technology portfolio of cloud, AI, smart assistant and other service offerings.", "\n\nWatch the video attached here. ", "The reporter seems to focus only on whether Amazon.com was a pure Internet play. ", "I suppose, with the hindsight of the dotcom bubble, it’s easy to to laugh at this reporter but at that time, everything internet was the rage. ", "I like how Bezos continuously deflects the questions back to the customer. ", "Whether the company was a pure internet play, or whether the investors are concerned. ", "It is about obsessive attention to the customer experience – end to end. ", "And the last line is the best : There is never any misalignment between customer interest and shareholder interest.", "\n\nSo, let’s start today with an obsessive attention to the customer experience." ]

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[ "Sneak Peek | Inside Out Magazine's Colour (April) Issue!", "\n\nInside Out Mag sent over a bundle of colourful pixels from their new \"Colour Issue\" (April edition) out this Thursday for a sneak peek! ", "The latest issue features a heap of palette-flirting throughout the whole magazine and Managing Editor, Lee Tran Lam gives us the details:\n\n\"The cover story is all about getting playful with colour – and how you don't have to do anything too dramatic (or regret-inducing!) ", "at home, but you can sneak in new tones in a friendly way; for instance, add a band of lilac to wrap around your room, or an ocean-like splash to a white wall – or just drop a bright trim on your kitchen window or colour-match the mood of an artwork in your bedroom, as you can see in these photos styled by Julia Green and photographed by Armelle Habib.\"", "\n\nPhoto styled by Julia Green and photographed by Armelle Habib\n\nPhoto styled by Julia Green and photographed by Armelle Habib\n\nPhoto styled by Julia Green and photographed by Armelle Habib\n\n\"Another fun story in the magazine is our feature on the home of stylist and international pilot (yes, that's right!) ", "LeeAnn Yare. ", "Her Auckland home is as worldly and vibrant as her border-crossing work itinerary. ", "There's not a single dull patch in her house – the kitchen bench is covered in harlequin-patterned colours while her office is a wild patchwork of her favourite wallpapers. \"", "This is where I admit I have really gone crazy with an explosion of colour – it's like working inside a giant moodboard!\" ", "she says. ", "I love how unapologeticaly vivid and over-detailed her place is!\"", "\n\n~Lee Tran Lam\nManaging Editor, Inside Out Magazine\n\nStyling Leeanne Yare | Photo Larnie Nicolson\n\nStyling Leeanne Yare | Photo Larnie Nicolson\n\nStyling Leeanne Yare | Photo Larnie Nicolson\n\nStyling Leeanne Yare | Photo Larnie Nicolson\n\nThank you Lee Tran! ", "The April issue of Inside Out Magazine is out Thursday and is available at newsagents or digitally via Zinio, Google Play, iTunes & Nook." ]

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[ "(1) Field of the Invention\n(2) Description of Related Art Including Information Disclosed Under 37 CFR 1.97 and 1.98\nThe disclosure and prior art relates to garden hose's and more particularly pertains to a new garden hose support for supporting a garden hose above a ground surface." ]

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[ "Dutch budget clothing store Zeeman plans to open 100 new outlets this year, most of them outside the Benelux region.", "\n\nThe retailer currently operates 1,236 stores across Europe, 550 of which are in the Netherlands and 279 in Belgium. ", "CEO Bart Karis told Belgian business daily De Tijd his company wants to expand further into other markets, ‘because we’re pretty much done with new stores in Belgium and the Netherlands’.", "\n\n‘Do we want to become a European chain? ", "We already are,’ said Karis, whose company also has outlets in Germany, Luxembourg and France.", "\n\nThe CEO said he saw his main competition coming from other cut-price retailers such as Primark. ‘", "Primark does indeed offer more fashionable clothing for low prices. ", "We sell more timeless clothing. ", "And yes, when a Primark opens up near a Zeeman we feel it.’", "\n\nZeeman scored an internet hit on Tuesday morning when it launched a wedding dress for €30. ", "The first batch of 1,500 garments was sold out within hours of going on sale at 6am." ]

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[ "Psychosocial factors influencing risk-taking in middle age for STIs.", "\nTo increase the knowledge of the psychosocial factors influencing sexual risk-taking for STIs among adults in late middle age. ", "Individual interviews were conducted either face to face or by telephone with 31 heterosexual men and women aged between 45 and 65. ", "They were recruited from NHS sexual health services (n=16) and council run culture and leisure facilities (n=15) in a large Scottish city. ", "A total of 18 women and 13 men were interviewed. ", "All interviews were transcribed in full and thematically analysed. ", "Analysis detailed important psychosocial and sociocultural factors; the prioritisation of intimacy above and beyond concerns about risks for STI in sexual partnerships; the importance of unwanted pregnancy in shaping risk perceptions throughout the life course; vulnerability associated with periods of relationship transition (eg, bereavement, divorce or separation); social norms and cultural expectations relating to age-appropriate sexual and health-seeking behaviours. ", "This is the first qualitative study to examine the factors associated with sexual risk-taking among heterosexual adults in late middle age in the UK. ", "Many factors associated with sexual risk-taking are similar to those reported within other populations. ", "However, we also detail population-specific factors, which should be considered in terms of the development of interventions for 'at risk' older adults, or the tailoring of wider behaviour change interventions to this specific age group." ]

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[ "Germany's 65-year-old former finance minister won 93.45 percent support from the Social Democrats (SPD), officially naming him as the party's man to challenge Angela Merkel in the next federal election, likely to take place in September. ", "Earlier in the week, Merkel won a similar Christian Democrat vote by an even clearer margin, claiming over 98 percent of her party's support.", "\n\nPrior to his election, Steinbrück - who had already been announced as candidate in waiting - delivered a combative 105-minute speech to the party at its conference in Hanover.", "\n\n\"I am running for the office of chancellor of the Federal Republic of Germany,\" Steinbrück said, telling his allies \"we owe it to this country to once again provide a Social Democratic chancellor.\"", "\n\nWatch video 01:06 Social Democrats place hopes in Steinbrück\n\nHe called the ruling Christian Democrats - who are comfortably the most popular single German party in opinion polls - a \"power machine.\"", "\n\n\"But retaining power is not the central target in politics,\" Steinbrück said, saying that Chancellor Merkel would too often speak in \"popcorn sentences\" - phrases that could be interpreted in many ways and offered little concrete substance.", "\n\n\"With Frau Merkel, many things remain vague - and that's not without its dangers,\" Steinbrück said.", "\n\nA Green or a Grand coalition?", "\n\nJudging by public broadcaster ARD's most recent opinion polls, a change in German government is currently likely at the next elections - but what shape that might take is unclear. ", "Merkel's junior coalition partners are in freefall, meaning that the current alliance with the pro-business Free Democrats looks unlikely to survive.", "\n\nSome say the most likely constellation would be a so-called \"grand coalition;\" an alliance between the Christian Democrats and the Social Democrats. ", "Steinbrück served as finance minister in such a government, but said he did not want to see it repeated.", "\n\nCalling for \"a full change in government,\" not half measures, Steinbrück told delegates \"the answer as to how this could work is quite obvious: red-green.\"", "\n\nThe SPD's party color is red, and its closest ally in opposition currently is the ecologist Green Party. ", "Combined, the two parties are six percent shy of the 50-percent level of support they would need to form a government. ", "Even though the SPD trails the Christian Democrats by nine percent, the combined pair are polling one-percent more strongly than the current coalition government.", "\n\nWith neither the natural left or right coalitions currently on course to win a majority, Steinbrück also urged his Social Democrats to stay unified during the election campaign to improve their standings.", "\n\n\"If we march side-by-side, then we will manage it,\" he told the delegates.", "\n\nmsh/pfd (AFP, dpa, Reuters)" ]

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[ "UPDATE (July 27, 2018):\n\nOn Thursday, a judge sentenced Perry Brown, Jr., of Elkton, to ten years in jail, with eight of those years suspended.", "\n\nBrown was accused of breaking into a home on 17th Street in Grottoes and assaulting two people in the house while wielding a handgun, sending Cotey Mitts, a 23-year-old Elkton man, to UVA Medical Center for treatment.", "\n\nIn fall of 2017, he was charged with felony attempted murder, felony malicious wounding, felony shooting into an occupied dwelling, felony assault and battery, and felony use of a firearm in the commission of a felony, in addition to breaking and entering.", "\n\nA school in the area was locked down as investigation happened, and police began a manhunt ending with Brown's arrest hours later.", "\n\nBut, through a plea deal, the only charge he was ultimately found guilty of was malicious discharge of a firearm into an occupied building.", "\n\nHis five additional felony charges were each dropped.", "\n\nThe eight years suspended from his jail time were given to Brown in probation instead.", "\n\nHowever, on July 27, he faced a probation violation hearing, which resulted in a 5-year sentence.", "\n\n________\n\nUPDATE (2:40 p.m. Sept. 14, 2017):\n\nPerry Brown Jr., the suspect in a Grottoes shooting that led to a school lockdown and manhunt last month, now faces additional charges.", "\n\nBrown was previously charged with breaking and entering, assault and battery, and possession of a firearm by a convicted felon.", "\n\nHe is now also charged with felony attempted murder, felony malicious wounding, felony shooting into an occupied dwelling and felony use of a firearm in the commission of a felony.", "\n\nHe is believed to have broken into a home on 17th Street in Grottoes and assaulted two people in the house while wielding a handgun, sending Cotey Mitts, a 23-year-old Elkton man, to UVA Medical Center for treatment.", "\n\n_____\n\nUPDATE (1:31 p.m. Sept. 1, 2017):\n\nThe Rockingham County Sheriff tells WHSV Perry Brown Jr. has been charged with breaking and entering, assault and battery, and possession of a firearm by a convicted felon. ", "Other charges are pending.", "\n\nHe is currently being held at the Rockingham County jail without bond.", "\n\n_____\n\nUPDATE (10:52 p.m. Aug. 31, 2017):\n\nAccording to Rockingham County Sheriff Bryan Hutcheson, the suspect was taken into custody. ", "WHSV has learned Perry Brown Jr. was arrested without incident at the Harris Garden Apartments in Harrisonburg on Thursday night.", "\n\n_____\n\nUPDATE (3:50 p.m. Aug. 31, 2017):\n\nFollowing a reported shooting Thursday morning in Grottoes, police are asking for the public's help to find the suspect involved.", "\n\nAccording to Rockingham County Sheriff Bryan Hutcheson, police are searching for Perry Brown, Jr., a 23-year-old Elkton man.", "\n\nAt about 10:30 a.m., the Rockingham County Sheriff's Office and the Grottoes Police Department responded to a call for a reported shooting in the 200 block of 17th Street, where Brown allegedly broke into a home with a handgun and assaulted a male and female inside at the time.", "\n\nThe incident occurred a few blocks from South River Elementary School, which led the school to be placed on a modified lockdown.", "\n\nAccording to the initial report, a loud noise sounded like a gun being fired in the home, which led police to describe the scene as a shooting investigation.", "\n\nHowever, the female in the home was assaulted without the use of any weapon. ", "The man, though, was airlifted from the scene to UVA Medcal Center with non-life threatening injuries. ", "Police did not confirm if the injuries he received were from a gunshot wound. ", "The woman suffered minor injuries and was not taken from the home.", "\n\nThe male victim has been identified as Cotey Mitts, a 23-year-old also from Elkton.", "\n\nThe sheriff's office says brown may be driving a blue 4-door Hyundai sedan, with license plate VUZ-7019.", "\n\nHe has multiple charges pending against him and has been previously arrested. ", "The mugshot above is from a prior arrest.", "\n\nAnyone with information is encouraged to contact the Crimesolvers hotline at 574-5050 or the Rockingham County Sheriff’s Office at 564-3800.", "\n\nNeighbors were shocked when they heard the first responders outside. ", "They say it is a quiet area to live in and events like this do not usually happen.", "\n\n\"You would expect something like this to happen in the city, or something like that... not a quiet suburban neighborhood,\" said Cynthia Reeves who lives next door to the victims.", "\n\n_____\n\nA shooting investigation is underway in the Town of Grottoes, resulting in the lockdown of two elementary schools.", "\n\nDeputies with the Rockingham County Sheriff's Office were on scene at 208 17th Street, which isn't far off of Dogwood Avenue, after a shooting that allegedly happened in the area around 11 a.m.\n\nNeighbors told WHSV's Marina Barnett they heard a woman screaming \"Get out of here\" before seeing a man speed down the home's driveway and flee.", "\n\nThe person believed to have been shot was taken from the scene in an ambulance to a spot where they could be picked up by AirCare and transported to UVA Medical Center. ", "Police on scene said the individual is expected to be alright.", "\n\nSouth River Elementary School, which is located just a few blocks away, was placed on modified lockdown due to what Rockingham County Public Schools Superintendent Dr. Oskar Scheikl called \"an incident in the area.\" ", "Parents of students at Elkton Elementary School also reported that school was placed on lockdown as well.", "\n\nDeputies were at South River as a precaution, but the superintendent stresses there was no incident at the school.", "\n\nNeighbors in the area said they were shocked by what had happened, because it's always been such a quiet neighborhood.", "\n\nInvestigation continues, and the Grottoes Police Department told WHSV they will be unable to talk for some time.", "\n\nStay with WHSV for updates." ]

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[ "The Korea Baseball Organization announced on Wednesday that Japan's Nippon Professional Baseball has requested a status check on Samsung Lions' closer Oh Seung-hwa n.\n\nThe KBO notified the Japanese that Oh still officially plays for Samsung Lions and that the team is willing to negotiate a transfer deal.", "\n\nThe Hanshin Tigers in the NPB's Central League are believed to be interested in acquiring Oh. ", "Japan's Sports Hochi reported that the two sides are close to hammering out a deal.", "\n\n" ]

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[ "Background\n==========\n\nThe key to effective chemotherapy responses in cancer is the presence of the Fas receptor (CD95, Apo-1), a member of the tumor necrosis factor superfamily of cell death receptors \\[[@B1]\\]. ", "These receptors form trimers in the plasma membrane and, upon the binding of their respective ligands, activate the initiator caspase-8 through the recruitment of adaptor proteins (FADD and/or TRADD) to the receptors' death domains. ", "In type I apoptosis, the activated caspase-8 directly activates executioner caspases. ", "In type II apoptosis, caspase-8 cleaves Bid triggering permeabilization of the mitochondrial outer membrane, cytochrome C release, and propagation of the apoptotic signal downstream of the cascade \\[[@B1]\\].", "\n\nMany studies suggest that drug-induced apoptosis occurs through Fas signaling; thus, defective Fas signaling could be responsible for the resistance to chemotherapy that is frequently observed in cancers \\[[@B2]-[@B5]\\]. ", "Several studies have shown that the Fas-mediated cell-death pathway is altered in malignant hematological cells \\[[@B6],[@B7]\\], which can be viewed as one of the mechanisms of resistance to chemotherapy. ", "The CD44 isoforms v6 and v9, hepatocyte growth factor receptor/Met (HGFR/Met), and HHV-8 oncoprotein K1 have been shown to bind to Fas and regulate its activity \\[[@B8]-[@B11]\\]. ", "Therefore, treatments targeting these Fas regulators in cancer cells could be an effective strategy to increase sensitivity to Fas-mediated apoptosis and to chemotherapy.", "\n\nLymphomas occur frequently in association with infectious agents such as the Epstein-Barr virus, human immunodeficiency virus, or HHV-8 \\[[@B12],[@B13]\\]. ", "We have shown that the HHV-8-derived K1 protein interacts with Fas and blocks apoptosis \\[[@B8],[@B10]\\]. ", "In the current study, we investigated whether peptides derived from the Ig-like domain of the K1 protein could alter K1-Fas interaction and, consequently, apoptosis in lymphoma cells. ", "For this purpose, we treated K1-expressing cells as well as B-cell lymphoma and T-lymphoblastic leukemia cells with peptides corresponding to the Ig-like domain of K1, followed by cell death analysis. ", "Our results show that the K1-derived S20-3 peptide kills lymphoma and leukemia cells *in vitro* and *in vivo* by a mechanism dependent on Fas and/or TNF-α receptors.", "\n\nMethods\n=======\n\nCells\n-----\n\nHuman lymphoblastoma cell lines BJAB, Daudi; HHV-8-positive primary effusion lymphoma-derived B-cell lines BC-3, BCBL-1, KS-1; human T-lymphoblastic cell line Jurkat (all from ATCC, Manassas, VA), a caspase-8-- and FADD--deficient Jurkat cell lines (I9.2 and I2.1) (donated by Dr. J. Chandra, The University of Texas MD Anderson Cancer Center) were grown in RPMI 1640 medium supplemented with 10% FBS (both from Mediatech, Herndon, VA) and maintained in a 5% CO~2~ atmosphere at 37°C. ", "The 293T cells (ATCC) were cultured in Dulbecco's modified Eagle\\'s medium (DMEM) (Mediatech) supplemented with 10% FBS. ", "Collection of blood samples was in accordance with approved MD Anderson Cancer Center protocol. ", "Peripheral blood mononuclear cells (PBMCs) from healthy volunteers were isolated from heparinized venous blood by density gradient centrifugation and used immediately in the experiments. ", "BJAB cells stably expressing K1 (BJABK1) were described previously \\[[@B8],[@B10]\\].", "\n\nPeptide synthesis\n-----------------\n\nPeptides were chemically synthesized by multiple peptide solid-phase synthesis (New England Peptide, Gardner, MA, and Celtek Bioscience, Nashville, TN). ", "All peptides were purified to \\>95% purity by high-performance liquid chromatography. ", "Peptide stocks (10 mM) were prepared in dimethyl sulfoxide (DMSO) (Thermo Fisher, Waltham, MA), and aliquots were stored at −20°C.", "\n\nApoptosis analysis\n------------------\n\nApoptosis analysis was performed using the FITC AnnexinV Apoptosis Detection Kit I, according to the manufacturer's protocol (BD Biosciences, San Jose, CA). ", "Cells were re-suspended in serum-free medium (1 × 10^6^/mL) and treated with either 100 μM peptide alone or combined with 20 μM z-VAD (BD Biosciences) for 1 hour, or pretreated for 15 minutes with the peptide and combined with 200 ng/mL of recombinant soluble Fas ligand (FasL) (Alexis, San Diego, CA) for the indicated times. ", "Subsequently, cells were washed, re-suspended in a binding buffer containing AnnexinV-FITC and propidium iodide (PI), and analyzed by flow cytometry (FACSCalibur; Beckman-Coulter, Brea, CA) after 15 minutes of incubation.", "\n\nCaspase activity assay\n----------------------\n\nThe activities of caspase-8, -9, and -3 were determined by flow cytometry using the CaspGLOW^TM^ Fluorescein Active Caspase Staining Kit (BioVision, Mountain View, CA), according to the specifications of the manufacturer. ", "Briefly, 1 × 10^6^ cells were seeded in serum-free medium and treated with 100 μM S20-3 peptide for 1 hour. ", "Cells were then washed, cultured in medium containing 10% FBS for 3 hours, and, subsequently, incubated with 1 μl of FITC-IETD-FMK (for caspase-8 activity), FITC-LEHD-FMK (for caspase-9 activity), or FITC-DEVD-FMK (for caspase-3 activity) for 60 minutes at 37°C. ", "Cells were washed twice and analyzed by flow cytometry.", "\n\nImmunoblotting\n--------------\n\nThe cells (10 × 10^6^) were resuspended in 1 mL of lysis buffer (Cell Signaling Technology, Beverly, MA) supplemented with protease inhibitors (Roche), and incubated 1 hour on ice. ", "One hundred micrograms of each extract were separated on 10% SDS-polyacrylamide gels (Bio-Rad Laboratories, Hercules, CA) and transferred to nitrocellulose membranes (Whatman Schleicher & Schuell, Keene, NH). ", "Membranes were blocked at room temperature for 1 hour in blocking buffer (5% nonfat dry milk, 0.1% Tween-20 in PBS). ", "Separated proteins were analyzed by Western blot with anti-GAPDH (1:1000, Santa Cruz Biotechnology, Santa Cruz, CA; loading control), anti-TNFRI and anti-TNFRII antibodies (1:1000, both kind gifts from Dr. B. B. Aggarwal, MD Anderson Cancer Center) overnight at 4°C. ", "Blots were washed and then incubated with either anti-mouse (Santa Cruz Biotechnology) or anti-rabbit (Cell Signaling Technology) horseradish peroxidase-conjugated antibody (1:5000). ", "The signal was visualized by chemiluminescence Western blot kit (PerkinElmer, Waltham, MA) and exposure to film (Amersham, Piscataway, NJ).", "\n\nLDH assay\n---------\n\nCells (1 × 10^6^) were pre-incubated for 1 hour with 5 μg/mL of TNFRI or TNFRII blocking antibodies (both from R&D Systems, Minneapolis, MN) at 37°C and then treated with TNF-α (10 ng/mL) (Life Technologies - Gibco, Carlsbad, CA) or the peptide S20-3 (100 μM) for 1 hour. ", "After treatment, the growth medium was removed and stored at −20°C. ", "An LDH assay was performed according to the manufacturer\\'s protocol (BioVision). ", "Standard media were used as blank controls; \"high control\" corresponds to the sample of cells treated with lysis solution. ", "Results were normalized to control cells, and the percentage of necrotic cells was calculated using the following formula: % cytotoxicity = \\[(treated-- control)/(high control-- control)\\] × 100.", "\n\n*In vivo* tumor growth assay\n----------------------------\n\nAll animal studies were conducted according to protocols approved by MD Anderson Cancer Center's Institutional Animal Care and Use Committee. ", "Jurkat cells (5 × 10^6^ per injection) were re-suspended in sterile PBS and subcutaneously injected into the right flank of 5-week-old CB17/SCID mice (Harlan Laboratories, Indianapolis, IN). ", "When xenograft tumors reached 100 mm^3^, the mice were given a single intratumoral injection of peptides (33.9 mg/kg): S20-3, TCR, or vehicle; 4 mice each. ", "The mice were killed 8 days after injection, and the tumor tissue was harvested. ", "Tumor width (W) and length (L) were measured by calipers, and size was calculated using the formula W^2^× L/2. ", "The tumoricidal activity was evaluated by comparison of tumor size among groups.", "\n\nStatistical analysis\n--------------------\n\nThe 2-tailed Student's *t* test was used to estimate the statistical significance of the differences between results from triplicate samples or experiments, and the results are expressed as mean values ± standard deviations or standard errors, respectively. ", "The level of significance was set at *P* \\< 0.05.", "\n\nResults\n=======\n\nS20-3 peptide induces cell death of BJABK1 cells\n------------------------------------------------\n\nOur previous studies demonstrated that wild-type K1, but not a truncated K1 with the Ig-like domain deleted, binds to Fas and prevents Fas activation by FasL or by an agonistic Fas antibody \\[[@B8],[@B10]\\]. ", "To further elucidate K1-mediated regulation of Fas, we designed peptides derived from the Ig-like domain of K1 (Table [1](#T1){ref-type=\"table\"}), targeting the K1 binding site on the Fas receptor.", "\n\n###### \n\nProtein sequence of the Ig-like domain of human herpesvirus 8 K1 protein and derived peptides\n\n      \n ---------------- -------------------------------- ----------------------------------------------\n K1 Ig-domain   HSLWITWYPQPVLQTLCGQPSNTVTCGQYVTLYCSTSGNYVTVW\n K1 peptides    \n 20 amino acids S20-1 HSLWITWYPQPVLQTLCGQP (84--103)\n S20-2 PVLQTLCGQPSNTVTCGQYV (94--113) \n   S20-3 SNTVTCGQYVTLYCSTSGNYV (104--124)\n 10 amino acids S10-1 SNTVTCGQYV (104--113)\n   S10-2 TVTCGQYVTL (106--115)\n 8 amino acids S8-1 TVTCGQYV (106--113)\n   S8-2 VTLYCSTS (113--120)\n\nWe first investigated whether K1 peptides could sensitize the Burkitt's lymphoma cell line BJAB stably expressing K1 (BJABK1) to Fas-mediated apoptosis. ", "Cells were treated with 100 μM peptide in combination with 200 ng/mL of FasL for 24 hours, followed by analysis of apoptosis by flow cytometry. ", "The combination of S20-3 and S10-1 peptides with FasL showed a significant (2.2- and 2.5-fold, respectively) increase in cell death compared with FasL alone (Figure [1](#F1){ref-type=\"fig\"}A). ", "No significant differences in apoptosis rates were seen with FasL in combination with other K1-derived peptides shown in Table [1](#T1){ref-type=\"table\"} (20--1, 20--2, S10-2, S8-1, S8-2).", "\n\n{#F1}\n\nIn the control experiment, BJABK1 cells were treated with 100 μM peptides or buffer for 1 hour, and apoptosis was evaluated 24 hours after treatment by flow cytometry. ", "Surprisingly, two of the longest overlapping peptides (S20-2 and S20-3) individually induced a significant (1.9- and 2.4-fold, respectively) increase in apoptotic cell death in the BJABK1 cells compared with buffer control (Figure [1](#F1){ref-type=\"fig\"}B). ", "None of the other peptides overlapping the 20-amino acid sequence of the peptide S20-3 (Table [1](#T1){ref-type=\"table\"}) showed a significant apoptotic effect.", "\n\nThe S20-3 peptide showed a reproducible, dose-dependent increase in apoptotic cell death (up to 40% at 100 μM) as early as 4 hours after treatment, while the control peptide S8-2 was ineffective at all tested concentrations (Figure [1](#F1){ref-type=\"fig\"}C). ", "Further studies were performed to understand the underlying mechanism for the induction of cell death by the S20-3 peptide.", "\n\nThe proper control for the peptide activity would have been a scrambled S20-3-derived peptide. ", "However, we encountered difficulty obtaining reasonable quantities of any S20-3-derived scrambled peptide of desired purity (\\>95%), suitable for the experiments. ", "One possibility was to use inactive 20-mer peptide S20-1 as a negative control, but this peptide does not share any residues with the active S20-3 peptide. ", "Based on the results in Figure [1](#F1){ref-type=\"fig\"}A and B, the S8-2 peptide, which overlaps part of S20-3 peptide, was included as negative control reagent in subsequent studies.", "\n\nThe S20-3 peptide activates caspases and triggers apoptosis in BJABK1 cells\n---------------------------------------------------------------------------\n\nStimulation of the Fas death receptor results in the recruitment of the adaptor protein, FADD, and activation of caspase-8, which initiates propagation of the death signal down the caspase cascade \\[[@B14],[@B15]\\]. ", "To determine the involvement of caspase-8, -9, and -3 in the cell death induced by the S20-3peptide, we used caspase-specific fluorescently-tagged substrates to monitor caspase activation. ", "In the BJABK1 cells, exposure to S20-3 significantly (*P* \\< 0.01) increased the activity of all caspases tested: caspase-8 (39.6% vs. 3.7%), caspase-9 (78.3% vs. 7.4%) and caspase-3 (75.2% vs. 10.2%) (Figure [1](#F1){ref-type=\"fig\"}D). ", "These findings indicate the role of the caspase-8--initiated apoptotic pathway in S20-3 peptide-induced cell death. ", "The control S8-2 peptide showed no effect on caspases' activity (Figure [1](#F1){ref-type=\"fig\"}D).", "\n\nAnother important feature of apoptosis is a decrease of the mitochondrial membrane potential (Ψm) \\[[@B16]\\]. ", "Changes in the Ψm in cells exposed to peptides S20-3 and S8-2, or the agonistic Fas antibody CH-11 as positive control, were measured by staining with tetramethylrhodamine ethyl ester (TMRE). ", "A decreased TMRE signal corresponding to decreased membrane potential was observed in a significant number of S20-3 peptide-treated (20%) and CH-11--treated (22%) cells as early as 4 hours after treatment, relative to treatment with buffer or the control S8-2 peptide (Additional file [1](#S1){ref-type=\"supplementary-material\"}: Figure S1).", "\n\nThe S20-3 peptide is effective against various hematological cancer cell lines\n------------------------------------------------------------------------------\n\nWe further investigated whether the S20-3 peptide would be effective in inducing cell death in HHV-8--positive cancer cell lines (KS-1, BC-3, BCBL-1), which have been shown to express K1 \\[[@B10]\\]. ", "All HHV-8--infected cell lines tested were sensitive to the S20-3 peptide, which induced death in about 20--35% of cells, whereas no significant effect on cell death was detected with the S8-2 control peptide (Figure [2](#F2){ref-type=\"fig\"}A).", "\n\n{#F2}\n\nTo evaluate whether the peptides were able to modulate the interaction between Fas and K1, 293T cells were transiently transfected with the vector expressing Flag-tagged K1 protein, lysed, and subjected to co-immunoprecipitation analysis used previously to show a direct physical interaction of Fas with K1 \\[[@B8]\\]. ", "We observed that K1-Fas interaction was not disrupted by incubation of cells with the S20-3 or other K1-derived peptides with the exception of the shorter peptide S10-1 (Additional file [1](#S1){ref-type=\"supplementary-material\"}: Figure S2).", "\n\nThe lack of S20-3 peptide's effect on the K1-Fas interaction suggested a possible cell-killing mechanism independent of K1. ", "To confirm this hypothesis, we tested the peptide's ability to kill K1-negative cell lines. ", "The S20-3 peptide was able to induce significant levels of cell death in K1-negative BJAB cells (30%) and in the T-cell leukemia Jurkat cell line (25%) (Figure [2](#F2){ref-type=\"fig\"}B). ", "Quite surprisingly, the S20-3 peptide was equally effective in killing Daudi cells (35%), which express low levels of Fas on the cell surface and are considered Fas-resistant \\[[@B17]\\].", "\n\nIn contrast, human PBMCs from healthy donors, treated with S20-3 peptide, showed no significant amount of cell death (Figure [2](#F2){ref-type=\"fig\"}C). ", "Overall, S20-3 peptide treatment induced a 4.6 ± 1.6% increase in cell death in 3 PBMC control samples from different donors, whereas the same treatment induced a 23.8 ± 5.7% increase in death of Jurkat cells. ", "These results suggest that the S20-3 peptide derived from the HHV-8 K1 protein selectively induces cell death in malignant hematological cells, but is not toxic to normal human cells.", "\n\nThe S20-3 peptide kills cells in the absence of the Fas receptor\n----------------------------------------------------------------\n\nTo investigate whether S20-3--induced apoptosis depends on the signaling of the Fas receptor, we tested the S20-3 peptide in Fas-resistant Jurkat cell lines I2.1 and I9.2, which have defective FADD and caspase-8 functions, respectively \\[[@B18]\\]. ", "The S20-3 peptide induced slightly less cell death in I2.1 cells than in the wild type Jurkat cells (21% vs. 24% above control; Figure [3](#F3){ref-type=\"fig\"}A). ", "The response of caspase-8 function-defective Jurkat cell line I9.2 to the S20-3 peptide was significantly blunted compared with that of wild-type Jurkat cells (14.4% vs. 24% above control; 60% reduction) but not completely eliminated (Figure [3](#F3){ref-type=\"fig\"}A). ", "In line with this result, we found that the pan-caspase inhibitor z-VAD also only partially blocked S20-3-induced death in BJAB cells (8.9% vs. 13.3% above control; 67% reduction) (Figure [3](#F3){ref-type=\"fig\"}B) as well as apoptosis induced by the Fas-agonistic antibody CH-11 (14% vs. 29% above control; 48% reduction) (data not shown).", "\n\n{#F3}\n\nFurther examination of the cell death induced by the S20-3 peptide in Daudi cells revealed that the S20-3 peptide induced necrosis (33.7% PI--positive cells) rather than apoptosis (0.3% AnnexinV--positive/PI--negative cells) in Fas-resistant Daudi cells (Figure [3](#F3){ref-type=\"fig\"}C and Additional file [1](#S1){ref-type=\"supplementary-material\"}: Figure S3A), and z-VAD further enhanced this effect (41.1% PI--positive cells) (Figure [3](#F3){ref-type=\"fig\"}C). ", "An LDH release assay further confirmed that the S20-3 peptide was causing necrosis as early as 1 hour post treatment (Additional file [1](#S1){ref-type=\"supplementary-material\"}: Figure S3B).", "\n\nCell killing by the S20-3 peptide involves TNF-α receptors\n----------------------------------------------------------\n\nThe fact that the S20-3 peptide induced necrosis of Fas-resistant Daudi cells, together with the observed rapid kinetics of cell killing (significant cell death at 4 hours), pointed to the possibility that the S20-3 peptide is promiscuous and interacts not only with Fas, but it may also engage one of the closely related death receptors sharing a significant structural similarity \\[[@B19]\\]. ", "Such promiscuity is not unprecedented. ", "For example, IFN-α--treated Daudi cells upregulate expression of TNF-α and Fas. ", "Produced TNF-α then activates the closely related Fas receptor \\[[@B20]\\]. ", "Based on these facts, we hypothesized that a peptide designed to bind Fas receptor may also interact with and affect the TNF receptor.", "\n\nWe first evaluated the expression levels of TNFRI and TNFRII in BJAB, Jurkat, and Daudi cells and found that all 3 cell lines expressed TNFRI, but only BJAB and Daudi cells expressed detectable levels of TNFRII (Figure [4](#F4){ref-type=\"fig\"}A). ", "We next evaluated the effect of TNFR-blocking antibodies on necrosis induced by TNF-α or S20-3 peptide by measuring LDH release as early as 1 hour after treatment to evaluate necrosis/necroptosis rather than post-apoptotic secondary necrosis \\[[@B21]\\]. ", "Figure [4](#F4){ref-type=\"fig\"}B clearly shows that pre-incubation of Daudi cells with the TNFRI blocking antibody decreased TNF-α and S20-3 peptide induced necrosis/necroptosis, while the TNFRII-blocking antibody showed a rather enhanced killing. ", "The latter finding is consistent with the inhibition of pro-survival signaling mediated by TNFRII \\[[@B22]\\] by the blocking antibody. ", "These results suggest that, besides Fas, TNFRI is also targeted by S20-3. ", "We then tested the effect of TNFRI-blocking antibody on peptide-induced necroptosis in TNFRI-positive BJABK1 and BJAB cells. ", "In both cell lines, the TNFRI-blocking antibody significantly decreased death induced by TNF-α and S20-3 peptide (Figure [4](#F4){ref-type=\"fig\"}C). ", "However, the TNFRI-blocking antibody-mediated inhibition of cell-killing was more prominent in BJABK1 cells, where the S20-3 peptide binding to Fas is blocked by K1 (a lack of displacement of K1 from Fas by S20-3 peptide; Additional file [1](#S1){ref-type=\"supplementary-material\"}: Figure S2). ", "Thus, in this case, the peptide acts primarily on TNFRI. ", "On the other hand, TNFRI-blocking antibody affected cytotoxicity of TNF-α and S20-3 peptide to a lesser extent in BJAB cells, consistent with the availability of Fas for peptide S20-3 binding in the absence of K1 and, thus, for primary peptide signaling effects.", "\n\n![**", "The S20-3 peptide--induced cell death involves TNFRI.** (**", "A**) Immunoblot analysis of total cellular levels of TNF receptors I and II in BJAB, Jurkat, and Daudi cells. ", "Numbers represent expression levels relative to GAPDH (loading control). (**", "B**) Daudi cells were pre-incubated for 1 hour with 5 μg/mL of TNFRI- or TNFRII-blocking antibodies, followed by 1 hour of treatment with 5 ng/mL of TNF-α or 100 μM peptide S20-3, and immediately analyzed for necrosis by LDH release assay. (**", "C**) BJABK1 cells (left panel) and BJAB cells (right panel) were pre-incubated for 1 hour with 5 μg/mL of TNFRI-blocking antibody, subsequently treated with 100 μM peptide S20-3 or 5 ng/mL of TNF-α for 1 hour, and analyzed as in (**B**). ", "The relative cytotoxicity values in (**B**) and (**C**) were calculated as LDH release in \\[(treated-control)/(high control-control)\\]x100 and are shown as means ± SD of triplicate wells; \\**P* \\< 0.005, \\*\\**P* \\< 0.02.](1756-9966-31-69-4){#F4}\n\nThe S20-3 peptide corresponds to the Ig-like domain of K1 and shares the conserved residues with other Ig-like domains (Figure [5](#F5){ref-type=\"fig\"}A). ", "To further explore structure-related promiscuity, we tested a 20--amino acid peptide derived from the Ig-like domain of the human T-cell receptor (TCR) (Figure [5](#F5){ref-type=\"fig\"}A), homologous to the peptide S20-3 from K1. ", "Both peptides share 5amino acid residues common to the Ig-like domains and exhibit high hydrophobicity. ", "The TCR peptide showed 60--80% of the cell death-inducing activity of the S20-3 peptide in 3 independent experiments (Figure [5](#F5){ref-type=\"fig\"}C), further underscoring a mechanism involving possible structural promiscuity of peptides and/or receptors.", "\n\n*)*. (**", "C**) Jurkat cells were treated with 100 μM peptides (S20-3, TCR) or buffer for 1 hour and, subsequently, incubated in complete medium for 24 hours. ", "Cell killing was analyzed by flow cytometry, and background death (buffer) was subtracted. ", "Values are presented as the means of the percentage of activity relative to the activity of S20-3 ± SE from 3 independent experiments. (**", "D**) Flanks of SCID mice were injected with 5 × 10^6^ Jurkat cells. ", "Two weeks later, tumors were injected with a single dose of S20-3, TCR peptide, or vehicle (DMSO) in 50 μL of saline (4 mice each). ", "Eight days after treatment, mice were killed and the tumors were harvested and measured. ", "Tumor measurements are reported as means ± SD; \\**P* \\< 0.05.](1756-9966-31-69-5){#F5}\n\nInhibition of tumor growth by the S20-3 peptide in a xenograft model\n--------------------------------------------------------------------\n\nThe SCID mice injected subcutaneously with Jurkat cells developed solid tumors at the inoculation site. ", "Using this model, we tested the ability of the peptide S20-3 to alter growth of xenograft tumors*.* ", "Mice received a single intratumoral injection of vehicle, S20-3, or TCR peptide. ", "Treatment with the S20-3 peptide resulted in a modest but significant (*P* \\< 0.05) suppression of tumor growth 8 days after injection compared with vehicle control (Figure [5](#F5){ref-type=\"fig\"}D). ", "In line with our *in vitro* results, the TCR peptide showed a smaller suppressive effect on tumor growth, without statistical significance. ", "Importantly, the mice treated with the peptides did not exhibit signs of toxicity, such as agitation or impaired movement and posture. ", "These results support intratumoral administration of the S20-3 peptide as a potentially safe approach for inducing significant inhibition of xenograft tumor growth.", "\n\nDiscussion\n==========\n\nIn this report, we present evidence showing that the peptide S20-3, corresponding to the Ig-like domain of the Fas-targeting K1 protein of HHV-8, selectively kills hematological cancer cells, and the mechanism involves the Fas and TNFRI receptors. ", "The cell-killing effect appears to be selective for cancer cells *in vitro. ", "In vivo,* even a single intratumoral dose of peptide was active against the growth of xenograft tumors.", "\n\nFrom the array of K1 Ig-like domain peptides tested (Table [1](#T1){ref-type=\"table\"}), only the S20-3 peptide demonstrated strong and reproducible cell-killing activity (Figure [1](#F1){ref-type=\"fig\"} and Figure [2](#F2){ref-type=\"fig\"}) in all 6 hematological cell lines tested but not in PBMC controls (Figure [2](#F2){ref-type=\"fig\"}). ", "While it is not clear as to why S20-3, and also less reproducibly S20-2, but not other K1 Ig-like domain-derived peptides, possess cell-killing activity, the structural features of the predicted Ig-domain (Figure [5](#F5){ref-type=\"fig\"}B) reveal a unique feature of the S20-3 peptide; a loop (centered at conserved glycine residue) linking 2 beta sheets, which are predicted to be destabilized or absent in the rest of peptides tested (Table [1](#T1){ref-type=\"table\"}). ", "A truncated version of the S20-3 peptide, S10-1, representing the first beta sheet and the loop (Figure [5](#F5){ref-type=\"fig\"}B), as well as S8-2 peptide, representing the second beta sheet (Figure [5](#F5){ref-type=\"fig\"}B), lack cell killing properties (Figure [1](#F1){ref-type=\"fig\"}B). ", "On the other hand, a TCR-derived peptide sharing 5 structure-defining residues with S20-3 (Figure [5](#F5){ref-type=\"fig\"}A) also showed cell-killing effect (Figure [5](#F5){ref-type=\"fig\"}C), suggesting that the biological effect of S20-3 is related to its structure.", "\n\nA seemingly contradictory effect of the whole Ig-like domain in K1 protein and S20-3 peptide on Fas signaling may also be explained by the structure-function relationship. ", "The fact that peptide S10-1, but not S20-3 or any other K1 peptide, was able to disrupt the K1-Fas complex (Additional file [1](#S1){ref-type=\"supplementary-material\"}: Figure S2) suggests that first beta sheet is involved in K1-Fas interaction. ", "This is further supported by the fact that peptide S10-2, lacking 3 residues from the first beta sheet, failed to displace K1 (Additional file [1](#S1){ref-type=\"supplementary-material\"}: Figure S2) and did not show any enhancement of FasL activity (Figure [1](#F1){ref-type=\"fig\"}A). ", "Additionally, peptide S20-2, which also contains S10-1 residues, showed cell-killing properties similar to peptide S20-3, but with reduced reproducibility, suggesting that the second beta sheet in peptide S20-3 increases structural stability of the peptide and the additional residues, preceding (S20-2) or following (S20-3) S10-1 region, affect peptide behavior. ", "Taking all this into account, we hypothesize that the smaller size and possible flexibility of the loop within S10-1peptide as compared to S20-3 peptide (Figure [5](#F5){ref-type=\"fig\"}B) allow access of this peptide to the K1 binding site and, thus, displacement of K1 from Fas (Additional file [1](#S1){ref-type=\"supplementary-material\"}: Figure S2). ", "The second beta sheet in the S20-3 peptide stabilizes the loop, but at the same time, it decreases loop flexibility and increases bulkiness of the peptide, limiting its access to the K1 binding site in the presence of the K1 protein.", "\n\nThis hypothesis also helps explain the differential effects of the K1 Ig-like domain, S10-1, and S20-3 on Fas receptor activation. ", "The S10-1 sequence within the Ig-like domain in the whole K1 protein is flanked by additional domains of K1 protein. ", "Assuming the S10-1 region within K1 is exposed and available to bind Fas, the limitations of the movement imposed by surrounding K1 domains \"lock\" the Fas receptor in the closed conformation, preventing binding of FasL described previously \\[[@B8]\\]. ", "On the other hand, the beta sheet and flexible loop in the S10-1 peptide can also bind the receptor, but without the rigidity of surrounding structures, its binding does not affect receptor conformation. ", "Therefore, the S10-1 peptide has no direct effect on the receptor on its own, but sensitizes K1-positive cells to FasL (Figure [1](#F1){ref-type=\"fig\"}A) by displacing the K1 protein (Additional file [1](#S1){ref-type=\"supplementary-material\"}: Figure S2). ", "The S20-3 peptide, more rigid and bulkier that S10-1peptide, can bind Fas only in the absence of K1. ", "Without the flanking domains of the K1 protein and the whole Ig-like domain, S20-3 (and S20-2) can bind Fas receptor similarly to S10-1, but the presence of additional residues/structures induces conformational change mimicking the active state of the receptor.", "\n\nThe extrinsic apoptotic pathway involves activation of death receptors, recruitment of FADD, cleavage of pro-caspase-8, activation of caspases\\' cascade, and a drop in mitochondrial membrane potential \\[[@B1]\\]. ", "While the precise target for the cell-killing activity of the S20-3 peptide is unclear, data presented here clearly show that the peptide activates caspase-8, -9, and -3 (Figure [1](#F1){ref-type=\"fig\"}D) and decreases mitochondrial membrane potential (Additional file [1](#S1){ref-type=\"supplementary-material\"}: Figure S1), suggesting involvement of a death receptor, such as Fas. ", "However, a conventional dose of the pancaspase inhibitor z-VAD blocked cell killing only incompletely (Figure [3](#F3){ref-type=\"fig\"}B), and Jurkat cells with mutated inactive caspase-8 or dominant-negative FADD also showed only partial blockage of S20-3--induced cell-killing (Figure [3](#F3){ref-type=\"fig\"}A), despite their inability to form the death-inducing signaling complex (DISC) \\[[@B23]\\]. ", "This persistence of the S20-3 peptide to kill mutant Jurkat cells (Figure [3](#F3){ref-type=\"fig\"}A), the killing of Daudi cells that are considered Fas-resistant \\[[@B17],[@B24]\\], the increase of necrotic death in the z-VAD-treated Daudi cells (Figure [3](#F3){ref-type=\"fig\"}C and Additional file [1](#S1){ref-type=\"supplementary-material\"}: Figure S3A), and their relatively fast killing \\[necrotic cell death in Daudi cells was detectable 1 hour after peptide exposure (Additional file [1](#S1){ref-type=\"supplementary-material\"}: Figure S3)\\] suggested to us that S20-3 also activates a TNF receptor.", "\n\nEven though Fas belongs to the TNF receptor family and shares a significant structural similarity with TNFR \\[[@B19]\\], the outcomes of activating these receptors can be quite different \\[[@B25]\\]. ", "For example, activation of Fas receptor in L929 cells triggers apoptosis, whereas activation of TNFR triggers necrosis \\[[@B26]\\]. ", "Owing to the structural similarity, TNF-α is able to also bind and activate the Fas receptor \\[[@B20]\\]. ", "We, thus, investigated the possibility that, because of the structural promiscuity (further supported by the killing properties of a structurally related TCR peptide), the S20-3 peptide designed to bind the Fas receptor may also bind TNFR and trigger necrosis. ", "We detected TNFRI expression in BJAB, Jurkat, and Daudi cells (Figure [3](#F3){ref-type=\"fig\"}), and the TNFRI-blocking antibody significantly inhibited S20-3-- and TNF-α--induced cell killing in all 3 cell lines (Figure [4](#F4){ref-type=\"fig\"}B and C). ", "On the contrary, the TNFRII-blocking antibody showed no inhibitory effect on the S20-3 cell-killing of TNFRII-positive Daudi cells (Figure [4](#F4){ref-type=\"fig\"}B). ", "This finding is not surprising considering the fact that activation of TNFRII triggers pro-survival signaling in hematological cancer cells \\[[@B22]\\], and activation of TNFRI is required for any death signaling from TNFRII due to the lack of a death domain in TNFRII \\[[@B27]\\].", "\n\nOur results with FADD-- and caspase-8--defective Jurkat cells are in agreement with the reports showing that under apoptosis-deficient conditions (such as non-functional caspase-8 or FADD), stimulation with FasL or TNF-α could induce cell death with morphological features of necrosis/necroptosis \\[[@B21],[@B28],[@B29]\\]. ", "Furthermore, lack of FADD, but not of caspase-8, was shown to sensitize Jurkat cells to TNF-α--induced necrosis \\[[@B30]\\]. ", "Smac mimetic BV6 enhanced TNF-induced cell death in leukemia cells in 2 different ways: necroptosis, when the cells were apoptosis resistant (FADD-- and caspase-8--deficient), and caspase-8--dependent apoptosis in apoptosis-proficient cells \\[[@B31]\\].", "\n\nWe hypothesize that the different death pathways can be activated in response to S20-3 treatment in Jurkat, Daudi, and BJAB cells, depending on the availability of and sensitivity to Fas and TNFRs. ", "Another possibility is a cross talk between signaling events from TNF and Fas receptors, as reported by Takada et al., ", "in which TNFRI is recruited by Fas to induce apoptosis \\[[@B32]\\].", "\n\nAn additional important observation is that the S20-3 peptide activity seemed to be specific to malignant cells; leukemia T cells displayed a much greater sensitivity to S20-3 than nonmalignant cells (Figure [2](#F2){ref-type=\"fig\"}C). ", "While the constitutive expression of TNF receptors was clearly demonstrated in most tumor cells, in normal peripheral lymphocytes, the expression of TNF receptors is subjected to a positive and negative regulation and can be induced by different stimuli \\[[@B33],[@B34]\\]. ", "However, normal unstimulated PBMCs express very low amounts of mRNAs for TNFRII \\> TNFRI \\> Fas \\[[@B35]\\], and normal lymphocytes were shown to be resistant to stimulation with activating antibodies targeting TNFRI, TNFRII, or Fas \\[[@B36]\\]. ", "Thus, our findings of cancer-specific killing by the S20-3 peptide are in agreement with these reports.", "\n\nConclusions\n===========\n\nThis is the first report where a peptide derived from the Ig-like domain of the virus-encoded protein effectively induces cell death, specifically in human lymphoma and leukemia cells with minimal toxicity to normal PBMCs and, thus, may expose a novel alternative to conventional chemotherapy, which may also be applied to other cancer types.", "\n\nCompeting interests\n===================\n\nThe authors declare that they have no competing interests.", "\n\nAuthors' contributions\n======================\n\nUD performed peptide experiments testing responses of Fas and wrote the manuscript; CK performed experiments testing responses of TNF receptors and wrote the manuscript; RHT, JW, XA performed mouse experiments and edited the manuscript; ZB and FS designed the experiments and wrote the manuscript. ", "All authors read and approved the final manuscript.", "\n\nSupplementary Material\n======================\n\n###### Additional file 1\n\nMethods.", "\n\n###### \n\nClick here for file\n\nAcknowledgements\n================\n\nWe thank Dr. Chad C. Bjorklund for assistance with mouse experiments, Dr. Joya Chandra for help with the mitochondrial membrane permeability measurements, Dr. Jagannadha K. Sastry for his peptide expertise and help with preparation of this manuscript, Mrs. Angelique Harkins and Mrs. Frances Dressman for proofreading the manuscript. ", "This work was supported by grants from the American Cancer Society (118447-MRSG-10-052-01-LIB to ZB), the National Institutes of Health (CA1206173, CA153170, CA158692, and DK091490 to F.S.), and the Leukemia & Lymphoma Society (R6132-06 and R6187-09 to F.S.). ", "We also thank the Richard Spencer Lewis Foundation, patients and their families for their support and willingness to join us in our efforts in developing new therapies for lymphoma.", "\n" ]

{ "pile_set_name": "PubMed Central" }

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[ "January 20, 2011\n\nThe Yankees finally found their fourth outfielder today. ", "Andruw Jones, a five-time All-Star and 10-time Gold Glover, agreed to a $2 million deal which includes an additional $1.2 million in performance bonuses.", "\n\nAs a backup the past few seasons with the Dodgers, Rangers and White Sox, Jones isn’t getting many hits but he’s making them count when he does — 50.3 percent of his hits have gone for extra bases.", "\n\nPlus, as he’s done his entire career, he still mashes against southpaws — last season to the tune of .272/.380/.565." ]

{ "pile_set_name": "Pile-CC" }

[ 0.000856917817145586, 0.0006098583107814193, 0.0013033051509410143, 0.0018796998774632812 ]

[ "from abc import ABC, abstractclassmethod\nfrom threading import Thread\nfrom rx.subject import Subject\n\n\nclass WakeButton(ABC, Thread):\n\n def __init__(self):\n super().__init__()\n self.subject = Subject()\n\n @abstractclassmethod\n def run(self):\n pass\n\n def on_detected(self):\n self.subject.on_next(\"Hotword\")\n" ]

{ "pile_set_name": "Github" }

[ 0.0007937116897664964 ]

[ "Q:\n\nMy coding seems inefficient... Any way to speed it up?", "\n\nSo I tried this program which was supposed to find out what position these doors are in. ", "They start out closed, and then you toggle every door. ", "The next time you toggle every second, then every third, fourth, so on. ", "I got the coding right but it seems really inefficient. ", "If I tried this with larger numbers, then the program would take too long. ", "Is there any way to do this more efficiently? ", "Here is my coding:\n public class doors\n {\n public static void main(String [] args)\n {\n int x, y = 1;\n boolean [] doors = new boolean[100];\n for (int a = 0; a < doors.length; a++)\n doors[a] = false; //false means closed\n do\n {\n for (x = 0; x < doors.length - 1; x++)\n {\n if ((x+1) % y == 0)\n {\n if (doors[x] == true)\n doors[x] = false;\n else if (doors[x] == false)\n doors[x] = true;\n } \n }\n y++;\n }while (y <= doors.length);\n for (boolean b : doors)\n System.out.println(b);\n }\n}\n // Thanks!!!", "\n\nA:\n\nLet's simplify the code one step at a time.", "\n\n1) When an array is allocated, all elements are initialized to their default value, which means 0, false, or null. ", "In your case that means false, so no need to loop through and do that.", "\n// before\nboolean [] doors = new boolean[100];\nfor (int a = 0; a < doors.length; a++)\n doors[a] = false; //false means closed\n\n// after\nboolean[] doors = new boolean[100];\n\n2a) Since the array is not a zero-length array, the do-while loop might as well be a normal while loop (it will execute at least once).", "\n2b) As a normal while loop, with an initializer right before the loop, and the increment at the end of the loop, it is the same as a for loop.", "\n2c) Since y is not used after the loop, it can be declared in the loop.", "\n// before\nint x, y = 1;\ndo\n{\n //code\n y++;\n}while (y <= doors.length);\n\n// after\nint x;\nfor (int y = 1; y <= doors.length; y++)\n{\n //code\n}\n\n3a) doors[x] == true is the same as doors[x]. ", "doors[x] == false is the same as ! ", "doors[x].", "\n3b) if (x) {} else if (! ", "x) {} is the same as if (x) {} else {}. ", "The test after else is redundant.", "\n3c) if (x) x = false; else x = true; is the same as x = ! ", "x;.", "\n3d) You can skip the double evaluation by doing ^= true (XOR).", "\n// before\nif (doors[x] == true)\n doors[x] = false;\nelse if (doors[x] == false)\n doors[x] = true;\n\n// after\ndoors[x] = ! ", "doors[x];\n\n// skip double evaluation of index lookup\ndoors[x] ^= true;\n\n4a) (x+1) % y == 0 will only be true for x values of y-1, 2*y-1, 3*y-1, and so on, so make loop start at y-1 and increment by y, eliminating the need for the if statement.", "\n4c) Since x is not used after the loop, it can be declared in the loop.", "\n// before\nint x;\nfor (x = 0; x < doors.length - 1; x++)\n{\n if ((x+1) % y == 0)\n {\n //code\n }\n}\n\n// after\nfor (int x = y - 1; x < doors.length - 1; x += y)\n{\n //code\n}\n\nResult so far (after also removing unnecessary braces)\nboolean[] doors = new boolean[100];\nfor (int y = 1; y <= doors.length; y++)\n for (int x = y - 1; x < doors.length - 1; x += y)\n doors[x] ^= true;\nfor (boolean b : doors)\n System.out.println(b);\n\n5a) Limiting x to < doors.length - 1 means that last value of the array will never be used/updated. ", "Drop the - 1.", "\n// before\nfor (int x = y - 1; x < doors.length - 1; x += y)\n\n// after\nfor (int x = y - 1; x < doors.length; x += y)\n\n6a) Printing the array with one boolean true/false value per lines is not very human readable. ", "Print is as a binary number on one line.", "\n// before\nfor (boolean b : doors)\n System.out.println(b);\n\n// after\nfor (boolean b : doors)\n System.out.print(b ? '", "1' : '0');\nSystem.out.println();\n\n7a) Move the printing inside the outer loop, and you'll see an interesting pattern.", "\nboolean[] doors = new boolean[100];\nfor (int y = 1; y <= doors.length; y++) {\n for (int x = y - 1; x < doors.length; x += y)\n doors[x] ^= true;\n for (boolean b : doors)\n System.out.print(b ? '", "1' : '0');\n System.out.println();\n}\n\n1111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111\n1010101010101010101010101010101010101010101010101010101010101010101010101010101010101010101010101010\n1000111000111000111000111000111000111000111000111000111000111000111000111000111000111000111000111000\n1001111100101001111100101001111100101001111100101001111100101001111100101001111100101001111100101001\n1001011101101011111000100001101100001000111110101101110100111001011101101011111000100001101100001000\n1001001101111011101000110001111100011000101110111101100100101001001101111011101000110001111100011000\n1001000101111111101010110000111100111000111110110101100000101011001100111011001000100001110100011100\n1001000001111110101010100000111000111001111110100101100100101010001100101011001100100000110100001100\n1001000011111110111010100010111000101001111100100101110100101000001100111011001110100000100100001110\n1001000010111110111110100010101000101000111100100001110100111000001101111011001010100000110100001111\n1001000010011110111111100010101010101000111000100001111100111000011101111011101010100001110100001101\n1001000010001110111111110010101010111000111000110001111100101000011101101011101010110001110100011101\n1001000010000110111111110110101010111010111000110000111100101000111101101011111010110001111100011101\n1001000010000010111111110111101010111010101000110000111000101000111100101011111010100001111100011001\n1001000010000000111111110111111010111010101010110000111000111000111100101001111010100001101100011001\n1001000010000001111111110111111110111010101010100000111000111001111100101001111110100001101100001001\n1001000010000001011111110111111111111010101010100010111000111001111000101001111110101001101100001001\n1001000010000001001111110111111111101010101010100010101000111001111000111001111110101001111100001001\n1001000010000001000111110111111111101110101010100010101010111001111000111000111110101001111100101001\n1001000010000001000011110111111111101111101010100010101010101001111000111000111010101001111100101000\n1001000010000001000001110111111111101111111010100010101010101011111000111000111010111001111100101000\n1001000010000001000000110111111111101111111110100010101010101011101000111000111010111000111100101000\n1001000010000001000000010111111111101111111111100010101010101011101010111000111010111000111000101000\n1001000010000001000000000111111111101111111111110010101010101011101010101000111010111000111000111000\n1001000010000001000000001111111111101111111111110110101010101011101010101010111010111000111000111001\n1001000010000001000000001011111111101111111111110111101010101011101010101010101010111000111000111001\n1001000010000001000000001001111111101111111111110111111010101011101010101010101000111000111000111001\n1001000010000001000000001000111111101111111111110111111110101011101010101010101000101000111000111001\n1001000010000001000000001000011111101111111111110111111111101011101010101010101000101010111000111001\n1001000010000001000000001000001111101111111111110111111111111011101010101010101000101010101000111001\n1001000010000001000000001000000111101111111111110111111111111111101010101010101000101010101010111001\n1001000010000001000000001000000011101111111111110111111111111110101010101010101000101010101010101001\n1001000010000001000000001000000001101111111111110111111111111110111010101010101000101010101010101011\n1001000010000001000000001000000000101111111111110111111111111110111110101010101000101010101010101011\n1001000010000001000000001000000000001111111111110111111111111110111111101010101000101010101010101011\n1001000010000001000000001000000000011111111111110111111111111110111111111010101000101010101010101011\n1001000010000001000000001000000000010111111111110111111111111110111111111110101000101010101010101011\n1001000010000001000000001000000000010011111111110111111111111110111111111111101000101010101010101011\n1001000010000001000000001000000000010001111111110111111111111110111111111111111000101010101010101011\n1001000010000001000000001000000000010000111111110111111111111110111111111111111100101010101010101011\n1001000010000001000000001000000000010000011111110111111111111110111111111111111101101010101010101011\n1001000010000001000000001000000000010000001111110111111111111110111111111111111101111010101010101011\n1001000010000001000000001000000000010000000111110111111111111110111111111111111101111110101010101011\n1001000010000001000000001000000000010000000011110111111111111110111111111111111101111111101010101011\n1001000010000001000000001000000000010000000001110111111111111110111111111111111101111111111010101011\n1001000010000001000000001000000000010000000000110111111111111110111111111111111101111111111110101011\n1001000010000001000000001000000000010000000000010111111111111110111111111111111101111111111111101011\n1001000010000001000000001000000000010000000000000111111111111110111111111111111101111111111111111011\n1001000010000001000000001000000000010000000000001111111111111110111111111111111101111111111111111111\n1001000010000001000000001000000000010000000000001011111111111110111111111111111101111111111111111110\n1001000010000001000000001000000000010000000000001001111111111110111111111111111101111111111111111110\n1001000010000001000000001000000000010000000000001000111111111110111111111111111101111111111111111110\n1001000010000001000000001000000000010000000000001000011111111110111111111111111101111111111111111110\n1001000010000001000000001000000000010000000000001000001111111110111111111111111101111111111111111110\n1001000010000001000000001000000000010000000000001000000111111110111111111111111101111111111111111110\n1001000010000001000000001000000000010000000000001000000011111110111111111111111101111111111111111110\n1001000010000001000000001000000000010000000000001000000001111110111111111111111101111111111111111110\n1001000010000001000000001000000000010000000000001000000000111110111111111111111101111111111111111110\n1001000010000001000000001000000000010000000000001000000000011110111111111111111101111111111111111110\n1001000010000001000000001000000000010000000000001000000000001110111111111111111101111111111111111110\n1001000010000001000000001000000000010000000000001000000000000110111111111111111101111111111111111110\n1001000010000001000000001000000000010000000000001000000000000010111111111111111101111111111111111110\n1001000010000001000000001000000000010000000000001000000000000000111111111111111101111111111111111110\n1001000010000001000000001000000000010000000000001000000000000001111111111111111101111111111111111110\n1001000010000001000000001000000000010000000000001000000000000001011111111111111101111111111111111110\n1001000010000001000000001000000000010000000000001000000000000001001111111111111101111111111111111110\n1001000010000001000000001000000000010000000000001000000000000001000111111111111101111111111111111110\n1001000010000001000000001000000000010000000000001000000000000001000011111111111101111111111111111110\n1001000010000001000000001000000000010000000000001000000000000001000001111111111101111111111111111110\n1001000010000001000000001000000000010000000000001000000000000001000000111111111101111111111111111110\n1001000010000001000000001000000000010000000000001000000000000001000000011111111101111111111111111110\n1001000010000001000000001000000000010000000000001000000000000001000000001111111101111111111111111110\n1001000010000001000000001000000000010000000000001000000000000001000000000111111101111111111111111110\n1001000010000001000000001000000000010000000000001000000000000001000000000011111101111111111111111110\n1001000010000001000000001000000000010000000000001000000000000001000000000001111101111111111111111110\n1001000010000001000000001000000000010000000000001000000000000001000000000000111101111111111111111110\n1001000010000001000000001000000000010000000000001000000000000001000000000000011101111111111111111110\n1001000010000001000000001000000000010000000000001000000000000001000000000000001101111111111111111110\n1001000010000001000000001000000000010000000000001000000000000001000000000000000101111111111111111110\n1001000010000001000000001000000000010000000000001000000000000001000000000000000001111111111111111110\n1001000010000001000000001000000000010000000000001000000000000001000000000000000011111111111111111110\n1001000010000001000000001000000000010000000000001000000000000001000000000000000010111111111111111110\n1001000010000001000000001000000000010000000000001000000000000001000000000000000010011111111111111110\n1001000010000001000000001000000000010000000000001000000000000001000000000000000010001111111111111110\n1001000010000001000000001000000000010000000000001000000000000001000000000000000010000111111111111110\n1001000010000001000000001000000000010000000000001000000000000001000000000000000010000011111111111110\n1001000010000001000000001000000000010000000000001000000000000001000000000000000010000001111111111110\n1001000010000001000000001000000000010000000000001000000000000001000000000000000010000000111111111110\n1001000010000001000000001000000000010000000000001000000000000001000000000000000010000000011111111110\n1001000010000001000000001000000000010000000000001000000000000001000000000000000010000000001111111110\n1001000010000001000000001000000000010000000000001000000000000001000000000000000010000000000111111110\n1001000010000001000000001000000000010000000000001000000000000001000000000000000010000000000011111110\n1001000010000001000000001000000000010000000000001000000000000001000000000000000010000000000001111110\n1001000010000001000000001000000000010000000000001000000000000001000000000000000010000000000000111110\n1001000010000001000000001000000000010000000000001000000000000001000000000000000010000000000000011110\n1001000010000001000000001000000000010000000000001000000000000001000000000000000010000000000000001110\n1001000010000001000000001000000000010000000000001000000000000001000000000000000010000000000000000110\n1001000010000001000000001000000000010000000000001000000000000001000000000000000010000000000000000010\n1001000010000001000000001000000000010000000000001000000000000001000000000000000010000000000000000000\n1001000010000001000000001000000000010000000000001000000000000001000000000000000010000000000000000001\n\nNow, when you look at the pattern of the result (last line), you'll see that your code could be reduced to (very fast):\nboolean[] doors = new boolean[100];\nfor (int idx = 0, incr = 1; idx < doors.length; idx += (incr += 2))\n doors[idx] = true;\n//print here\n\n1001000010000001000000001000000000010000000000001000000000000001000000000000000010000000000000000001\n\n" ]

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[ "LONDON — These are salutary times for the English. ", "Their clubs have wealthy foreign backers, and their Premier League has just netted the biggest overseas television contract ever written, yet when Chelsea plays Manchester City in London on Sunday, they do so as European failures.", "\n\nChelsea’s Russian owner has responded by firing the coach yet again. ", "City’s Abu Dhabi benefactors have made no public announcement after that team — the English champion — went out in the first round of the Champions League for the second year in a row.", "\n\nLet’s try an experiment and for once not mention the extreme costs involved here. ", "Let’s acknowledge that the Spanish and the Germans, with all seven of their teams headed to the last 16, appear to have a better understanding of what it takes to win Europe’s big league than the British do at the moment.", "\n\nTo be fair, Chelsea could, still, squeak through if the results of the final group games go its way Dec. 5. ", "That will be no succor to Roberto Di Matteo, who was fired Wednesday to allow Rafael BenC-tez to be Chelsea’s ninth new coach since 2004.", "\n\nTo be fair to Manchester City, its group was by far the toughest anyone could draw in the first round. ", "Even so, with five games gone and not a single victory, City’s coach was asked the inevitable question following a 1-1 home tie Wednesday against Real Madrid.", "\n\nGiven what happened at Chelsea, does Mancini fear losing his job?", "\n\n“No,” was the Italian’s reply. “", "Why? ", "I don’t fear this. ", "If we think we can win a Champions League after two years, I think we are crazy.", "\n\n“The Champions League is strange, is difficult. ", "Probably we need to improve our team. ", "There are a lot of teams better than us in the Champions League.”", "\n\nHis side, he pointed out, goes into its game Sunday as leader of the Premier League. ", "But as he tries to rationalize the inexperience of his club in Europe, others point out that City has amassed a core of world-renowned figures.", "\n\nIn the words of Joe Hart, City’s goalie: “This has been a bad campaign for us. ", "We have surprised ourselves in a very, very bad way.”", "\n\nThe goalkeeper made no excuses, and the opposing coach on Wednesday, Jose Mourinho, offered no sympathy. “", "We knew before the start that in this group, a big team would go out,” he said.", "\n\n“And it’s good that it is City, because Roberto can work on without any problem,” Mourinho said, referring to Mancini. “", "If it was me, the press wouldn’t let me back in Madrid.”" ]

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[ "Oogenesis in the leech Glossiphonia heteroclita (Annelida, Hirudinea, Glossiphonidae). ", "I. Ovary structure and previtellogenic growth of oocytes.", "\nGlossiphonia heteroclita has paired ovaries whose shape and dimensions change as oogenesis proceeds: during early previtellogenesis they are small and club-shaped, whereas during vitellogenesis they broaden and elongate considerably. ", "During early oogenesis (previtellogenesis), each ovary is composed of an outer envelope (ovisac) that surrounds the ovary cavity and is filled with hemocoelomic fluid, in which a single and very convoluted ovary cord is bathed. ", "The ovary cord consists of germline cells, including nurse cells and young oocytes surrounded by a layer of elongated follicle cells. ", "Additionally, follicle cells with long cytoplasmic projections occur inside the ovary cord, where they separate germ cells from each other. ", "The ovary cord contains thousands of nurse cells. ", "Each nurse cell has one intercellular bridge, connecting it to a central anucleate cytoplasmic mass, the cytophore (rachis); it in turn is connected by one intercellular bridge with each growing oocyte. ", "Numerous mitochondria, RER cisternae, ribosomes, and Golgi complexes are transported from the nurse cells, via the intercellular bridge and cytophore, to the growing oocytes. ", "Oogenesis in G. heteroclita is synchronous with all oocytes in the ovary in the same stage of oogenesis. ", "The youngest observed oocytes are slightly larger than nurse cells, and usually occupy the periphery of the ovary cord. ", "As previtellogenesis proceeds, the oocytes gather a vast amount of cell organelles and become more voluminous. ", "As a result, in late previtellogenesis the oocytes gradually protrude into the ovary cavity. ", "Simultaneously with oocyte growth, the follicle cells differentiate into two subpopulations. ", "The morphology of the follicle cells surrounding the nurse cells and penetrating the ovary cord does not change, whereas those enveloping the growing oocytes become more voluminous. ", "Their plasma membrane invaginates deeply, forming numerous broad vesicles that eventually seem to form channels or conducts through which the hemocoelomic fluid can easily access the growing oocytes." ]

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[ "Prostate cancer has high incidence in both the United States and Russian Federation. ", "An unresolved problem with a large impact on public health is differential diagnosis of its progressive and metastatic forms. ", "Prostate cancer progression presents a number of fundamental questions that concern the heterogeneity of cell populations within the tumor environment, cell-cell communication, and what defines the invasive phenotype mechanistically. ", "This proposal addresses these issues in an integrative collaboration format within the framework of the U.S.-Russia Bilateral Collaborative Research Partnerships on Cancer. ", "Capitalizing on the complementary expertise of the two collaborating teams, the project aims to improve the differentiation of progressive phenotypes using a recently discovered myosin isoform and to study its mechanistic underpinnings. ", "The unconventional molecular motor myosin IC (isoform A) has been shown to be differentially expressed in samples of progressive prostate cancer. ", "Preliminary results point to its involvement in exosome secretion and an epigenetic transmission of its expression from invasive to noninvasive cells. ", "One aim is to study this process on the electron-microscopic level and its impact on the motility of the recipient cells. ", "We will test the hypothesis of myosin IC involvement in the exosome uptake, which would make its upregulation in the recipient cells adaptive on the cellular level yet contributing to the tissue invasivity via an increased total secretion. ", "This will be tested using shRNA and mutant forms of the isoform. ", "The second aim is to improve differentiation of invasive phenotypes by the isoform A expression. ", "A battery of new samples will be tested and a method developed for cell sorting based on the isoform A expression. ", "If successful, this method will be applied to break down each sample into cell subpopulations in order to increase the differentiation of isoform A-expressing components. ", "The hypothesis is that their relative mass will have a higher correlation with tumor progression, improving the prognostic use of this biomarker. ", "Both aims are fully integrated research plans building on the complementary expertise with the applicant for the linked Russian grant, namely myosin IC molecular biology and biomarker work in the American and electron microscopy and sorting in the Russian laboratory." ]

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[ "1. ", "Field of the Invention\nThis invention relates to in situ doping of polycrystalline silicon with phosphorous trichloride, tertiary butyl phosphine, isobutyl phosphine, trimethyl phosphate and tetramethyl phosphate.", "\n2. ", "Brief Description of the Prior Art\nIn situ doping of polycrystalline silicon (polysilicon) is known in the art, such doping generally using phosphine as the phosphorous containing dopant and diborane as the boron containing dopant. ", "However, special techniques are required when phosphine is the dopant to improve sheet resistance and thickness uniformity and to achieve an acceptable deposition rate. ", "Also, the prior art phosphorous-containing dopants are highly toxic and therefore require a great deal of care in handling. ", "This prior art is set forth in an article by B. S. Meyerson and M. L. Yu, ECS Extended Abstracts 83-1. ", "651(1983), an article by D. L. Flowers in the same publication 84-1. ", "256(1984) and an article of H. Kurokawa, Journal of the Electrochemical Society, 129.26.20(1982).", "\nIn situ doping of polysilicon is attractive because the dopant distribution is uniform throughout the film if the dopant is incorporated during and along with the deposition of the polysilicon. ", "This dopant uniformity is extremely advantageous in the refilling of trenches with polysilicon since doping concentrations will then be the same throughout the entire trench, thereby eliminating the need for complicated implants and anneals currently used to fill trenches.", "\nIn situ doping differs from other prior art doping methods, such as ion implantation and solid solid source diffusion in a furnace tube, wherein the dopant is put down interstitially with the polysilicon and simultaneously therewith. ", "This provides the uniform build-up of the polysilicon film with the dopant uniformly distributed therein. ", "However, as stated above, the dopants utilized in the prior art have been extremely toxic and have led to the requirement that measures be taken to protect against the fumes and other effluent thereof, this requiring a great deal of expense. ", "It is therefore a need of the art to provide a dopant for use in the in situ doping process which does not have the toxic effect of prior art dopants, yet can provide the same results." ]

{ "pile_set_name": "USPTO Backgrounds" }

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[ "Mass Alex: Mass Effect 2 - Part 16\n\nCommander Navarro finds himself dealing with swings ranging from the consequences of headbutting a Krogran to the fallout from a planet-wide sterility campaign.", "\n\nThere are billions of stories in the universe, so why not play the best one?", "\n\nMay. 14 2019\n\nCast: Vinny, Alex\n\nPosted by: Vinny" ]

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[ "Deadbeat Illinois: Highland students pay more as state falters\n\nFREEPORT — Jake Olberding enrolled at Highland Community College thinking it would be an affordable higher education option, but he’ll pay more for tuition this fall because his school is squeezed by Illinois’ $5.8 billion backlog of delinquent bills.", "\n\nBy Nick Crow\n\nJournal Standard\n\nBy Nick Crow\n\nPosted Jun. 4, 2013 at 12:01 AM\nUpdated Jun 4, 2013 at 3:00 AM\n\nBy Nick Crow\n\nPosted Jun. 4, 2013 at 12:01 AM\nUpdated Jun 4, 2013 at 3:00 AM\n\nClick on the graphic to go to\n\nthe series' Facebook page.", "\n\nFREEPORT — Jake Olberding enrolled at Highland Community College thinking it would be an affordable higher education option, but he’ll pay more for tuition this fall because his school is squeezed by Illinois’ $3.3 billion backlog of delinquent bills.", "\n\nHighland trustees approved a 9.5 percent tuition hike in March, which means Olberding will pay $115 per credit hour to take classes this fall, his second year of college. ", "However, the tuition increase hasn’t derailed the Lena student’s college path.", "\n\n“It’d have to be a pretty big (tuition) increase for me not to go,” Olberding said.", "\n\nHighland administrators worry that not all students will share his resolve.", "\n\nRevenue supporting the city’s community college has historically resembled a three-legged stool of property taxes, tuition and state aid. ", "Today, the stool is tipping over because HCC’s state aid is a fraction of what it used to be and those payments typically arrive three months later than they’re supposed to.", "\n\nCommunity colleges and practically any public or private sector agency that does business with Illinois is feeling the pinch of the state’s fiscal crisis.", "\n\nComptroller Judy Barr Topinka warned May 22 that the state’s $3.3 billion backlog of unpaid bills — down from $8.5 billion in early April — may swell back to $7.5 billion by August. ", "Longer payment delays could be in store, too.", "\n\nIllinois is $380,000 in arrears to HCC. ", "State aid once accounted for a third of the college’s revenue, but has fallen by $500,000 a year for the last three years. ", "This year, state aid accounts for about 14 percent of HCC’s budgeted revenue, said HCC Vice President of Administrative Services Jill Janssen.", "\n\n“It’s been the perfect storm where property values have gone down 2 to 3 percent per year for the past four years in addition to losing state money and having a decrease in enrollment,” Janssen said. “", "With all these changes we may have to rethink the paradigm of college education.”", "\n\nTaxes and tuition\n\nBetween 2009 and 2012, property values fell 9 percent within the Highland Community College district, which includes Stephenson and Jo Daviess counties and parts of Ogle and Carroll counties.", "\n\nCollege trustees have held the line on the district’s tax levy, and HCC property tax revenues fell in lockstep from $9 million to $8.2 million during those years.", "\n\nStudents, not taxpayers, are filling the gap created by the college’s declining and delinquent state aid.", "\n\nHighland’s tuition rate has risen between 3 percent and 5 percent each year over the past five years. ", "The most recent increase came in March when trustees approved a 9.5 percent hike, raising the per-credit hour tuition rate from $105 to $115. ", "In 2012, trustees approved a $10-per-credit-hour tuition rate increase.", "\n\nPage 2 of 3 -\nThis trend, college officials say, is unsustainable. ", "Sooner or later, HCC will become unaffordable for students and enrollment will suffer. ", "In fiscal 2012, HCC enrollment fell 5.4 percent to 5,110 full- and part-time students.", "\n\n“We keep looking for new things we can do,” said President Joe Kanosky. “", "We keep looking to try new things. ", "We may have to discontinue some programs to get by. ", "It’s going to be a challenge for everyone for the next few years.”", "\n\n‘Just no payments’\n\nSome state funding to community colleges hasn’t come at all, such as money for the Illinois Veteran Grants program, which subsidizes higher education for vets.", "\n\nThe state is no longer funding the program, forcing Illinois community colleges to waive tuition for eligible veterans to the collective tune of $13 million to $14 million, said Ellen Andres, chief financial officer for the Illinois Community College Board.", "\n\n“Waiving tuition causes problems in the sense that it’s unfunded liability,” Andres said. “", "Community colleges are now having to waive payments that 10 years ago the state would have covered. ", "That’s not late payments by the state, that’s just no payments.”", "\n\nAndres said that the state budget for fiscal year 2014 again leaves out funding for vets. ", "She said that schools can expect most of their state funding, but shouldn’t expect it to come on time.", "\n\n“We’re basically telling them that their fiscal year 2013 funds won’t be received before Dec. 30 this year,” Andres said. “", "We don’t anticipate that they will stop making payments, they will just come late.”", "\n\nFuture uncertain\n\nHighland and other Illinois community colleges face many financial uncertainties in the years ahead, Kanosky said.", "\n\n“The game and model are changing,” Kanosky said. “", "The way we do business will have to be looked at as we move forward. ", "There’s different things we’re having to look at.”", "\n\nOne option Kanosky mentioned: beefing up HCC’s menu of online courses, which don’t cost the college as much to offer as a traditional courses.", "\n\n“Online classes aren’t expensive as far as technology goes, but if there’s no new funding you can’t keep up on technology and there are certain things you can’t do online,” Andres said. “", "It’s not the answer.”", "\n\nThe answer, Andres said, may be hard to swallow.", "\n\n“At colleges with a small tax base, student tuition can only be raised so much or students can’t come,” Andres said. “", "They will have to increase class sizes or not offer as many classes. ", "Student services like tutoring and counseling will go away and you end up with a staff that is a jack-of-all-trades. ", "It’s definitely a disadvantage to the colleges. ", "Most end up with more part-time than full-time faculty. ", "I can tell you that the services already probably aren’t where they were five years ago.”" ]

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[ "Bolsonaro diz que está 90% fechado com o PSL.", "\n\nMudaram-se os planos. ", "Segundo colocado nas pesquisas eleitorais, o deputado Jair Bolsonaro (PSC-RJ) não irá mais disputar a presidência da República pelo Patriota, novo nome do Partido Ecológico Nacional (PEN). ", "A razão é um racha com o presidente do PEN, Adilson Barroso. ", "Bolsonaro está seguindo para o Partido Social Liberal (PSL). ", "Ele afirmou à Gazeta do Povo que está “90%” fechado com essa nova legenda.", "\n\nLEIA MAIS: Presidente do Patriota diz que só aceitaria pedidos de Bolsonaro ‘se fosse débil mental’\n\n“No Patriota, o cara prometeu que eu teria a maioria das ações do partido. ", "Mas não entrega. ", "E agora chegou num limite. ", "Estou namorando o PSL. ", "Tive uma conversa excelente com o presidente [do partido] Luciano Bivar e terei 51% das ações. ", "Conversamos ontem e anteontem”, disse Bolsonaro à Gazeta do Povo, na noite desta quarta-feira (20). “", "E tem mais. ", "O PR também está interessado no meu passe. ", "Converso com todo mundo, menos com aqueles ‘partidecos’ de esquerda.”", "\n\nBolsonaro: de estrela do Patriota a incômodo dentro do partido\n\nBolsonaro já havia anunciado oficialmente sua ida para o Patriota. ", "Foi a estrela de um programa partidário do PEN e chegou até a assinar uma ficha simbólica de filiação, como prova de seu compromisso. ", "Mas a coisa desandou.", "\n\nO racha com Adilson Barroso, o presidente do Patriota, envolve não só cargos de direção no partido mas também o fundo partidário. ", "Bolsonaro criticou o dirigente do PEN e disse que, sem ele como candidato do partido, dificilmente a legenda vai atingir a cláusula mínima de 1,5% dos votos válidos para deputados federais no país. ", "Só assim, com esse desempenho, uma legenda tem direito a tempo na TV e acesso ao fundo partidário.", "\n\nLEIA TAMBÉM: PEN/Patriota chegou a mudar seu estatuto e seus princípios para receber Bolsonaro\n\nBolsonaro afirmou que, no PEN, está tendo problemas de uso do fundo partidário – que, no seu entendimento, deveria pagar as despesas de viagens que ele têm feito país afora. ", "Ele afirmou que o fundo do partido é minúsculo.", "\n\n“Sei que vai entrar muito dinheiro [na minha campanha]. ", "De pessoas mais simples, que vão depositar de R$ 5 a R$ 10, e gente com mais condições financeiras”, disse Bolsonaro. “", "Faço minha campanha, no máximo, com R$ 2 milhões.”", "\n\nPSL vai perder a ala mais liberal para que Bolsonaro possa entrar\n\n“Esse partido [o PSL] é liberal. ", "Vai mudar seu regimento. ", "Além de defender valores familiares, vão defender a questão do armamento. ", "Tem uma ala, o ‘Livres’, que vai deixar de existir e não terá mais espaços no partido”, afirmou Bolsonaro. ", "O PSL, antes de Bolsonaro, inclusive cogitava a ideia de mudar de nome para virar “Livres”, adotando um liberalismo mais radical.", "\n\nFavorável à adesão de Bolsonaro, o presidente do partido, Luciano Bivar é deputado federal (PSL-PE) e comanda há anos o PSL. ", "Bolsonaro afirmou que Bivar é um empresário bem sucedido e que não sobrevive do fundo. ", "O presidente da sigla atua no ramo de previdência privada.", "\n\nEm nota, PSL nega filiação\n\nAinda na noite desta quarta-feira, o PSL divulgou nota no Facebook informando que não fará a filiação de Bolsonaro. ", "Leia a íntegra:\n\n1. ", "Não procedem, de forma alguma, as notícias de que o deputado federal Jair Bolsonaro possa se filiar ao PSL.", "\n\n2. ", "Após solicitação feita por Bolsonaro, o presidente nacional do PSL e também deputado federal, Luciano Bivar, recebeu-o em reunião. ", "Conversaram sobre o Imposto Único, histórica bandeira do PSL.", "\n\n3. ", "Em função das evidentes e conhecidas divergências de pensamento, o projeto político de Jair Bolsonaro é absolutamente incompatível com os ideais do LIVRES e o profundo processo de renovação política com o qual o PSL está inteiramente comprometido.", "\n\n4. ", "Bolsonaro representa o autoritarismo e a intolerância tanto na economia quanto nos costumes, sendo a antítese completa das nossas ideias." ]

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[ "Q:\n\nJquery : To redirect from one page to another page\n\nI have two js pages(Source.js and Target.js) at two different location, now all i want to do is when user clicks on dropdown list of source page , it redirects user to target page and vice-versa. ", "I am providing you the exact coding with all location and everthing, i just want to know how to switch from one page to second page.", "\nSource.js coding\nvar SourceSc = function() {\nvar that = {};\nvar _view = null;\nvar _childPanel = \"#content\";\nvar _sourceDlgMgrC = null;\nvar BEGIN = \"BEGIN\";\nvar STARTING = \"STARTING\";\nvar END = \"END\";\nvar TARGET = \"TARGET\"; \nvar _state = BEGIN;\nthat.create = function(parent, panel) {\n\n _parent = parent;\n _panel = panel;\n _transition(STARTING);\n};\nthat.destroy = function() {\n _transition(END);\n};\nthat.eventTargetLanguageView = function() {\n _transition(TARGET_LANGUAGE_VIEW);\n};\nvar _transition = function(newState) {\n _state = newState;\n switch(_state) { \n case STARTING: _enterStarting(); break;\n case TARGET: _enterTargetDlg(); break;\n case END: _enterEnd(); break;\n }\n};\nvar _enterStarting = function() {\n modelMgr.loadInclude('code/app/sc/LoggedIn/sc/Source/c/SourceDlgMgrC.js', function() {\n modelMgr.getHTML('code/app/sc/LoggedIn/sc/Source/Source.html', function(html) {\n _sourceDlgMgrC = SourceDlgMgrC();\n _sourceDlgMgrC.create(_childPanel);\n var req = {};\n var fnSuccess = function(res) {\n _view = SourceV();\n _view.create(that, _panel, html, res); \n }; \n });\n });\n}; \nvar _enterTargetDlg = function() \n{\n//now what i have to write here, to load target page\n};\nvar _enterEnd = function() {\n //coding of destroy \n}; \nreturn that;};\nvar SourceV = function() {\nvar that = {};\n\nvar _sc = null;\nvar _panel = null;\n\nthat.create = function(sc, panel, html, res) {\n _sc = sc;\n _panel = panel;\n that.layoutUi(html);\n that.bindEvents(); \n}; \nthat.layoutUi = function(html) {\n\n $(_panel).html(html); \n};\nthat.bindEvents = function() {\n\n $('#viewList').change(_sc.eventTargetLanguageView);\n};\nthat.destroy = function() {\n $(_panel).html('');\n _panel = null;\n _sc = null;\n};\nreturn that; };\n\ni can post source.html full coding but i guess that'll be use less so i'll post only the dropdown list coding\n <select id = \"viewList\" class=\"fl width160\">\n <option>Source</option>\n <option>Target</option>\n </select>\n\nnow coding of target page is also exact same but location of Target.js is \"code/app/sc/LoggedIn/sc/Target/Target.js\"\n\nA:\n\ntry this...(just for example)\n codeLoadingMgr.loadInclude( path + '/AdminSc.js', function() {\n _adminSc = AdminSc();\n _adminSc.create(that, path, _childPanel,_selectedAdminTab, _programId); \n });\n\n" ]

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[ "The organization of serotonergic projections to cerebral cortex in primates: retrograde transport studies.", "\nRetrograde axonal transport and immunocytochemical methods were utilized to determine the origin of serotonergic afferents to selected primary projection and association areas of cerebral cortex in macaque monkeys. ", "After injections of Fast Blue or Diamidino Yellow in primary motor, somatosensory, or visual cortex, retrogradely labeled neurons are found in both the dorsal and median raphe nuclei. ", "The sets of dorsal raphe neurons which innervate these cortical areas differ in their spatial distributions along the rostrocaudal axis of the brainstem; a coarse rostrocaudal topographic relationship is found between these groups of dorsal raphe neurons and their cortical targets. ", "In contrast, neurons in the median raphe which innervate these primary projection areas are not differentially distributed along the rostrocaudal axis. ", "However, in both the median and dorsal raphe nuclei, most neurons projecting to primary visual cortex are situated lateral to the cells which project to motor and somatosensory areas; many of these visually projecting neurons lie among the fascicles of the medial longitudinal fasciculus. ", "For comparison with the serotonergic innervation of primary projection areas, the locations of raphe cells projecting to three areas of association cortex were examined: dorsolateral prefrontal cortex, area 5 and area 7b. ", "Neurons projecting to each of these association areas are found throughout the dorsal and median raphe nuclei. ", "Their distributions are similar to one another; however, more cells projecting to dorsolateral prefrontal cortex are in the rostral part of the dorsal raphe. ", "The dorsal and median raphe neurons projecting to these association areas are intermingled with neurons projecting to motor and somatosensory cortex, but are medial to most of those projecting to visual cortex. ", "Thus, separate cortical areas are innervated by different sets of raphe neurons; these sets partially overlap, yet differ in their rostrocaudal and mediolateral distributions. ", "Ascending serotonergic projections to cerebral cortex form a widely distributed system which exhibits a highly intricate anatomic organization. ", "The present observations support the hypothesis that the dorsal raphe nucleus is comprised of distinct sets of neurons whose output is distributed to multiple, interconnected cortical areas; these serotonergic projections may play a role in the coordination of excitability in functionally related areas of cortex. ", "In contrast, the serotonergic projections arising from the median raphe appear to be more divergent and are likely to have a global influence on cortical activity. ", "Since these individual raphe nuclei have different projection patterns, they are likely to have distinct functional roles." ]

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[ "Marine dinoflagellate cysts as indicators of eutrophication and industrial pollution: a discussion.", "\nThe results from an investigation of dinoflagellate cysts as indicators of eutrophication in Tokyo Bay, Japan, by Matsuoka [Sci Total Environ 231 (1999) 17] are discussed with reference to other pertinent literature not discussed in the original article. ", "Both the Japanese study and previous work from Norwegian fjords show that pollution (including cultural eutrophication) may produce changes in the phytoplankton reflected by a shift from more autotrophic--to more heterotrophic--dominance of cyst assemblages. ", "However, this is a proportional change that seems likely to result from reduced autotrophic production rather than the increased heterotrophic production suggested by Matsuoka. ", "This is not unequivocal evidence of eutrophication, since Tokyo Bay is impacted also by heavy industrial pollution, the possible effects of which cannot be distinguished, and the quantitative method used for estimating changes in cyst productivity is flawed." ]

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[ "11/2/2007\n\nThe Japanese American National Museum once again displays its amazing ability to hone in on topics of widespread interest while still staying true to its mission in its new exhibition, “Giant Robot Biennnale”!", "\n\nDeveloped in collaboration with Eric Nakamura of Giant Robot and the Japanese American National Museum\n\nIn celebration of its 50th issue and in collaboration with the Japanese American National Museum, the pop-culture magazine Giant Robot has assembled works by ten cutting-edge artists from around the country in Giant Robot Biennale: 50 Issues. ", "APAK | Gary Baseman | David Choe | Seonna Hong | Sashie Masakatsu | Saelee Oh | Pryor Praczukowski | Souther Salazar | Eishi Takaoka | Adrian Tomine\n\nThe curator of the exhibition and owner/co-editor of Giant Robot is Eric Nakamura, a fascinating character who has been pursuing his passions in the pages of this amazing magazine for the past 13 years. ", "Part of what is exciting about his work in the magazine is that his and other authors’ articles perfectly measure the pulse of Asian and Asian American pop culture as a living, breathing entity rather than as a somewhat stale object of scholarly enquiry. ", "Rather than linking interest in Japanese video games and J-pop stars with the now common stereotype of the urban otaku teenagers locked in their rooms, Giant Robot exposes the likes and dislikes, the artistic and musical travels, and the subtle but omni-present cultural politics of diverse individuals who identify with Japan while not being contained by it.", "\n\nIt’s also worth noting that as Giant Robot has increased its subscription base and attracted more attention and funding, Eric and his partner have become serious patrons of local and international artists, setting up galleries and improving their communities in various ways. ", "I wish more academic institutions approached community relations the way these entrepreneurs do!" ]

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", "Corners will have a targeting program which teaches you where the ball can go. ", "If you aren't a lover with this method, you should use the old method of swinging the baseball in. ", "The targeting system didn't seem all that helpful, especially when you're using somebody locally who can discover exactly what you're performing.", "\n\nA very important factor that's for certain is the fact that we will see lots of 'dabbing' in recreation this season, after the Frenchmanis hallmark party was added to gameplay. ", "The overall game is already available to preorder plus a demo model of FIFA 17 will soon be launched by EA Sports two-weeks prior to the principal discharge. ", "For a while, Germany simply delivered three squads for the Champions League, but they exceeded Italy and, lately, Serie A continues to be the next league with no next rep staff. ", "Previously just the top-three national links received then four Champions League allocations as well as merely three were guaranteed. ", "There is no fun in taking control of Nyc in FIFA 16 and being educated that any (or all) of David Accommodation, Andrea Pirlo and Frank Lampard were quitting by the end of season one, without any way of dissuading them.", "\n\nEurope's soccer governing body UEFA have popped disciplinary proceedings against Celtic after having an area of their support exhibited Palestine flags during Saturday's Champions League play-off first leg against Hapoel Beer-Sheva of Israel. ", "Command, control as well as a determination to large-level performance will be trophy winners' hallmarks - implementing these attributes towards football's organisation is among the principal goals of the course. ", "Uefa has assured the ‘Champions' route for champions of domestic leagues that were smaller will stay. ", "There have been murmurs of the entrant but UEFA established that these programs never got the ground off. ", "http://www.cofifa.com/fifa-17-point.html\n\nUEFA works land and membership competitions like UEFA Super Pot, UEFA Champions League, UEFA Europa League, and the fifa 17 points European Tournament, represents the national football links of Europe, and handles the award cash, rules, and advertising rights to these games. ", "Though this concept is quite similar to the Career function of preceding Winners League activities, and the likes of Become A Pro, this can be almost a cross of both. ", "The diminutive Spaniard is Area's next and ultimate person to characteristic within the all-star listing, shedding in FIFA 16 by way of a simple figure from his 88. ", "With Guardiola in-charge at the Etihad, Silva like Aguero and De Bruyne might have his best season to-date and come back to his past rating next period. ", "Already a lot more than 4 lacs fans have casted their ballots and also have picked their favorite leagues and which leagues they wished to discover in the next FIFA game.", "\n\nOne of many sights of organization football is that a sport that is casual may be played with only equipment that is nominal - a simple sport can be enjoyed with items and only a ball on nearly every open area of affordable measurement to mark the placements of two models of goalposts. ", "This is actually the new FIFA 17 style for 2016 that can come alongside other game modes that are standard as well as Ultimate Team. ", "Every year EA presents new hit of FIFA a number of gamin consoles within the couple of days of its launch, i.e. Xbox 360, PS4, Xbox One and afterall PC. ", "If you are considering FIFA 17 Release-Date then mark this dates on your own gambling calender right now!", "\n\nThe separate UEFA Handle, Honesty and Disciplinary Body (CEDB) met on 24 July in Paris to manage the disciplinary cases opened against the after the situations which happened in the Belgium-Republic of Ireland (3-0) match played on 18 August in Bordeaux. ", "By 2018, the top four leagues will present four teams each for the group periods of the Champions League as a result of the modifications announced by UEFA on Friday. ", "As the final treatment happens in Ny, where players learn about the American type of activity, exceptionally, the very first period occurs at headquarters in Switzerland. ", "Since EA produces these games for the forthcoming season although we are in 2016, we're truly looking forward to the FIFA 17 release-date. ", "This change might come into result from your 2018/19 season - the growing season which immediately Follows the 2018 World Cup.", "\n\nPlease enable 10 business days from vessel of one's purchase before informing us of any delayed deliveries. ", "Chosen players who successfully listed for the Beta may receive a minute mail around July 18 with access signal for ps 4. ", "More are focused by KR Basketball Enjoyment, another headline font to the true soccer than tops or helmets. ", "The winners and runners-up of the fifth and sixth-placed leagues, at present Italy and Paris, may proceed to possess two places as the winners of the seventh to 10th rated leagues, currently Italy, Ukraine, Belgium and Turkey, may also qualify automatically. ", "Somewhat, a leagueis coefficient and so a team will soon be swayed by ancient success” - for example past European wins - as opposed to just their performance in more modern periods. ", "Thus, FIFA 2017 release-date will remain pretty much the same as the prior years. ", "http://www.mmovc.com/fifa-17/fifa-17-comfort-trade\n\nIn its newest quote to stick out from fifa 17 point for sale broadcasting competitor BT, Atmosphere is releasing a brand new sports station that will not be unavailable to clients who do not buy a Sports pack. ", "What's good relating to this predicament for basketball video-editing by displaying a player on the industry or adding arrows is that Apple Activity is very wording focused. ", "After the demonstration version was launched and presently the speculation about person rankings went into overdrive,. ", "Another soccer template can be used as a scrapbook format or an university layout. ", "This kind of event - while beautiful for your relaxed soccer supporter - might have ruined the integrity of not just the Champions Europeis prime domestic leagues but additionally League also.", "\n\nThe Gaelic policies were used by Davin and published inside the Usa Ireland magazine on January 7, 1887. ", "Davin's regulations exhibited the effect of games such as hurling as well as a need to formalise a definitely Irish rule of football. ", "The numberone of System joins Mesut Ozil one of the leagueis better to complete the make. ", "On his rating of 85, Cech has improved at the age of 34 after featuring sparsely for Chelsea while in the build-up to FIFA 16. ", "Operated by Frostbite, how you play, participate, and emotionally relate to the sport is transformed by FIFA 17. ", "The perfect example of the differentiation was having less an offside rule (a feature which, for many years, was provided solely by other Irish activities like hurling, and by Foreign rules football). ", "You play as Finder as he embarks on his prodigious career alongside lifelong friend Walker.", "\n\nAnimation: the most important thing of the sport which in fact makes it appear and feel better is animation and we already have seen some engaging & fascinating animation added to Professional Evolution Soccer 2016, that doesn't really suggest EA had done nothing in regard to FIFA 2017 but it doesn't really feel different than the prior hit. ", "The sophomore quarterback put together as remarkable a performance as has been wished for, leading the Bucs to ratings on the first four offensive possesions and joining with No. ", "1 receiver Mike Evans on several situations. ", "RealScorz Football can be a software that enables consumers participate in a mobile model of Fantasy Football. ", "www.fifasale.com\n\nChildren of all ages enjoy activities, and normally buy fifa 17 coins you'll find games which are not inappropriate for various age brackets. ", "When it comes to 5-yearold boys the games should be participating and fun without seeking too much control because kids haven't yet formulated accurate control capabilities at this era. ", "What's promising is that there are plenty of games that entertained for awhile and will maintain them chaotic.", "\n\nMake wedding cake, wedding cake, a customized birthday cake, and celebration cake. ", "It is as you really are a skilled pastry cook. ", "Create your own personal bakeshop and become like a professional pastry chef and FIFA 17 create efforts that could preserve your online customers coming back for more.", "\n\nNintendo launched the eShop at launch for that Wii-U last year and it is very similar to Xboxlive. ", "You'll be able to 2016 new games, whether it be a retail or indie concept. ", "It will likely be super easy for Developers to release games at the same time on Smartphones along with the Wii-U together With The Wiiu having a controller that resembles a capsule. 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", "Particularly when it comes to exciting games for boys.", "\n\nTramadol is actually a medication that is used-to alleviate moderate to moderately severe pain. ", "Additionally it works extremely well to deal with pain caused by surgery and chronic ailments for example cancer or joint pain and functions reducing response and the mind's understanding to pain. ", "It also lowers scale or the dimension of the pain signal passed to a different FIFA 17 in one nerve. ", "Like a product form to become consumed orally every 4-6 hours as needed tramadol comes. ", "It could be obtained with or without food. ", "Follow the recommendations on your own prescription label cautiously, and ask your doctor or pharmacist to describe any part you don't realize. ", "Take Tramadol directed. ", "Tramadol can be habitforming. 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", "There a number of other activities made particularly for boys, where they are able to struggle with bad people and conserve the princess from your system, but these dinosaur games be cheap FIFA 17 PS4 coins seemingly less crazy and more right for all ages.", "\n\nThis holidays, we keep in mind that it is the thought that matters. ", "If you plan to purchase a reward for your child, why don't you obtain buy fifa 17 coins the money's best offer price. ", "A gift that'll not merely provide delight and grin to your child, but in the same time a toy which will enhance the skills. ", "Below will be the list of the Very Best 10 Christmas Gadgets 7 Yrs Old, and Ladies 5, 6.", "\n\nThe very first thing to accomplish is make a listing. ", "Virtually, you cannot make note of what you don't understand however and the finest point to guide you with all the record may be the web. ", "Browse for colors and types that look best for you personally. ", "Record along or save some images of the spring sneakers that goes well together with your attire. ", "There is variety to decide on in virtually any online merchants, that provides bargains that are warm aswell. ", "It does not matter should you FIFA 17 spring sneakers or a costly one, a lot of people could not even inform the difference. ", "Way too long, everbody knows just how to carry oneself, up until the day last.", "\n\nOpening the lucky solutions truly way to pay an enormous sum for them? ", "Not necessarily . ", "For using the games that you don't need to pay huge dollars. ", "A number are of sites available online which provides the center to download-free games. ", "Nevertheless, you'll also get the sites which impose a moderate amount to 2016 new games and their solutions around you would like . ", "Both varieties of sites might be seen from your web. ", "However , a trusted site to download free games for PSP is difficult to find .", "\n\nGame titles involving Barbie are truly undemanding. ", "You will quickly play with the sport without having looking for secrets and secrets as well as manuals. ", "Clicking and dragging are primarily the duties that you simply do. ", "their convenience as well as dress-Up games for boys is among the reasons why people appreciate them so much.", "\n\nStore a video game match. ", "These could be a lot of enjoyment for you along with your gaming pals. ", "You're able to both do this online, your own house or in a friends area. ", "Offer some fun treats when you can concerned and get as many individuals,. ", "This can be a great way to savor your game playing .", "\n\nCertainly a selection are of techniques on what the seized cars were placed for the government's person. ", "Reason or the most frequent and also the most sensible reason will be that bad people, or those that broke guidelines or breached rules used these vehicles.", "\n\nBoth of these devices that are red are part of the click here number of green gadgets of Device Epoint that has certainly been rocking the world that is system. ", "And women have certainly been drooling to own them.", "\n\nAmong the finest items that could have \"2k17 coins\" occurred towards the videogame sector was the discharge of the Sony PlayStation. ", "There has been many versions of the PS video game system. ", "The newest version being the PlayStation 3, which has been quite effective to date with people. ", "The ps3 was provided for videogame people worldwide in 2006. ", "Since that time, it's managed to develop a significant large user-base for itself.", "\n\nMark: Does Pong count? ", "When the NHL problem did not make me feel outdated, this one surely does. ", "I am truly found myself in enjoying with them rather than not of the gaming technology. ", "It only seemed to me that if you were going to play video-games, it had been kind of foolish to play with things like activities you could do in actual life. ", "I would much rather perform Missile Command or Area Invaders or Asteroids.", "\n\nYou would think that a four player co op game that happens in a scifi universe and includes an immeasurable amount of guns available, could go for a thing that might stress teamwork. ", "I had been imagining something of getting the Borderlands concept on-top having a still shot of the four key figures walking deprived leave over the lines. ", "It'd provide a calm assurance in a badass type of way. ", "What 2K games delivered nevertheless, is just something I didnot anticipate.", "\n\nPrepare a home heating, cocktail or potluck celebration and request people to come over. ", "You can also make tokens that are tiny to give out for your guests at the party's end. ", "This would be your opportunity to be introduced to a lot of people in one single venue.", "\n\nAn Xbox or other nba 2k17 technique is usually a welcome addition to a sailor's possessions. ", "Look like a few of the later -generation PS2s, for anything slimline; sailors don't possess lots of space in their bunking places, and something they own needs to be locked up. ", "In case you ship activities or shows, ship them sans appearance, as only a cardboard-secured DVD, and save for once they get home the situation. ", "Whatever decreases area filled may help.", "\n\nFree visitor MMOGs will be the type you could use your browser while not having to download or deploy something and so are also absolve to play (f2p). ", "These elements practically reduce best games 2016's several troubles. ", "They may be exciting, simple about may be enjoyed on any computer and the budget and not needing to publicity over assembly or compatibility problems .", "\n\nThe model packages in \"BioShock\", \"BioShock 2\" and all the DLC information into one offer for $ 29.99's good purchase end cost. ", "Likewise, the \"Challenge Locations Pack\" that has been only on the PS3 will now be around to the Xbox 360 Console.", "\n\nOkay, let's take a look . ", "It was actually Rashad Evans, who was planned to combat Mauricio \"Shogun\" Rua but instances own it that has to be Jon Jones. ", "We have now Smith against the Shogun, who do you consider will earn? ", "Several MMA fans believe that Johnson can battle to beat the shogun. ", "But you will find those who believe that Jones cando. ", "But I personally think that Shogun is physically \"buy NBA 2K17 PS3 MT coins\" stronger in comparison to Jon Jones. ", "Well, that is only my estimation. ", "But I am persuaded that this struggle will be prevailed within by Shogun.", "\n\nVideo game sure got a place currently with NBA 2k17 coins for sale numerous adults claiming its \"bad\" for children to play with game. ", "Although there sure are some activities which are not conducive to healthy improvement, it is actually just a small percentage of activities which might be not good. ", "Naturally playing games 12 hours aday is bad for you, but playing soccer 12 hours there is a-day just as detrimental to you. ", "Balance could be the key whatever it's for balanced progress. ", "In reality, system games offers kids an incredible range of amusement and also training and create for good gifts.", "\n\nNumerous gamers dream of starting their online video game shop that is personal someday. ", "What could not be inferior than doing work close-to nba 2k17 games and always owning a substantial selection of video game titles you'll be able to perform? ", "If you're currently seeking to open your individual video nba 2k17 retail store listed below are five suggestions to keep up in mind.", "\n\nWhile Steam's year-end income are nearly over (less than a-day remains) several popular brands continue to be available inexpensive. ", "Newer activities like Battleground: Bad Business 2, Borderlands and also the Adults of Light can be found for 50%-66% off their original charges. ", "Steam offers recreation packages (with numerous games) aswell, from your likes of 2K games, THQ, and Square Enix. ", "The packs are usually while in the number of thousands range, but are actually readily available for less than one-hundred, purchasing Computer players that are so happy!", "\n\nThe final action ought to be to hardship the outfit to get a difficult impact. ", "Very well, these guidelines are of building the costume on the initial stage,! ", "Nevertheless it might be predicted that the look that was completed will likely be a genuine return of Assassin's Creed Altair.", "\n\nIt's 50mm speakers and also the audio delivers clean heights and lows that are heavy. ", "The in-line amplifier allows to quantity controls for the game and conversations for easy access. ", "The distinct contacts for your line sign makes the X12 an excellent headset for enjoying with best games 2016.", "\n\nThe Xbox 360 Console game that I own could be dealt in for $9.00. ", "The Playstation 2 game I discovered was the Gamecube game as well as $5.50 I came across was $6.50. ", "Entirely that is $21.00 or $ 7.00 per game. ", "That is a decent amount. ", "You're never going to reunite a sizable fraction of what you originally paid. ", "If you get $5 - $10 you're doing pretty good and it was definitely better than my first experience with trading in games.", "\n\nYou will find plenty of additional factors you could update for greater Computer effectiveness such as your Disc/ other peripherals, Monitor, sound cards, along with DVD Writers. ", "As well as a large amount of them are usually to enhance your experience using your Computer. ", "In upgrading, generally consider your budget and everything you must have. ", "In my opinion, go for that midstream components (prices at midrange) since opting for the top class pieces could really set you back a whole lot unless you are doing have a lot of extra cash to shell out. ", "Their charges could decline in several weeks. ", "But you will have times when you actually have to enhance you Laptop so do not hesitate look for the least expensive upgrade you may get with the maximum amount of performance and to mmovc.com/nba-2k17-mt ask questions when you can attain on your computer." ]

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[ "1. ", "Field of the Invention.", "\nThe present invention relates to a compensation circuit used for providing a selected output impedance and which is mounted on a board having breakaway tabs so that selected tabs can be removed for quickly and accurately selecting circuit connections for adjusting an output value of the impedance.", "\n2. ", "Description of the Prior Art.", "\nIn the prior art, after testing communication loops for obtaining the proper loop loss, compensating for such loss has required making individual connections to the selected impedance. ", "Manual connections are needed to obtain the correct output compensation impedance from a circuit board containing a variable impedance, such a multi-tap resistor." ]

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[ "March 15th is a national holiday in Hungary. ", "It stands for democracy and freedom and it commemorates the Hungarian Revolution of 1848, which grew into a war for independence from Habsburg rule.", "\nEvery year before that day students of SKAID KODALY ZOLTAN PRIMARY SCHOOL decorate their classrooms with symbols of the holiday. ", "On Friday (14 March) they held a ceremony (commemoration) in the school gym with participation of 6th graders\n\nNATIONAL HOLIDAY IN HUNGARY\n\nHigh School of KORINOS, Greece\n\nThis is an article written by the student Dimitris Prothromidis which has come first in the writing competition of articles on the value of reading books. ", "The article in question will be published shortly, in «PEN», the school newspaper as well as in local newspapers.", "\n\nTHE BOOKS AND THE READING VALUE\n\nThe book, a timeless medium of knowledge, hides in its pages an entire treasure. ", "It reveals the past, it judges the present, and it prepares for the future. ", "What is then, its value for man?", "\n\nFrom the early historic times, man has felt the need to record his knowledge and experiences, so that they will remain intact through time ensuring that the future generations would learn some information with certainty. ", "After all, with oral speech, some important pieces of historical facts get lost, as they pass on, by word of mouth .It is for this reason that man has created books. ", "With books, man could also make guesses about the future. ", "Writers such as Julius Vern, painted with their writings a picture about the future that has been verified today, to a certain point. ", "Therefore the book has a priceless value for man.", "\n\nUnfortunately though, young people aren’t interested in reading books today. ", "They aren’t fond of coming in contact with something which is considered old and obsolete. ", "They prefer to spend their time on new technological inventions such as the television and the Internet. ", "This way however, not only do they not read books but also they become isolated from the world around them. ", "The computer screen is their entire world, without the least bit of paper.", "\n\nHowever it is never too late for something to change. ", "The same stands in this case too. ", "The disengagement from the television screen or from the computer screen and the immediate contact with reality can contribute to the return of young people to the book. ", "The publication of books, which will attract the interest of the contemporary reading audience, can also help. ", "After all there are books of electronic nature as well.", "\n\nTake a look at a library for a while, either your home library or a public one. ", "You will see thousands of books waiting for you there. ", "They are always there. ", "It is just enough, to search for them.", "\n\nMIHAI EMINESCU NATIONAL COLLEGE\n\n\"Carnival of literary person\" is an activity that reminds us of the beautiful days of Winter and its celebrations. ", "Held within the Comenius project, \"Learn to Read and Read to Learn\", it was organised by Maths teacher Adriana Luca, Romanian teacher Monica Dumitras, followed as judges by Maria Hulber and Laura Costa. ", "Deputy director Eniko Hochhauser honoured the participants with her presence.", "\n\nVery enthusiastmatic and very cheerful, the young actors of classes 6 A and 6 B, encouraged by their parents, presented their role in a theatre play, with talent. ", "The play's end was spoken in English, because that's the international language of the project. ", "The students received 14 diplomas, and the most beautiful outfits will be featured in a calendar made by the Comenius project. ", "The most talented kids will play in a theatre play in Romanian, but also in English, when the partners of the National College \"Mihai Eminescu\" will visit.", "\n\nMIHAI EMINESCU NATIONAL COLLEGE: Reading Contest\n\nIn January 2014 we celebrated two years since the first meeting of Reading Club in foreign languages. ", "The partnership with the Faculty of Letters from Oradea and with ”Gheorghe Șincai” County Library involves organizing a reading club in different languages for primary school pupils.", "The languages in wich we read are: Romanian, English, French, German and Hungarian.", "\nThe activity is held on the last Wednesday of each month.", "\nIf in the beginning adults were those who read to the children, the novelty is that now highschoolers and students are addressing to the children.", "\nTwo meetings - one in December and one in June - are dedicated to reading competitions.", "\nThe project team wants to bring the little readers closer to the idea of book and to that of library. ", "The central objective is to train students to come to the library both accompanied and on their own, to borrow books and, as they advance in age, to study in the reading room.", "\nOn December 16th, 2013 the second edition of the reading contest in Romanian, Hungarian, English and German was held.", "\nThe team coordinated by Laura-Teodora Ardelean was responsible for the Romanian language section of the competition and was composed of: Emilia Ciordaş, student at the Faculty of Letters, University of Oradea, Andrada Belenyesi, Beatrice Bungo and Denik Jurcsik, students in twelfth grade at ”Mihai Eminescu” National College; Paul Zoț, librarian and spokesman for ”Gheorghe Șincai” County Library.", "\nThe fragments were chosen from a book written by Florian Cristescu. ", "The title is Familia Roademult. ", "The text was divided into sequences on which a question was formulated.", "\nTwenty primary school students enrolled in the competition for this particular section.", "\nThe jury paid attention to the following aspects: reading accuracy, expressiveness, fluency, adapting to the situation of communication, the understanding of the text.", "\nThe winner of the first prize received a book from Gutenberg bookstore which was the sponsor of the competition.", "\nAll participants were given the opportunity to make free pass to County Library .", "\nLaura-Teodora Ardelean\n\nNews\n\nLEARNING ENGLISH IS FUN\nLiterary and Musical Spectacle of the students from the after-school-care groups – 3rd A and 3rd B classes\nThird graders from the after school care groups (3rd A and 3rd B classes) showed wonderful knowledge in English language at the celebration LEARNING ELNGLISH IS FUN....\n\n\"Biographies. ", "The Romanian writers, as they (really) were\"\nby Maria Hulber (translated by Ioana Pantor)\nThe national curriculum for Romanian Language and Literature for the 10th grade, brings to the students’ attention a series of great writers who influenced the evolution of the epic discourse and...\n\nReading session dedicated to the World Book and Copyright Day - 23rd April\nThe magical world of books\nThe celebration is dedicated to the World Book and Copyright Day – 23rd April\nReading session in Bulgarian, English and French languages with the participation...\n\nThe “Historical Tales” Competition\nby Sorina Duică (translated by Ioana Pantor)\nAs part of the multilateral Comenius Learn to Read and Read to Learn, on Friday February 20th, 2015, at “Mihai Eminescu” National College, took place the reading competition entitled Historical Tales.", "\nAiming at...\n\n\"Word Images\"\nby Maria Hulber (translated by Ioana Pantor)\nIn November 2014, throughout a period of four weeks, the students from class 7th B, coordinated by their teacher, Mrs. Maria Hulber, explored the poems for children written by the Romanian writer Tudor Arghezi, poems inspired by the...\n\nThe youngest students from the High School \"Mihai Eminescu\" are celebrating \"100 Days of School\". ", "The activity was part of Comenius Project \"Learn to Read and Read to Learn\" through the meeting with the actors from the local Theater \"Regina Maria\". ", "They performed and draw parts of Romanian...\n\nThe 1st March – Baba Marta (4th D class, V. Petkova, class teacher)\nA very loved and respected Bulgarian tradition – Baba Marta – was celebrated by the students from 4th D class and their class teacher.", "\nChildren had started their preparation...\n\n27. ", "11 .2014г. ", "In the magical world of the fairy tales\n“Snow-white and the seven dwarfs”\n( in English)\nClass: 4th V, teacher – Desislava Stoyanova\nThe date of 27th November 2015 was a real fairy-tales holiday for the fourth graders from Vazrazhdane Secondary School, working on the Learn to...\n\n27. ", "11 .2014г. – ", "In the magical world of the fairy tales\n‘Who will have taste of the rod’ folk tale\n4th G grade, Teacher: Stefka Kolarova\nHow can a tale become more interesting to children? ", "How can it provoke students’ imagination and make them read..." ]

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