tbuckley/cabot-search huggingface dataset:
Abstract LB-232: Tumor clonality detection using next generation sequencing data.
Authors: Nathan D. Dees, Christopher A. Miller, Brian S. White, William Schierding, Ravi Vij, Michael H. Tomasson, John S. Welch, Timothy A. Graubert, Matthew J. Walter, Timothy J. Ley, John F. DiPersio, Elaine R. Mardis, Richard K. Wilson, Li Ding
Journal: Cancer Research (2013)

Abstract A tumor's somatic variants, regardless of their significance in disease etiology, serve as genetic markers that capture the evolutionary history of clones and thus may be used for identifying them. We have previously identified steps along this evolutionary trajectory by discovering a broad range of variants, including exonic, intronic, and intergenic mutations, using whole genome sequencing (WGS) and by obtaining deep read counts of those variants using capture-based, targeted re-sequencing. Most of these variants, in most of the tumors analyzed, form clusters. This has revealed that most tumors are multi-clonal in composition with cellular sub-populations having distinct genomes harboring diverse somatic variants. Understanding the clonal diversity and composition of a tumor sample may have implications for clinical treatment, while the clonal evolution across tumor and relapse samples provides insight into disease progression. Here we describe our approach for inferring clones using standard single nucleotide variant (SNV) and copy number alteration (CNA) data obtained from next-generation sequencing of a normal sample and one or more diseased (e.g., tumor or relapse) samples. Variants are clustered according to their deep-read-count-derived frequencies using a variational Bayesian approach to Beta mixture modeling, through which outliers and the number of clusters are identified automatically. The method's probabilistic interpretation provides a quantifiable measure of confidence in a resulting cluster, for example, through a standard error of the mean. We show that amplifications and deletions may induce artifactual clones, thus highlighting the importance of accounting for copy number events in interpreting SNV data for inferring clones. We demonstrate the performance of our approach using published acute myeloid leukemia tumor and relapse pairs as well as unpublished multiple myeloma WGS data sets. However, the approach is applicable to solid tumors as well and has been used to cluster six-dimensional variant data from a breast tumor and five relapses originating from the same patient. Citation Format: Nathan D. Dees, Christopher A. Miller, Brian S. White, William Schierding, Ravi Vij, Michael H. Tomasson, John S. Welch, Timothy A. Graubert, Matthew J. Walter, Timothy J. Ley, John F. DiPersio, Elaine R. Mardis, Richard K. Wilson, Li Ding. Tumor clonality detection using next generation sequencing data. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-232. doi:10.1158/1538-7445.AM2013-LB-232
US adolescents get a fifth of their calories from fast food, study finds
Authors: B. Roehr
Journal: BMJ (2010)

A study of the 12 largest fast food chains in the United States has criticised the energy, sugar, fat, and sodium content in the foods they market to children. Its authors hope that a combination of public outrage and the threat of new laws and enforcement of existing laws on truth in advertising may bring about the changes they seek.

The report, by the Rudd Center for Food Policy and Obesity at Yale University, was presented on 8 November at the 138th annual meeting of the American Public Health Association in Denver.

It found that every day a third of US children and teenagers eat fast food; it is …
Comparative value of transthoracic and transesophageal echocardiography in the assessment of congenital abnormalities of the atrioventricular junction
Authors: Narayanswami Sreeram, Oliver F.W. Stümper, Renate Kaulitz, John Hess, Jos R.T.C. Roelandt, George R. Sutherland
Journal: Journal of the American College of Cardiology (1990)
METASTATIC PANOPHTHALMITIS FOLLOWING PNEUMOCOCCIC OTITIS MEDIA
Authors: Lawrence J. Lawson
Journal: JAMA (1933)

A boy, aged 4 years, who was anemic, was seen in consultation because of difficulty in maintaining drainage from a suppurative right otitis media of four weeks' duration. The drum had been incised at the end of the second week and again at the end of the third week. At the time that the child was examined, the temperature was 102; the patient was lethargic and irritable. When the drum membrane incision was enlarged there appeared a quantity of thick pus under pressure. At this time it was noted that the left eye was sensitive to light and that the pupil was contracted. No surface lesion could be detected even after staining with fluorescein. A culture taken from the ear revealed the pneumococcus as the offending organism. On the succeeding five days the eye became progressively worse, the cornea became clouded, the globe became inflamed, pus appeared in the anterior
Quantitation of transplacental haemorrhage.
Authors: P L Mollison
Journal: BMJ (1972)

On four occasions over a period of four years samples of adult blood to which known amounts of fetal blood had been added were distributed to 8-12 different laboratories taking part in clinical trials organized by an M.R.C. Working Party. Estimates were made of the proportion of fetal: adult red cells in the samples after preparing films by the acid-elution method. When the proportion of fetal: adult red cells was less than about 1:10,000, the highest and lowest estimates were separated by a factor of about 10. However, when the number of cells present was between about 1:100 and 1:1,000, most results were between half and twice the true number of cells present.It is pointed out that since fetal red cells are approximately 30% larger than adult red cells, and since only about 90% of fetal cells stain darkly in the acid-elution method, estimates of the proportion of darkly-staining cells in a film underestimate the volume of fetal red cells present by about one-third. A simple formula is proposed which corrects for this factor and which gives an estimate of the total volume of fetal red cells present, deduced from the ratio of fetal: adult red cells and assuming a maternal red cell volume at term of 1,800 ml.A method of screening blood films is suggested which, firstly, endeavours to standardize the density of adult red cells on films, and, secondly, takes into account the Poisson distribution. Thus limits are set for the number of fetal red cells which can be seen in scanning a given number of adult cells before the suspicion is aroused that a transplacental haemorrhage exceeding a certain amount is present.It is emphasized that the density of adult red cells on blood films varies very widely, and unless the cell density and the size of the low-power field are defined the practice of deducing the extent of transplacental haemorrhage from the number of fetal red cells seen per low-power field may lead to large errors.
IVABRADINE CAUSES MARKED USE-DEPENDENT SLOWING OF AV NODE CONDUCTION AND REDUCES VENTRICULAR RATE DURING ATRIAL FIBRILLATION
Authors: Richard Verrier, Rodolfo Bonatti, Ana Flavia Garcia Silva, Julio AP Batatinha, Bruce Nearing, Dewan Zeng, Luiz Belardinelli
Journal: Journal of the American College of Cardiology (2014)
Voltage-Sensing Domain of Voltage-Gated Proton Channel Hv1 Shares Mechanism of Block with Pore Domains
Authors: Liang Hong, Medha M. Pathak, Iris H. Kim, Dennis Ta, Francesco Tombola
Journal: Neuron (2013)

SummaryVoltage-gated sodium, potassium, and calcium channels are made of a pore domain (PD) controlled by four voltage-sensing domains (VSDs). The PD contains the ion permeation pathway and the activation gate located on the intracellular side of the membrane. A large number of small molecules are known to inhibit the PD by acting as open channel blockers. The voltage-gated proton channel Hv1 is made of two VSDs and lacks the PD. The location of the activation gate in the VSD is unknown and open channel blockers for VSDs have not yet been identified. Here, we describe a class of small molecules which act as open channel blockers on the Hv1 VSD and find that a highly conserved phenylalanine in the charge transfer center of the VSD plays a key role in blocker binding. We then use one of the blockers to show that Hv1 contains two intracellular and allosterically coupled gates.Highlights•Voltage-sensing domain and pore domain have similar mechanisms of block•Each VSD of Hv1 has a gate facing the inner side of the membrane•Gating-charge transfer center in the VSD is involved in blocker binding•Blocker release from one subunit depends on the state of the other subunit
Cerebral autoregulation in patients with cirrhosis and ascites
Authors: Alfonso Lagi, Giorgio La Villa, Giuseppe Barletta, Simone Cencetti, Stefano Bacalli, Marcello Cipriani, Marco Foschi, Chiara Lazzeri, Riccarda Del Bene, Paolo Gentilini, Giacomo Laffi
Journal: Journal of Hepatology (1997)
An Analysis of the Cost-Effectiveness of Pharyngitis Management and Acute Rheumatic Fever Prevention
Authors: RICHARD K. TOMPKINS
Journal: Annals of Internal Medicine (1977)

The cost-effectiveness of preventing primary acute rheumatic fever attacks by oral or benzathine penicillin treatment was analyzed for both epidemic and endemic streptococcal pharyngitis situations. Decision analysis was used: the probabilities and the outcome values were calculated from published data. Three penicillin strategies were compared: (A) treating only patients with group A streptococci-positive throat cultures; (B) treating all patients; (C) treating none of the patients. In the epidemic situation it is medically most effective and least costly to treat all patients with penicillin (Strategy B). In the endemic situation, Strategy B is also most cost-effective when oral penicillin is used in patient populations where the positive throat culture yield is at least 20%. Strategy A is optimal when the yield is between 5% and 20%; below a 5% yield, Strategy C is appropriate. For any individual patient, it is possible that choice of the most cost-effective treatment strategy could be based on the patient's clinical findings.
A Consumer-Choice Health Plan for the 1990s
Authors: Alain Enthoven, Richard Kronick
Journal: New England Journal of Medicine (1989)

Abstract America's health care economy is a paradox of excess and deprivation. We spend more than 11 percent of the gross national product on health care, yet roughly 35 million Americans have no financial protection from medical expenses. To an increasing degree, the present financing system is inflationary, unfair, and wasteful. In its place we need a strategy that addresses the whole system, offers financial protection from health care expenses to all, and promotes the development of economical financing and delivery arrangements. Such a strategy must be designed to be broadly acceptable in our society. To remedy the deprivation, we propose that everyone not covered by Medicare, Medicaid, or some other public program be enabled to buy affordable coverage, either through their employers or through a "public sponsor." To attack the excess, we propose a strategy of managed competition in which collective agents, called sponsors, such as the Health Care Financing Administration and large employers, contract with competing health plans and manage a process of informed cost-conscious consumer choice that rewards providers who deliver high-quality care economically. (N Engl J Med 1989; 320:29–37.)
Reliability of self reported smoking status by pregnant women for estimating smoking prevalence: a retrospective, cross sectional study
Authors: D. Shipton, D. M Tappin, T. Vadiveloo, J. A Crossley, D. A Aitken, J. Chalmers
Journal: BMJ (2009)

<b>Objective</b> To determine what impact reliance on self reported smoking status during pregnancy has on both the accuracy of smoking prevalence figures and access to smoking cessation services for pregnant women in Scotland. <b>Design</b> Retrospective, cross sectional study of cotinine measurements in stored blood samples. <b>Participants</b> Random sample (n=3475) of the 21 029 pregnant women in the West of Scotland who opted for second trimester prenatal screening over a one year period. <b>Main outcome measure</b> Smoking status validated with cotinine measurement by maternal area deprivation category (Scottish Index of Multiple Deprivation). <b>Results</b> Reliance on self reported smoking status underestimated true smoking by 25% (1046/3475 (30%) from cotinine measurement <i>v</i> 839/3475 (24%) from self reporting, z score 8.27, P&lt;0.001). Projected figures suggest that in Scotland more than 2400 pregnant smokers go undetected each year. A greater proportion of smokers in the least deprived areas (deprivation categories 1+2) did not report their smoking (39%) compared with women in the most deprived areas (22% in deprivation categories 4+5), but, because smoking was far more common in the most deprived areas (706 (40%) in deprived areas compared with 142 (14%) in affluent areas), projected figures for Scotland suggest that twice as many women in the most deprived areas are undetected (n=1196) than in the least deprived areas (n=642). <b>Conclusion</b> Reliance on self reporting to identify pregnant smokers significantly underestimates the number of pregnant smokers in Scotland and results in a failure to detect over 2400 smokers each year who are therefore not offered smoking cessation services.
Manganese oxide-based multifunctionalized mesoporous silica nanoparticles for pH-responsive MRI, ultrasonography and circumvention of MDR in cancer cells
Authors: Yu Chen, Qi Yin, Xiufeng Ji, Shengjian Zhang, Hangrong Chen, Yuanyi Zheng, Yang Sun, Haiyun Qu, Zheng Wang, Yaping Li, Xia Wang, Kun Zhang, Linlin Zhang, Jianlin Shi
Journal: Biomaterials (2012)
Abstract 3852: Improved coiled-coil design enhances interaction with Bcr-Abl and induces apoptosis
Authors: Geoffrey D. Miller
Journal: Cancer Research (2012)

Abstract The fusion protein Bcr-Abl responsible for the oncogenic activity in chronic myelogenous leukemia (CML) depends heavily on oligomerization for function. Formation of Bcr-Abl oligomers occurs through a coiled-coil domain existing at the N-terminal portion of the Bcr segment. Previously, we have shown that disruption of this oligomerization utilizing a modified coiled-coil domain (CCmut2) both decreases the proliferation of CML cells and results in the induction of apoptosis. An important contributing factor to these results stems from the increased destabilization of CCmut2 homo-dimers. This phenomenon occurs due to the rationally mutated residues in the modified coiled-coil which allow for favorable interactions with the wild-type Bcr-Abl, but destabilizing interactions with other CCmut2 molecules, thus discouraging the formation of CCmut2 homo-dimers. In turn, this increases the availability and affinity for the modified coiled-coil to interact with and inhibit endogenous Bcr-Abl in CML cells. An additional mutation (K39E) was included that could potentially further destabilize the mutant homo-dimer. Added to the other mutations found in CCmut2 (C38A, S41R, L45N, E48R, Q60E), the new construct was termed CCmut3. To show that CCmut3 results in enhanced binding to a wild-type coiled-coil domain (representative of endogenous Bcr-Abl), 2 separate assays were performed. Colocalization studies were used to show the degree to which CCmut3 localizes intracellularly with Bcr-Abl. Additionally, a mammalian two-hybrid assay was conducted to show the relative selective dimerization between CCmut3 and the Bcr-Abl coiled-coil. Next, caspase 3/7 assays were performed and showed the ability of CCmut3 to induce apoptosis. The CCmut 3 also showed nuclear segmentation (a measurement of late-stage apoptosis) and decrease in oncogenic proliferation (via the colony forming assay). Taken together, these results provide strong evidence for using CCmut3 as a therapeutic for CML. Lastly, attempts to truncate the CCmut3 to find the smallest possible sequence needed (e.g., helix 2) to bind and kill cells effectively is currently underway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3852. doi:1538-7445.AM2012-3852
Creation of Nonischemic Functional Mitral Regurgitation by Annular Dilatation and Nonplanar Modification in a Chronic In Vivo Swine Model
Authors: Haruo Yamauchi, Eric N. Feins, Nikolay V. Vasilyev, Shogo Shimada, David Zurakowski, Pedro J. del Nido
Journal: Circulation (2013)

Mechanisms and treatments of nonischemic functional mitral regurgitation (NIMR) are not fully established, in part, because of a lack of proper large animal models. We developed a novel technique of NIMR creation in a swine model by making multiple small incisions in the mitral annulus.Ex vivo experiments using isolated swine hearts (n=10) showed a 15% increase in annular area (6.8-7.8 cm(2)) after 16 incisions were made along the posterior mitral annulus of a pressurized left ventricle. In an in vivo swine model (n=7; 46.4 ± 2.2 kg), NIMR was created by making fourteen to twenty-six 2-mm incisions in the atrial aspect of the mitral annulus using a cardioport video-assisted imaging system in the beating heart. Animals were euthanized at 4 weeks (n=4) and 6 weeks (n=3). Three-dimensional (3D) echocardiography was obtained before and immediately after NIMR creation and at euthanasia; vena contracta area, mitral annular dimension, left ventricular volume, and inter-papillary muscle distance were measured. The mitral annular incisions resulted in mild to moderate mitral regurgitation and an increased vena contracta area. NIMR creation altered mitral valve geometry by decreasing mitral annular nonplanarity and increasing annular area, primarily in the anteroposterior dimension. NIMR creation did not significantly change left ventricular volume or inter-papillary muscle distance. Longer follow-up period did not significantly affect these outcomes.NIMR can successfully be created in a beating heart swine model and results in dilatation and 3D changes in mitral annular geometry. This model can enhance the experimental validation of new valve repair devices and techniques.
Cellular Calcium Metabolism
Authors: HOWARD RASMUSSEN
Journal: Annals of Internal Medicine (1983)

Recent developments in our knowledge of cellular calcium metabolism are reviewed. Changes in the Ca2+ concentration in the cell cytosol are a nearly universal means of coupling stimulus with response in both neural and endocrine cells. In particular, Ca2+ serves as an important intracellular messenger in the regulation of cardiac and smooth muscle function, the regulation of aldosterone secretion by K+ and angiotensin II, and the secretion of renin. Several points about the messenger role of Ca2+ are emphasized: small changes in Ca2+ concentration bring about large changes in cell response; the regulation of calcium fluxes across the plasma membrane are critical to proper cell function; and excessive calcium is a cellular toxin. An attempt is made to integrate our knowledge of the function and properties of intracellular Ca2+ receptor proteins with our knowledge of cellular calcium homeostasis, and relate this to the pathogenesis of hypertension.
Proportionate Mortality Trends: 1950 Through 1986
Authors: John E. Sutherland
Journal: JAMA (1990)

Mortality trends in the United States from 1950 through 1986 were analyzed for the conditions that are or have recently been among the six leading causes of death. The age-adjusted mortality rate for all causes has decreased from 841.5 to 541.7 per 100,000 population. Cause-specific, age-adjusted mortality rates have declined from 1950 through 1986 for cerebrovascular disease, injuries, perinatal conditions, heart disease, and influenza and pneumonia. Time trends in the proportion of persons dying of each of these diseases, however, have varied; the proportion dying of cerebrovascular disease, injuries, and perinatal conditions has decreased, and the proportion of persons dying of heart disease and influenza and pneumonia has remained fairly stable from 1950 through 1986. During this same time, age-adjusted death rates have increased for chronic obstructive pulmonary disease and have remained fairly stable for malignant neoplasms, while the proportions of persons dying of chronic obstructive pulmonary disease and malignant neoplasms have increased dramatically. For people aged 35 to 64 years, malignant neoplasms have now overtaken heart disease as the leading cause of death. For those aged 65 years and older, heart disease remains the leading cause of death, accounting for almost 50% of all deaths in persons 85 years and older.
Conditions for discovery
Authors: P. H. Abelson
Journal: JAMA (1965)

As I thought about "Conditions for Discovery," it seemed desirable to relate some of my remarks to the new Institute for Biomedical Research, for in this venture reside opportunities to be especially creative in biomedical research. There also exists an opportunity to innovate with respect to mechanisms of achieving excellence through an optimal environment for research—in brief, creativity in being creative. Let us consider first some fundamentals of the general environment in which this Institute will function. In order for a scientist to be productive he must work in fields in which there are opportunities for great discoveries. As one surveys the various fields of science, one can note great variation in their present potential. Some areas show definite signs of being mined out. For instance, at one time a number of scientists were active in discovering all stable isotopes of the elements. That work is at least 99% complete.
In vivo studies of cartilage regeneration after damage induced by catabolin/interleukin-1.
Authors: D P Page Thomas, B King, T Stephens, J T Dingle
Journal: Annals of the Rheumatic Diseases (1991)

The response of the rabbit knee joint to a brief episode of cytokine induced damage is described. After three intra-articular injections of catabolin/interleukin-1 all joint cartilages showed an immediate extensive loss of proteoglycan (glycosaminoglycan), which was gradually replaced over three to four weeks. Glycosaminoglycan biosynthesis (measured by 35SO4 uptake) was initially depressed, but at one week had almost doubled its rate as compared with the normal side. This increased synthetic activity was further maintained throughout the duration of the experiment (28 days), though the rate gradually fell. Histological cartilage metachromasia to toluidine blue mirrored the glycosaminoglycan changes. No disturbance of the articular cartilage collagen network was found. It is considered, therefore, that during treatment for arthritis the indigenous chondrocyte must continue to be capable of carrying out regenerative matrix repair and that antiarthritic agents should first be screened for interference with that process.
THE THERAPY OF THE COOK COUNTY HOSPITAL
Authors: BERNARD FANTUS
Journal: JAMA (1934)

<h3>THERAPY OF CHANCROID AND BUBO DIAGNOSIS</h3> A few days after exposure there is a soft, flabby erosion and then an ulcer, which is inflammatory, painful and tender. It may be single or multiple and has an irregular, undermined border and an uneven base covered by a dirty purulent exudate. The streptobacillus of Ducrey can be found in the exudate. Chancroid and its bubo must be differentiated from (1) syphilitic infection, (2) fusospirochetal balanitis, (3) granuloma inguinale, (4) lymphogranulomatosis inguinalis, (5) herpes progenitalis and (6) epithelioma. Every ulcer on the genitalia of a sexually active person should be considered a syphilitic chancre until proved otherwise and no treatment should be addressed to it until an absolute diagnosis has been made. In untreated cases, dark field examination for Spirochaeta pallida is positive in more than 90 per cent of syphilitic cases even on first examination. If the ulcer has received treatment,