tbuckley/cabot-search huggingface dataset:
Effect of Onartuzumab Added to Erlotinib on Metastasis in Patients With Lung Cancer
Authors: Aspasia Soultati, Debra H. Josephs, James F. Spicer
Journal: Journal of Clinical Oncology (2014)

TO THE EDITOR: A randomized phase II trial suggests improved outcome with the addition of onartuzumab to erlotinib in patients with advanced non–small-cell lung cancer (NSCLC) expressing MET. Overall survival (OS) is improved disproportionately in the combination arm compared with progression-free survival (PFS). Median OS improvement of 8.8 months compares with a 1.4-month improvement for median PFS, and response rates in both groups were low and not significantly different. In considering the current understanding of MET biology, the authors suggest that the therapeutic benefit of onartuzumab may arise from inhibition of migration and invasion rather than direct inhibition of tumor growth. Upregulation of oncogenic MET signaling results in features of epithelial to mesenchymal transition, including increased protease production, cell dissociation, and increased motility. This can contribute to cellular invasion through extracellular matrix, enabling tumor invasion and metastasis. In mouse models, silencing of endogenous overexpressed MET gene in tumor cells suppresses tumor growth and metastasis. Onartuzumab may have had a similar effect in the patients on this trial. We suggest that clinical support for this mechanism of action may be available in the data collected by Spigel et al. Review of computed tomography scans documenting progression could categorize patients according to increase in size of target lesions identified at baseline, or detection of new metastatic sites. If, compared with erlotinib controls, MET-positive patients who experience disease progression in the combination arm are less likely to have new distant metastases, indirect clinical support for their hypothesis would be provided. In addition, if confirmed, this finding would provide a possible explanation for the observed impressive survival benefit with the addition of onartuzumab to erlotinib, despite a low response rate and the absence of significant PFS difference seen with the combination. In an era of individualized treatment with expensive targeted therapies, early prediction of clinical benefit is of great value. However, current radiological tools, including response, may not be sufficient to evaluate the complex biology that underlies the mode of action of these drugs. The results presented by Spigel et al offer an exciting new perspective for patients with MET-positive NSCLC, but further exploration of the mode of disease progression, as suggested above, is warranted.
Sodium Content of Koshered Meat
Authors: Edward R. Burns
Journal: JAMA (1984)

<h3>To the Editor.—</h3> Strict dietary restriction of sodium is seldom necessary for the control of heart failure when the use of diuretics is employed.<sup>1</sup>Observant Jews eat meat that has been ritually prepared by a process called "koshering" that involves the addition of salt to raw meat to remove its blood.<sup>2</sup>In response to reports of pulmonary edema being precipitated by ingestion of koshered meat, we compared the sodium content of various types of koshered and unkoshered meats. The koshered meats were then subjected to an additional soaking procedure before analysis of their sodium content. Meat that had undergone the koshering process and equivalent samples that had not been salted were obtained from a local meat supplier. Ten-gram samples of trimmed beef, veal, and chicken were used for each of three groups: (1) nonkoshered meat, (2) koshered meat, and (3) koshered meat that had been soaked for an
The Pattern of Interleukin-1β (IL-1β) and Its Modulating Agents IL-1 Receptor Antagonist and IL-1 Soluble Receptor Type II in Acute Meningococcal Infections
Authors: Marcel van Deuren, Johanna van der Ven-Jongekrijg, Edouard Vannier, Roelof van Dalen, Gerard Pesman, Anton K.M. Bartelink, Charles A. Dinarello, Jos W.M. van der Meer
Journal: Blood (1997)
Brief Report: T Cell Expression of Granulocyte–Macrophage Colony‐Stimulating Factor in Juvenile Arthritis Is Contingent Upon Th17 Plasticity
Authors: Christopher Piper, Anne M. Pesenacker, David Bending, Balathas Thirugnanabalan, Hemlata Varsani, Lucy R. Wedderburn, Kiran Nistala
Journal: Arthritis & Rheumatology (2014)

Granulocyte-macrophage colony stimulating factor (GM-CSF) is a potent inflammatory mediator that is responsible for recruitment and activation of innate immune cells. Recent data from murine studies have identified Th17 cells as a key source of GM-CSF and suggest that T cell-derived GM-CSF is instrumental in the induction of autoimmune disease. The present study was undertaken to analyze the expression of T cell-derived GM-CSF in the joints of patients with juvenile idiopathic arthritis (JIA) and to investigate the differentiation of Th17 cells and how this relates to GM-CSF+ T helper cells. Synovial fluid (SF) and peripheral blood (PB) samples from 24 patients with JIA were analyzed, by flow cytometry and reverse transcription-polymerase chain reaction, for expression of GM-CSF and the Th17 marker CD161. A cytokine capture assay was used to purify Th17 cells and test the plasticity of cytokine production in response to interleukin-12 (IL-12) and IL-23. The frequency of GM-CSF-producing T helper cells was significantly enriched in SF mononuclear cells compared to PB mononuclear cells from the patients with JIA (24.1% of CD4+ T cells versus 2.9%) and closely correlated with the erythrocyte sedimentation rate (r(2) = 0.91, P < 0.001). Synovial GM-CSF+ T cells were predominantly CD161+ and coexpressed interferon-γ (IFNγ), but not IL-17. Culture of Th17 cells in the presence of IL-12 led to rapid up-regulation of GM-CSF and IFNγ, recapitulating the phenotype of GM-CSF-expressing cells within the joint. Our results identify a novel outcome of Th17 plasticity in humans that may account for the enrichment of GM-CSF-expressing T cells in the joints of patients with JIA. The association of GM-CSF expression with systemic inflammation highlights the potential role of Th17-related cytokines in the pathology of JIA.
Reactive and reparative myocardial fibrosis in arterial hypertension in the rat
Authors: C. G Brilla, K. T Weber
Journal: Cardiovascular Research (1992)

Objective: Myocardial fibrosis is an important determinant of pathological hypertrophy. In two experimental models of arterial hypertension the purpose of the study was (a) to determine total collagen volume fraction and relative contribution of scarring and perivascular/interstitial fibrosis; and (b) to assess the effects of the aldosterone receptor antagonist spironolactone on these patterns of fibrosis. Methods: 76 eight week old Sprague-Dawley rats weighing 180 to 200 g were used for the studies. Using videodensitometry total collagen volume fraction was separated into the various components for the left and right ventricles in the following experimental models: renovascular hypertension occurring following unilateral renal ischaemia; continuous aldosterone administration via osmotic minipumps with either high (AL) or low (ALLO) sodium diet; renovascular hypertension and AL after pretreatment and continuous treatment with either 20 or 200 mg·kg−1·d−1 subcutaneously of the competitive aldosterone receptor antagonist spironolactone. All groups were compared to age and sex matched controls. Results: After eight weeks, systolic pressure was comparably increased in renovascular hypertension and AL and it remained raised with low dose spironolactone treatment in either model, but was normal with high dose spironolactone or low sodium diet. Left ventricular hypertrophy, expressed as a significant increase in left to right ventricular weight and left ventricle to body weight ratios, was present in renovascular hypertension, AL, and AL + low dose spironolactone compared to control (p<0.005). In either ventricle: (1) the amount of interstitial/perivascular fibrosis and myocardial scarring was increased (p<0.005) in renovascular hypertension and AL compared to control; (2) each was reduced (p<0.005) with either dose of spironolactone; and (3) only scars were seen in ALLO. Conclusions: Myocardial fibrosis of either ventricle was comparable in renovascular hypertension and AL. Spironolactone was able largely to prevent the perivascular/interstitial fibrosis and scarring in either model irrespective of the development of left ventricular hypertrophy and arterial hypertension. Low sodium diet in hyperaldosteronism prevented hypertension and left ventricular hypertrophy, but not scarring. These findings suggest that a rise in plasma aldosterone, relative to sodium intake, may play a role in mediating collagen accumulation in the heart during the development of experimental arterial hypertension.
Identification of Lineage-Specific<i>Cis</i>-Regulatory Modules Associated with Variation in Transcription Factor Binding and Chromatin Activity Using Ornstein–Uhlenbeck Models
Authors: Marina Naval-Sánchez, Delphine Potier, Gert Hulselmans, Valerie Christiaens, Stein Aerts
Journal: Molecular Biology and Evolution (2015)

Scoring the impact of noncoding variation on the function of cis-regulatory regions, on their chromatin state, and on the qualitative and quantitative expression levels of target genes is a fundamental problem in evolutionary genomics. A particular challenge is how to model the divergence of quantitative traits and to identify relationships between the changes across the different levels of the genome, the chromatin activity landscape, and the transcriptome. Here, we examine the use of the Ornstein–Uhlenbeck (OU) model to infer selection at the level of predicted cis-regulatory modules (CRMs), and link these with changes in transcription factor binding and chromatin activity. Using publicly available cross-species ChIP-Seq and STARR-Seq data we show how OU can be applied genome-wide to identify candidate transcription factors for which binding site and CRM turnover is correlated with changes in regulatory activity. Next, we profile open chromatin in the developing eye across three Drosophila species. We identify the recognition motifs of the chromatin remodelers, Trithorax-like and Grainyhead as mostly correlating with species-specific changes in open chromatin. In conclusion, we show in this study that CRM scores can be used as quantitative traits and that motif discovery approaches can be extended towards more complex models of divergence.
An outbreak of gastrointestinal illness associated with consumption of raw depurated oysters.
Authors: D Heller, O N Gill, E Raynham, T Kirkland, P M Zadick, R Stanwell-Smith
Journal: BMJ (1986)

QesophagealobduratorsOesophageal obdurators are popular in the USA.The obdurator is a long cuffed tube attached to a facemask.The tube is passed blindly into the oesophagus and the cuffis then inflated to isolate the oesophagus and stomach from the airway.In the origmial version the oesophageal obdurator tube is blocked distally and a series of holesat laryngeal level permit air blown down the tube to pass from the tubei-to the larynx.In a later version the oesophageal tube is-not terminally seaed and this allows~for aspirato or pressure relief of gastric contents.A-second orifice in the mask is used for ventilation.Hazards in the use ofthese tubes include trauma to the oesophagus and stomach, the risk ofinducing vomiting and gastric rupture, and, paradoxically, the rare occurence ofunrecogmsed tracheal intubation.
<i>RUNX1</i> Mutations Are Associated With Poor Outcome in Younger and Older Patients With Cytogenetically Normal Acute Myeloid Leukemia and With Distinct Gene and MicroRNA Expression Signatures
Authors: Jason H. Mendler, Kati Maharry, Michael D. Radmacher, Krzysztof Mrózek, Heiko Becker, Klaus H. Metzeler, Sebastian Schwind, Susan P. Whitman, Jihane Khalife, Jessica Kohlschmidt, Deedra Nicolet, Bayard L. Powell, Thomas H. Carter, Meir Wetzler, Joseph O. Moore, Jonathan E. Kolitz, Maria R. Baer, Andrew J. Carroll, Richard A. Larson, Michael A. Caligiuri, Guido Marcucci, Clara D. Bloomfield
Journal: Journal of Clinical Oncology (2012)

Purpose To determine the association of RUNX1 mutations with therapeutic outcome in younger and older patients with primary cytogenetically normal acute myeloid leukemia (CN-AML) and with gene/microRNA expression signatures. Patients and Methods Younger (&lt; 60 years; n = 175) and older (≥ 60 years; n = 225) patients with CN-AML treated with intensive cytarabine/anthracycline-based first-line therapy on Cancer and Leukemia Group B protocols were centrally analyzed for RUNX1 mutations by polymerase chain reaction and direct sequencing and for established prognostic gene mutations. Gene/microRNA expression profiles were derived using microarrays. Results RUNX1 mutations were found in 8% and 16% of younger and older patients, respectively (P = .02). They were associated with ASXL1 mutations (P &lt; .001) and inversely associated with NPM1 (P &lt; .001) and CEBPA (P = .06) mutations. RUNX1-mutated patients had lower complete remission rates (P = .005 in younger; P = .006 in older) and shorter disease-free survival (P = .058 in younger; P &lt; .001 in older), overall survival (P = .003 in younger; P &lt; .001 in older), and event-free survival (P &lt; .001 for younger and older) than RUNX1 wild-type patients. Because RUNX1 mutations were more common in older patients and almost never coexisted with NPM1 mutations, RUNX1 mutation–associated expression signatures were derived in older, NPM1 wild-type patients and featured upregulation of genes normally expressed in primitive hematopoietic cells and B-cell progenitors, including DNTT, BAALC, BLNK, CD109, RBPMS, and FLT3, and downregulation of promoters of myelopoiesis, including CEBPA and miR-223. Conclusion RUNX1 mutations are twice as common in older than younger patients with CN-AML and negatively impact outcome in both age groups. RUNX1-mutated blasts have molecular features of primitive hematopoietic and lymphoid progenitors, potentially leading to novel therapeutic approaches.
Topics in Type 2 Diabetes and Insulin Resistance
Authors: Zachary T. Bloomgarden
Journal: Diabetes Care (2009)

This is the second of six articles based on presentations at the American Diabetes Association Scientific Sessions held 6–10 June 2008 in San Francisco, California.

Frederick Brancati (Baltimore, MD) discussed diabetes screening. Approaches using age, sex, BMI, family history, hypertension, and lifestyle as predictive measures have shown good performance in cross-sectional and prospective studies, and capillary glucose measurement adds further value, although the public health impact of such approaches has not been determined. In the Diabetes Prevention Program (DPP), 158,177 individuals were screened, with 3,819 randomized. Those whose fasting capillary glucose was 90–115 mg/dl had increased risk of impaired glucose tolerance (IGT); levels ≥130 mg/dl were 250 times as likely as levels <90 mg/dl to be associated with IGT. Patrick O'Connor (Minneapolis, MN) pointed out that health plans have become very interested in identifying and treating diabetes and addressed the question of whether systematic identification of pre-diabetes by screening leads to better health outcomes than would occur without screening. Developing an approach to identification and subsequent interventions that would be cost-effective is an important priority. O'Connor reviewed responses to a survey of medical directors of 35 plans, caring for a total of 47 million individuals, focused on awareness of cardiometabolic risk. At-risk enrollees can be identified by age, BMI, sex, race, laboratory test results, physician diagnoses, smoking history, and prescription data based on pharmacy claims, although lack of electronic medical records is “a weak link.” Duration of treatment and of illnesses (including diabetes) and other aspects of medical history are not readily available.

Nonetheless, using all the available information, it certainly is possible to identify individuals at increased diabetes risk. Two approaches are taken: 1 ) direct outreach to large numbers of people for prevention of adverse outcome or 2 ) case management of smaller numbers of people at much higher risk. …
Vinyl sulfones: Synthetic preparations and medicinal chemistry applications
Authors: D. Christopher Meadows, Jacquelyn Gervay-Hague
Journal: Medicinal Research Reviews (2006)

Vinyl sulfones have long been known for their synthetic utility in organic chemistry, easily participating in 1,4-addition reactions and cycloaddition reactions. This functional group has also recently been shown to potently inhibit a variety of enzymatic processes providing unique properties for drug design and medicinal chemistry. This review includes traditional methods used for the synthesis of vinyl sulfones, but focuses mainly on newer reactions applied to vinyl sulfones, including olefin metathesis, conjugate reduction, asymmetric dihydroxylation (AD), and the use of vinyl sulfones to arrive at highly functionalized targets, all illustrating the rich and versatile chemistry this group can efficiently perform. In addition, geminal disulfones are discussed with respect to their formation, reactions, and medicinal applications of this underutilized functional group. © 2006 Wiley Periodicals, Inc. Med Res Rev
Hormone-receptor expression and ovarian cancer survival: an Ovarian Tumor Tissue Analysis consortium study
Authors: Weiva Sieh, Martin Köbel, Teri A Longacre, David D Bowtell, Anna deFazio, Marc T Goodman, Estrid Høgdall, Suha Deen, Nicolas Wentzensen, Kirsten B Moysich, James D Brenton, Blaise A Clarke, Usha Menon, C Blake Gilks, Andre Kim, Jason Madore, Sian Fereday, Joshy George, Laura Galletta, Galina Lurie, Lynne R Wilkens, Michael E Carney, Pamela J Thompson, Rayna K Matsuno, Susanne Krüger Kjær, Allan Jensen, Claus Høgdall, Kimberly R Kalli, Brooke L Fridley, Gary L Keeney, Robert A Vierkant, Julie M Cunningham, Louise A Brinton, Hannah P Yang, Mark E Sherman, Montserrat García-Closas, Jolanta Lissowska, Kunle Odunsi, Carl Morrison, Shashikant Lele, Wiam Bshara, Lara Sucheston, Mercedes Jimenez-Linan, Kristy Driver, Jennifer Alsop, Marie Mack, Valerie McGuire, Joseph H Rothstein, Barry P Rosen, Marcus Q Bernardini, Helen Mackay, Amit Oza, Eva L Wozniak, Elizabeth Benjamin, Aleksandra Gentry-Maharaj, Simon A Gayther, Anna V Tinker, Leah M Prentice, Christine Chow, Michael S Anglesio, Sharon E Johnatty, Georgia Chenevix-Trench, Alice S Whittemore, Paul DP Pharoah, Ellen L Goode, David G Huntsman, Susan J Ramus
Journal: The Lancet Oncology (2013)
Does the way concussion is portrayed affect public awareness of appropriate concussion management: the case of rugby league
Authors: Tracey L McLellan, Audrey McKinlay
Journal: British Journal of Sports Medicine (2011)

It is important to identify factors that might adversely affect appropriate medical consultation and management of concussion. One factor that might present a barrier to timely intervention is media portrayal of concussion in sporting events, such as professional rugby league. Accordingly, the current study employed a surveillance method of publicly available broadcast information to establish the incidence rate of probable concussion in the National Rugby League's Telstra Premiership 2010 season and examined how these injury events were shown to be managed with respect to return-to-play procedures. The incident rate for probable concussion was higher than previously reported: 11.10\1000 player hours (95% CI 5.78 to 16.40) and was likely underestimated. Importantly, most injured players were shown to continue playing or return to play despite being visibly concussed and described as such by the commentary team. Although ‘return-to-play decisions’ for professional players are guided by medical assessment, the authors discuss whether the way concussion is portrayed might affect public awareness of appropriate concussion management.
Effects of Prostate-Specific Antigen Testing on Familial Prostate Cancer Risk Estimates
Authors: O. Bratt, H. Garmo, J. Adolfsson, A. Bill-Axelson, L. Holmberg, M. Lambe, P. Stattin
Journal: JNCI Journal of the National Cancer Institute (2010)

BackgroundFamily history is a strong risk factor for prostate cancer. The aim of this study was to investigate whether increased diagnostic activity is related to the incidence of prostate cancer among brothers of men with prostate cancer.
Effective prevention of sports injuries: a model integrating efficacy, efficiency, compliance and risk-taking behaviour
Authors: D Van Tiggelen, S Wickes, V Stevens, P Roosen, E Witvrouw
Journal: British Journal of Sports Medicine (2008)

In 1992 van Mechelen et al published a “sequence of prevention model” based on a four-step process. This model has been widely used to implement preventive measures in response to sports injuries. However, the execution of this model has been shown to lack validity in determining the success of a preventive measure. A modified model has therefore been proposed which incorporates additional steps that enable the inclusion of external factors with a significant effect on the outcome of a prevention intervention. This expansion of van Mechelen’s model leads to a more global model in which the compliance level and risk-taking behaviour of the individual and the assessment of efficiency of the stakeholders have a key influence on the preventive measure. This model gives a better insight into the different processes in injury prevention that can be used by clinicians, coaches and managers to decide whether to implement a preventive measure programme.
The Laparoscopic Dividend
Authors: C. Randle Voyles
Journal: JAMA (1992)

<h3>To the Editor.</h3> —The cost of laparoscopic cholecystectomy can be lowered. In the recent Letters section of<i>JAMA</i>,<sup>1</sup>the hospital cost was $4633 and $6750 at two different centers. Our group has done more than 1200 laparoscopic cholecystectomies. A recent audit of 50 cases (age less than 60 years, elective cases) showed an average hospital charge of $1817. Here are the ways we lower costs. We use electrosurgical dissection instead of laser<sup>2</sup>: savings, $546 to $800. We use reusable cannulas with limited use trocars instead of completely disposable systems: savings, $400 to $650. We use reusable graspers, scissors, dissectors, suctionirrigators: savings, $250 to $600. We do operative cholangiograms only when indicated, not routinely: savings, $300 to $500. There has been no reduction in quality of care; our morbidity, mortality, and operating efficiency compare favorably with all reports.<sup>3</sup>An increasing number of patients are treated as outpatients with