tbuckley/cabot-search huggingface dataset:
Lavage of the Uterine Cavity for Molecular Detection of Müllerian Duct Carcinomas: A Proof-of-Concept Study
Authors: Elisabeth Maritschnegg, Yuxuan Wang, Nina Pecha, Reinhard Horvat, Els Van Nieuwenhuysen, Ignace Vergote, Florian Heitz, Jalid Sehouli, Isaac Kinde, Luis A. Diaz, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Paul Speiser, Robert Zeillinger
Journal: Journal of Clinical Oncology (2015)

Type II ovarian cancer (OC) and endometrial cancer (EC) are generally diagnosed at an advanced stage, translating into a poor survival rate. There is increasing evidence that Müllerian duct cancers may exfoliate cells. We have established an approach for lavage of the uterine cavity to detect shed cancer cells.Lavage of the uterine cavity was used to obtain samples from 65 patients, including 30 with OC, five with EC, three with other malignancies, and 27 with benign lesions involving gynecologic organs. These samples, as well as corresponding tumor tissue, were examined for the presence of somatic mutations using massively parallel sequencing (next-generation sequencing) and, in a subset, singleplex analysis.The lavage technique could be applied successfully, and sufficient amounts of DNA were obtained in all patients. Mutations, mainly in TP53, were identified in 18 (60%) of 30 lavage samples of patients with OC using next-generation sequencing. Singleplex analysis of mutations previously determined in corresponding tumor tissue led to further identification of six patients. Taken together, in 24 (80%) of 30 patients with OC, specific mutations could be identified. This also included one patient with occult OC. All five analyzed lavage specimens from patients with EC harbored mutations. Eight (29.6%) of 27 patients with benign lesions tested positive for mutations, six (75%) as a result of mutations in the KRAS gene.This study proved that tumor cells from ovarian neoplasms are shed and can be collected via lavage of the uterine cavity. Detection of OC and EC and even clinically occult OC was achieved, making it a potential tool of significant promise for early diagnosis.
Unmet Challenges in the Use of Novel Agents in Locally Advanced Non–Small-Cell Lung Cancer
Authors: Roy H. Decker, Thomas J. Lynch
Journal: Journal of Clinical Oncology (2012)

It has been almost three decades since the addition of chemotherapy was shown to improve survival when added to definitive thoracic radiotherapy in patients with stage III non–small-cell lung cancer (NSCLC). Soon thereafter we learned that concurrent chemoradiotherapy was slightly better than sequential treatment. Unfortunately, despite much effort during the last 20 years, we have witnessed little progress in treating this common presentation of lung cancer. Radiation dose, intensity-modulated radiation, newer chemotherapy, induction treatment, consolidation treatment, and incorporation of novel agents have failed to significantly improve outcome. Almost all of the improvement in outcomes of patients with stage III disease in 2011 (16-month median overall survival) compared with 1984 (10-month median overall survival) can likely be explained by stage migration during this period as a result of enhancements in imaging. Contrast this with our progress in approaching metastatic disease. The last decade has witnessed an explosion in our understanding of lung cancer biology and treatment. Agents targeting epidermal growth factor receptor, anaplastic lymphoma kinase, and vascular endothelial growth factor (VEGF) have made a major impact in the treatment of selected patients with advanced lung cancer, and molecular profiling has emerged as central to the treatment of patients with
Endocrine Functions of Adipose Tissue
Authors: Hironori Waki, Peter Tontonoz
Journal: Annual Review of Pathology Mechanisms of Disease (2006)

Obesity is a risk factor for type 2 diabetes, dyslipidemia, and cardiovascular disease. Dissection of the molecular mechanisms underlying obesity and its relationship to insulin resistance and the metabolic syndrome are essential for developing new strategies for prevention and treatment of these disorders. Both excess adipose tissue and lack of adipose tissue cause insulin resistance and dyslipidemia, suggesting that normal fat is required for the maintenance of systemic glucose and lipid homeostasis. Recent advances in obesity research have led to the recognition that adipose tissue is an active endocrine organ that secretes multiple bioactive factors termed adipokines. Secretion of adipokines provides a link between adipose tissue lipid accumulation and the metabolic function of other tissues such as liver and muscle. Dysregulation of adipokines is emerging as an important mechanism by which adipose tissue contributes to systemic insulin resistance and metabolic disease.
Cost-Effectiveness of HIV Treatment as Prevention in Serodiscordant Couples
Authors: Rochelle P. Walensky, Eric L. Ross, Nagalingeswaran Kumarasamy, Robin Wood, Farzad Noubary, A. David Paltiel, Yoriko M. Nakamura, Sheela V. Godbole, Ravindre Panchia, Ian Sanne, Milton C. Weinstein, Elena Losina, Kenneth H. Mayer, Ying Q. Chen, Lei Wang, Marybeth McCauley, Theresa Gamble, George R. Seage, Myron S. Cohen, Kenneth A. Freedberg
Journal: New England Journal of Medicine (2013)

The cost-effectiveness of early antiretroviral therapy (ART) in persons infected with human immunodeficiency virus (HIV) in serodiscordant couples is not known. Using a computer simulation of the progression of HIV infection and data from the HIV Prevention Trials Network 052 study, we projected the cost-effectiveness of early ART for such persons.
Detection of Bronchial and Arterial Obstruction by Continuous Gas Analysis from Individual Lobes and Segments of the Lung
Authors: P. Hugh-Jones, J. B. West
Journal: Thorax (1960)

A mass spectrometer was designed specially for clinical respiratory investigation (Fowler, 1957) and it has been in use for general tests of lung function for three years. It performs continuous automatic gas analysis, and has a gas-sampling tube of only about I mm. external diameter at its tip. This fine sampling tube, which is placed at the patient's lips during general tests of lung function, has now been adapted so that it can be inserted down a bronchoscope into any lobar or segmental orifice which can be seen directly. From the results of bronchoscopic experiments on anaesthetized dogs it has been found that characteristic patterns of gas concentration changes are observed from regional bronchi during the breathing cycle and that these can be related to the ventilation, blood flow, and mechanical properties of the relevant lobe or segment. In this paper we shall first summarize these results from animal experiments and then present some examples of these characteristic patterns seen during routine diagnostic bronchoscopy in man and discuss their significance.
Risk of Type 2 Diabetes Attributable to C-Reactive Protein and Other Risk Factors
Authors: Abbas Dehghan, Mandy van Hoek, Eric J.G. Sijbrands, Theo Stijnen, Albert Hofman, Jacqueline C.M. Witteman
Journal: Diabetes Care (2007)

To calculate the population-attributable risk (PAR) of C-reactive protein (CRP) and other risk factors for type 2 diabetes.The Rotterdam Study is a population-based, prospective follow-up study among 7,983 participants aged > or = 55 years. Risk factors including serum CRP were determined at baseline. Participants with diabetes at baseline were excluded, and the cohort was followed for a mean of 10.8 years. The hazard ratio (HR) and PAR for diabetes were computed for all studied risk factors.Serum CRP > 1 mg/l (HR 1.67, PAR 0.33), BMI > 25 kg/m2 (HR 2.51, PAR 0.51), waist circumference > 102 for men and > 88 cm for women (HR 1.36, PAR 0.14), current smoking (HR 1.16, PAR 0.03), age > 65 years (HR 1.35, PAR 0.15), and family history of diabetes (HR 1.87, PAR 0.16) were related to diabetes and contributed to the risk of the disease. Serum CRP was a greater contributor to the risk of diabetes in women than in men (PAR values of 0.37 vs. 0.28, respectively). Age and current smoking PARs were not statistically significantly contributing to the risk of diabetes in women. Combined PAR was 0.80 (95% CI 0.74-0.85) for all six studied risk factors and 0.71 (0.64-0.78) for modifiable risk factors (serum CRP, BMI, waist circumference, and current smoking).High CRP is one of the major contributors to the risk of type 2 diabetes. The contribution of modifiable risk factors to the risk of diabetes is considerable.
Tight glycemic control and computerized decision-support systems: a systematic review
Authors: Saeid Eslami, Ameen Abu-Hanna, Evert de Jonge, Nicolette F. de Keizer
Journal: Intensive Care Medicine (2009)

To identify and summarize characteristics of computerized decision-support systems (CDSS) for tight glycemic control (TGC) and to review their effects on the quality of the TGC process in critically ill patients.We searched Medline (1950-2008) and included studies on critically ill adult patients that reported original data from a clinical trial or observational study with a main objective of evaluating a given TGC protocol with a CDSS.Seventeen articles met the inclusion criteria. Eleven out of seventeen studies evaluated the effect of a new TGC protocol that was introduced simultaneously with a CDSS implementation. Most of the reported CDSSs were stand-alone, were not integrated in any other clinical information systems and used the "passive" mode requiring the clinician to ask for advice. Different implementation sites, target users, and time of advice were used, depending on local circumstances. All controlled studies reported on at least one quality indicator of the blood glucose regulatory process that was improved by introducing the CDSS. Nine out of ten controlled studies either did not report on the number of hypoglycemia events (one study), or reported on no change (six studies) or even a reduction in this number (two studies).While most studies evaluating the effect of CDSS on the quality of the TGC process found improvement when evaluated on the basis of the quality indicators used, it is impossible to define the exact success factors, because of simultaneous implementation of the CDSS with a new or modified TGC protocol and the hybrid solutions used to integrate the CDSS into the clinical workflow.
Assessment of Self-Injurious Thoughts Using a Behavioral Test
Authors: Matthew Nock
Journal: American Journal of Psychiatry (2007)

Objective: The assessment of self-injurious thoughts has been limited by a reliance on what individuals are willing or able to report explicitly. The authors examined a new method that measures self-injurious thoughts by using individuals' reaction times to self-injury-related stimuli on a computerized test. Method: Eighty-nine adolescents who were not self-injurious (N=36) or had recently engaged in nonsuicidal self-injury (N=53) completed two versions of the Self-Injury Implicit Association Test, which measure the automatic association of self-injury with oneself and with favorableness. Results The tests revealed significant behavioral differences between the self-injurers and noninjurers. Moreover, test scores significantly improved the statistical prediction of nonsuicidal self-injury beyond that achieved with demographic and psychiatric factors. Conclusions: These initial results support the validity of the Self-Injury Implicit Association Test as a performance-based measure of self-injurious thoughts. Future research should further examine the usefulness of incorporating implicit measures in risk assessment and decision-making procedures for self-injury and other sensitive clinical behaviors.
Downmodulation of key inflammatory cell markers with a topical Janus kinase 1/2 inhibitor
Authors: N. Punwani, T. Burn, P. Scherle, R. Flores, J. Shi, P. Collier, D. Hertel, P. Haley, Y. Lo, P. Waeltz, J. Rodgers, S. Shepard, K. Vaddi, S. Yeleswaram, R. Levy, W. Williams, A.B. Gottlieb
Journal: British Journal of Dermatology (2015)

INCB018424 is a novel, potent Janus kinase (JAK)1/JAK2 inhibitor that blocks signal transduction of multiple proinflammatory cytokines.To evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of topical INCB018424 phosphate cream in patients with plaque psoriasis.Topical INCB018424 phosphate 1·0% or 1·5% cream was applied once daily (QD) or twice daily (BID) for 4 weeks to 2-20% body surface area in five sequential cohorts of five patients aged 18-65 years. Target lesions were scored on a scale of 0-4 for erythema, scaling and thickness. Additionally, the overall disease activity in each patient was measured using Physician's Global Assessment. INCB018424 concentrations were measured in plasma, and cytokine stimulated phosphorylated signal transducer and activator of transcription 3 phosphorylation (pSTAT3) levels in peripheral blood cells were evaluated. Pretreatment and post-treatment skin biopsies were compared with healthy skin, including evaluation of histopathology, immunohistochemistry and mRNA expression.Treatment with INCB018424 phosphate cream either 1·0% QD or 1·5% BID resulted in improvements in lesion scores. No significant inhibition of pSTAT3 in peripheral blood cells was observed following topical application, consistent with the generally low steady-state plasma concentrations of INCB018424 measured. Transcriptional markers of immune cell lineage/activation in lesional skin were reduced by topical INCB018424, with correlations observed between clinical improvement and decreases in markers of T helper 17 lymphocyte activation, dendritic-cell activation and epidermal hyperplasia. INCB018424 treatment reduced epidermal hyperplasia and dermal inflammation in most patient samples, with reductions in CD3, CD11c, Ki67 and keratin 16 observed by immunohistochemical analysis.Topical INCB018424 dosed for 28 days QD or BID is pharmacologically active in patients with active psoriasis and modulates proinflammatory cytokines in the pathogenesis of psoriatic lesions.
Dysfunctional CD8+ T cells in hepatitis B and C are characterized by a lack of antigen-specific T-bet induction
Authors: Peter D. Kurktschiev, Bijan Raziorrouh, Winfried Schraut, Markus Backmund, Martin Wächtler, Clemens-Martin Wendtner, Bertram Bengsch, Robert Thimme, Gerald Denk, Reinhart Zachoval, Andrea Dick, Michael Spannagl, Jürgen Haas, Helmut M. Diepolder, Maria-Christina Jung, Norbert H. Gruener
Journal: The Journal of Experimental Medicine (2014)

The transcription factor T-bet regulates the production of interferon-γ and cytotoxic molecules in effector CD8 T cells, and its expression correlates with improved control of chronic viral infections. However, the role of T-bet in infections with differential outcome remains poorly defined. Here, we report that high expression of T-bet in virus-specific CD8 T cells during acute hepatitis B virus (HBV) and hepatitis C virus (HCV) infection was associated with spontaneous resolution, whereas T-bet deficiency was more characteristic of chronic evolving infection. T-bet strongly correlated with interferon-γ production and proliferation of virus-specific CD8 T cells, and its induction by antigen and IL-2 stimulation partially restored functionality in previously dysfunctional T-bet–deficient CD8 T cells. However, restoration of a strong interferon-γ response required additional stimulation with IL-12, which selectively induced the phosphorylation of STAT4 in T-bet+ CD8 T cells. The observation that T-bet expression rendered CD8 T cells responsive to IL-12 suggests a stepwise mechanism of T cell activation in which T-bet facilitates the recruitment of additional transcription factors in the presence of key cytokines. These findings support a critical role of T-bet for viral clearance and suggest T-bet deficiency as an important mechanism behind chronic infection.
Long working hours and alcohol use: systematic review and meta-analysis of published studies and unpublished individual participant data
Authors: M. Virtanen, M. Jokela, S. T. Nyberg, I. E. H. Madsen, T. Lallukka, K. Ahola, L. Alfredsson, G. D. Batty, J. B. Bjorner, M. Borritz, H. Burr, A. Casini, E. Clays, D. De Bacquer, N. Dragano, R. Erbel, J. E. Ferrie, E. I. Fransson, M. Hamer, K. Heikkila, K.-H. Jockel, F. Kittel, A. Knutsson, M. Koskenvuo, K.-H. Ladwig, T. Lunau, M. L. Nielsen, M. Nordin, T. Oksanen, J. H. Pejtersen, J. Pentti, R. Rugulies, P. Salo, J. Schupp, J. Siegrist, A. Singh-Manoux, A. Steptoe, S. B. Suominen, T. Theorell, J. Vahtera, G. G. Wagner, P. J. M. Westerholm, H. Westerlund, M. Kivimaki
Journal: BMJ (2015)

<b>Objective</b> To quantify the association between long working hours and alcohol use. <b>Design</b> Systematic review and meta-analysis of published studies and unpublished individual participant data. <b>Data sources</b> A systematic search of PubMed and Embase databases in April 2014 for published studies, supplemented with manual searches. Unpublished individual participant data were obtained from 27 additional studies. <b>Review methods</b> The search strategy was designed to retrieve cross sectional and prospective studies of the association between long working hours and alcohol use. Summary estimates were obtained with random effects meta-analysis. Sources of heterogeneity were examined with meta-regression. <b>Results</b> Cross sectional analysis was based on 61 studies representing 333 693 participants from 14 countries. Prospective analysis was based on 20 studies representing 100 602 participants from nine countries. The pooled maximum adjusted odds ratio for the association between long working hours and alcohol use was 1.11 (95% confidence interval 1.05 to 1.18) in the cross sectional analysis of published and unpublished data. Odds ratio of new onset risky alcohol use was 1.12 (1.04 to 1.20) in the analysis of prospective published and unpublished data. In the 18 studies with individual participant data it was possible to assess the European Union Working Time Directive, which recommends an upper limit of 48 hours a week. Odds ratios of new onset risky alcohol use for those working 49-54 hours and ≥55 hours a week were 1.13 (1.02 to 1.26; adjusted difference in incidence 0.8 percentage points) and 1.12 (1.01 to 1.25; adjusted difference in incidence 0.7 percentage points), respectively, compared with working standard 35-40 hours (incidence of new onset risky alcohol use 6.2%). There was no difference in these associations between men and women or by age or socioeconomic groups, geographical regions, sample type (population based <i>v</i> occupational cohort), prevalence of risky alcohol use in the cohort, or sample attrition rate. <b>Conclusions</b> Individuals whose working hours exceed standard recommendations are more likely to increase their alcohol use to levels that pose a health risk.
Dupilumab in Persistent Asthma with Elevated Eosinophil Levels
Authors: Sally Wenzel, Linda Ford, David Pearlman, Sheldon Spector, Lawrence Sher, Franck Skobieranda, Lin Wang, Stephane Kirkesseli, Ross Rocklin, Brian Bock, Jennifer Hamilton, Jeffrey E. Ming, Allen Radin, Neil Stahl, George D. Yancopoulos, Neil Graham, Gianluca Pirozzi
Journal: New England Journal of Medicine (2013)

Moderate-to-severe asthma remains poorly treated. We evaluated the efficacy and safety of dupilumab (SAR231893/REGN668), a fully human monoclonal antibody to the alpha subunit of the interleukin-4 receptor, in patients with persistent, moderate-to-severe asthma and elevated eosinophil levels.We enrolled patients with persistent, moderate-to-severe asthma and a blood eosinophil count of at least 300 cells per microliter or a sputum eosinophil level of at least 3% who used medium-dose to high-dose inhaled glucocorticoids plus long-acting beta-agonists (LABAs). We administered dupilumab (300 mg) or placebo subcutaneously once weekly. Patients were instructed to discontinue LABAs at week 4 and to taper and discontinue inhaled glucocorticoids during weeks 6 through 9. Patients received the study drug for 12 weeks or until a protocol-defined asthma exacerbation occurred. The primary end point was the occurrence of an asthma exacerbation; secondary end points included a range of measures of asthma control. Effects on various type 2 helper T-cell (Th2)-associated biomarkers and safety and tolerability were also evaluated.A total of 52 patients were assigned to the dupilumab group, and 52 patients were assigned to the placebo group. Baseline characteristics were similar in the two groups. Three patients had an asthma exacerbation with dupilumab (6%) versus 23 with placebo (44%), corresponding to an 87% reduction with dupilumab (odds ratio, 0.08; 95% confidence interval, 0.02 to 0.28; P<0.001). Significant improvements were observed for most measures of lung function and asthma control. Dupilumab reduced biomarkers associated with Th2-driven inflammation. Injection-site reactions, nasopharyngitis, nausea, and headache occurred more frequently with dupilumab than with placebo.In patients with persistent, moderate-to-severe asthma and elevated eosinophil levels who used inhaled glucocorticoids and LABAs, dupilumab therapy, as compared with placebo, was associated with fewer asthma exacerbations when LABAs and inhaled glucocorticoids were withdrawn, with improved lung function and reduced levels of Th2-associated inflammatory markers. (Funded by Sanofi and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT01312961.).
Purification and characterization of eight class 5 outer membrane protein variants from a clone of Neisseria meningitidis serogroup A.
Authors: M Achtman, M Neibert, B A Crowe, W Strittmatter, B Kusecek, E Weyse, M J Walsh, B Slawig, G Morelli, A Moll
Journal: The Journal of Experimental Medicine (1988)

Methods published for the purification of P.II proteins from Neisseria gonorrhoea have been modified to allow the purification of class 5 proteins from Neisseria meningitidis serogroup A bacteria. The five class 5 protein electrophoretic variants detected within an epidemic in the Gambia (a, b, c, d, and e) and three other variants (f, g, and h) found within other isolates of the same clone in West Africa have been purified with yields of 6-28 mg. The NH2-terminal amino acid sequence for variant c differs from those of the other class 5 proteins, whereas the latter are very similar to the sequence predicted for two class 5 proteins from DNA analyses of serogroup C meningococci and determined for 8 P.II proteins from gonococci. Numerous other regulatory, chemical, and serological differences were found between the c protein and the other class 5 proteins such that we recommend that the class 5 proteins be subdivided into two subclasses. mAbs have been isolated that distinguish between these two protein subclasses and Western blotting with these antibodies enabled us to conclude that both protein subclasses were found in bacteria isolated from different epidemics and pandemics of the last 50 yr.
SRL172 (killed Mycobacterium vaccae) in addition to standard chemotherapy improves quality of life without affecting survival, in patients with advanced non-small-cell lung cancer: phase III results
Authors: M.E.R. O’Brien, H. Anderson, E. Kaukel, K. O’Byrne, M. Pawlicki, J. von Pawel, M. Reck
Journal: Annals of Oncology (2004)
High-sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: correlation with clonal cytogenetic evolution but not response to therapy
Authors: Stephanie G. Willis, Thoralf Lange, Shadmehr Demehri, Sandra Otto, Lucy Crossman, Dietger Niederwieser, Eric P. Stoffregen, Shannon McWeeney, Ines Kovacs, Byung Park, Brian J. Druker, Michael W. Deininger
Journal: Blood (2005)