tbuckley/cabot-search huggingface dataset:
Randomized Phase II Trial Designs With Biomarkers
Authors: Boris Freidlin, Lisa M. McShane, Mei-Yin C. Polley, Edward L. Korn
Journal: Journal of Clinical Oncology (2012)

Efficient development of targeted therapies that may only benefit a fraction of patients requires clinical trial designs that use biomarkers to identify sensitive subpopulations. Various randomized phase III trial designs have been proposed for definitive evaluation of new targeted treatments and their associated biomarkers (eg, enrichment designs and biomarker-stratified designs). Before proceeding to phase III, randomized phase II trials are often used to decide whether the new therapy warrants phase III testing. In the presence of a putative biomarker, the phase II trial should also provide information as to what type of biomarker phase III trial is appropriate. A randomized phase II biomarker trial design is proposed, which, after completion, recommends the type of phase III trial to be used for the definitive testing of the therapy and the biomarker. The recommendations include the possibility of proceeding to a randomized phase III of the new therapy with or without using the biomarker and also the possibility of not testing the new therapy further. Evaluations of the proposed trial design using simulations and published data demonstrate that it works well in providing recommendations for phase III trial design.
Complement C3 Variant and the Risk of Age-Related Macular Degeneration
Authors: John R.W. Yates, Tiina Sepp, Baljinder K. Matharu, Jane C. Khan, Deborah A. Thurlby, Humma Shahid, David G. Clayton, Caroline Hayward, Joanne Morgan, Alan F. Wright, Ana Maria Armbrecht, Baljean Dhillon, Ian J. Deary, Elizabeth Redmond, Alan C. Bird, Anthony T. Moore
Journal: New England Journal of Medicine (2007)

Age-related macular degeneration is the most common cause of blindness in Western populations. Susceptibility is influenced by age and by genetic and environmental factors. Complement activation is implicated in the pathogenesis.
Effectiveness of Outpatient, Day Hospital, and Inpatient Psychotherapeutic Treatment for Patients with Cluster B Personality Disorders
Authors: Anna Bartak, Helene Andrea, Marieke D. Spreeuwenberg, Uli M. Ziegler, Jack Dekker, Bert V. Rossum, Elisabeth F.M. Hamers, Wubbo Scholte, Janneke Aerts, Jan J.V. Busschbach, Roel Verheul, Theo Stijnen, Paul M.G. Emmelkamp
Journal: Psychotherapy and Psychosomatics (2010)

&lt;i&gt;Background:&lt;/i&gt; For patients with cluster B personality disorders there is no consensus regarding the optimal treatment setting. The aim of this study was to compare the effectiveness of different psychotherapeutic settings for patients with cluster B personality disorders, i.e. outpatient, day hospital, and inpatient treatment. &lt;i&gt;Methods:&lt;/i&gt; The study was conducted between March 2003 and June 2008 in 6 mental health care centres in the Netherlands, with a sample of 207 patients with a DSM-IV-TR axis II cluster B diagnosis. Patients were assigned to 3 different settings of psychotherapeutic treatment and effectiveness was assessed at 18 months after baseline. An intention-to-treat analysis was conducted for psychiatric symptoms (Brief Symptom Inventory), psychosocial functioning (Outcome Questionnaire-45), and quality of life (EQ-5D), using multilevel statistical modelling. As the study was non-randomised, the propensity score method was used to control for initial differences. &lt;i&gt;Results:&lt;/i&gt; Patients in all 3 settings improved significantly in terms of psychiatric symptoms, social and interpersonal functioning, and quality of life 18 months after baseline. The inpatient group showed the largest improvements. The comparison of outpatient and inpatient treatment regarding psychiatric symptoms showed a marginally significant result (p = 0.057) in favour of inpatient treatment. &lt;i&gt;Conclusions:&lt;/i&gt; Patients with cluster B personality disorders improved in all investigated treatment settings, with a trend towards larger improvements of psychiatric symptoms in the inpatient setting compared to the outpatient setting. Specialised inpatient treatment should be considered as a valuable treatment option for cluster B personality disorders, both in research and in clinical practice.
TREATMENT OF VASOMOTOR RHINITIS WITH INTRANASAL BECLOMETHASONE DIPROPIONATE (BECOTIDE®)
Authors: THORVALD LÖFKVIST, GUNNAR SVENSSON
Journal: Allergy (1976)

The effect of beclomethasone dipropionate (Becotide) intranasally in vasomotor rhinitis has been studied on 39 adult volunteers in a double-blind cross-over study during 9 weeks in February-April 1975. The dose of beclomethasone dipropionate was 300 mug/day. Twenty-five patients preferred the beclomethasone dipropionate period, 5 patients the placebo period, and 9 patients had no preference. About three-quarters (74 per cent) of the patients considered themselves free of symptoms or greatly improved after the treatment with beclomethasone dipropionate. Statistical calculation of the daily nasal symptoms score confirms the improvement. The speediest effect was registered for sneezing, followed by nasal catarrh, nasal itching, and blocking. No changes in the levels of cortisol occurred during the treatment. The bacteriological and mycological findings (analysed with regard to Candida albicans) were fairly constant.
Embracing the local: enriching scientific research, education, and outreach on the Texas-Mexico border through a participatory action research partnership.
Authors: Marlynn L May, Gloria J Bowman, Kenneth S Ramos, Larry Rincones, Maria G Rebollar, Mary L Rosa, Josephine Saldana, Adelina P Sanchez, Teresa Serna, Norma Viega, Gregoria S Villegas, Maria G Zamorano, Irma N Ramos
Journal: Environmental Health Perspectives (2003)

Cameron Park, Texas, is a colonia (an isolated, unincorporated rural settlement without municipal improvements) on the Texas-Mexico border in the Lower Rio Grande Valley, in Cameron County near Brownsville, Texas. Cameron Park has a population of 5,961 residents, 99.3% of whom are Hispanic. The annual median income is 16,934 US dollars, about one-half of the state median. Fifty-eight percent of families generally and 68% of those with children younger than 5 years have incomes below poverty level. Cameron Park resides geographically in a region where agriculture has been, and continues to be, a dominant industry, a fact consistent with the intensive use of pesticides and increased potential for air, water, and ground contamination. The practice of good environmental health is extremely difficult under these conditions. In 1999 the Texas A&amp;M University Center for Housing and Urban Development's Colonias Program and the Center for Environmental and Rural Health teamed up to create an environmental health education and outreach program called the Cameron Park Project (CPP). The CPP focused on how to reduce potential environmental exposures associated with human illness by providing residents with scientifically sound information on positive health practices and how to deal with environmental hazards. In this article we discuss the research methodology used in the CPP, a methodology specifically chosen to address four challenges presented by colonias to conducting valid and reliable research.
Analysis of Specific Transcriptional Regulators as Early Predictors of Independent Prognostic Relevance in Resected Colorectal Cancer
Authors: Gabriele D. Maurer, Joerg H. Leupold, Denis M. Schewe, Tobias Biller, Ronald E. Kates, Hans-Martin Hornung, Ulla Lau-Werner, Stefan Post, Heike Allgayer
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Prognostic studies on transcription factors acting at specific promoter elements have never been done so far. However, in tumors with long necessary follow-up, such as colorectal cancer, early-risk predictors would be needed. The invasion-related gene u-PAR is regulated via an activator protein 2 (AP-2)/Sp1 (−152/−135) and an AP-1 binding promoter motif (−190/−171), mediating u-PAR induction by K-Ras and Src. The present study was done to give first evidence for early prognostic relevance of transcription factors differentially bound to the u-PAR promoter, and their molecular inducers, in colorectal cancer. Experimental Design: Tumor/normal tissues of 92 prospectively followed (median = 26.3 months) patients were analyzed for Src activity/protein, K-ras mutations, and transcription factor binding to both u-PAR promoter motifs (in vivo gel shift, kinase assay, and PCR). Results: Kaplan-Meier/Mantel-Cox analysis showed a significant correlation among elevated Sp1/Sp3 binding to region −152/−135 (P = 0.002 and P = 0.006), the combinations of Sp1/AP-2 and Sp1/AP-1 binding to both motifs (P = 0.010 and P = 0.005), and Sp1 binding/high Src protein in tumors (P &amp;lt; 0.001), with poor survival. Survival decreased with the number of bound transcription factors to both motifs, with binding of three factors defining a high-risk group (P = 0.021). In multivariate analysis, elevated Sp1 binding, combinations of Sp1/AP-2 binding and Sp1/AP-1 binding, or Sp1 binding/high Src were independent prognostic variables; u-PAR expression itself being not yet prognostic. A first molecular staging model (CART) was defined, providing novel early high-risk groups (mean survival time as low as for non-curatively resected patients) from these variables. Conclusions: This study defines transcription factors acting at specific promoter elements of an invasion-related gene, mediating specific signaling, as novel, independent, early predictors of prognosis in colorectal cancer.
Role of FRNK tyrosine phosphorylation in vascular smooth muscle spreading and migration
Authors: Yevgeniya E. Koshman, Steven J. Engman, Taehoon Kim, Rekha Iyengar, Kyle K. Henderson, Allen M. Samarel
Journal: Cardiovascular Research (2009)

AimsFocal adhesion kinase (FAK) and its autonomously expressed, C-terminal inhibitor FAK-related non-kinase (FRNK), are important regulators of vascular smooth muscle cell (VSMC) spreading and migration. However, the mechanisms of FRNK-mediated inhibition of FAK-dependent signalling are not fully defined. The aim of this study was to determine the potential role of FRNK tyrosine phosphorylation in regulating these processes.
Spatial variation of the colonic microbiota in patients with ulcerative colitis and control volunteers
Authors: A Lavelle, G Lennon, O O'Sullivan, N Docherty, A Balfe, A Maguire, H E Mulcahy, G Doherty, D O'Donoghue, J Hyland, R P Ross, J C Coffey, K Sheahan, P D Cotter, F Shanahan, D C Winter, P R O'Connell
Journal: Gut (2015)

<h3>Objectives</h3> The relevance of spatial composition in the microbial changes associated with UC is unclear. We coupled luminal brush samples, mucosal biopsies and laser capture microdissection with deep sequencing of the gut microbiota to develop an integrated spatial assessment of the microbial community in controls and UC. <h3>Design</h3> A total of 98 samples were sequenced to a mean depth of 31 642 reads from nine individuals, four control volunteers undergoing routine colonoscopy and five patients undergoing surgical colectomy for medically-refractory UC. Samples were retrieved at four colorectal locations, incorporating the luminal microbiota, mucus gel layer and whole mucosal biopsies. <h3>Results</h3> Interpersonal variability accounted for approximately half of the total variance. Surprisingly, within individuals, asymmetric Eigenvector map analysis demonstrated differentiation between the luminal and mucus gel microbiota, in both controls and UC, with no differentiation between colorectal regions. At a taxonomic level, differentiation was evident between both cohorts, as well as between the luminal and mucosal compartments, with a small group of taxa uniquely discriminating the luminal and mucosal microbiota in colitis. There was no correlation between regional inflammation and a breakdown in this spatial differentiation or bacterial diversity. <h3>Conclusions</h3> Our study demonstrates a conserved spatial structure to the colonic microbiota, differentiating the luminal and mucosal communities, within the context of marked interpersonal variability. While elements of this structure overlap between UC and control volunteers, there are differences between the two groups, both in terms of the overall taxonomic composition and how spatial structure is ascribable to distinct taxa.
Proposal for the Reconsideration of the Definition of Gestational Diabetes
Authors: Yasue Omori, Lois Jovanovic
Journal: Diabetes Care (2005)

In 1997, the American Diabetes Association (ADA) announced a new diagnostic criterion for diabetes and set the definition of gestational diabetes mellitus (GDM). Before 1991, GDM was defined as “a transient abnormality of glucose tolerance during pregnancy” (2–4). However, the 1997 definition of GDM by the ADA includes diabetes diagnosed during pregnancy. This definition ignores the added risks to the mother and to the fetus when the mother has undiagnosed type 2 diabetes. We propose reconsideration of the definition, which would separate diabetes and slight abnormal carbohydrate, so-called GDM, to provide a better model of care for type 2 diabetic pregnant women.

There are three problems concerning an undiagnosed type 2 diabetic woman that …
Relation of pulmonary lymphangio-leiomyomatosis to use of the oral contraceptive pill and fertility in the UK: a national case control study.
Authors: I Wahedna, S Cooper, J Williams, I C Paterson, J R Britton, A E Tattersfield
Journal: Thorax (1994)

Pulmonary lymphangioleiomyomatosis is a rare progressive disease of unknown aetiology affecting premenopausal women. Since the oral contraceptive pill has been implicated in its pathogenesis, a case control study was carried out to determine whether women with the disease were more likely to have taken the oral contraceptive pill, and whether the disease was associated with other conditions related to sex hormones including pregnancy, parity, and fibroids.All chest physicians in the UK were asked for details of all live patients with pulmonary lymphangioleiomyomatosis; the patient's family doctor was then asked for four age and sex matched control subjects from their patient register. Details of lifetime use of the oral contraceptive pill, pregnancy, parity, history of fibroids, and smoking were obtained from cases and controls. Relative odds of exposure to potential risk factors were estimated by conditional logistic regression.Medical details were obtained from all 23 cases of lymphangioleiomyomatosis identified; questionnaires were completed by 21 cases (one by proxy) and by 46 matched controls of mean (SD) age 43 (10) and 44 (11) years, respectively. The patients had a mean age of 34 (9) years at onset of symptoms and a median (range) time of 2 (0-29) years from onset of symptoms to diagnosis. Compared with control subjects, cases did not differ in the use of the oral contraceptive pill (odds ratio (OR) 0.39, 95% CI 0.09 to 1.68), diagnosis of fibroids (OR 3.12; 95% CI 0.52 to 18.7), age of menarche, menstrual history, or lifetime smoking. They were, however, less likely to have been pregnant (OR 0.14, 95% CI 0.03 to 0.71) or to have had children (OR 0.13, 95% CI 0.03 to 0.67). More pregnancies had ended in spontaneous abortion (28% v 8%) but the proportion of women undergoing spontaneous abortion was similar in cases and controls (OR 2.13, 95% CI 0.47 to 9.3).This study does not support the hypothesis that use of the oral contraceptive pill is causally associated with the development of pulmonary lymphangioleiomyomatosis. Sex hormones may be involved, however, since patients were less likely to have been pregnant or to have had children, and tended to have had more spontaneous abortions and an increased incidence of fibroids.
Bax translocation and mitochondrial fragmentation induced by Helicobacter pylori
Authors: H Ashktorab, S Frank, A R Khaled, S K Durum, B Kifle, D T Smoot
Journal: Gut (2004)

Previous in vitro and in vivo studies have revealed an association between Helicobacter pylori infection and apoptosis in gastric epithelial cells. Although involvement of the Bcl-2 family of proteins as well as cytochrome c release has been demonstrated in H pylori induced cell death, the exact role of the mitochondria during this type of programmed cell death has not been fully elucidated. Therefore, we sought to determine whether or not Bax translocation and mitochondrial fragmentation occur on exposure of gastric epithelial cells to H pylori, resulting in cell death.Experiments were performed with human gastric adenocarcinoma (AGS) cells, AGS cells transfected with the HPV-E6 gene (which inactivates p53 function), AGS-neo cells (transfected with the backbone construct), mouse embryonic fibroblasts (MEFs), and p19(ARF) null (ARF(-/-)) MEFs. Cells were incubated with a cag positive H pylori strain for up to 24 hours, lysed, and cytoplasmic and mitochondrial membrane fractions were analysed by western blot for Bax translocation.Bax translocation was detected in AGS, AGS-neo, and normal MEF cells after exposure to H pylori for three hours, but not in ARF(-/-) MEFs cells. Translocation of Bax after H pylori incubation was also detected in AGS-E6 cells (inactive p53 gene) but to a lesser degree than in AGS-neo cells. In parallel studies, the mitochondrial morphology of living cells infected with H pylori was assessed by confocal microscopy. Mitochondrial fragmentation was detectable after 10 hours of H pylori incubation with AGS cells and after seven hours with MEF cells. In wild-type MEFs, mitochondrial fragmentation was significantly increased in comparison with ARF null MEFs (43% v 10.4%, respectively). Furthermore, mitochondrial depolarisation and caspase-3 activity were initiated within four hours in cells incubated with H pylori, and these events were inhibited by forced expression of Bcl-2.These data suggest that during H pylori induced apoptosis, Bax translocates to the mitochondria which subsequently undergo depolarisation and profound fragmentation. Functional ARF and p53 proteins may play an important role in H pylori induced mitochondrial modification.
A community empowerment approach to the HIV response among sex workers: effectiveness, challenges, and considerations for implementation and scale-up
Authors: Deanna Kerrigan, Caitlin E Kennedy, Ruth Morgan-Thomas, Sushena Reza-Paul, Peninah Mwangi, Kay Thi Win, Allison McFall, Virginia A Fonner, Jennifer Butler
Journal: The Lancet (2014)
Psychological Factors and Heart Disease
Authors: STANLEY H. FISHER
Journal: Circulation (1963)

A number of studies have revealed that perceived emotional stress can produce various transient cardiovascular responses. The reactions may include changes in heart rate and cardiac output. They may include abnormalities in heart rhythm, changes in blood pressure, peripheral resistance, blood viscosity, blood clotting time, and serum cholesterol levels. A hypothesis suggested by the findings which requires further research follows: If these cardiovascular responses were sustained for a period of time, they would ultimately influence the onset or course of coronary artery disease. These studies also suggest that emotional tension at one's work may place an additional strain on an already diseased heart. In patients whose cardiovascular system is already impaired, investigators have traced the sequence from emotional upset to heart disease. Since the reported evidence has been based on cardiac subjects, it is still possible that "gradual increase in tension" is perceived only after illness occurs, but not necessarily perceived as stressful before beart disease. Owing to the lack of prospective studies in which the life stress factors are studied prior to heart disease, emotion as a cause or contributory factor to heart disease has not been fully accepted. These studies suggest that certain personality traits may be common to certain forms of heart disease. Most of this evidence has been observed from time-consuming, detailed personality analysis, and the evidence depends on studies of relatively few patients and poor or no controls. It is important to note that these studies on personality type and heart disease were conducted after heart disorders developed. This raises the question of whether the reported personality characteristics preceded or followed the heart disease. The investigations to date assume that the personality structure occurred before the appearance of the heart disease, but before we can answer this question, a longitudinal study of the personality of individuals prior to cardiovascular disease would be necessary.
Critical roles of c-Rel in autoimmune inflammation and helper T cell differentiation
Authors: Brendan A. Hilliard, Nicola Mason, Lingyun Xu, Jing Sun, Salah-Eddine Lamhamedi-Cherradi, Hsiou-Chi Liou, Christopher Hunter, Youhai H. Chen
Journal: Journal of Clinical Investigation (2002)

Different members of the Rel/NF-κB family may play different roles in immunity and inflammation. We report here that c-Rel–deficient mice are resistant to autoimmune encephalomyelitis and are defective in Th1, but not Th2 responses. The Th1 deficiency appears to be caused by selective blockade of IL-12 production by c-Rel–deficient antigen-presenting cells, as well as by a complete abrogation of IFN-γ expression in c-Rel–deficient T cells. Interestingly, c-Rel deficiency does not affect T-bet expression, suggesting that c-Rel may act downstream of T-bet during Th1 cell differentiation. Thus, unlike NF-κB1, which selectively regulates Th2 cell differentiation, c-Rel is essential for Th1 cell differentiation and Th1 cell–mediated autoimmune inflammation.
Diagnosing One Letter at a Time
Authors: Christopher Smith, Sanjay Saint, Raymond Price, Ammar Al-Zoubi, Brian Callaghan
Journal: New England Journal of Medicine (2014)

A 45-year-old woman presented with lower-extremity weakness. She first noted weakness in her ankles and feet 5 months previously. The weakness progressed to involve her knees and hips, and she had been unable to walk without support for the prior 2 months.
N<scp>OVEL</scp>N<scp>EURAL</scp>M<scp>ODULATORS</scp>
Authors: Darren Boehning, Solomon H. Snyder
Journal: Annual Review of Neuroscience (2003)

▪ Abstract The discovery that nitric oxide (NO) is produced by neurons and regulates synaptic activity has challenged the definition of a neurotransmitter. NO is not stored in synaptic vesicles and does not act at conventional receptors on the surface of adjacent neurons. The toxic gases carbon monoxide (CO) and hydrogen sulfide (H 2 S) are also produced by neurons and modulate synaptic activity. D-serine synthesis and release by astrocytes as an endogenous ligand for the “glycine” site of N-methyl D-aspartate (NMDA) receptors defy the concept that a neurotransmitter must be synthesized by neurons. We review the properties of these “atypical” neural modulators.