tbuckley/cabot-search huggingface dataset:
A Signal Transducer and Activator of Transcription (Stat)4-independent Pathway for the Development of T Helper Type 1 Cells
Authors: Mark H. Kaplan, Andrea L. Wurster, Michael J. Grusby
Journal: The Journal of Experimental Medicine (1998)

The differentiation of T helper (Th) cells is regulated by members of the signal transducer and activator of transcription (STAT) family of signaling molecules. We have generated mice lacking both Stat4 and Stat6 to examine the ability of Th cells to develop in the absence of these two transcription factors. Stat4, Stat6(-/-) lymphocytes fail to differentiate into interleukin (IL)-4-secreting Th2 cells. However, in contrast to Stat4(-/-) lymphocytes, T cells from Stat4, Stat6(-/-) mice produce significant amounts of interferon (IFN)-gamma when activated in vitro. Although Stat4, Stat6(-/-) lymphocytes produce less IFN-gamma than IL-12-stimulated control lymphocytes, equivalent numbers of IFN-gamma-secreting cells can be generated from cultures of Stat4, Stat6(-/-) lymphocytes activated under neutral conditions and control lymphocytes activated under Th1 cell-promoting conditions. Moreover, Stat4, Stat6(-/-) mice are able to mount an in vivo Th1 cell-mediated delayed-type hypersensitivity response. These results support a model of Th cell differentiation in which the generation of Th2 cells requires Stat6, whereas a Stat4-independent pathway exists for the development of Th1 cells.
Significant and Sustained Antitumor Activity in Post-Docetaxel, Castration-Resistant Prostate Cancer With the CYP17 Inhibitor Abiraterone Acetate
Authors: Alison H.M. Reid, Gerhardt Attard, Daniel C. Danila, Nikhil Babu Oommen, David Olmos, Peter C. Fong, L. Rhoda Molife, Joanne Hunt, Christina Messiou, Christopher Parker, David Dearnaley, Joost F. Swennenhuis, Leon W.M.M. Terstappen, Gloria Lee, Thian Kheoh, Arturo Molina, Charles J. Ryan, Eric Small, Howard I. Scher, Johann S. de Bono
Journal: Journal of Clinical Oncology (2010)

The principal objective of this trial was to evaluate the antitumor activity of abiraterone acetate, an oral, specific, irreversible inhibitor of CYP17 in docetaxel-treated patients with castration-resistant prostate cancer (CRPC).In this multicenter, two-stage, phase II study, abiraterone acetate 1,000 mg was administered once daily continuously. The primary end point was achievement of a prostate-specific antigen (PSA) decline of > or = 50% in at least seven of 35 patients. Per an attained phase II design, more than 35 patients could be enrolled if the primary end point was met. Secondary objectives included: PSA declines of > or = 30% and > or = 90%; rate of RECIST (Response Evaluation Criteria in Solid Tumors) responses and duration on study; time to PSA progression; safety and tolerability; and circulating tumor cell (CTC) enumeration.Docetaxel-treated patients with CRPC (N = 47) were enrolled. PSA declines of > or = 30%, > or = 50% and > or = 90% were seen in 68% (32 of 47), 51% (24 of 47), and 15% (seven of 47) of patients, respectively. Partial responses (by RECIST) were reported in eight (27%) of 30 patients with measurable disease. Median time to PSA progression was 169 days (95% CI, 113 to 281 days). The median number of weeks on study was 24, and 12 (25.5%) of 47 patients remained on study > or = 48 weeks. CTCs were enumerated in 34 patients; 27 (79%) of 34 patients had at least five CTCs at baseline. Eleven (41%) of 27 patients had a decline from at least five to less than 5 CTCs, and 18 (67%) of 27 had a > or = 30% decline in CTCs after starting treatment with abiraterone acetate. Abiraterone acetate was well tolerated.Abiraterone acetate has significant antitumor activity in post-docetaxel patients with CRPC. Randomized, phase III trials of abiraterone acetate are underway to define the future role of this agent.
Results at Recruitment From a Randomized Controlled Trial Comparing Human Papillomavirus Testing Alone With Conventional Cytology as the Primary Cervical Cancer Screening Test
Authors: G. Ronco, P. Giorgi-Rossi, F. Carozzi, M. Confortini, P. D. Palma, A. Del Mistro, A. Gillio-Tos, D. Minucci, C. Naldoni, R. Rizzolo, P. Schincaglia, R. Volante, M. Zappa, M. Zorzi, J. Cuzick, N. Segnan
Journal: JNCI Journal of the National Cancer Institute (2008)

In the first recruitment phase of a randomized trial of cervical cancer screening methods (New Technologies for Cervical Cancer Screening [NTCC] study), we compared screening with conventional cytology with screening by human papillomavirus (HPV) testing in combination with liquid-based cytology. HPV-positive women were directly referred to colposcopy if aged 35 or older; if younger, they were retested after 1 year. In the second recruitment phase of NTCC, we randomly assigned women to conventional cytology (n = 24661) with referral to colposcopy if cytology indicated atypical squamous cells of undetermined significance or more severe abnormality or to testing for high-risk HPV DNA alone by Hybrid Capture 2 (n = 24535) with referral to colposcopy if the test was positive at a concentration of HPV DNA 1 pg/mL or greater. For the main endpoint of the study, histologic detection of cervical intraepithelial neoplasia of grade 2 or more (CIN2+), we calculated and compared sensitivity and positive predictive value (PPV) of the two screening methods using HPV DNA cutoffs of 1 pg/mL and 2 pg/mL. All statistical tests were two-sided. For women aged 35–60 years, the relative sensitivity of HPV testing for detection of CIN2+ at a cutoff of 1 pg/mL vs conventional cytology was 1.92 (95% CI = 1.28 to 2.87) and the relative PPV was 0.80 (95% CI = 0.55 to 1.18). At a cutoff of 2 pg/mL HPV DNA, the relative sensitivity was 1.81 (95% CI = 1.20 to 2.72) and the relative PPV was 0.99 (95% CI = 0.67 to 1.46). In this age group, there was no evidence of heterogeneity between study phases. Among women aged 25–34 years, the relative sensitivity for detection of CIN2+ of HPV testing at a cutoff of 1 pg/mL vs cytology was 3.50 (95% CI = 2.11 to 5.82), statistically significantly larger ( P = .019) than that observed in phase 1 at this age (1.58; 95% CI = 1.03 to 2.44). For women aged 35–60 years, HPV testing with a cutoff of 2 pg/mL achieves a substantial gain in sensitivity over cytology with only a small reduction in PPV. Among women aged 25–34 years, the large relative sensitivity of HPV testing compared with conventional cytology and the difference between relative sensitivity during phases 1 and 2 suggests that there is frequent regression of CIN2+ that are detected by direct referral of younger HPV-positive women to colposcopy. Thus, triage test or repeat testing is needed if HPV is to be used for primary testing in this context.
Beclomethasone/formoterol <i>vs</i> fluticasone/salmeterol inhaled combination in moderate to severe asthma
Authors: A. Papi, P. Paggiaro, G. Nicolini, A. M. Vignola, L. M. Fabbri
Journal: Allergy (2007)

Background: Recommended treatment for moderate to severe asthma is the combination of an inhaled corticosteroid and a long‐acting beta 2 ‐agonist. The present study was designed to compare a new fixed combination of extrafine beclomethasone and formoterol, with the fixed combination fluticasone and salmeterol. Methods: This was a phase III, multinational, multicentre, double‐blind, randomized, two‐arm parallel groups, controlled study. After a 2‐week run‐in period, 228 patients with moderate to severe asthma were randomized to a 12‐week treatment with either beclomethasone 100 μg plus formoterol 6 μg or fluticasone 125 μg plus salmeterol 25 μg, both delivered two inhalations b.i.d. via a pressurized metered dose inhaler. Results: The analysis of noninferiority on the primary outcome, morning peak expiratory flow in the last 2 weeks of treatment, showed no difference between groups (difference −3.32 l/min; 95% CI −17.92 to 11.28). A significant improvement from baseline in lung function, symptom score and rescue medication use was observed in both groups at all time points. Beclomethasone plus formoterol combination showed a significantly faster onset of bronchodilation when compared with fluticasone plus salmeterol with the difference maintained for up to 1 h postdosing. No differences were observed between treatments in the rate of asthma exacerbations, frequency of adverse events and overnight urinary cortisol/creatinine ratio. Conclusions: The new combination of extrafine beclomethasone plus formoterol is not inferior to the marketed combination of fluticasone and salmeterol in terms of efficacy and tolerability, with the advantage of a faster onset of bronchodilation. (ClinicalTrials.gov number, NCT00394368).
Metabolic stress regulates cytoskeletal dynamics and metastasis of cancer cells
Authors: M. Cecilia Caino, Young Chan Chae, Valentina Vaira, Stefano Ferrero, Mario Nosotti, Nina M. Martin, Ashani Weeraratna, Michael O’Connell, Danielle Jernigan, Alessandro Fatatis, Lucia R. Languino, Silvano Bosari, Dario C. Altieri
Journal: Journal of Clinical Investigation (2013)

Metabolic reprogramming is an important driver of tumor progression; however, the metabolic regulators of tumor cell motility and metastasis are not understood. Here, we show that tumors maintain energy production under nutrient deprivation through the function of HSP90 chaperones compartmentalized in mitochondria. Using cancer cell lines, we found that mitochondrial HSP90 proteins, including tumor necrosis factor receptor–associated protein-1 (TRAP-1), dampen the activation of the nutrient-sensing AMPK and its substrate UNC-51–like kinase (ULK1), preserve cytoskeletal dynamics, and release the cell motility effector focal adhesion kinase (FAK) from inhibition by the autophagy initiator FIP200. In turn, this results in enhanced tumor cell invasion in low nutrients and metastatic dissemination to bone or liver in disease models in mice. Moreover, we found that phosphorylated ULK1 levels were correlated with shortened overall survival in patients with non–small cell lung cancer. These results demonstrate that mitochondrial HSP90 chaperones, including TRAP-1, overcome metabolic stress and promote tumor cell metastasis by limiting the activation of the nutrient sensor AMPK and preventing autophagy.
Angiotensin II Receptor Antagonists and Angiotensin-Converting Enzyme Inhibitors Lower In Vitro the Formation of Advanced Glycation End Products
Authors: Toshio Miyata, Charles van Ypersele de Strihou, Yasuhiko Ueda, Kohji Ichimori, Reiko Inagi, Hiroshi Onogi, Naoyoshi Ishikawa, Masaomi Nangaku, Kiyoshi Kurokawa
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. The implication of advanced glycation end products (AGE) in the pathogenesis of atherosclerosis and of diabetic and uremic complications has stimulated a search for AGE inhibitors. This study evaluates the AGE inhibitory potential of several well-tolerated hypotensive drugs. Olmesartan, an angiotensin II type 1 receptor (AIIR) antagonist, as well as temocaprilat, an angiotensin-converting enzyme (ACE) inhibitor, unlike nifedipine, a calcium blocker, inhibit in vitro the formation of two AGE, pentosidine and Nε-carboxymethyllysine (CML), during incubation of nonuremic diabetic, nondiabetic uremic, or diabetic uremic plasma or of BSA fortified with arabinose. This effect is shared by all tested AIIR antagonists and ACE inhibitors. On an equimolar basis, they are more efficient than aminoguanidine or pyridoxamine. Unlike the latter two compounds, they do not trap reactive carbonyl precursors for AGE, but impact on the production of reactive carbonyl precursors for AGE by chelating transition metals and inhibiting various oxidative steps, including carbon-centered and hydroxyl radicals, at both the pre- and post-Amadori steps. Their effect is paralleled by a lowered production of reactive carbonyl precursors. Finally, they do not bind pyridoxal, unlike aminoguanidine. Altogether, this study demonstrates for the first time that widely used hypotensive agents, AIIR antagonists and ACE inhibitors, significantly attenuate AGE production. This study provides a new framework for the assessment of families of AGE-lowering compounds according to their mechanisms of action. E-mail: [email protected]
Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of chronic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study
Authors: Marcelo E Bigal, Lars Edvinsson, Alan M Rapoport, Richard B Lipton, Egilius L H Spierings, Hans-Christoph Diener, Rami Burstein, Pippa S Loupe, Yuju Ma, Ronghua Yang, Stephen D Silberstein
Journal: The Lancet Neurology (2015)
THE ROLE OF METABOLIC ACTIVATION IN DRUG-INDUCED HEPATOTOXICITY
Authors: B. Kevin Park, Neil R. Kitteringham, James L. Maggs, Munir Pirmohamed, Dominic P. Williams
Journal: The Annual Review of Pharmacology and Toxicology (2004)

The importance of reactive metabolites in the pathogenesis of drug-induced toxicity has been a focus of research interest since pioneering investigations in the 1950s revealed the link between toxic metabolites and chemical carcinogenesis. There is now a great deal of evidence that shows that reactive metabolites are formed from drugs known to cause hepatotoxicity, but how these toxic species initiate and propagate tissue damage is still poorly understood. This review summarizes the evidence for reactive metabolite formation from hepatotoxic drugs, such as acetaminophen, tamoxifen, diclofenac, and troglitazone, and the current hypotheses of how this leads to liver injury. Several hepatic proteins can be modified by reactive metabolites, but this in general equates poorly with the extent of toxicity. Much more important may be the identification of the critical proteins modified by these toxic species and how this alters their function. It is also important to note that the toxicity of reactive metabolites may be mediated by noncovalent binding mechanisms, which may also have profound effects on normal liver physiology. Technological developments in the wake of the genomic revolution now provide unprecedented power to characterize and quantify covalent modification of individual target proteins and their functional consequences; such information should dramatically improve our understanding of drug-induced hepatotoxic reactions.
Rheumatology: What should all doctors know?
Authors: M. Doherty
Journal: Annals of the Rheumatic Diseases (2000)

Although training (acquisition of specific skills) may be distinguished from education (an important value base, broader in concept) both are required for medical practice. Undergraduate education should adequately prepare students for their next career stage and lay the foundation upon which postgraduate training and continuing education build. For “rheumatology” the key essential competencies that all doctors should acquire as an undergraduate are: the ability through appropriate inquiry and examination to differentiate normality from abnormality within the system; accurate recognition of common locomotor conditions and locomotor emergencies; and the ability to outline appropriate investigation and management plans for common or urgent conditions. Linked to these are the understanding of applied anatomy/physiology and basic disease mechanisms , and professional and humanitarian attitudes . Most undergraduate education, therefore, needs to focus on informed holistic patient assessment . Learning objectives need to be clearly stated in the curriculum; the most efficient learning methods then need to be employed; and an assessment that accurately reflects the learning objectives needs to be applied. Each of these three elements needs constant review in the light of learner requirement and performance. Given the primacy of patient assessment in the objectives, clinical competencies should be prominent in the teaching and assessments. Published guidelines on development of a European core curriculum should usefully act as a focus for curriculum development within Europe. Each school can build additional objectives around this core, leading to appropriate diversity of interests and more specialised expertise in young doctors. Medical training from medical school entry onwards ideally should be viewed and organised as a single longitudinal integrated programme rather than as disjointed autonomous units. Before considering the justification and content of “rheumatology” in the undergraduate core curriculum it is germane to consider:
Serum Estradiol Level and Risk of Breast Cancer During Treatment With Raloxifene
Authors: Steven R. Cummings
Journal: JAMA (2002)

As endogenous estradiol increases, risk of breast cancer increases. Raloxifene competes with endogenous estrogen for binding to estrogen receptors in breast tissue. A woman's estradiol level may alter the effects of raloxifene on breast cancer and other outcomes.To test the hypothesis that raloxifene reduces breast cancer risk more in women with relatively high estradiol levels than in women with very low estradiol levels.Analysis of the Multiple Outcomes of Raloxifene Evaluation, a randomized, double-blind, placebo-controlled trial conducted from 1994 to 1999.One hundred eighty community settings and medical practices in 25 countries including the United States.A total of 7290 postmenopausal women aged 80 years or younger with osteoporosis who had baseline serum estradiol concentrations measured by a central laboratory using a sensitive assay. Women with a history of breast cancer or estrogen use were excluded.Participants were randomly assigned to receive 60 mg/d or 120 mg/d of raloxifene (n = 4843) or matching placebo (n = 2447) for 4 years.New cases of histopathologically confirmed breast cancer in the treatment and placebo groups, stratified by estradiol levels.In the placebo group, women with estradiol levels greater than 10 pmol/L (2.7 pg/mL) had a 6.8-fold higher rate of breast cancer (3.0% per 4 years; 95% confidence interval [CI], 1.8%-4.1%) than that of women with undetectable estradiol levels (0.6% per 4 years; 95% CI, 0%-1.1%; P =.005 for trend). Women with estradiol levels greater than 10 pmol/L in the raloxifene group had a rate of breast cancer that was 76% (95% CI, 53%-88%) lower than that of women with estradiol levels greater than 10 pmol/L in the placebo group (absolute rate reduction, 2.2% [95% CI, 1.0%-3.5%; number needed to treat = 45]). In contrast, women with undetectable estradiol levels had similar breast cancer risk whether or not they were treated with raloxifene (risk difference, -0.1%; 95% CI, -0.8% to 0.6%; P =.02 for the interaction). In this cohort, treating women with estradiol levels greater than 10 pmol/L with raloxifene for 4 years would have avoided 47% of breast cancer cases.Measurement of estradiol level by sensitive assay in postmenopausal women identifies those at high risk of breast cancer who may benefit most from raloxifene. If confirmed, this suggests that measuring estradiol and treating women with high estradiol levels could substantially reduce the rate of breast cancer among postmenopausal women.
Expression of structurally diverse Qa-2-encoded molecules on the surface of cloned cytotoxic T lymphocytes.
Authors: D H Sherman, D M Kranz, H N Eisen
Journal: The Journal of Experimental Medicine (1984)

Extracts of 125I-labeled cloned murine cytotoxic T lymphocytes (CTL) were immunoprecipitated with alloantisera to the cloned CTL and rabbit antisera to beta-2 microglobulin. Polyacrylamide gel electrophoresis (PAGE) of the specific precipitates revealed, as expected, 125I-labeled components that corresponded to products of class I genes of the major histocompatibility complex (MHC). However, additional class I gene products of relatively low apparent molecular weight (Mr) were also observed. Similar analyses of spleen cells from a variety of MHC-congenic mouse strains suggested that the class I molecules of relatively low Mr are encoded in the Qa-2 region of the MHC, and this was confirmed by immunoprecipitation with a monoclonal antibody to Qa-2. Surprisingly, however, the cell surface Qa-2 molecules of different CTL clones differed in Mr, in isoelectric focusing (IEF) pattern, and in the number of distinguishable molecules expressed per clone: some clones seemed to express only a single Qa-2-encoded molecule while others expressed two distinct ones. Treatment of the immunoprecipitated Qa-2 with endoglycosidase F (Endo F) resulted in a decrease in Mr of approximately 5,000-6,000, corresponding to the expected loss of N-linked oligosaccharides, but the decrease did not eliminate structural variability among the clones. Structural diversity of the Qa-2-encoded molecules expressed on CTL could arise because CTL clones differ (a) in the particular Qa-2 genes they express, (b) in the way they splice Qa-2 gene transcripts or, perhaps, (c) in Endo F-resistant oligosaccharides on their Qa-2 molecules.
Patient Interpretation of Neuropathy (PIN) Questionnaire
Authors: Loretta Vileikyte, Jeffrey S. Gonzalez, Howard Leventhal, Mark F. Peyrot, Richard R. Rubin, Adam Garrow, Jan S. Ulbrecht, Peter R. Cavanagh, Andrew J.M. Boulton
Journal: Diabetes Care (2006)

OBJECTIVE—Using the common-sense model of illness behavior, we developed and validated a self-report instrument for assessment of patients’ cognitive and emotional representations of diabetic peripheral neuropathy (DPN) influencing foot self-care. RESEARCH DESIGN AND METHODS—The Patient Interpretation of Neuropathy (PIN) questionnaire, generated from discussions with clinicians and interviews with patients with DPN, was administered to patients with DPN attending U.K. (n = 325) and U.S. (n = 170) diabetes centers. Psychometric tests of the PIN questionnaire comprised factor analysis, internal consistency, and test-retest reliability. Partial correlations and multivariate regressions established construct and criterion-related validity. The associations of PIN scales to past foot ulceration and foot self-care behaviors were compared with those using a generic measure of illness perception and emotion, the Revised Illness Perception Questionnaire (IPQ-R), which was adapted to neuropathy. RESULTS—Factor analysis of the PIN questionnaire produced 11 scales, which explained 69% of item variance. Nine factors measured patients’ common-sense beliefs about DPN and their levels of understanding of DPN-related medical information. Two factors assessed the emotions of worry about potential consequences and anger at practitioners. Most scales demonstrated adequate internal (Cronbach’s α = 0.62–0.90) and test-retest reliability (Pearson’s r = 0.51–0.64). Partial correlations between the PIN and IPQ-R scales in corresponding domains were significant but modest (rp = 0.15–0.26). Finally, PIN scales showed significant associations with past foot ulceration and foot self-care behaviors, thereby confirming criterion validity. CONCLUSIONS—The 39-item PIN questionnaire is a reliable and valid measure of patients’ cognitive and emotional representations of neuropathy affecting foot self-care.