tbuckley/cabot-search huggingface dataset:
A Useful Approach to Identify Novel Small-Molecule Inhibitors of Wnt-Dependent Transcription
Authors: Kenneth Ewan, Bożena Pająk, Mark Stubbs, Helen Todd, Olivier Barbeau, Camilo Quevedo, Hannah Botfield, Rodrigo Young, Ruth Ruddle, Lee Samuel, Alysia Battersby, Florence Raynaud, Nicholas Allen, Stephen Wilson, Branko Latinkic, Paul Workman, Edward McDonald, Julian Blagg, Wynne Aherne, Trevor Dale
Journal: Cancer Research (2010)

Abstract The Wnt signaling pathway is frequently deregulated in cancer due to mutations in genes encoding APC, β-catenin, and axin. To identify small-molecule inhibitors of Wnt signaling as potential therapeutics, a diverse chemical library was screened using a transcription factor reporter cell line in which the activity of the pathway was induced at the level of Disheveled protein. A series of deconvolution studies was used to focus on three compound series that selectively killed cancer cell lines with constitutive Wnt signaling. Activities of the compounds included the ability to induce degradation of β-catenin that had been stabilized by a glycogen synthase kinase-3 (GSK-3) inhibitor. This screen illustrates a practical approach to identify small-molecule inhibitors of Wnt signaling that can seed the development of agents suitable to treat patients with Wnt-dependent tumors. Cancer Res; 70(14); 5963–73. ©2010 AACR.
New Perspectives on Regeneration of the Heart
Authors: Christine L. Mummery, Robert Passier
Journal: Circulation Research (2011)

C an the adult mammalian heart regenerate and re- place lost or damaged tissue?Text books suggest it cannot but recent studies suggest we may have to revisit this issue.Until recently, regeneration of the heart was thought to be restricted to fish and amphibians.For instance, hearts of zebrafish can regenerate completely within just 2 months of surgical amputation of up to 20% of the ventricle. 1This occurs by proliferation and dedifferentiation of mature cardiac myocytes. 2By contrast, severe injury of the adult mammalian heart leads to the formation of scar tissue, which replaces damaged and lost cardiac myocytes.Interestingly, neonatal mammalian hearts were recently shown to have some regenerative capacity, not unlike zebrafish, although this was lost beyond 7 days of age. 3 In the last decade, several studies have described evidence for cardiac stem cell populations within the postnatal mammalian heart, which appear able to form cells with cardiac myocyte properties in culture and after transplantation back into the heart (reviewed in Rasmussen et al 4 ).This has encouraged the search for ways to stimulate these endogenous cardiac stem cells to proliferate and differentiate into cardiac myocytes and vascular cells in situ to regenerate the injured heart even though their exact identity is unknown.In a recent study for example, Loffredo et al cleverly used genetically engineered mice to demonstrate at least some degree of endogenous myocardial replacement after an experimentally induced heart attack (myocardial infarction). 5Cardiac myocytes were permanently marked by green fluorescent protein (GFP) whilst non-cardiac myocytes were marked blue by ␤-galactosidase.Upon myocardial infarction (MI), new cardiac myocytes formed, some of which expressed GFP indicating they were derived by division of endogenous cardiac myocytes, whilst the majority were blue, indicating they were derived from a noncardiac myocyte progenitor population.Transplantation of some types of stem cells from bone marrow enhanced this process whilst others did not.Unequivocal demonstration of slowThe opinions expressed in this Commentary are not necessarily those of the editors or of the American Heart Association.Commentaries serve as a forum in which experts highlight and discuss articles (published elsewhere) that the editors of Circulation Research feel are of particular significance to cardiovascular medicine.
Disease severity of 100 patients with systemic sclerosis over a period of 14 years: using a modified Medsger scale
Authors: A J Geirsson
Journal: Annals of the Rheumatic Diseases (2001)

To assess organ involvement according to a modified Medsger severity scale and its relation to outcome and prognosis in patients with systemic sclerosis.One hundred consecutive patients observed in Lund with systemic sclerosis were followed up for a period of 14 years. The mean follow up time was 7.7 years. Initial assessment and an annual evaluation was performed for each patient, with a mean visit frequency of 5.6 per patient.Age at referral, high total skin score, truncal skin involvement, low vital capacity, low static lung compliance, low Cr-EDTA clearance, and ECG abnormalities at the initial assessment predict poor outcome. A severity scoring system for five organ systems indicates a slow progression of organ dysfunction after recruitment into the study. The female: male ratio was 2:1, the mean age at onset of symptoms was 42.3 (range 3-82), and the mean age at recruitment was 47.2 years (range 17-82). Thirty patients died during the follow up period at the mean age of 61.3 years (range 33-85). The causes of death were directly related to systemic sclerosis in at least 10 patients, infections in six, cancers in nine, and other causes in four patients. The standardised mortality ratio was 3.5 and 3.7 for men and women, respectively.A high severity score for function of vital organs was shown to predict shortened survival. In this study a severity score based on simple clinical assessment variables was able to predict poor outcome from extensive skin changes, ECG changes, and compromised lung and renal function. Organ dysfunction mainly became manifest during the first five years of the disease, whereafter organ function remained largely stable.
Targeting keratinocyte apoptosis in the treatment of atopic dermatitis and allergic contact dermatitis
Authors: Axel Trautmann, Mübeccel Akdis, Peter Schmid-Grendelmeier, Rainer Disch, Eva-B. Bröcker, Kurt Blaser, Cezmi A. Akdis
Journal: Journal of Allergy and Clinical Immunology (2001)
Twenty years of breast cancer in Iran: downstaging without a formal screening program
Authors: I. Harirchi, S. Kolahdoozan, M. Karbakhsh, N. Chegini, S.M. Mohseni, A. Montazeri, A.J. Momtahen, A. Kashefi, M. Ebrahimi
Journal: Annals of Oncology (2010)
Elevated LDH and paranasal sinus involvement are risk factors for central nervous system involvement in patients with peripheral T-cell lymphoma
Authors: J.H. Yi, J.H. Kim, K.K. Baek, T. Lim, D.J. Lee, Y.C. Ahn, K. Kim, S.J. Kim, Y.H. Ko, W.S. Kim
Journal: Annals of Oncology (2011)

BackgroundThe incidence and risk factors of central nervous system (CNS) involvement in peripheral T-cell lymphomas (PTCLs) are still unclear.Patients and methodsWe analyzed 228 patients with PTCLs, excluding cases of extranodal natural killer/T-cell lymphoma and primary cutaneous T-cell lymphoma, by retrospectively collecting the clinical features and outcomes of the patients.ResultsTwenty events (8.77%, 20/228) of CNS involvement were observed during a median follow-up period of 13.9 months (range 0.03–159.43). Based on univariate analysis, elevated serum lactate dehydrogenase (LDH) level [P = 0.019, relative risk (RR) 5.904, 95% confidence interval (CI) 1.334–26.123] and involvement of the paranasal sinus (P = 0.032, RR 3.137, 95% CI 1.105–8.908) adversely affect CNS involvement. In multivariate analysis, both were independently poor prognostic factors for CNS relapse [elevated LDH level: P = 0.011, hazard ratio (HR) 6.716, 95% CI 1.548–29.131; involvement of the paranasal sinus: P = 0.008, HR 3.784, 95% CI 1.420–10.083]. The survival duration of patients with CNS involvement was significantly shorter than that of the patients without CNS involvement (P = 0.009), with median overall survival of 7.60 months (95% CI of 4.92–10.28) versus 27.43 months (95% CI of 0.00–57.38), respectively.ConclusionsElevated LDH level and involvement of the paranasal sinus are two risk factors for CNS involvement in patients with PTCLs. Considering the poor prognoses after CNS relapse, prophylaxis should be considered with the presence of any risk factor.
Evidence for Prostate Cancer-Associated Diagnostic Marker-1
Authors: Akira Ohkia, Youji Hu, Min Wang, Fernando U. Garcia, Mark E. Stearns
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The purpose of this study was to characterize a novel gene/protein associated with prostate cancer, termed prostate cancer-associated diagnostic marker-1 [PCADM-1 (Hu Y, Wang M, Garcia FU, Aoyaki K, Stearns ME. Identification of PCADM-1 as a novel diagnostic marker for prostate cancer, submitted for publication)]. Experimental Design and Results: Immunological studies revealed that rabbit polyclonal antibodies generated against recombinant PCADM-1 specifically recognize the protein in crude protein extracts from a variety of prostate cancer cell lines (i.e., PC-3 ML, LNCaP, DU145, and CPTX-1532) and prostate cancer tissue. Combined immunolabeling and in situ hybridization studies demonstrated that PCADM-1 mRNA was expressed by the luminal epithelial cells of prostate cancer glands and was not expressed by high-grade prostatic intraepithelial neoplasia or HPV-MLC7 cells. Immunolabeling studies of tissue arrays from biopsies of archival material (n = 200 samples) confirmed that PCADM-1 was expressed by the luminal epithelial cells of prostate cancer. Conclusions: Taken together, the data suggest that PCADM-1 is a specific marker for human prostate cancer.
Baroceptor and Sympathetic Activity in Experimental Renal Hypertension in the Dog
Authors: PAUL KEZDI, JAMES R. WENNEMARK
Journal: Circulation (1958)

Response to tetraethylammonium chloride was studied in normal and renal hypertensive dogs in which the carotid sinus was isolated and intrasinusal pressure was maintained by a pump. Normal, chronic, and acute renal hypertensive animals differed in their response at different intrasinusal pressure levels and indicated resetting of the baroceptors in the chronic hypertensive phase but not in the acute phase. This resetting may play a role in the maintenance of chronic renal hypertension.
Acinetobacter baumannii outbreak in an orthopedic ward: analysis of strain relatedness by RAPD and quantitative antibiogram techniques
Authors: Véronique Leflon-Guibout, Virginie Métral-Bétina, Béate Heym, Alain Lortat-Jacob, Marie-Hélène Nicolas-Chanoine
Journal: Clinical Microbiology and Infection (1998)
Antigen-specific, H-2-restricted helper T cell hybridomas.
Authors: N W Roehm, P Marrack, J W Kappler
Journal: The Journal of Experimental Medicine (1982)

We have examined the carrier-specific helper activity of a number of antigen-specific, I region-restricted T cell hybridomas prepared in our laboratory. The hybridomas were assayed for helper activity in the presence or absence of exogenously added nonspecific factors found in the concanavalin A-activated supernatants of normal mouse spleen cells. Of six hybridomas tested, all six could stimulate the IgM anti-hapten response of hapten-primed B cells in the presence of the appropriate hapten-carrier conjugates. At low or moderate carrier doses, the response was dependent upon hapten-carrier linkage and the ability of the hybridoma cells to interact with carrier in association with H-2 products of the responding B cells themselves. Plaque-forming cell responses stimulated by some of the hybridomas were absolutely dependent upon the addition of nonspecific factors, suggesting that anti hapten-protein responses require both an antigen specific I region restricted signal from the T cell hybridomas and nonspecific helper factors, made either by the T cell hybridomas or added exogenously. Under two sets of circumstances, B cells were stimulated in the absence of a simultaneous signal delivered through their immunoglobulin receptor. This occurred either when hapten-primed B cells were stimulated with an ovalbumin/I-Ak-specific hybridoma in the presence of very high concentrations of ovalbumin, or when H-2b B cells were incubated with a hybridoma specific for I-Ab alone. This was interpreted to mean that B cells can be stimulated by reaction of T cells with surface I molecules.
Pre-TCR expression cooperates with TEL-JAK2 to transform immature thymocytes and induce T-cell leukemia
Authors: Nuno R. dos Santos, David S. Rickman, Aurélien de Reynies, Françoise Cormier, Maryvonne Williame, Camille Blanchard, Marc-Henri Stern, Jacques Ghysdael
Journal: Blood (2006)
Out of Bounds? A Critique of the New Policies on Hyperandrogenism in Elite Female Athletes
Authors: Katrina Karkazis, Rebecca Jordan-Young, Georgiann Davis, Silvia Camporesi
Journal: The American Journal of Bioethics (2012)

In May 2011, more than a decade after the International Association of Athletics Federations (IAAF) and the International Olympic Committee (IOC) abandoned sex testing, they devised new policies in response to the IAAF's treatment of Caster Semenya, the South African runner whose sex was challenged because of her spectacular win and powerful physique that fueled an international frenzy questioning her sex and legitimacy to compete as female. These policies claim that atypically high levels of endogenous testosterone in women (caused by various medical conditions) create an unfair advantage and must be regulated. Against the backdrop of Semenya's case and the scientific and historical complexity of "gender verification" in elite sports, we question the new policies on three grounds: (1) the underlying scientific assumptions; (2) the policymaking process; and (3) the potential to achieve fairness for female athletes. We find the policies in each of these domains significantly flawed and therefore argue they should be withdrawn.
Endogenous airway mucins carry glycans that bind Siglec-F and induce eosinophil apoptosis
Authors: Takumi Kiwamoto, Toshihiko Katoh, Christopher M. Evans, William J. Janssen, Mary E. Brummet, Sherry A. Hudson, Zhou Zhu, Michael Tiemeyer, Bruce S. Bochner
Journal: Journal of Allergy and Clinical Immunology (2014)
Management and Outcomes of Major Bleeding During Treatment With Dabigatran or Warfarin
Authors: Ammar Majeed, Hun-Gyu Hwang, Stuart J. Connolly, John W. Eikelboom, Michael D. Ezekowitz, Lars Wallentin, Martina Brueckmann, Mandy Fraessdorf, Salim Yusuf, Sam Schulman
Journal: Circulation (2013)

The aim of this study was to compare the management and prognosis of major bleeding in patients treated with dabigatran or warfarin.Two independent investigators reviewed bleeding reports from 1034 individuals with 1121 major bleeds enrolled in 5 phase III trials comparing dabigatran with warfarin in 27 419 patients treated for 6 to 36 months. Patients with major bleeds on dabigatran (n=627 of 16 755) were older, had lower creatinine clearance, and more frequently used aspirin or non-steroid anti-inflammatory agents than those on warfarin (n=407 of 10 002). The 30-day mortality after the first major bleed tended to be lower in the dabigatran group (9.1%) than in the warfarin group (13.0%; pooled odds ratio, 0.68; 95% confidence interval, 0.46-1.01; P=0.057). After adjustment for sex, age, weight, renal function, and concomitant antithrombotic therapy, the pooled odds ratio for 30-day mortality with dabigatran versus warfarin was 0.66 (95% confidence interval, 0.44-1.00; P=0.051). Major bleeds in dabigatran patients were more frequently treated with blood transfusions (423/696, 61%) than bleeds in warfarin patients (175/425, 42%; P<0.001) but less frequently with plasma (dabigatran, 19.8%; warfarin, 30.2%; P<0.001). Patients who experienced a bleed had shorter stays in the intensive care unit if they had previously received dabigatran (mean 1.6 nights) compared with those who had received warfarin (mean 2.7 nights; P=0.01).Patients who experienced major bleeding on dabigatran required more red cell transfusions but received less plasma, required a shorter stay in intensive care, and had a trend to lower mortality compared with those who had major bleeding on warfarin.http://www.ClinicalTrials.gov. Unique identifiers: NCT00262600, NCT00291330, NCT00680186, NCT00329238 and NCT00558259.
Pathophysiological Consequences of TAT-HKII Peptide Administration Are Independent of Impaired Vascular Function and Ensuing Ischemia
Authors: Rianne Nederlof, Chaoqin Xie, Otto Eerbeek, Anneke Koeman, Dan M.J. Milstein, Markus W. Hollmann, Egbert G. Mik, Alice Warley, Richard Southworth, Fadi G. Akar, Coert J. Zuurbier
Journal: Circulation Research (2013)

We have shown that partial dissociation of hexokinase II (HKII) from mitochondria in the intact heart using low-dose transactivating transcriptional factor (TAT)-HKII (200 nmol/L) prevents the cardioprotective effects of ischemic preconditioning, whereas high-dose TAT-HKII (10 μmol/L) administration results in rapid myocardial dysfunction, mitochondrial depolarization, and disintegration. In this issue of Circulation Research, Pasdois et al argue that the deleterious effects of TAT-HKII administration on cardiac function are likely because of vasoconstriction and ensuing ischemia.To investigate whether altered vascular function and ensuing ischemia recapitulate the deleterious effects of TAT-HKII in intact myocardium.Using a variety of complementary techniques, including mitochondrial membrane potential (ΔΨm) imaging, high-resolution optical action potential mapping, analysis of lactate production, nicotinamide adenine dinucleotide epifluorescence, lactate dehydrogenase release, and electron microscopy, we provide direct evidence that refutes the notion that acute myocardial dysfunction by high-dose TAT-HKII peptide administration is a consequence of impaired vascular function. Moreover, we demonstrate that low-dose TAT-HKII treatment, which abrogates the protective effects of ischemic preconditioning, is not associated with ischemia or ischemic injury.Our findings challenge the notion that the effects of TAT-HKII are attributable to impaired vascular function and ensuing ischemia, thereby lending further credence to the role of mitochondria-bound HKII as a critical regulator of cardiac function, ischemia-reperfusion injury, and cardioprotection by ischemic preconditioning.
A Case of Shwachman-Diamond Syndrome Presenting With Diabetes From Early Infancy
Authors: Tomohiro Kamoda, Takashi Saito, Hideyo Kinugasa, Nobuaki Iwasaki, Ryo Sumazaki, Youko Mouri, Isho Izumi, Takeki Hirano, Akira Matsui
Journal: Diabetes Care (2005)

hwachman-Diamond syndrome (SDS; OMIM 260400) is a rare autosomal recessive disorder characterized by pancreatic insufficiency, bone marrow failure, skeletal dysplasia, and short stature (1).Diabetes is a rare complication of SDS, and only a few SDS patients have been reported to develop diabetes (2-6).We report the first case of SDS with diabetes in which mutations of the SBDS gene have been identified. RESEARCH DESIGN AND METHODS-A 15-month-old Japanese girl was born uneventfully to a healthy mother after 36 weeks gestation.Pregnancy was complicated by intrauterine growth retardation.Her parents are nonconsanguineous.There was no family history of inherited disorders.The birth weight was 1,530 g (Ϫ2.4 SD) and length was 41.0 cm (Ϫ2.5 SD).After birth, she developed respiratory distress syndrome and pulmonary hemorrhage.Neutropenia was noted from the neonatal period, and a bone marrow examination revealed a maturation arrest of myelopoiesis.After 3 weeks of age, she developed postprandial hyperglycemia with Ͼ200 mg/dl in blood glucose.The treatment with insulin was not begun because of normal insulin response in the oral glucose tolerance test performed at the age of 3 months.At 5
Leukotriene Antagonists as First-Line or Add-on Asthma-Controller Therapy
Authors: David Price, Stanley D. Musgrave, Lee Shepstone, Elizabeth V. Hillyer, Erika J. Sims, Richard F.T. Gilbert, Elizabeth F. Juniper, Jon G. Ayres, Linda Kemp, Annie Blyth, Edward C.F. Wilson, Stephanie Wolfe, Daryl Freeman, H. Miranda Mugford, Jamie Murdoch, Ian Harvey
Journal: New England Journal of Medicine (2011)

Most randomized trials of treatment for asthma study highly selected patients under idealized conditions.We conducted two parallel, multicenter, pragmatic trials to evaluate the real-world effectiveness of a leukotriene-receptor antagonist (LTRA) as compared with either an inhaled glucocorticoid for first-line asthma-controller therapy or a long-acting beta(2)-agonist (LABA) as add-on therapy in patients already receiving inhaled glucocorticoid therapy. Eligible primary care patients 12 to 80 years of age had impaired asthma-related quality of life (Mini Asthma Quality of Life Questionnaire [MiniAQLQ] score ≤6) or inadequate asthma control (Asthma Control Questionnaire [ACQ] score ≥1). We randomly assigned patients to 2 years of open-label therapy, under the care of their usual physician, with LTRA (148 patients) or an inhaled glucocorticoid (158 patients) in the first-line controller therapy trial and LTRA (170 patients) or LABA (182 patients) added to an inhaled glucocorticoid in the add-on therapy trial.Mean MiniAQLQ scores increased by 0.8 to 1.0 point over a period of 2 years in both trials. At 2 months, differences in the MiniAQLQ scores between the two treatment groups met our definition of equivalence (95% confidence interval [CI] for an adjusted mean difference, -0.3 to 0.3). At 2 years, mean MiniAQLQ scores approached equivalence, with an adjusted mean difference between treatment groups of -0.11 (95% CI, -0.35 to 0.13) in the first-line controller therapy trial and of -0.11 (95% CI, -0.32 to 0.11) in the add-on therapy trial. Exacerbation rates and ACQ scores did not differ significantly between the two groups.Study results at 2 months suggest that LTRA was equivalent to an inhaled glucocorticoid as first-line controller therapy and to LABA as add-on therapy for diverse primary care patients. Equivalence was not proved at 2 years. The interpretation of results of pragmatic research may be limited by the crossover between treatment groups and lack of a placebo group. (Funded by the National Coordinating Centre for Health Technology Assessment U.K. and others; Controlled Clinical Trials number, ISRCTN99132811.).
Fasting and Nonfasting Lipid Levels
Authors: Anne Langsted, Jacob J. Freiberg, Børge G. Nordestgaard
Journal: Circulation (2008)

Background— Lipid profiles are usually measured after fasting. We tested the hypotheses that these levels change only minimally in response to normal food intake and that nonfasting levels predict cardiovascular events. Methods and Results— We cross-sectionally studied 33 391 individuals 20 to 95 years of age from the Copenhagen General Population Study. We also studied 9319 individuals 20 to 93 years of age from the Copenhagen City Heart Study, 1166 of whom developed cardiovascular events during 14 years of follow-up. Compared with fasting levels, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein (HDL) cholesterol, and albumin levels were reduced up to 3 to 5 hours after the last meal; triglycerides levels were increased up to 6 hours after the last meal; and non-HDL cholesterol level, apolipoprotein A1 level, apolipoprotein B level, ratio of total cholesterol to HDL cholesterol, and ratio of apolipoprotein B to apolipoprotein A1 did not change in response to normal food intake. The maximum changes after normal food and fluid intake from fasting levels were −0.2 mmol/L for total cholesterol, −0.2 mmol/L for low-density lipoprotein cholesterol, −0.1 mmol/L for HDL cholesterol, and 0.3 mmol/L for triglycerides. Highest versus lowest tertile of nonfasting total cholesterol, non-HDL cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, triglycerides, ratio of total cholesterol to HDL cholesterol, and ratio of apolipoprotein B/apolipoprotein A1 and lowest versus highest tertile of nonfasting HDL cholesterol and apolipoprotein A1 predicted 1.7- to 2.4-fold increased risk of cardiovascular events. Conclusions— Lipid profiles at most change minimally in response to normal food intake in individuals in the general population. Furthermore, nonfasting lipid profiles predicted increased risk of cardiovascular events.