tbuckley/cabot-search huggingface dataset:
ABT-199 (venetoclax) and BCL-2 inhibitors in clinical development
Authors: Shundong Cang, Chaitanya Iragavarapu, John Savooji, Yongping Song, Delong Liu
Journal: Journal of Hematology & Oncology (2015)

With the advent of new agents targeting CD20, Bruton's tyrosine kinase, and phosphoinositol-3 kinase for chronic lymphoid leukemia (CLL), more treatment options exist than ever before. B-cell lymphoma-2 (BCL-2) plays a major role in cellular apoptosis and is a druggable target. Small molecule inhibitors of BCL-2 are in active clinical studies. ABT-199 (venetoclax, RG7601, GDC-0199) has been granted breakthrough designation by FDA for relapsed or refractory CLL with 17p deletion. In this review, we summarized the latest clinical development of ABT-199/venetoclax and other novel agents targeting the BCL-2 proteins.
Letter by Coffey et al Regarding Article, “Temporal Trends in the Incidence and Prognosis of Aortic Stenosis: A Nationwide Study of the Swedish Population”
Authors: Sean Coffey, Brian Cox, Michael J.A. Williams
Journal: Circulation (2015)

We were interested to read the recent article by Martinsson et al 1 on the changing epidemiology of aortic stenosis (AS) in Sweden between 1989 and 2009.This highlights the growing burden of AS on healthcare systems, with increasing numbers of AS diagnoses and procedures.In addition to the valid points in the accompanying editorial, 2 we wish to raise 2 issues.The use of age standardization is problematic in diseases such as AS for which the ages of the patient group in question lie outside the main body of the standard population distribution.Those 20 to 74 years of age make up 69.5% of the most recent European standard population, whereas those ≥75 years of age make up only 9%.This weights the adjusted mortality figures firmly toward the younger members of the group studied and hides major differences between age groups.For example, in our analysis of valvular heart disease mortality data from the United States, we found that although younger age groups had improved age-specific mortality rates, the very elderly (≥85 years of age) had an increase in age-specific mortality rate in the 1990s, followed by a plateauing in the 2000s. 3The decrease in agestandardized incidence reflects the increase in mean age at diagnosis.Because AS is often discovered incidentally at the time of echocardiography for another indication such as an admission for acute coronary syndrome, this increase in mean age at diagnosis may simply be due to a reduction in coronary artery disease incidence.Our second point relates to the apparent improvement in outcomes after diagnosis.Although traditional cardiovascular risk factors are associated with the incidence of AS, disease progression is associated with nonmodifiable risk factors (age, male sex, severity of AS, and valve calcification). 4This raises the potential of lead time and length time bias as explanations for the improved outcomes seen. 5Wider availability of echocardiography may have allowed AS to be detected earlier in its natural history, leading to a spurious improvement in outcome (lead time bias).Similarly, length time bias arises from different rates of disease progression at various stages of disease severity.Disease progression in AS occurs more rapidly with increasing severity, meaning that AS diagnosed at an earlier stage in its natural history will appear to be less severe for a period of time.Questions about the relative contribution of true improvements in outcomes and bias resulting from more widespread cardiac imaging are unlikely to be resolved with the use of administrative data alone, but this valuable study identifies a number of areas for further investigation.
Hyperthermia Selectively Targets Human Papillomavirus in Cervical Tumors via p53-Dependent Apoptosis
Authors: Arlene L. Oei, Caspar M. van Leeuwen, Rosemarie ten Cate, Hans M. Rodermond, Marrije R. Buist, Lukas J.A. Stalpers, Johannes Crezee, H. Petra Kok, Jan Paul Medema, Nicolaas A.P. Franken
Journal: Cancer Research (2015)

Human papillomavirus (HPV) is associated with cervical cancer, the third most common cancer in women. The high-risk HPV types 16 and 18 are found in over 70% of cervical cancers and produce the oncoprotein, early protein 6 (E6), which binds to p53 and mediates its ubiquitination and degradation. Targeting E6 has been shown to be a promising treatment option to eliminate HPV-positive tumor cells. In addition, combined hyperthermia with radiation is a very effective treatment strategy for cervical cancer. In this study, we examined the effect of hyperthermia on HPV-positive cells using cervical cancer cell lines infected with HPV 16 and 18, in vivo tumor models, and ex vivo-treated patient biopsies. Strikingly, we demonstrate that a clinically relevant hyperthermia temperature of 42 °C for 1 hour resulted in E6 degradation, thereby preventing the formation of the E6-p53 complex and enabling p53-dependent apoptosis and G2-phase arrest. Moreover, hyperthermia combined with p53 depletion restored both the cell-cycle distribution and apoptosis to control levels. Collectively, our findings provide new insights into the treatment of HPV-positive cervical cancer and suggest that hyperthermia therapy could improve patient outcomes.
Cultured adult cardiac myocytes Future applications, culture methods, morphological and electrophysiological properties
Authors: J Mitcheson
Journal: Cardiovascular Research (1998)

Isolated adult cardiac myocytes maintained in primary culture have been used as a model of the adult myocardium for 20 years. With the recent advances and current interest in using molecular biological techniques to investigate cardiac physiology, culturing myocytes is becoming an increasingly important technique. Acutely isolated myocytes do not remain viable for the time needed for the changes in gene expression to occur, and therefore it is necessary to maintain myocytes in culture. The aims of this review are: (1) To describe a method for isolating and culturing myocytes in serum-free medium. This section is targeted at new researchers in the field, with particular emphasis on aspects of the isolation procedure which are important for optimising myocyte culture. (2) To review current knowledge of how contractile, electrophysiological and morphological properties of adult myocytes are preserved in culture. Over the past 5 to 10 years significant advances have been made in developing novel techniques which help maintain the in-vivo properties of myocytes in culture. Efficient methods for transporting exogenous genes and anti-sense oligonucleotides into adult myocytes are now available. We anticipate that in future these advances will make cultured myocytes more attractive for use in biophysical and molecular investigations of cardiac physiology.
Prevalence of comorbidities and evaluation of their screening in spondyloarthritis: results of the international cross-sectional ASAS-COMOSPA study
Authors: Anna Moltó, Adrien Etcheto, Désirée van der Heijde, Robert Landewé, Filip van den Bosch, Wilson Bautista Molano, Ruben Burgos-Vargas, Peter P Cheung, Eduardo Collantes-Estevez, Atul Deodhar, Bassel El-Zorkany, Shandor Erdes, Jieruo Gu, Najia Hajjaj-Hassouni, Uta Kiltz, Tae-Hwan Kim, Mitsumasa Kishimoto, Shue-Fen Luo, Pedro M Machado, Walter P Maksymowych, José Maldonado-Cocco, Helena Marzo-Ortega, Carlo-Maurizio Montecucco, Salih Ozgoçmen, Floris van Gaalen, Maxime Dougados
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Increased risk of some comorbidities has been reported in spondyloarthritis (SpA). Recommendations for detection/management of some of these comorbidities have been proposed, and it is known that a gap exists between these and their implementation in practice. <h3>Objective</h3> To evaluate (1) the prevalence of comorbidities and risk factors in different countries worldwide, (2) the gap between available recommendations and daily practice for management of these comorbidities and (3) the prevalence of previously unknown risk factors detected as a result of the present initiative. <h3>Methods</h3> Cross-sectional international study with 22 participating countries (from four continents), including 3984 patients with SpA according to the rheumatologist. <h3>Statistical analysis</h3> The prevalence of comorbidities (cardiovascular, infection, cancer, osteoporosis and gastrointestinal) and risk factors; percentage of patients optimally monitored for comorbidities according to available recommendations and percentage of patients for whom a risk factor was detected due to this study. <h3>Results</h3> The most frequent comorbidities were osteoporosis (13%) and gastroduodenal ulcer (11%). The most frequent risk factors were hypertension (34%), smoking (29%) and hypercholesterolaemia (27%). Substantial intercountry variability was observed for screening of comorbidities (eg, for LDL cholesterol measurement: from 8% (Taiwan) to 98% (Germany)). Systematic evaluation (eg, blood pressure (BP), cholesterol) during this study unveiled previously unknown risk factors (eg, elevated BP (14%)), emphasising the suboptimal monitoring of comorbidities. <h3>Conclusions</h3> A high prevalence of comorbidities in SpA has been shown. Rigorous application of systematic evaluation of comorbidities may permit earlier detection, which may ultimately result in an improved outcome of patients with SpA.
The Indolizidine Alkaloids, Slaframine and Swainsonine: Contaminants in Animal Forages
Authors: H P Broquist
Journal: Annual Review of Nutrition (1985)

The objective of this review is to provide an overview of intermittent fasting regimens, summarize the evidence on the health benefits of intermittent fasting, and discuss physiological mechanisms by which intermittent fasting might lead to improved ...Read More
Predictors of improved outcome for patients with localized prostate cancer treated with neoadjuvant androgen ablation therapy and three-dimensional conformal radiotherapy.
Authors: M J Zelefsky, O Lyass, Z Fuks, T Wolfe, C Burman, C C Ling, S A Leibel
Journal: Journal of Clinical Oncology (1998)

To identify prognostic variables that predict for improved biochemical and local control outcome in patients with localized prostatic cancer treated with neoadjuvant androgen deprivation (NAAD) and three-dimensional conformal radiotherapy (3D-CRT).Between 1989 and 1995, 213 patients with localized prostate cancer were treated with a 3-month course of NAAD that consisted of leuprolide acetate and flutamide before 3D-CRT. The purpose of NAAD in these patients was to reduce the preradiotherapy target volume so as to decrease the dose delivered to adjacent normal tissues and thereby minimize the risk of morbidity from high-dose radiotherapy. The median pretreatment prostate-specific antigen (PSA) level was 15.3 ng/mL (range, 1 to 560 ng/mL). The median 3D-CRT dose was 75.6 Gy (range, 64.8 to 81 Gy), and the median follow-up time was 3 years (range, 1 to 7 years).The significant predictors for improved outcome as identified in a multivariate analysis included pretreatment PSA level < or = 10.0 ng/mL(P < .00), NAAD-induced preradiotherapy PSA nadir < or = 0.5 ng/mL (P < .001), and clinical stage < or = T2c (P < .04). The 5-year PSA relapse-free survival rates were 93%, 60%, and 40% for patients with pretreatment PSA levels < or = 10 ng/mL, 10 to 20 ng/mL, and greater than 20 ng/mL, respectively (P < .001). Patients with preradiotherapy nadir levels < or = 0.5 ng/mL after 3 months of NAAD experienced a 5-year PSA relapse-free survival rate of 74%, as compared with 40% for patients with higher nadir levels (P < .001). The incidence of a positive biopsy among 34 patients pretreated with androgen ablation was 12%, as compared with 39% for 117 patients treated with 3D-CRT alone who underwent a biopsy (P < .001).For patients treated with NAAD and high-dose 3D-CRT, pretreatment PSA, preradiotherapy PSA nadir response, and clinical stage are important predictors of biochemical outcome. Patients with NAAD-induced PSA nadir levels greater than 0.5 ng/mL before radiotherapy are more likely to develop biochemical failure and may benefit from more aggressive therapies.
Which approach is appropriate for spontaneous portosystemic shunt embolization in patients with post‐transjugular intrahepatic portosystemic shunt refractory hepatic encephalopathy: Antegrade or retrograde?
Authors: Wenbin Wu, Guohong Han
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. To the Editor: Based on our recently published case in a patient with cirrhosis with variceal bleeding1, we are pleased to read the letter of Doshi et al., which was regarding large spontaneous portosystemic shunt (SPSS) embolization for post‐transjugular intrahepatic portosystemic shunt (TIPS) hepatic encephalopathy (HE). We are in agreement with Doshi et al. Recently, SPSS has attracted increasing attention. Because the coils may not completely occlude the shunt of large diameter, an Amplatzer plugging device is often used for large SPSS embolization. In our center, the Amplatzer plugging device is preferred in TIPS patients, so as to embolize the large SPSS through an antegrade transjugular approach. Moreover, the retrograde approach by femoral vein will be the next choice only when the transjugular approach is complicated. Similarly, by employing the antegrade transjugular approach, varices of small diameter or SPSS are almost embolized with coils, as with Doshi et al. (Fig. 1). The study of Laleman et al., concerning the efficacy and safety of large portosystemic shunts embolization for refractory HE management, reported on the same procedure approach, in which the SPSS was embolized using coils in an antegrade way and the Amplatzer plugging device in a retrograde way.2Figure 1: Portal venogram of a 72‐year‐old man with cirrhosis and SPSS, who undergoes a TIPS procedure with subsequent antegrade SPSS embolization. Besides, the Amplatzer plugging device is employed for post‐TIPS refractory HE. (A) A TIPS stent (black arrow) is shown; (b) a TIPS stent (black arrow) and Amplatzer plugging device (white arrow) are shown.In order to embolize the large SPSS in patients without TIPS implantation, the retrograde femoral vein approach is preferred on account of the feasibility and efficacy, as well as balloon‐occluded retrograde transvenous obliteration.3 Provided that the retrograde way is not accessible, the antegrade transjugular approach will be established without stent insertion. Nevertheless, both antegrade and retrograde approaches may increase portal vein pressure. Furthermore, no final conclusion has yet been reached on the possibility of the retrograde approach increasing the risk of variceal bleeding when compared to the antegrade approach. During the procedure, hepatic venous pressure gradient (HVPG) is always measured. In our center, the majority of patients maintained HVPG <12 mm Hg or at least 20% reduction. Taken together, we appreciate that Doshi et al. have proven a different approach, which confirmed that large SPSS embolization is feasible, safe, and effective for refractory post‐TIPS HE. Currently, no clear therapeutic strategy regarding post‐TIPS HE management is available by making use of the antegrade or retrograde approach. Therefore, more researches concerning SPSS and post‐HE are warranted.
The CD4-gpl20 Interaction and Aids Pathogenesis
Authors: D J Capon, R H Ward
Journal: Annual Review of Immunology (1991)

Infection by the human immunodeficiency virus (HIV) leads to progressive destruction of the CD4+ subset of T lymphocytes, resulting in immunodeficiency and AIDS. The selectivity of CD4+ cell destruction is due to the specific binding of gp120, the external envelope glycoprotein of HIV, to CD4, initiating viral entry. Binding of gp120 to CD4 on the cell surface may also lead to CD4+ cell depletion by inappropriate immune targeting, and may interfere with CD4+ cell function and ontogeny by disrupting CD4-mediated cell signaling. The CD4-gp120 interaction is thus an obvious target for AIDS therapeutics.
Identification of global regulators of T-helper cell lineage specification
Authors: Kartiek Kanduri, Subhash Tripathi, Antti Larjo, Henrik Mannerström, Ubaid Ullah, Riikka Lund, R. David Hawkins, Bing Ren, Harri Lähdesmäki, Riitta Lahesmaa
Journal: Genome Medicine (2015)
p53: Protection against Tumor Growth beyond Effects on Cell Cycle and Apoptosis
Authors: Xuyi Wang, Evan R. Simpson, Kristy A. Brown
Journal: Cancer Research (2015)

The tumor suppressor p53 has established functions in cancer. Specifically, it has been shown to cause cell-cycle arrest and apoptosis in response to DNA damage. It is also one of the most commonly mutated or silenced genes in cancer and for this reason has been extensively studied. Recently, the role of p53 has been shown to go beyond its effects on cell cycle and apoptosis, with effects on metabolism emerging as a key contributor to cancer growth in situations where p53 is lost. Beyond this, the role of p53 in the tumor microenvironment is poorly understood. The publication by Wang and colleagues demonstrates for the first time that p53 is a key negative regulator of aromatase and, hence, estrogen production in the breast tumor microenvironment. It goes further by demonstrating that an important regulator of aromatase, the obesity-associated and tumor-derived factor prostaglandin E2, inhibits p53 in the breast adipose stroma. This review presents these findings in the context of established and emerging roles of p53 and discusses possible implications for the treatment of breast cancer.
Correction: CLEC-2 in megakaryocytes is critical for maintenance of hematopoietic stem cells in the bone marrow
Authors: Ayako Nakamura-Ishizu, Keiyo Takubo, Hiroshi Kobayashi, Katsue Suzuki-Inoue, Toshio Suda
Journal: The Journal of Experimental Medicine (2015)

Hematopoietic stem cells (HSCs) depend on the bone marrow (BM) niche for their maintenance, proliferation, and differentiation. The BM niche is composed of nonhematopoietic and mature hematopoietic cells, including megakaryocytes (Mks). Thrombopoietin (Thpo) is a crucial cytokine produced by BM niche cells. However, the cellular source of Thpo, upon which HSCs primarily depend, is unclear. Moreover, no specific molecular pathway for the regulation of Thpo production in the BM has been identified. Here, we demonstrate that the membrane protein C-type lectin-like receptor-2 (CLEC-2) mediates the production of Thpo and other factors in Mks. Mice conditionally deleted for CLEC-2 in Mks (Clec2(MkΔ/Δ)) produced lower levels of Thpo in Mks. CLEC-2-deficient Mks showed down-regulation of CLEC-2-related signaling molecules Syk, Lcp2, and Plcg2. Knockdown of these molecules in cultured Mks decreased expression of Thpo. Clec2(MkΔ/Δ) mice exhibited reduced BM HSC quiescence and repopulation potential, along with extramedullary hematopoiesis. The low level of Thpo production may account for the decline in HSC potential in Clec2(MkΔ/Δ) mice, as administration of recombinant Thpo to Clec2(MkΔ/Δ) mice restored stem cell potential. Our study identifies CLEC-2 signaling as a novel molecular mechanism mediating the production of Thpo and other factors for the maintenance of HSCs.
Response to antiviral therapy in haematopoietic stem cell transplant recipients with cytomegalovirus (CMV) reactivation according to the donor CMV serological status
Authors: S. Servais, N. Dumontier, L. Biard, N. Schnepf, M. Resche-Rigon, R. Peffault de Latour, C. Scieux, M. Robin, M. Meunier, A. Xhaard, F. Sicre de Fontbrune, J. Le Goff, G. Socié, F. Simon, M.-C. Mazeron
Journal: Clinical Microbiology and Infection (2015)
Comorbidity in psychosis at first hospitalization
Authors: S M Strakowski, M Tohen, A L Stoll, G L Faedda, P V Mayer, M L Kolbrener, D C Goodwin
Journal: American Journal of Psychiatry (1993)

The authors sought to determine the prevalence and effects of medical and psychiatric comorbidity on initial outcome in a group of patients experiencing a first episode of psychosis.Patients with a first episode of psychosis who were consecutively admitted to a hospital (N = 102) were examined for the presence of psychiatric and medical disorders. Patients were given psychiatric diagnoses with the use of the Structured Clinical Interview for DSM-III-R and were rated weekly on symptom rating scales. Outcome variables at discharge were final symptom rating scale scores, length of hospitalization, and recovery on the basis of operationalized criteria.Comorbid diagnoses were present in 52.0% (N = 53) of the patients, and 37.7% (N = 20) had multiple comorbid diagnoses. The most common comorbid diagnosis was substance abuse. Patients with affected psychoses were significantly more likely than those with nonaffective psychoses to have a comorbid substance abuse diagnosis. Patients with psychiatric comorbidity had poorer initial outcomes, while those with medical comorbidity had fewer symptoms at discharge.Comorbidity is common and may be a useful predictor of the outcome of a first episode of psychosis.
Androgen Deprivation Therapy (ADT) Plus Docetaxel Versus ADT Alone in Metastatic Non castrate Prostate Cancer: Impact of Metastatic Burden and Long-term Survival Analysis of the Randomized Phase 3 GETUG-AFU15 Trial
Authors: Gwenaelle Gravis, Jean-Marie Boher, Florence Joly, Michel Soulié, Laurence Albiges, Franck Priou, Igor Latorzeff, Remy Delva, Ivan Krakowski, Brigitte Laguerre, Frédéric Rolland, Christine Théodore, Gael Deplanque, Jean-Marc Ferrero, Stéphane Culine, Loïc Mourey, Philippe Beuzeboc, Muriel Habibian, Stéphane Oudard, Karim Fizazi
Journal: European Urology (2015)
Prenatal phthalate and early childhood bisphenol A exposures increase asthma risk in inner-city children
Authors: Robin M. Whyatt, Andrew G. Rundle, Matthew S. Perzanowski, Allan C. Just, Kathleen M. Donohue, Antonia M. Calafat, Lori Hoepner, Frederica P. Perera, Rachel L. Miller
Journal: Journal of Allergy and Clinical Immunology (2014)
CoAle Multicenter Study: Diagnostic Tests As Predictors of Clinical Reactivity in the Follow-up of the Milk-Allergic Infants
Authors: Mariangelica Bermudez Martinez, Cristina Vlaicu, Melissa Olano Rocha, Ibon Eguiluz Gracia, Soledad Terrados Cepeda, Inmaculada Cerecedo Carballo, Maria Del Carmen Dieguez, Belen De La Hoz, Montserrat Fernandez-Rivas
Journal: Journal of Allergy and Clinical Immunology (2013)
Stochastic spontaneous calcium release events trigger premature ventricular complexes by overcoming electrotonic load
Authors: Fernando O. Campos, Yohannes Shiferaw, Anton J. Prassl, Patrick M. Boyle, Edward J. Vigmond, Gernot Plank
Journal: Cardiovascular Research (2015)

AimsPremature ventricular complexes (PVCs) due to spontaneous calcium (Ca) release (SCR) events at the cell level can precipitate ventricular arrhythmias. However, the mechanistic link between SCRs and PVC formation remains incompletely understood. The aim of this study was to investigate the conditions under which delayed afterdepolarizations resulting from stochastic subcellular SCR events can overcome electrotonic source–sink mismatch, leading to PVC initiation.
PI3 Kinase and FOXO1 Transcription Factor Activity Differentially Control B Cells in the Germinal Center Light and Dark Zones
Authors: Sandrine Sander, Van Trung Chu, Tomoharu Yasuda, Andrew Franklin, Robin Graf, Dinis Pedro Calado, Shuang Li, Koshi Imami, Matthias Selbach, Michela Di Virgilio, Lars Bullinger, Klaus Rajewsky
Journal: Immunity (2015)