tbuckley/cabot-search huggingface dataset:
Bone Morphogenetic Protein Receptor Type 2 Mutation in Pulmonary Arterial Hypertension
Authors: Cathelijne E. van der Bruggen, Chris M. Happé, Peter Dorfmüller, Pia Trip, Onno A. Spruijt, Nina Rol, Femke P. Hoevenaars, Arjan C. Houweling, Barbara Girerd, Johannes T. Marcus, Olaf Mercier, Marc Humbert, M. Louis Handoko, Jolanda van der Velden, Anton Vonk Noordegraaf, Harm Jan Bogaard, Marie-José Goumans, Frances S. de Man
Journal: Circulation (2016)

The effect of a mutation in the bone morphogenetic protein receptor 2 (BMPR2) gene on right ventricular (RV) pressure overload in patients with pulmonary arterial hypertension is unknown. Therefore, we investigated RV function in patients who have pulmonary arterial hypertension with and without the BMPR2 mutation by combining in vivo measurements with molecular and histological analysis of human RV and left ventricular tissue.In total, 95 patients with idiopathic or familial pulmonary arterial hypertension were genetically screened for the presence of a BMPR2 mutation: 28 patients had a BMPR2 mutation, and 67 patients did not have a BMPR2 mutation. In vivo measurements were assessed using right heart catheterization and cardiac MRI. Despite a similar mean pulmonary artery pressure (noncarriers 54±15 versus mutation carriers 55±9 mm Hg) and pulmonary vascular resistance (755 [483-1043] versus 931 [624-1311] dynes·s(-1)·cm(-5)), mutation carriers presented with a more severely compromised RV function (RV ejection fraction: 37.6±12.8% versus 29.0±9%: P<0.05; cardiac index 2.7±0.9 versus 2.2±0.4 L·min(-1)·m(-2)). Differences continued to exist after treatment. To investigate the role of transforming growth factor β and bone morphogenetic protein receptor II signaling, human RV and left ventricular tissue were studied in controls (n=6), mutation carriers (n=5), and noncarriers (n=11). However, transforming growth factor β and bone morphogenetic protein receptor II signaling, and hypertrophy, apoptosis, fibrosis, capillary density, inflammation, and cardiac metabolism, as well, were similar between mutation carriers and noncarriers.Despite a similar afterload, RV function is more severely affected in mutation carriers than in noncarriers. However, these differences cannot be explained by a differential transforming growth factor β, bone morphogenetic protein receptor II signaling, or cardiac adaptation.
Dysregulation of Antiviral Function of CD8<sup>+</sup>T Cells in the Chronic Obstructive Pulmonary Disease Lung. Role of the PD-1–PD-L1 Axis
Authors: Richard T. McKendry, C. Mirella Spalluto, Hannah Burke, Ben Nicholas, Doriana Cellura, Aymen Al-Shamkhani, Karl J. Staples, Tom M. A. Wilkinson
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Patients with chronic obstructive pulmonary disease (COPD) are susceptible to respiratory viral infections that cause exacerbations. The mechanisms underlying this susceptibility are not understood. Effectors of the adaptive immune response-CD8(+) T cells that clear viral infections-are present in increased numbers in the lungs of patients with COPD, but they fail to protect against infection and may contribute to the immunopathology of the disease.
South Africa’s sex workers will receive HIV prevention and treatment
Authors: Pat Sidley
Journal: BMJ (2016)

South Africa is to supply sex workers with pre-exposure prophylaxis (PrEP) and treat those who test HIV positive with antiretroviral medication without waiting for their CD4 counts to drop, the country’s deputy president, Cyril Ramaphosa, has said.1 The proposals are part of a comprehensive plan for sex workers that was announced last week.

Sex work is illegal in South Africa but this status is being tackled, said Ramaphosa. He said that, while sex workers may carry condoms, the police often confiscate them to use as …
Abstract 12231: Antidepressant Use is Associated With Reduced Cardiovascular Reactivity and Myocardial Ischemia During Mental Stress
Authors: Ronnie Ramadan, David Sheps, Fabio Esteves, Paolo Raggi, Michael H Kutner, Douglas Bremner, Arshed Quyyumi, Viola Vaccarino
Journal: Circulation (2013)

Background: Mental Stress Induced Myocardial Ischemia (MSI) portends a worse prognosis in patients with CAD. Exaggerated cardiovascular reactivity to mental stress has been suggested as a possible ...
Enhanced Histone Deacetylase Activity in Malignant Melanoma Provokes RAD51 and FANCD2-Triggered Drug Resistance
Authors: Andrea Krumm, Christina Barckhausen, Pelin Kücük, Karl-Heinz Tomaszowski, Carmen Loquai, Jörg Fahrer, Oliver Holger Krämer, Bernd Kaina, Wynand Paul Roos
Journal: Cancer Research (2016)

DNA-damaging anticancer drugs remain a part of metastatic melanoma therapy. Epigenetic reprogramming caused by increased histone deacetylase (HDAC) activity arising during tumor formation may contribute to resistance of melanomas to the alkylating drugs temozolomide, dacarbazine, and fotemustine. Here, we report on the impact of class I HDACs on the response of malignant melanoma cells treated with alkylating agents. The data show that malignant melanomas in situ contain a high level of HDAC1/2 and malignant melanoma cells overexpress HDAC1/2/3 compared with noncancer cells. Furthermore, pharmacologic inhibition of class I HDACs sensitizes malignant melanoma cells to apoptosis following exposure to alkylating agents, while not affecting primary melanocytes. Inhibition of HDAC1/2/3 caused sensitization of melanoma cells to temozolomide in vitro and in melanoma xenografts in vivo HDAC1/2/3 inhibition resulted in suppression of DNA double-strand break (DSB) repair by homologous recombination because of downregulation of RAD51 and FANCD2. This sensitized cells to the cytotoxic DNA lesion O(6)-methylguanine and caused a synthetic lethal interaction with the PARP-1 inhibitor olaparib. Furthermore, knockdown experiments identified HDAC2 as being responsible for the regulation of RAD51. The influence of class I HDACs on DSB repair by homologous recombination and the possible clinical implication on malignant melanoma therapy with temozolomide and other alkylating drugs suggests a combination approach where class I HDAC inhibitors such as valproic acid or MS-275 (entinostat) appear to counteract HDAC- and RAD51/FANCD2-mediated melanoma cell resistance. Cancer Res; 76(10); 3067-77. ©2016 AACR.
Abstract 334: Slight Therapeutic Hypothermia (35°C) is Effective and Safe as a Post Cardiac Arrest Care for Low Left Cardiac Function PCAS Patients
Authors: Tomohiko Orita, Yukitoshi Toyoda, Motoyasu Yamazaki, Tomohiro Funabiki, Masayuki Shimizu, Shokei Matsumoto, Tomohiro Sato, Motojiro Takebe, Nao Hiroe, Taku Kazamaki, Yoshimi Nakamichi, Mitsuhide Kitano
Journal: Circulation (2013)

Background: Mild therapeutic hypothermia (32-34°C, 24-48 hours: mild TH) for post cardiac arrest syndrome (PCAS) due to ventricular fibrillation (VF) has been recommended in the American Heart Association (AHA) Guidelines 2010 (class I) and the International Liaison Committee on Resuscitation (ILCOR). But it is still unknown what temperature is good for low left cardiac function patients including acute myocardial infarction (AMI) cases. Sometimes executing mild TH for patients with severe left ventricular dysfunction are difficult because of hypotension, arrhythmias, unstable vital signs and so on. So we studied whether slight therapeutic hypothermia (35°C: Slight TH) was effective and safe compare with mild TH for PCAS due to VF. Methods: Consecutive PCAS patients who were witnessed, confirmed VF caused by cardiac or coronary events and introduced therapeutic hypothermia for the latest 58 months were sorted into the GroupM (Mild TH, 34°C, 24-48 hours) and the GroupS (Slight TH, 35°C, 24-48 hours).The primary end point was a favorable neurologic outcome (cerebral performance category: CPC 1 or 2) in 90th days after cardiac arrest. Secondary end points were the changes of cardiac index (CI) after introducing therapeutic hypothermia, the time required to reach target temperature and the rate of complications (infections, bleeding, arrhythmias etc.) within fourteen days. Results: forty-eight patients (twenty-two AMI cases) were studied (GroupM 24 patients and GroupS 24 patients). The rate of favorable neurologic outcome was available and did not differ significantly between the two groups (13/24 54% vs. 17/24 71%, p=0.34). The time to reach target temperature was significantly shorter in the GroupS (5.4h vs. 1.6h, p&lt;0.01). The decrease of CI was remarkable in the groupM (before TH/during TH, GroupM 2.8/2.1, p&lt;0.01, GroupS 2.2/2.1, p=0.33). The rate of complications did not differ significantly between them and there were no major complications. Conclusion: Slight therapeutic hypothermia for PCAS due to VF with low left cardiac function is effective and safe possibility.
Qualitative research, observational research, and<i>The BMJ</i>
Authors: Mark J Bolland, Alison Avenell, Andrew Grey
Journal: BMJ (2016)

Many of the reasons that qualitative research is given low priority at The BMJ also apply to observational studies.1 Their results are often not definitive or “likely to change clinical practice and help doctors make better decisions.” Their design means causality cannot be inferred, and confounding is invariably present and difficult to control for. Analyses …
The British Society of Gastroenterology
Authors: R H Riddell
Journal: Gut (1974)

ProfessorSheila Sherlock) on 'The carrier of hepatitis B antigen'.In the afternoon there was a symposium shared by the British Society for Digestive Endoscopy on 'Diagnosis of pancreatic disease' (Moderator, Dr Sheila Waller), and a clinicopathological conference on 'Progressive intestinal disease in an adolescent' (Moderator, Dr W. T. Cooke).
Immune Response in the Hamster. VI. Antibody Response in Polyoma Oncogenesis
Authors: J. E. Coe, K. K. Takemoto
Journal: JNCI Journal of the National Cancer Institute (1972)

Sera were obtained from neonatal and young-adult hamsters that had been given injections of polyoma virus or polyoma tumor. The immunoglobulins containing tumor (T) and virus (V) antibody were detected by indirect fluorescent microscopy with Auorescein-labeled antisera specific for hamster 7Sγ1-, 7Sγ2-, γA -, or γM-globulins. γA antibody was never found and a 7Sγ2 antibody response was always detected. 7Sγ1 anti-T was found in the two situations associated with tumor growth, i.e., after virus inoculation of neonates and tumor injection of adults. Because hamster 7Sγ1 globulins do not fix complement like the 7Sγ2 globulins, the presence of tumor antibody in the 7Sγ1 globulins may have an enhancing effect on tumor growth.
GASTRIC EMPTYING IN PATIENTS WITH SUPRAVENTRICULAR TACHYCARDIA.
Authors: Doina E. Tanasescu, Angas W. Hamer, Jay W. Marks, William J. Mandel, Mary E. Chappel, David E. Brown, Dennis R. Chapman, Alan D. Waxman
Journal: Clinical Nuclear Medicine (1983)

Tanasescu, Doina E.; Hamer, Angas W.; Marks, Jay W.; Mandel, William J.; Chappel, Mary E.; Brown, David E.; Chapman, Dennis R.; Waxman, Alan D. Author Information
Long-term regulation of inner medullary collecting duct urea transport in rat.
Authors: A Kato, M Naruse, M A Knepper, J M Sands
Journal: Journal of the American Society of Nephrology (1998)

Facilitated urea transport is regulated acutely by arginine vasopressin (AVP) and hyperosmolality in rat terminal inner medullary collecting duct (IMCD). This study tested whether chronic diuresis or antidiuresis regulates facilitated urea transport. Basal and AVP-stimulated urea permeabilities (Purea) were measured in perfused IMCD subsegments. Rats were made: (1) diuretic by giving them sugar water (with or without food) or furosemide; or (2) antidiuretic by water deprivation. They were then compared with untreated rats given food and water ad libitum. Terminal IMCD from untreated rats had a high basal Purea that was significantly increased by AVP. Diuresis significantly increased basal Purea in terminal IMCD in all five diuresis protocols. Water deprivation for 1 or 3 d had no effect on basal or AVP-stimulated Purea in the IMCD2 subsegment of the terminal IMCD. In contrast, 3 d of water deprivation significantly increased both basal and AVP-stimulated Purea in the IMCD3 subsegment; 1 d of water deprivation had no effect on basal or AVP-stimulated Purea. Next, initial IMCD (IMCD1) were studied. Initial IMCD from untreated rats had a low basal Purea that was not increased by AVP (10 nM). Water diuresis (with or without food) for 3 to 5 d had no effect on basal Purea but significantly increased AVP-stimulated Purea. Furosemide diuresis and water diuresis for 1 or 7 d had no effect on either basal or AVP-stimulated Purea in initial IMCD. Water deprivation for 2 to 3 d, but not for 1 d, significantly increased basal Purea in initial IMCD, whereas water deprivation for 1 d increased AVP-stimulated Purea. It is concluded that chronic changes in hydration cause heterogeneous changes in facilitated urea transport in rat IMCD subsegments.
Autism-like syndrome is induced by pharmacological suppression of BET proteins in young mice
Authors: Josefa M. Sullivan, Ana Badimon, Uwe Schaefer, Pinar Ayata, James Gray, Chun-wa Chung, Melanie von Schimmelmann, Fan Zhang, Neil Garton, Nicholas Smithers, Huw Lewis, Alexander Tarakhovsky, Rab K. Prinjha, Anne Schaefer
Journal: The Journal of Experimental Medicine (2015)

Studies investigating the causes of autism spectrum disorder (ASD) point to genetic, as well as epigenetic, mechanisms of the disease. Identification of epigenetic processes that contribute to ASD development and progression is of major importance and may lead to the development of novel therapeutic strategies. Here, we identify the bromodomain and extraterminal domain–containing proteins (BETs) as epigenetic regulators of genes involved in ASD-like behaviors in mice. We found that the pharmacological suppression of BET proteins in the brain of young mice, by the novel, highly specific, brain-permeable inhibitor I-BET858 leads to selective suppression of neuronal gene expression followed by the development of an autism-like syndrome. Many of the I-BET858–affected genes have been linked to ASD in humans, thus suggesting the key role of the BET-controlled gene network in the disorder. Our studies suggest that environmental factors controlling BET proteins or their target genes may contribute to the epigenetic mechanism of ASD.
Review: PCSK9 inhibitors reduce mortality but increase neurocognitive events in hypercholesterolemia
Authors: Raul D. Santos
Journal: Annals of Internal Medicine (2016)

Source Citation Lipinski MJ, Benedetto U, Escarcega RO, et al. The impact of proprotein convertase subtilisin-kexin type 9 serine protease inhibitors on lipid levels and outcomes in patients with primary hypercholesterolaemia: a network meta-analysis. Eur Heart J. 2015 Nov 17. [Epub ahead of print] 26578202
Early switch to a docetaxel-cisplatin (DP) doublet allows higher conversion to response for patients (pts) with advanced NSCLC in stable disease (SD) after 2 courses of gemcitabine-cisplatin (GP): Preliminary results of a pilot study
Authors: L. Moscetti, F. Nelli, A. de Pasquale Ceratti, I. Sperduti, D. Giannarelli, C. Signorelli, S. Santiccioli, R. Saltarelli, E. Capomolla, C. F. Pollera
Journal: Journal of Clinical Oncology (2005)

7276 Background: For non-responding pts, no more than 4 courses of a platinum doublet are currently recommended (Pfister et al. JCO 04). Better results might be achieved using different approaches for specific pt subsets (i.e. elderly, PS 2). Based on both the low rate of conversion to response expected continuing the same chemotherapy for pts in SD after 2 courses of GP and the potential hazard of an early discontinuation of P (Novello, ASCO 04 abs. 7069), the present study was designed. Methods: To evaluate the impact of an early switch of P-doublets in pts with advanced NSCLC showing a SD after 2 courses of GP (G 1250 mg/m2 days 1+8, P 75 mg/m2 day 2), 16 eligible pts were switched to ≥2 courses of DP (D 75 mg/m2 and P 75 mg/m2 both on day 1, with CSF primary prophylaxis). Main characteristics were: Age (median): 68 yrs (54–78); M/F: 13/3; ECOG-PS 0/1–2: 4/12; Stage IIIB/IV: 3/10; Histology adeno/others: 7/9. Results: After 2 courses of DP, 5/16 pts (31%) were converted to a PR, 6 remained in SD and 5 progressed. After the 4th course, an additional conversion was seen, for an overall response of 37% (6/16). Median PFS and survival were 6 and 13 mos., respectively. The 1-yr survival was 52%. Main toxicity (G3/4) with sequential DP was greater than with GP, including (% of pts): neutropenia 14% (with no febrile event), anemia and stomatitis 6%, G1–2 asthenia 50%, G1 fluid retention 6%. Dose reductions were required in 32% of courses (18/55). Conclusions: These preliminary results suggest that for pts in SD after 2 courses of chemotherapy this approach is feasible, allowing a promising improvement of response with a conversion rate (37%) greater than expected maintaining the same regimen according to the Novello’s phase III trial (6%). Outcome data also compare favourably with those expected for pts in SD (12 mos.; Hoang WCLC 2003 abs O-274). Although the 2nd step of the trial design continues to the target sample, these preliminary findings may generate hypothesis to be tested in larger randomized trials. (partly supported by AMAN-onlus) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis
Sequential biochemotherapy for metastatic colorectal cancer using fluorouracil, folinic acid, thymopentin and interleukin-2: Clinical and immunological effects
Authors: M. Lopez, L. Di Lauro, G. Paoletti, S. Santini, G.M. Gandolfo, G. Vitelli, A.M. Frasca, F. Ameglio, G. Rasi, E. Garaci
Journal: Annals of Oncology (1995)
Primary care‐based screening for cardiovascular risk factors in patients with psoriasis
Authors: M.K. Rutter, K. Kane, M. Lunt, L. Cordingley, A. Littlewood, H.S. Young, C.A. Chew‐Graham, R. Hilton, D.P.M. Symmons, C.E.M. Griffiths
Journal: British Journal of Dermatology (2016)

Studies assessing cardiovascular disease (CVD) risk factors in patients with psoriasis have been limited by selection bias, inappropriate controls or a reliance on data collected for clinical reasons.To investigate whether screening for CVD risk factors in patients with psoriasis in primary care augments the known prevalence of CVD risk factors in a cross-sectional study.Patients listed as having psoriasis in primary care were recruited, screened and risk assessed by QRISK2.In total, 287 patients attended (mean age 53 years, 57% women, 94% white British, 22% severe disease, 33% self-reported psoriatic arthritis). The proportion with known and screen-detected (previously unknown) risk factors was as follows: hypertension 35% known and 13% screen-detected; hypercholesterolaemia 32% and 37%; diabetes 6·6% and 3·1% and chronic kidney disease 1·1% and 4·5%. At least one screen-detected risk factor was found in 48% and two or more risk factors were found in 21% of patients. One in three patients (37%) not previously known to be at high risk were found to have a high (> 10%) 10-year CVD risk. Among the participants receiving treatment for known CVD risk factors, nearly half had suboptimal levels for blood pressure (46%) and cholesterol (46%).Cardiovascular risk factor screening of primary care-based adults with psoriasis identified a high proportion of patients (i) at high CVD risk, (ii) with screen-detected risk factors and (iii) with suboptimally managed known risk factors. These findings need to be considered alongside reports that detected limited responses of clinicians to identified risk factors before universal CVD screening can be recommended.
Astrocytes are central in the pathomechanisms of vanishing white matter
Authors: Stephanie Dooves, Marianna Bugiani, Nienke L. Postma, Emiel Polder, Niels Land, Stephen T. Horan, Anne-Lieke F. van Deijk, Aleid van de Kreeke, Gerbren Jacobs, Caroline Vuong, Jan Klooster, Maarten Kamermans, Joke Wortel, Maarten Loos, Lisanne E. Wisse, Gert C. Scheper, Truus E.M. Abbink, Vivi M. Heine, Marjo S. van der Knaap
Journal: Journal of Clinical Investigation (2016)

Vanishing white matter (VWM) is a fatal leukodystrophy that is caused by mutations in genes encoding subunits of eukaryotic translation initiation factor 2B (eIF2B). Disease onset and severity are codetermined by genotype. White matter astrocytes and oligodendrocytes are almost exclusively affected; however, the mechanisms of VWM development remain unclear. Here, we used VWM mouse models, patients' tissue, and cell cultures to investigate whether astrocytes or oligodendrocytes are the primary affected cell type. We generated 2 mouse models with mutations (Eif2b5Arg191His/Arg191His and Eif2b4Arg484Trp/Arg484Trp) that cause severe VWM in humans and then crossed these strains to develop mice with various mutation combinations. Phenotypic severity was highly variable and dependent on genotype, reproducing the clinical spectrum of human VWM. In all mutant strains, impaired maturation of white matter astrocytes preceded onset and paralleled disease severity and progression. Bergmann glia and retinal Müller cells, nonforebrain astrocytes that have not been associated with VWM, were also affected, and involvement of these cells was confirmed in VWM patients. In coculture, VWM astrocytes secreted factors that inhibited oligodendrocyte maturation, whereas WT astrocytes allowed normal maturation of VWM oligodendrocytes. These studies demonstrate that astrocytes are central in VWM pathomechanisms and constitute potential therapeutic targets. Importantly, astrocytes should also be considered in the pathophysiology of other white matter disorders.