tbuckley/cabot-search huggingface dataset:
Abstract 19228: Lack of Uncoupling Protein 2 (UCP2) Reduces Mitochondrial Calcium Uptake from the Endoplasmic Reticulum (ER), Triggering Mitochondrial Suppression and Pulmonary Hypertension (PHT)
Authors: Peter Dromparis, Roxane Paulin, Gopinath Sutendra, Evangelos D Michelakis
Journal: Circulation (2012)

A metabolic shift from glucose oxidation to glycolysis due to suppressed mitochondrial function contributes to the hyperproliferation and resistance to apoptosis in resistance pulmonary arteries (PA) in PHT. Disruption of the ER-mitochondria unit, which can result from many PHT-triggers including hypoxia, prevents the transfer of ER Ca2+ to mitochondria, reducing the activity of Ca2+-sensitive mitochondrial enzymes and causing mitochondrial suppression. Emerging links between PHT and insulin resistance suggest a global metabolic dysfunction. The mitochondrial protein UCP2 is implicated in the uptake of ER-derived Ca2+ and loss-of-function UCP2 polymorphisms are associated with insulin resistance/obesity. We hypothesized that reduced UCP2-mediated mitochondrial Ca2+ uptake suppresses mitochondrial function and causes PHT. UCP2 is expressed in PA smooth muscle cells (PASMCs) from wild-type (WT), but not knockout (KO) mice. KO-PASMCs had lower mitochondrial Ca2+ levels than WT-PASMCs, at baseline and during histamine-stimulated ER Ca2+ release (FRET-imaging), despite intact ER-mitochondrial morphology (electron microscopy). In keeping with reduced mitochondrial Ca2+, KO-PASMCs had mitochondrial hyperpolarization, lower activity of Ca2+-sensitive mitochondrial enzymes, reduced mitochondrial reactive oxygen species and resistance to apoptosis. UCP2 KO-mice (which have an apparently normal phenotype) had a modest, but significant elevation in mean PA pressure (catheterization; 26±2 vs. 19±1 mmHg), total pulmonary resistance (1.37±.14 vs. 0.89±0.07 mmHg ml-1 min), %medial thickness, PASMC proliferation (% Ki67-positive), and resistance PA muscularization (n=6, p&lt;0.05 for all). Chronic Hypoxia increased PA pressure in WT-mice to the level of the normoxic UCP2 KO-mice. However the UCP2 KO-mice were resistant to further exacerbation of PHT in vivo or hypoxia-induced PASMC changes in vitro. Since in hypoxia-induced PHT the ER-mitochondria unit is disrupted, the loss of UCP2 does not have additional effects. We conclude that lack of UCP2 causes mitochondrial suppression in PASMC and predisposes to PHT. UCP2 polymorphisms may predispose to PHT and potentially underlie the unexplained systemic metabolic abnormalities in PHT.
Consultant and junior doctor contracts to be reviewed by DDRB after talks stalled
Authors: Abi Rimmer
Journal: BMJ (2014)

The government has asked the Review Body on Doctors’ and Dentists’ Remuneration (DDRB) to consider the consultant and junior doctor contracts after the breakdown of negotiations with the BMA.

Dan Poulter, undersecretary of state for health services, wrote to the DDRB last Thursday to ask it to look at the consultant contract and make recommendations for a new junior doctor contract.1 Last month the BMA announced that negotiations on consultants and junior doctors contracts between itself and NHS Employers, the organisation that represents the government in negotiations, had stalled.2

Poulter has now asked the DDRB to comment on …
CPD should focus on motivation rather than administration, Danish researchers say
Authors: Abi Rimmer
Journal: BMJ (2014)

Continuous professional development (CPD) should focus on “how to stimulate and support professional motivation” rather than on administration, researchers have argued.1

A group of researchers looked at how general practitioners in Denmark used CPD. In Denmark CPD is voluntary for GPs and is based on funded accredited activities. The researchers found that the doctors chose their …
NHS sets out plan to ensure ethnic minority staff get fair treatment
Authors: Abi Rimmer
Journal: BMJ (2014)

The NHS Equality and Diversity Council has announced plans to ensure that staff members from ethnic minority groups have equal access to career opportunities.

The move comes after the publication of a report that found that experiences of racism, exclusion, and discrimination contributed to low levels of wellbeing among ethnic minorities, including staff in the NHS.1 The council said that, by the start of April 2015, it would implement …
CLINICAL OUTCOMES AT 5 YEARS FOLLOWING SELF-EXPANDING TRANSCATHETER AORTIC VALVE REPLACEMENT IN THE COREVALVE US EXTREME RISK PIVOTAL TRIAL
Authors: George Petrossian, James Hermiller, Steven J. Yakubov, Michael Reardon, G. Michael Deeb, David Adams, Jeffrey Popma
Journal: Journal of the American College of Cardiology (2018)
OPTICAL COHERENCE TOMOGRAPHY FINDINGS OF CHRONIC TOTAL OCCLUSION LESIONS
Authors: Miho Tada, Yusuke Fujino, Satoko Tahara, Hiroto Yabushita, Kenjiro Tani, Toru Naganuma, Hisaaki Ishiguro, Naoyuki Kurita
Journal: Journal of the American College of Cardiology (2018)
Abstract P6-09-11: Ki67 cut offs and oncotype DX recurrence score in early breast cancer
Authors: F Namuche, R Ruiz, C Flores, HL Gomez, A Aguilar
Journal: Cancer Research (2018)

Abstract Background: The gene expression profiling assay OncotypeDx (ODX) predicts the likelihood of estrogen receptor (ER) positive breast cancer (BC) recurrence and assesses the likely benefit from both hormonal therapy and chemotherapy. Many clinical scores that estimate the risk category of ODX are being tested. Ki67 is frequently incorporated into these assessments, although there is no standard cut-off for its use. Methods: We retrospectively reviewed the electronic medical records of 190 patients with early stage ER+ BC for whom ODX recurrence score (RS) was available. Patients were diagnosed and treated at a specialized cancer center between 2014 and 2016. Our objective was to find out the degree to which an optimal ki67 cut-off correlates with ODX risk category. We also aim to determine an association between classical clinicopathological variables (St. Gallen (SG) 2015) could predict ODX risk category. Chi square test was used. Results: The characteristics of patients according to ODX risk category are shown in Table 2. Mean age at diagnosis was 59 years (range 28-89). Mean tumor diameter was 15mm, 84.2% were intermediate grade and 4.7% patients had lymph node involvement. Mean expression of ER, PR and Ki67 were 87%, 53% and 22%, respectively. According to ODX 62.1% patients were low risk, 30.5% were intermediate risk and 7.4% were high risk. An overall concordance of 46.8% (73/190) was found between SG 2015 and the risk category of ODX (75.7% for low, 33.3% for intermediate and 23.9% for high RS). When changing SG Ki67 cutoffs to ≤20% (for low Ki67) and ≥30% (for high Ki67), an overall concordance of 56.3% (107/190) was found (69.6% for low, 47.3% for intermediate and 23.9% for high RS) and this was statistically significant (p=0.00) (Table 3). Conclusion: In our population there is no a direct correlation between classical clinicopathological variables and ODX score. Despite being a specialized center, the utility of classical clinicopathological variables for predicting ODX risk category is limited. Citation Format: Namuche F, Ruiz R, Flores C, Gomez HL, Aguilar A. Ki67 cut offs and oncotype DX recurrence score in early breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-09-11.
P101 DOT1L inhibition increases dermal fibroblast proliferation but has no effects on in vitro or in vivo collagen deposition in models of fibrosis
Authors: N Berghen, E De Langhe, R Lories
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> Fibrosis is a key process in Systemic Sclerosis, a devastating disease that is not well understood. The role of epigenetic disease mechanisms is increasingly explored. DOT1L, the unique H3K79-methyltransferase, methylates histone 3 at the Lysine residue at position 79, and regulates gene expression. Inhibition of DOT1L has cell-type specific effects on Wnt-signalling, a pathway suggested to play an important role in fibrosis. <h3>Objectives</h3> To study the role of DOT1L in fibrosis. <h3>Methods</h3> Primary cell cultures of fibroblasts, isolated from healthy human skin and treated with DOT1L-inhibitor EPZ-5676 or vehicle for 14 days, were stimulated with TGFβ 5 ng/ml after starvation. Smooth muscle alpha 2 actin (ACTA2) gene expression was measured by RT-qPCR. Efficiency of DOT1L-inhibition was analysed with Western Blot for dimethylated H3K79. Picrosirius Red staining measured collagen I and III deposition. Proliferation was analysed with 5-Bromo-2'-deoxy-uridine (BrdU) labelling. 7–9 week old Col1a2; Cre-ERT<sup>2</sup>; DOT1l<sup>fl/fl</sup> mice were injected intraperitoneally with tamoxifen (1 mg/day,5 days) to induce a fibroblast-specific DOT1L knockout. Bleomycin (0.1 mg) or vehicle was injected subcutaneously (5 days/week, 4 weeks). Injected skin was analysed by OH-prolin assay for collagen content, and by histology for dermal thickness measurement. <h3>Results</h3> The DOT1L-inhibitor EPZ-5676 reduced H3K79 dimethylation in all samples. TGFβ increased expression of ACTA2 but 3 out of 4 DOT1L inhibited samples showed a significantly reduced effect of TGFβ on ACTA2 expression. The amount of collagen I and III in the extracellular matrix after 72 hours of TGFβ, was comparable between control and EPZ treated fibroblasts. BrdU labelling assay showed increased proliferation with DOT1L inhibition. <i>In vivo</i>, subcutaneous bleomycin induced an increased dermal thickness and skin collagen content in mice. No difference in the effect of bleomycin was found between mice with a conditional fibroblast-specific DOT1L knockout or wild type mice. <h3>Conclusions</h3> In an <i>in vitro</i> model of fibrosis, primary human dermal fibroblasts treated with a DOT1L-inhibitor showed increased proliferation and reduced upregulation of ACTA2 but did not result in detectable differences in collagen deposition. In an <i>in vivo</i> murine model of skin fibrosis, no difference in bleomycin-induced skin thickness and collagen content was found when DOT1L was knocked out in fibroblasts. <h3>Disclosure of interest</h3> None declared
CCGs swamped by red tape, warns NHS Clinical Commissioners
Authors: Caroline White
Journal: BMJ (2012)

Nascent clinical commissioning groups (CCGs) are being swamped with so much red tape that they are being left with no time to shape the structure and delivery of the new commissioning arrangements, NHS Clinical Commissioners (NHSCC) has warned.

NHSCC—a partnership of the National Association of Primary Care, NHS Alliance, and the NHS Confederation—is calling on the government to give CCGs some much needed breathing space and practical support to free up some thinking time.

If real and innovative change to the way …
I am interested in returning to the UK. I graduated in 1988, completed GP training in 1992, and moved to the USA, where I have worked as a GP ever since. I have applied for salaried posts without much luck. Any other recommendations? How do I apply for the returner scheme?
Authors: Kay Mohanna
Journal: BMJ (2006)

Have a career or related problem that needs answering? Can9t find the right person to point you in the right direction? Log on to the Advice Zone for reliable medical careers advice. You can post a question or see if one of our 300 advisers has already answered a similar question. Here is a selection of questions and answers posted on the site. <b>www.bmjcareers.com/advicezone</b>
Human Papillomavirus DNA Methylation as a Biomarker for Cervical Precancer: Consistency across 12 Genotypes and Potential Impact on Management of HPV-Positive Women
Authors: Megan A. Clarke, Ana Gradissimo, Mark Schiffman, Jessica Lam, Christopher C. Sollecito, Barbara Fetterman, Thomas Lorey, Nancy Poitras, Tina R. Raine-Bennett, Philip E. Castle, Nicolas Wentzensen, Robert D. Burk
Journal: Clinical Cancer Research (2018)

Purpose: Human papillomavirus (HPV) DNA methylation testing is a promising triage option for women testing HPV positive during cervical cancer screening. However, the extent to which methylation indicates precancer for all 12 carcinogenic HPV types has not been evaluated.Experimental Design: In this nested case-control study, we tested up to 30 cases of precancer [cervical intraepithelial neoplasia grade 3 (CIN3)/adenocarcinoma in situ (AIS)] and 30 normal controls for each carcinogenic type (single infections with 16/18/31/33/35/39/45/51/52/56/58/59). Next-generation bisulfite sequencing was performed on CpG sites within the L1 and L2 genes. We calculated differences in methylation, ORs, and AUC. Using a fixed sensitivity of 80%, we evaluated the specificity and the risk of CIN3/AIS for best performing CpG sites, and compared the performance of an explorative multi-type methylation assay with current triage strategies.Results: Methylation was positively associated with CIN3/AIS across all 12 types. AUCs for the top sites ranged from 0.71 (HPV51 and HPV56) to 0.86 (HPV18). A combined 12-type methylation assay had the highest Youden index (0.46), compared with cytology (0.31) and a 5-type methylation assay, including only previously described types (0.26). The 12-type methylation assay had higher sensitivity (80% vs. 76.6%) and lower test positivity compared with cytology (38.5% vs. 48.7%). The risk of CIN3/AIS was highest for methylation positives and lowest for cytology or HPV16/18 positives.Conclusions: HPV DNA methylation is a general phenomenon marking the transition from HPV infection to precancer for all 12 carcinogenic types. Development of a combined multitype methylation assay may serve as a triage test for HPV-positive women. Clin Cancer Res; 24(9); 2194-202. ©2018 AACR.
Response by Beach et al to Letter Regarding Article, “Idiopathic Ventricular Fibrillation in a 29-Year-Old Man”
Authors: Leila Y. Beach, Nora Goldschlager, Joshua D. Moss, Melvin M. Scheinman
Journal: Circulation (2018)

In Response: Thank you for your interest in our article and for your keen observations. 1The word limitations for case reports precluded a detailed description of the case.You appropriately raise the issue of arrhythmogenic right ventricular cardiomyopathy in view of the premature ventricular contraction origin.However, apart from high-density premature ventricular contractions, there were no other major or minor criteria supporting this diagnosis.In addition, limited endocardial voltage mapping in the region of the triggering premature ventricular contraction was normal.You also appropriately raised the possibility of catecholaminergic polymorphic ventricular tachycardia in view of the RYR2 mutation found.However, all episodes of ventricular arrhythmia occurred at rest, there was no family history of exercise-related syncope or sudden death, and an exercise stress test performed 3 weeks after his ablation was unremarkable.We do not know long-term outcomes for these patients, but mid-term follow-up of patients with successful ablation has suggested an excellent prognosis. 2We felt that a myocardial biopsy at this stage would be a low-yield procedure in view of the normal cardiac magnetic resonance study.Thanks again for your interest and cogent comments.
Blood pressure and sympathetic nervous function in spontaneously hypertensive rats derived from breeders on low sodium diet.
Authors: Koshiro Fukiyama, Shuichi Takishita, Tanenao Eto, Yorio Kimura, Yuji Tomita, Nobuyuki Kawazoe, Teruo Omae, Tatsumi Tsumagari, Kenichi Ohnishi
Journal: Circulation (1986)

We investigated the effect of dietary salt restriction in spontaneously hypertensive rat (SHR) breeders to determine if the development of hypertension of offspring would be blunted. Weaning SHRs (F-0) were divided into 3 groups and were given a diets containing sodium of 0.4% (G1), 0.05% (G2), or 0.4% plus mefruside 0.001% (G3) with distilled water. Potassium content was 0.75% and the other ingredients except chloride were identical in all the diets. Offsprings (F-1) were derived from selective inbreeding within each group. Systolic blood pressure rose over 160 mmHg by 8 weeks of age in all the male rats of all the groups in both F-0 and F-1. There was no difference in blood pressure between G 1 and G 2 at any age, while in G 3 blood pressure was significantly lower than in G 1 at 12 and 20 weeks of age in F-1. The findings in pressure were ascertained by heart-body weight ratio determined at autopsy, which was similar between G 1 and G 2, and was smaller in G 3 than the others at 20 weeks of age. Aldostrone excretion rate was markedly higher in G 2 than G 1 and G 3 at all study points, whereas plasma renin content was similar between G 1 and G 2, and higher in G 3. Plasma concentrations of noradrenaline and adrenaline did not differ among the 3 groups at any age in both F-0 and F-1. There was also no difference in cardiovascular responsiveness to intravenous noradenaline or hexamethonium among the groups at any age in both F-0 and F-1. It is concluded that life-long sodium restriction does not blunt the development of hypertension in SHR, which might be attributed to failure of suppression in sympathetic nervous function.
Identification of cardiac long non-coding RNA profile in human dilated cardiomyopathy
Authors: Huaping Li, Chen Chen, Jiahui Fan, Zhongwei Yin, Li Ni, Katherine Cianflone, Yan Wang, Dao Wen Wang
Journal: Cardiovascular Research (2018)

Dilated cardiomyopathy (DCM) induced chronic heart failure is a life-threatening disease worldwide. Long non-coding RNAs (lncRNAs) are potential new therapeutic targets and may provide new pathophysiological mechanisms for development of DCM.Microarray assays in 14 DCM and 10 control human heart samples identified 313 significantly differentially expressed lncRNAs. SiRNAs were used to explore the potential function of specific lncRNAs (RP11-544D21.2 and XLOC_014288) in human cardiac myocytes, human cardiac fibroblasts and human cardiac microvascular endothelial cells, respectively. RNA-seq and pathway analyses revealed the function of lncRNA RP11-544D21.2 and XLOC_014288 in three heart cells. Furthermore, impaired tube formation and migration were observed in si-RP11-544D21.2-treated endothelial cells. Moreover, TAF10 was predicted and verified to be one of the causes of some up-regulated lncRNAs. Then, we found that the left ventricular ejection fraction correlated with these changed lncRNAs.This study provides a comparison of human cardiac lncRNA profiles in control and DCM. It illustrates the function and complex roles of the differentially expressed lncRNAs in different cell types in the heart, which may lead to new insights into the mechanisms and treatment strategies for DCM in the future.
Desmin Phosphorylation Triggers Preamyloid Oligomers Formation and Myocyte Dysfunction in Acquired Heart Failure
Authors: Peter P. Rainer, Peihong Dong, Matteo Sorge, Justyna Fert-Bober, Ronald J. Holewinski, Yuchuan Wang, Catherine A. Foss, Steven S. An, Alessandra Baracca, Giancarlo Solaini, Charles G. Glabe, Martin G. Pomper, Jennifer E. Van Eyk, Gordon F. Tomaselli, Nazareno Paolocci, Giulio Agnetti
Journal: Circulation Research (2018)

Rationale: Disrupted proteostasis is one major pathological trait that heart failure (HF) shares with other organ proteinopathies, such as Alzheimer and Parkinson diseases. Yet, differently from the latter, whether and how cardiac preamyloid oligomers (PAOs) develop in acquired forms of HF is unclear. Objective: We previously reported a rise in monophosphorylated, aggregate-prone desmin in canine and human HF. We now tested whether monophosphorylated desmin acts as the seed nucleating PAOs formation and determined whether positron emission tomography is able to detect myocardial PAOs in nongenetic HF. Methods and Results: Here, we first show that toxic cardiac PAOs accumulate in the myocardium of mice subjected to transverse aortic constriction and that PAOs comigrate with the cytoskeletal protein desmin in this well-established model of acquired HF. We confirm this evidence in cardiac extracts from human ischemic and nonischemic HF. We also demonstrate that Ser31 phosphorylated desmin aggregates extensively in cultured cardiomyocytes. Lastly, we were able to detect the in vivo accumulation of cardiac PAOs using positron emission tomography for the first time in acquired HF. Conclusions: Ser31 phosphorylated desmin is a likely candidate seed for the nucleation process leading to cardiac PAOs deposition. Desmin post-translational processing and misfolding constitute a new, attractive avenue for the diagnosis and treatment of the cardiac accumulation of toxic PAOs that can now be measured by positron emission tomography in acquired HF.
Abstract 16769: Sequential Treatment With Sustained-release of Basic Fibroblast Growth Factor Followed by Transplantation of Human Induced Pluripotent Stem Cell-derived Cardiac Tissue Improved Left Ventricular Function in a Rat Chronic Myocardial Infarction Model
Authors: Zipeng Li, Hidetoshi Masumoto, Kenji Minakata, Masahide Kawatou, Shinya Takimoto, Shingo Hirao, Tadashi Ikeda, Yasuhiko Tabata, Jun K. Yamashita, Ryuzo Sakata
Journal: Circulation (2016)

Backgrounds:  Cell-based therapy using human induced pluripotent stem (iPS) cell-derived Cardiac Tissue Sheets (CTSs) including cardiomyocytes and vascular cells shows promise for cardiac regeneration following myocardial infarction (MI). However, severe ischemia limits engraftment of cells after transplantation and it is still challenging to show functional advantages especially for chronic MI. Recently, we have generated Human iPS cell-derived Cardiac Tissue with 15-layered CTSs (HiCT-15) by inserting gelatin hydrogel (GH) microspheres between each CTS to overcome the stacking limitation of hypoxia. On the other hand, sustained-release of basic fibroblast growth factor (bFGF) using GH is known to improve left ventricular (LV) function in chronic MI through induction of angiogenesis. Here we aimed to take advantage of bFGF to enhance engraftment and efficiency of HiCT-15 in a rat chronic MI model.   Methods:  Studies were conducted in male athymic nude rats (12-16 weeks old) 4 weeks after ligation of the proximal left anterior descending coronary artery. GH sheets (GHSs) with or without bFGF (100μg) were implanted to MI models to evaluate the effect of bFGF-GHS on chronic scar tissue. Four weeks later, HiCT-15 with bFGF (100μg) were transplanted to the rats received bFGF-GHS treatment. Cardiac functions were evaluated with echocardiogram.   Results:  Four weeks after treatment, bFGF-GHS significantly improved cardiac contractile function accompanied with neovascularization. Immunohistochemical studies revealed that bFGF-GHS increased collagen III/I ratio indicating attenuation of solid scar tissue. Quantitative RT-PCR results showed a decrease of collagen I expression within border ischemic zone. HiCT-15 transplantation following bFGF-GHS treatment further promoted systolic function compared to the baseline of bFGF-GHS treatment. The beneficial effects sustained 12 weeks till sacrifice.   Conclusion:  Sustained-release of bFGF altered collagen distribution and increased angiogenesis in ischemic myocardium, thereby enhanced the efficiency of HiCT transplantation. The sequential treatment of sustained-release of bFGF and HiCT may be a promising treatment for heart failure due to chronic pathology such as ischemic cardiomyopathy.