tbuckley/cabot-search huggingface dataset:
Abstract P284: Inhibition of the Rheb/mTORC1 Pathway During Prolonged Ischemia Is Protective Through Autophagy Activation in Cardiomyocytes
Authors: Sebastiano Sciarretta, Peiyong Zhai, Junichi Sadoshima
Journal: Circulation Research (2011)

The mTOR complex 1 (mTORC1) mediates the cellular response to energy stress. However, the role of mTORC1 signaling in mediating cardiomyocyte (CM) tolerance of nutrient starvation and ischemia remains unclear. mTORC1 activity, as evaluated by the phosphorylation status of p70S6K and 4E-BP1, was decreased in CMs during glucose deprivation (GD) in vitro , and was accompanied by decreases in the activity of Rheb, a positive regulator of mTORC1 (31.7% reduction in Rheb-bound GTP, p&lt;0.05). Exogenous Rheb was sufficient to restore mTORC1 activity, suggesting that Rheb regulates the activity of mTOR during GD. Rheb overexpression reduced CM survival during GD (42.6% reduction at 18 hours, p&lt;0.01), whereas knock-down of Rheb increased CM survival (158.6% increase at 18 hours, p&lt;0.05). Rheb overexpression significantly inhibited autophagy, reduced expression of autophagic genes, including Atg7, reduced the ATP content, and increased ER stress in CMs during GD. Under these conditions, restoration of autophagy through Atg7 overexpression or trehalose inhibited cell death, increased ATP content, and reduced ER stress. The activity of Rheb/mTORC1 is also inhibited during myocardial ischemia in vivo . After 3 hours of ischemia, transgenic mice with cardiac-specific and inducible Rheb overexpression (Tg-Rheb) exhibited a larger myocardial infarction (MI) (59.7% vs. 37.8%, p&lt;0.05) and a significant reduction in autophagy compared to control mice, both of which were reversed by rapamycin, a selective mTORC1 inhibitor. Interestingly, both Rheb (+135% in Rheb-bound GTP, p&lt;0.05) and mTORC1 (+158% in phospho-p70S6K, p&lt;0.05) were activated in the hearts of mice with high fat diet-induced obesity. Prolonged ischemia induced less autophagy and a larger MI (60.6% vs. 37.2%, p&lt;0.05) in the obese mice, effects which were reversed in the presence of rapamycin. However, rapamycin failed to protect the obese mice in the presence of genetic downregulation of Beclin 1 ( beclin1 +/− mice fed with high fat diet). In summary, inhibition of the Rheb/mTORC1 pathway during energy deprivation is protective through activation of autophagy. Rheb and mTORC1 represent potential therapeutic targets to reduce myocardial damage during prolonged myocardial ischemia in obese patients. .
P12.11 Seizure prophylaxis in meningioma surgery - is it time for a randomized controlled trial?
Authors: M. D. Jenkinson, E. Chavredakis, R. Zakaria, A. R. Brodbelt
Journal: Neuro-Oncology (2017)

Introduction: Seizures affect up to 50% of patients with meningioma. Anti-epileptic drugs (AEDs) cause adverse effects in ~20% of patients. Guidelines recommend against routine use of prophylactic AEDs. The aim of this study was to evaluate the use of AEDs in meningioma surgery in the UK. Materials and methods: Email survey of UK neurosurgeons to ascertain: (i) use of prophylactic AED; (ii) preferred AED, dose and duration of use; (iii) tumour location and radiological factors that influence use of AED; (iv) willingness to participate in a future randomised controlled trial. Results: 60 completed surveys from 25 neurosurgical centres. Use of prophylactic AED was ‘almost never’ in 37/61 (61%); ‘rarely’ 10/61 (16%); ‘often’ 8/61 (13%) and ‘almost always’ 6/61 (10%). 42 surgeons had prescribed AEDs at some point; Levitoracetam (n=23) and phenytoin (n=18) were the commonest. Duration of prescription ranged from single dose at surgery to 3 months. Commonest duration was 7 days (n=18) and 14 days (n=8). Sphenoid (24/49; 49%) and olfactory (17/49; 35%) location, oedema (26/49; 53%) and mass effect/midline shift (20/49; 41%) were factors associated with prophylactic AED use. 80% of surgeons would participate in a randomised controlled trial. Conclusions: Most UK neurosurgeons follow guidelines and do not routinely prescribe prophylactic AEDs. Sphenoid and olfactory meningiomas and those with oedema are more likely to receive prophylactic AEDs which suggests neurosurgeons are more concerned about the consequences of seizures in these patients. A randomised controlled trial is required to provide class I evidence of those patients that may benefit from prophylactic AEDs in meningioma surgery and a proposal will be presented.
Abstract 67: miR-19 Deficiency Impairs Cardiac Repolarization in Zebrafish
Authors: Alexander Benz, Hugo A Katus, David Hassel
Journal: Circulation Research (2015)

The most common outcome of heart failure (HF) is sudden cardiac death which results mostly from prolonged action potential duration (APD) and arrhythmias. During the pathogenesis and progression of HF, a vast number of signaling pathways are altered. microRNAs are small noncoding RNAs that post-transcriptionally finetune gene expression. Interestingly, several microRNAs are dysregulated during HF, suggesting a potential involvement in the development and progression of the disease. Here, we identified miR-19 as an important regulator of heart function. Zebrafish lacking miR-19 developed severe bradycardia and reduced cardiac contractility. While the mammalian genome encodes for two isoforms of miR-19, zebrafish express four members (19a-d). We found that the reduction of miR-19b specifically is sufficient to cause bradycardia and reduced cardiac contractility. Imaging of ventricular APs from whole hearts revealed that APD is significantly prolonged and repolarization is impaired in miR-19b deficient zebrafish. By qRT-PCR experiments we showed that the expression of several cardiac ion channels is altered. Moreover, miR-19b deficiency results in increased sensitivity to an AV-Block, which is a characteristic feature of long QT-Syndrome in zebrafish. In conclusion, we identified miR-19b as a novel and essential modulator of the electrical activity of the heart and establish miR-19b as a potential candidate gene causative for human long QT syndrome.
What are the Benefits and Harms of Ureteroscopy Compared with Shock-wave Lithotripsy in the Treatment of Upper Ureteral Stones? A Systematic Review
Authors: Tamsin Drake, Nikolaos Grivas, Saeed Dabestani, Thomas Knoll, Thomas Lam, Steven Maclennan, Ales Petrik, Andreas Skolarikos, Michael Straub, Christian Tuerk, Cathy Yuhong Yuan, Kemal Sarica
Journal: European Urology (2017)
NHS must “get its act together” to secure cash for new buildings
Authors: Gareth Iacobucci
Journal: BMJ (2017)

NHS hospitals must be willing to dispose of surplus land to help convince the Treasury to invest in new premises that are fit for purpose, the head of a major government review has urged.

Robert Naylor, former chief executive of University College London Hospitals, who was asked by the health secretary, Jeremy Hunt, to produce a review of NHS property and estates,1 said that the NHS needed to “get its act together” to free up the cash required to develop new integrated services throughout England.

Speaking at the King’s Fund on Tuesday 25 April, Naylor said that the Treasury’s 2017 budget commitment of £325m for NHS capital funding and extra …
Effects of ferric carboxymaltose on hospitalisations and mortality rates in iron‐deficient heart failure patients: an individual patient data meta‐analysis
Authors: Stefan D. Anker, Bridget‐Anne Kirwan, Dirk J. van Veldhuisen, Gerasimos Filippatos, Josep Comin‐Colet, Frank Ruschitzka, Thomas F. Lüscher, Gregory P. Arutyunov, Michael Motro, Claudio Mori, Bernard Roubert, Stuart J. Pocock, Piotr Ponikowski
Journal: European Journal of Heart Failure (2017)

Abstract Aims Iron deficiency ( ID ) is a common co‐morbidity in patients with heart failure ( HF ) and has been suggested to be associated with poor prognosis. Recently completed double‐blind randomised controlled trials ( RCTs ) studying HF patients with ID have shown improvements in functional capacity, symptoms and quality of life when treated with i.v. ferric carboxymaltose ( FCM ). This individual patient data meta‐analysis investigates the effect of FCM vs. placebo on recurrent hospitalisations and mortality in HF patients with ID . Methods and results Individual patient data were extracted from four RCTs comparing FCM with placebo in patients with systolic HF and ID . The main outcome measures were recurrent cardiovascular ( CV ) hospitalisations and CV mortality. Other outcomes included cause‐specific hospitalisations and death. The main analyses of recurrent events were backed up by time‐to‐first‐event analyses. In total, 839 patients, of whom 504 were randomised to FCM , were included. Compared with those taking placebo, patients on FCM had lower rates of recurrent CV hospitalisations and CV mortality [rate ratio 0.59, 95% confidence interval ( CI ) 0.40–0.88; P = 0.009]. Treatment with FCM also reduced recurrent HF hospitalisations and CV mortality (rate ratio 0.53, 95% CI 0.33–0.86; P = 0.011) and recurrent CV hospitalisations and all‐cause mortality (rate ratio 0.60, 95% CI 0.41–0.88; P = 0.009). Time‐to‐first‐event analyses showed similar findings, with somewhat attenuated treatment effects. The administration of i.v. FCM was not associated with an increased risk for adverse events. Conclusions Treatment with i.v. FCM was associated with a reduction in recurrent CV hospitalisations in systolic HF patients with ID .
P04.19 Recommendations for computation of textural measures obtained from 3D brain tumor MRIs: A robustness analysis points out the need for standardization.
Authors: D. Molina, J. Pérez-Beteta, A. Martínez-González, C. Velásquez, J. Martino, B. Luque, A. Revert, I. Herruzo, E. Arana, V. M. Pérez-García
Journal: Neuro-Oncology (2017)

Introduction: Textural analysis refers to a variety of mathematical methods used to quantify the spatial variations in grey levels within images. In brain tumors, textural features have a great potential as imaging biomarkers having been shown to correlate with survival, tumor grade, tumor type, etc. However, these measures should be reproducible under dynamic range and matrix size changes for their clinical use. Our aim is to study this robustness in brain tumors with 3D magnetic resonance imaging, not previously reported in the literature. Materials and methods: 3D T1-weighted images of 20 patients with glioblastoma (64.80 ± 9.12 years-old) obtained from a 3T scanner were analyzed. Tumors were segmented using an in-house semi-automatic 3D procedure. A set of 16 3D textural features of the most common types (co-occurrence and run-length matrices) were selected, providing regional (run-length based measures) and local information (co-ocurrence matrices) on the tumor heterogeneity. Feature robustness was assessed by means of the coefficient of variation (CV) under both dynamic range (16, 32 and 64 gray levels) and/or matrix size (256x256 and 432x432) changes. Results: None of the textural features considered were robust under dynamic range changes. The textural co-occurrence matrix feature Entropy was the only textural feature robust (CV < 10%) under spatial resolution changes. Conclusions: In general, textural measures of three-dimensional brain tumor images are neither robust under dynamic range nor under matrix size changes. Thus, it becomes mandatory to fix standards for image rescaling after acquisition before the textural features are computed if they are to be used as imaging biomarkers. For T1-weighted images a dynamic range of 16 grey levels and a matrix size of 256x256 (and isotropic voxel) is found to provide reliable and comparable results and is feasible with current MRI scanners. The implications of this work go beyond the specific tumor type and MRI sequence studied here and pose the need for standardization in textural feature calculation of oncological images. FUNDING: James S. Mc. Donnell Foundation (USA) 21st Century Science Initiative in Mathematical and Complex Systems Approaches for Brain Cancer [Collaborative award 220020450 and planning grant 220020420], MINECO/FEDER [MTM2015-71200-R], JCCM [PEII-2014-031-P].
Abstract 201: Enhancing Pgc-1α Activity Improves Heart Function Through Activating Mitochondrial Biogenesis in Chagas Disease
Authors: Xianxiu Wan, Jianjun Wen, Koo Sue-jie
Journal: Circulation Research (2015)

Chronic chagasic cardiomyopathy (CCM) is presented with ventricular hypertrophy and contractile dysfunction that can lead to heart failure. I have found that a substantial decline in mitochondrial biogenesis and SIRT1/PGC-1α activity ensue in chronic chagasic mice. It was evidenced by the decline in mitochondrial DNA content as well as mRNA levels of mitochondrial encoded genes and mtDNA replication machinery. Further, the activity of SIRT1 (required for PGC-1α activation) was decreased and associated with decreased nuclear levels of PGC-1-regulated NRF1 transcription factor in chagasic hearts. The mitochondrial size and number were also reduced in chagasic heart, determined by electron microscopy. Therefore, we hypothesized that enhancing the SIRT1/PGC-1α activity by SIRT1 agonist would improve heart function through activating mitochondrial biogenesis in Chagasic disease. Mice were infected with T. cruzi, and beginning at day 90 post-infection (pi), treated with resveratrol (SIRT1 agonist) or metformin (AMPK agonist, can enhance SIRT1 activity) for 21 days; and then heart function was monitored at 150 days pi. We found that treatment with resveratrol partially attenuated the heart dysfunction (stroke volume, cardiac output, ejection fraction, heart rate) and cardiac hypertrophy in chagasic mice. These benefits were associated with improved expression of the mitochondrial DNA encoded genes and mtDNA content though the expression of genes involved in mtDNA replication was not improved. Treatment with metformin was not significantly beneficial in improving the CCM outcomes. The partial beneficial effects of resveratrol could be due to inefficient activation of SIRT1 or delayed start of the treatment. We plan to treat mice with SIRT1 agonist SIRT1720 (10 fold more active than resveratrol) during the indeterminate phase of T. cruzi infection in next set of experiments. This study will improve our understanding of the molecular and immune mechanisms of chagasic heart disease and will provide a novel treatment for chronically-infected chagasic patients.
Recent advances of highly selective CDK4/6 inhibitors in breast cancer
Authors: Hanxiao Xu, Shengnan Yu, Qian Liu, Xun Yuan, Sridhar Mani, Richard G. Pestell, Kongming Wu
Journal: Journal of Hematology & Oncology (2017)

Uncontrolled cell division is the hallmark of cancers. Full understanding of cell cycle regulation would contribute to promising cancer therapies. In particular, cyclin-dependent kinases 4/6 (CDK4/6), which are pivotal drivers of cell proliferation by combination with cyclin D, draw more and more attention. Subsequently, extensive studies were carried out to explore drugs inhibiting CDK4/6 and assess the efficacy and safety of these drugs in cancer, especially breast cancer. Due to the insuperable adverse events and the less activity observed in vivo, the drug development of the initial pan-CDK inhibitor flavopiridol was consequently discontinued, and then highly specific inhibitors were extensively researched and developed, including palbociclib (PD0332991), ribociclib (LEE011), and abemaciclib (LY2835219). Food and Drug Administration has approved palbociclib and ribociclib for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer, and recent clinical trial data suggest that palbociclib significantly improved clinical outcome when combined with letrozole or fulvestrant. Besides, the favorable effects of abemaciclib on prolonging survival of breast cancer patients have also been observed in clinical trials both for single-agent and combination strategy. In this review, we outline the preclinical and clinical advancement of these three orally bioavailable and highly selective CDK4/6 inhibitors in breast cancer.
Phase I study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the oral inhibitor of indoleamine 2,3-dioxygenase (IDO1) INCB024360 in patients (pts) with advanced malignancies.
Authors: Gregory Lawrence Beatty, Peter J. O'Dwyer, Jason Clark, Jack G Shi, Robert Charles Newton, Richard Schaub, Janet Maleski, Lance Leopold, Thomas Gajewski
Journal: Journal of Clinical Oncology (2013)

3025 Background: INCB024360 is a potent, selective inhibitor of IDO1. As the catabolism of tryptophan (Trp) to kynurenine (Kyn) by IDO1 inhibits immune responses and IDO1 expression is elevated in many human cancers, IDO1 inhibition may potentiate effective antitumor immune responses. Methods: This dose-escalation study in adult pts with advanced malignancies used a 3+3 design to determine MTD, toxicity, PK, PD, and tumor response rate. Daily doses of INCB024360 were evaluated in 28-day cycles in 8 cohorts (50 mg once daily; 50 mg, 100 mg, 300 mg, 400 mg, 500 mg, 600 mg, or 700 mg BID). Treatment continued until disease progression or unacceptable toxicity. PK and PD samples were drawn on days 1 and 15. Results: 52 pts have been treated. Tumor types included colorectal (56%), melanoma (12%), and other (33%). The most common adverse events (≥20%) were fatigue, nausea, decreased appetite, vomiting, constipation, abdominal pain, diarrhea, dyspnea, back pain, and cough. The most common grade 3 or 4 adverse events were abdominal pain, hypokalemia, and fatigue (9.6% each). One DLT each was observed at 300 mg BID (grade 3 radiation pneumonitis) and 400 mg BID (grade 3 fatigue); no DLTs were observed in the 18 pts treated with 600 mg or 700 mg BID. There were no objective responses. At 56 days, stable disease was seen in 15 patients and lasted ≥112 days in 7 patients. Significant dose-dependent reductions in plasma Kyn/Trp ratios and Kyn levels were detected at all doses and in all pts. Maximal effects were observed at doses ≥300 mg BID. With repeat dosing, 700 mg BID provided an average plasma concentration ~5-fold the projected IC 90 . Overall, doses ≥300 mg BID achieved greater than 90% inhibition of IDO1 throughout the dosing period. Conclusions: INCB024360 was generally well tolerated at doses of up to 700 mg BID and there appears to be no correlation of dose with toxicity. Doses ≥300 mg BID were capable of &gt;90% inhibition of IDO1 activity and found to effectively normalize plasma Kyn levels. The recommended dose as monotherapy is 600 mg BID. Clinical trial information: NCT01195311.
Hired Help
Authors: Henry Scovern
Journal: New England Journal of Medicine (1988)

The emergence of health maintenance organizations (HMOs) has kindled considerable debate. The issues in question include the role of the physician as gatekeeper,1 , 2 the offering of monetary incentives to physicians for restricting the use of health care services,3 , 4 the conflicting obligations of physicians to the corporation and the patient,4 , 5 and the corporation's conflicting obligations to patients, corporate clients, and stockholders.6 There is also concern that primary care and medical subspecialties that lack a technological orientation may be dehumanized.7 On the other hand, staff-model HMOs also promise improved efficiency and reduced costs because of the emphasis on preventive health care and . . .
P04.07 Terahertz reflectometry imaging for low and high grade gliomas
Authors: J. Chang, Y. Ji, S. Oh, S. Kang, S. Kim, C. Joo
Journal: Neuro-Oncology (2017)

Gross total resection (GTR) of glioma is critical for improving the survival rate of glioma patients. One of the greatest challenges for achieving GTR is the difficulty in discriminating low grade tumor or peritumor regions that have an intact blood brain barrier (BBB) from normal brain tissues and delineating glioma margins during surgery. Here we present a highly sensitive, label-free terahertz reflectometry imaging (TRI) that overcomes current key limitations for intraoperative detection of World Health Organization (WHO) grade II (low grade), and grade III and IV (high grade) gliomas. We demonstrate that TRI provides tumor discrimination and delineation of tumor margins in brain tissues with high sensitivity on the basis of Hematoxylin and eosin (H&E) stained image. TRI may help neurosurgeons to remove gliomas completely by providing visualization of tumor margins in WHO grade II, III, and IV gliomas without contrast agents, and hence, improve patient outcomes.
Towards the Human Cancer Genome Project: A Sequence-Ready Physical Map of a Follicular Lymphoma Genome.
Authors: Marco A. Marra, Martin Krzywinski, Readman Chiu, Matthew Field, Inanc Birol, Brian D’Souza, Ian Bosdet, Carrie Mathewson, Darlene Lee, Agnes Baross, Randy D. Gascoyne, Douglas Horsman, Robert Holt, Jacqueline Schein, Joseph M. Connors
Journal: Blood (2005)
Expansion and Reactivation of Human Naïve T-Cells Transition into CD4+CD25+FoxP3+CD127-Regulatory T Cells, In Vitro, for the Potential Use of Graft-Versus-Host Disease Prevention
Authors: Tzeon-Jye Chiou, Tien-Hua Chu, Wei-Hao Wu, Sin-Tak Chu, Woan-Fang Tzeng
Journal: Blood (2016)
Desmoplastic Reaction in 3D‐Pancreatic Cancer Tissues Suppresses Molecular Permeability
Authors: Michiya Matsusaki, Misaki Komeda, Simona Mura, Hiroyoshi Y. Tanaka, Mitsunobu R. Kano, Patrick Couvreur, Mitsuru Akashi
Journal: Advanced Healthcare Materials (2017)

The survival rate of pancreatic ductal adenocarcinoma is still the lowest among all types of cancers, primarily as a consequence of an important desmoplastic reaction. Although the presence of thick stromal tissues in pancreatic tumors has been reported, in vivo animal studies do not enable a clear understanding of the crosstalk between cancer cells and fibroblasts. Accordingly, this paper reports the design and characterization of an in vitro pancreatic cancer-stromal 3D-tissue model, which enhances the understanding of the interactions between cancer cells and fibroblasts and their influence on the secretion of extracellular matrix (ECM). 3D-tissue models comprising fibroblasts and pancreatic cancer cells (MiaPaCa-2 cell line) or colon cancer cells (HT29 cell line, used as a control) show decreased molecular permeability with increased cancer cell ratios. The 3D-MiaPaCa-2 tissues display an increase in the secretion of collagen as a function of the cancer cell ratio, whereas 3D-HT29 tissues do not show a significant difference. Notably, the secretion of ECM proteins from single fibroblasts in 3D-tissue models containing 90% MiaPaCa-2 cells is ten times higher than that under 10% cancer cell conditions. In vitro pancreatic cancer 3D-tissues will be a valuable tool to obtain information on the interactions between cancer and stromal cells.