tbuckley/cabot-search huggingface dataset:
NVP-LBH589, a novel histone deacetylase inhibitor, activates caspase-3 and induces apoptosis of human tumor cells in vivo
Authors: Peter T. Lassota, Erik Sorensen, Rudi Bao, Peter Atadja, Lawrence Perez, Brian Ross, Alnawaz Rehemtulla
Journal: Cancer Research (2004)

4013  NVP-LBH589 is a potent inhibitor of histone deacetylases. The compound inhibits proliferation of human tumor cells in culture, and causes regressions of established human tumor xenografts in athymic nude mice. These effects are associated with the induction of expression of a cyclin-dependent kinase inhibitor, p21WAF-1. Here we report that the compound activates caspase-3-dependent apoptotic pathway in vitro and in vivo. Treatment of human tumor cells with the NVP-LBH589 resulted in the cleavage of the pro-caspase-3 and generation of the active form of the enzyme as determined by the IHC staining. The presence of the functional caspase-3 was also verified by a functional reporter assay. We have used previously described construct where luciferase is flanked by Estrogen Responsive (ER) Elements linked to the enzyme by the caspase-3 recognition sequence. This construct was stably transfected into D54 human glioma cell line. When caspase-3 is inactive in these cells, ER Elements inhibit luciferase-dependent light emission. Caspase-3 activation results in the cleavage and separation of the ER elements, and in light emission by resulting free luciferase. The D54 reporter cell line was encapsulated in hollow fibers, the fibers were implanted subcutaneously into athymic, nude mice, animals were treated systemically with the NVP-LBH589, the fibers were retrieved, and light emission was quantified with the CCD IVIS camera. The role of p21WAF-1 expression in activation of caspase-3-dependent apoptotic pathway will be also discussed.
Dexamethasone versus standard treatment for postoperative nausea and vomiting in gastrointestinal surgery: randomised controlled trial (DREAMS Trial)
Journal: BMJ (2017)

<b>Objectives</b>&nbsp;To determine whether preoperative dexamethasone reduces postoperative vomiting in patients undergoing elective bowel surgery and whether it is associated with other measurable benefits during recovery from surgery, including quicker return to oral diet and reduced length of stay. <b>Design</b>&nbsp;Pragmatic two arm parallel group randomised trial with blinded postoperative care and outcome assessment. <b>Setting</b>&nbsp;45 UK hospitals. <b>Participants</b>&nbsp;1350 patients aged 18 or over undergoing elective open or laparoscopic bowel surgery for malignant or benign pathology. <b>Interventions</b>&nbsp;Addition of a single dose of 8 mg intravenous dexamethasone at induction of anaesthesia compared with standard care. <b>Main outcome measures</b>&nbsp;Primary outcome: reported vomiting within 24 hours reported by patient or clinician. Secondary outcomes: vomiting with 72 and 120 hours reported by patient or clinician; use of antiemetics and postoperative nausea and vomiting at 24, 72, and 120 hours rated by patient; fatigue and quality of life at 120 hours or discharge and at 30 days; time to return to fluid and food intake; length of hospital stay; adverse events. <b>Results</b>&nbsp;1350 participants were recruited and randomly allocated to additional dexamethasone (n=674) or standard care (n=676) at induction of anaesthesia. Vomiting within 24 hours of surgery occurred in 172 (25.5%) participants in the dexamethasone arm and 223 (33.0%) allocated standard care (number needed to treat (NNT) 13, 95% confidence interval 5 to 22; P=0.003). Additional postoperative antiemetics were given (on demand) to 265 (39.3%) participants allocated dexamethasone and 351 (51.9%) allocated standard care (NNT 8, 5 to 11; P&lt;0.001). Reduction in on demand antiemetics remained up to 72 hours. There was no increase in complications. <b>Conclusions</b>&nbsp;Addition of a single dose of 8 mg intravenous dexamethasone at induction of anaesthesia significantly reduces both the incidence of postoperative nausea and vomiting at 24 hours and the need for rescue antiemetics for up to 72 hours in patients undergoing large and small bowel surgery, with no increase in adverse events. <b>Trial registration</b>&nbsp;EudraCT (2010-022894-32) and ISRCTN (ISRCTN21973627).
Efficacy and toxicity of topotecan in pretreated metastatic extrapulmonary neuroendocrine carcinoma.
Authors: Leonidas Apostolidis, Dirk Jaeger, Eva Caroline Winkler
Journal: Journal of Clinical Oncology (2015)

e15194 Background: Therapeutic options for metastatic poorly differentiated extrapulmonary neuroendocrine carcinoma (NEC) after prior platinum-based chemotherapy are limited. Topotecan is an approved second-line chemotherapy for small cell lung cancer (SCLC) which is often considered to show a biological behavior similar to NEC. The aim of this study was to analyze the efficacy and toxicity of topotecan in pretreated metastatic NEC patients. Methods: We performed a retrospective analysis of all patients treated with topotecan for metastatic NEC who presented at our center between January 2005 and January 2015. Topotecan was administered intravenously at a dose of 1.25 mg/m² per day on days 1-5, the cycle was repeated every 22 days. Results: Out of 30 identified patients all had received at least a platinum and etoposide (PE) containing regimen as prior chemotherapy. Median proliferation rate (Ki67) was 80 %. Best response to topotecan was stable disease in 5 patients, partial remission in 2, resulting in a disease control rate of 23.4 %. Of the remaining 23 patients, 14 (46.7 %) showed a progressive disease and 9 (30.0 %) died before radiologic response could be evaluated. Median progression free (PFS) and overall survival (OS) after start of topotecan was 2.1 and 4.1 months respectively. In the subgroup analysis, patients with unknown primary vs. those with known primary showed a significantly prolonged PFS of 3.5 vs. 1.9 months (p = 0.009) and OS of 6.7 vs. 2.6 months (p = 0.012). There was no notable difference in PFS or OS with respect to performance status, large cell or small cell histology, proliferation rate (Ki67), duration of disease control under PE or response to PE. Grade 3/4 hematotoxicity was observed in 60 % of patients. Conclusions: In this largest analysis of a single therapeutic regimen in pretreated metastatic NEC so far, topotecan shows only moderate antitumor activity, lower than reported for SCLC. However, activity of topotecan seems higher in patients with unknown primary.
All Types of Hemorrhagic Stroke Are Not Created Equally
Authors: Marion Hanley, Laura Morrison, Rónán O’Caoimh
Journal: JAMA Internal Medicine (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Recommendations for mechanical ventilation of critically ill children from the Paediatric Mechanical Ventilation Consensus Conference (PEMVECC)
Authors: Martin C J Kneyber, Daniele de Luca, Edoardo Calderini, Pierre-Henri Jarreau, Etienne Javouhey, Jesus Lopez-Herce, Jürg Hammer, Duncan Macrae, Dick G Markhorst, Alberto Medina, Marti Pons-Odena, Fabrizio Racca, Gerhard Wolf, Paolo Biban, Joe Brierley, Peter C Rimensberger
Journal: Intensive Care Medicine (2017)

Much of the common practice in paediatric mechanical ventilation is based on personal experiences and what paediatric critical care practitioners have adopted from adult and neonatal experience. This presents a barrier to planning and interpretation of clinical trials on the use of specific and targeted interventions. We aim to establish a European consensus guideline on mechanical ventilation of critically children.The European Society for Paediatric and Neonatal Intensive Care initiated a consensus conference of international European experts in paediatric mechanical ventilation to provide recommendations using the Research and Development/University of California, Los Angeles, appropriateness method. An electronic literature search in PubMed and EMBASE was performed using a combination of medical subject heading terms and text words related to mechanical ventilation and disease-specific terms.The Paediatric Mechanical Ventilation Consensus Conference (PEMVECC) consisted of a panel of 15 experts who developed and voted on 152 recommendations related to the following topics: (1) general recommendations, (2) monitoring, (3) targets of oxygenation and ventilation, (4) supportive measures, (5) weaning and extubation readiness, (6) normal lungs, (7) obstructive diseases, (8) restrictive diseases, (9) mixed diseases, (10) chronically ventilated patients, (11) cardiac patients and (12) lung hypoplasia syndromes. There were 142 (93.4%) recommendations with "strong agreement". The final iteration of the recommendations had none with equipoise or disagreement.These recommendations should help to harmonise the approach to paediatric mechanical ventilation and can be proposed as a standard-of-care applicable in daily clinical practice and clinical research.
Nondestructive tissue analysis for ex vivo and in vivo cancer diagnosis using a handheld mass spectrometry system
Authors: Jialing Zhang, John Rector, John Q. Lin, Jonathan H. Young, Marta Sans, Nitesh Katta, Noah Giese, Wendong Yu, Chandandeep Nagi, James Suliburk, Jinsong Liu, Alena Bensussan, Rachel J. DeHoog, Kyana Y. Garza, Benjamin Ludolph, Anna G. Sorace, Anum Syed, Aydin Zahedivash, Thomas E. Milner, Livia S. Eberlin
Journal: Science Translational Medicine (2017)

A handheld and biocompatible mass spectrometry system provides nondestructive molecular diagnosis of cancer tissue samples.
Mesenchymal stem cells for hepatitis B patients with acute on chronic liver failure—are we there?
Authors: Wuttiporn Manatsathit, Hrishikesh Samant, Warapan Nakayuenyongsuk
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. TO THE EDITOR: We read with great interest regarding the recent publication by Lin et al.1 Recently, there has been increasing interest in the utilization of stem cells and growth factors as a salvage therapy for severe liver diseases, such as alcoholic hepatitis and acute on chronic liver failure (ACLF), despite a limited supporting mechanism.2 Although most studies demonstrated that such a practice appeared to be tolerable and safe, its long‐term benefits remains unclear. In this article, the investigators demonstrated significant survival benefit of mesenchymal stem cells (MSCs) among hepatitis B patients with ACLF compared with standard medical treatment (SMT) attributed to decreased serious infection. The patients appeared to be properly randomized and there were no significant differences in baseline characteristic between both groups; however, there were a few aspects worthy for discussion. First, all patients in this study received entecavir as a part of SMT, and information regarding previous exposure to lamivudine or entecavir was not available. These pieces of information are, in fact, crucially important in this study, considering that several studies have demonstrated that effectiveness of entecavir is significantly lower when patients are previously treated with lamivudine.4 Second, although viral load appeared similar between the two groups, subsequent viral load is important in determining response to antivirals. Last, serious infection appeared to be the cause of lower survival in the SMT group; however, the patients in both groups were not blinded as mentioned in the weakness of this study. As a result, antibiotic stewardship of patients in each group could be distinctly managed and respectively created bias in this study. In summary, providing some information regarding previous antiviral use, viral load, and antibiotic use might alleviate these problems and help readers interpreting the result of this study. Regardless, this study proved that MSC infusion is safe, but potential benefit needs to be confirmed in a double‐blind fashion.
Zika virus has oncolytic activity against glioblastoma stem cells
Authors: Zhe Zhu, Matthew J. Gorman, Lisa D. McKenzie, Jiani N. Chai, Christopher G. Hubert, Briana C. Prager, Estefania Fernandez, Justin M. Richner, Rong Zhang, Chao Shan, Eric Tycksen, Xiuxing Wang, Pei-Yong Shi, Michael S. Diamond, Jeremy N. Rich, Milan G. Chheda
Journal: The Journal of Experimental Medicine (2017)

Glioblastoma is a highly lethal brain cancer that frequently recurs in proximity to the original resection cavity. We explored the use of oncolytic virus therapy against glioblastoma with Zika virus (ZIKV), a flavivirus that induces cell death and differentiation of neural precursor cells in the developing fetus. ZIKV preferentially infected and killed glioblastoma stem cells (GSCs) relative to differentiated tumor progeny or normal neuronal cells. The effects against GSCs were not a general property of neurotropic flaviviruses, as West Nile virus indiscriminately killed both tumor and normal neural cells. ZIKV potently depleted patient-derived GSCs grown in culture and in organoids. Moreover, mice with glioblastoma survived substantially longer and at greater rates when the tumor was inoculated with a mouse-adapted strain of ZIKV. Our results suggest that ZIKV is an oncolytic virus that can preferentially target GSCs; thus, genetically modified strains that further optimize safety could have therapeutic efficacy for adult glioblastoma patients.
Could Tranexamic Acid Bias the Optimal Ratio of Fresh Frozen Plasma to Red Blood Cells During Massive Transfusion?—Reply
Authors: D. Dante Yeh, Tomaz Mesar, Walter Dzik
Journal: JAMA Surgery (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Immunotherapy in pancreatic ductal adenocarcinoma: an emerging entity?
Authors: I.H. Sahin, G. Askan, Z.I. Hu, E.M. O’Reilly
Journal: Annals of Oncology (2017)

The genomic-plasticity of the immune system creates a broad immune repertoire engaged to tackle cancer cells. Promising clinical activity has been observed with several immune therapy strategies in solid tumors including melanoma, lung, kidney, and bladder cancers, albeit as yet immunotherapy-based treatment approaches in pancreatic ductal adenocarcinoma (PDAC) remain to have proven value. While translational and early clinical studies have demonstrated activation of antitumor immunity, most recent late-phase clinical trials have not confirmed the early promise in PDAC except in MSI-High PDAC patients. These results may in part be explained by multiple factors, including the poorly immunogenic nature of PDAC along with immune privilege, the complex tumor microenvironment, and the genetic plasticity of PDAC cells. These challenges have led to disappointments in the field, nonetheless they have also advanced our understanding that may tailor the future steps for immunotherapy for PDAC. Therefore, there is significant hope that progress is on the horizon.
Disentangling puberty: novel neuroendocrine pathways and mechanisms for the control of mammalian puberty
Authors: M S Avendaño, M J Vazquez, M Tena-Sempere
Journal: Human Reproduction Update (2017)

Puberty is a complex developmental event, controlled by sophisticated regulatory networks that integrate peripheral and internal cues and impinge at the brain centers driving the reproductive axis. The tempo of puberty is genetically determined but is also sensitive to numerous modifiers, from metabolic and sex steroid signals to environmental factors. Recent epidemiological evidence suggests that the onset of puberty is advancing in humans, through as yet unknown mechanisms. In fact, while much knowledge has been gleaned recently on the mechanisms responsible for the control of mammalian puberty, fundamental questions regarding the intimate molecular and neuroendocrine pathways responsible for the precise timing of puberty and its deviations remain unsolved.By combining data from suitable model species and humans, we aim to provide a comprehensive summary of our current understanding of the neuroendocrine mechanisms governing puberty, with particular focus on its central regulatory pathways, underlying molecular basis and mechanisms for metabolic control.A comprehensive MEDLINE search of articles published mostly from 2003 to 2017 has been carried out. Data from cellular and animal models (including our own results) as well as clinical studies focusing on the pathophysiology of puberty in mammals were considered and cross-referenced with terms related with central neuroendocrine mechanisms, metabolic control and epigenetic/miRNA regulation.Studies conducted during the last decade have revealed the essential role of novel central neuroendocrine pathways in the control of puberty, with a prominent role of kisspeptins in the precise regulation of the pubertal activation of GnRH neurosecretory activity. In addition, different transmitters, including neurokinin-B (NKB) and, possibly, melanocortins, have been shown to interplay with kisspeptins in tuning puberty onset. Alike, recent studies have documented the role of epigenetic mechanisms, involving mainly modulation of repressors that target kisspeptins and NKB pathways, as well as microRNAs and the related binding protein, Lin28B, in the central control of puberty. These novel pathways provide the molecular and neuroendocrine basis for the modulation of puberty by different endogenous and environmental cues, including nutritional and metabolic factors, such as leptin, ghrelin and insulin, which are known to play an important role in pubertal timing.Despite recent advancements, our understanding of the basis of mammalian puberty remains incomplete. Complete elucidation of the novel neuropeptidergic and molecular mechanisms summarized in this review will not only expand our knowledge of the intimate mechanisms responsible for puberty onset in humans, but might also provide new tools and targets for better prevention and management of pubertal deviations in the clinical setting.
Challenges and Opportunities in Adapting Clinical Trial Design for Immunotherapies
Authors: Lillian L. Siu, S. Percy Ivy, Erica L. Dixon, Amy E. Gravell, Steven A. Reeves, Gary L. Rosner
Journal: Clinical Cancer Research (2017)

Abstract Immunotherapy adds an exciting new dimension to the treatment of cancer, joining other approaches as a key pillar in the oncotherapeutics armamentarium. Immuno-oncology agents harbor unique mechanisms of antitumor activity by leveraging the host immune system, which may result in response patterns, resistance kinetics, and toxicity profiles that differ from other systemic therapies. These features have led to many discussions on ways to optimally integrate immunotherapy into cancer clinical trials. This overview provides an introduction to the four CCR Focus articles that ensue, with special thoughts paid to clinical trial endpoints, biomarker development and validation, combination strategies, and limitations that arise with increasing use of these agents. In addition, this overview examines design concepts that may be applied to invigorate clinical trials and to maximize their impact in the immuno-oncology era. Clin Cancer Res; 23(17); 4950–8. ©2017 AACR. See all articles in this CCR Focus section, “Clinical Trial Design Considerations in the Immuno-oncology Era.”
経口インシュリンデリバリーに対する解離可能な「粘液‐不活性」剤で被覆したトリメチルキトサンナノ粒子による効果的な粘膜浸透性とタイトジャンクション開放
Authors: Liu Min, Zhang Jian, Zhu Xi, Shan Wei, Li Lian, Zhong Jiaju, Zhang Zhirong, Huang Yuan
Journal: Journal of Controlled Release (2016)
Abstract P163: Rescue of Preexisting Severe Pulmonary Hypertension and Right Ventricular Failure by Intralipid
Authors: Soban Umar, Humann Matori, Reza Foroughi, Parisa Partownavid, Mansoureh Eghbali
Journal: Circulation Research (2011)

Pulmonary hypertension (PH) is characterized by pulmonary vascular remodeling leading to right ventricular (RV) hypertrophy and failure (RVF). Intralipid (ILP) is the first safe lipid emulsion for human use. Several constituents of ILP, like γ-linolenic acid and soy- phytoestrogens are protective for lungs and heart. Previously we showed that ILP prevents the development of PH. Here we test a more clinically relevant hypothesis if ILP can rescue pre-existing severe PH and RV dysfunction. To induce PH, male rats received single monocrotaline (MCT, 60mg/kg) injection. At day 21, when severe PH had been well-established (PH group, n=7), rats were given ILP (1mL of 20% ILP/day, i.p., n=7) from day 21-30. Other MCT rats were left untreated to develop RVF (RVF group, n=9) by day 30. Saline treated rats were control (CTRL, n=5). Serial echocardiography was done to monitor cardiopulmonary hemodynamics. Cardiac catheterisation was performed just before sacrifice to record RV pressure (RVP). CD31 staining for RV capillary density and smooth muscle actin staining for pulmonary arteriolar medial hypertrophy were performed. Rats developed severe PH and RV dysfunction 21 days after MCT in PH group [RVP=67±1 vs. 31±1mmHg in CTRL, RV-ejection fraction (RVEF)=39% vs. 65±1%; RV/(LV+IVS)=0.64±0.05 vs. 0.24±0.02; medial hypertrophy=2.8 fold vs. CTRL; all p&lt;0.05]. Interestingly, we found that even 10-day ILP therapy not only prevented the progression of PH to RVF but also rescued pre-existing PH and RV dysfunction [RVP=44±1 mmHg vs. 70±2 mmHg in RVF; RVEF=53±1 vs. 30±1%; RV/(LV+IVS)=0.39±0.02 vs. 0.66±0.08; medial hypertrophy=3 fold less vs. RVF; all p&lt;0.05]. ILP therapy resulted in 100% survival compared to only 25% survival in RVF. Next we investigated if ILP rescue was associated with stimulation of RV neoangiogenesis. We found that RV capillary density was decreased in PH (0.7±0.07 vs. 1±0.07 capillaries per myocyte in CTRL; p&lt;0.05) and worsened in RVF (0.52±0.07 capillaries per myocyte; p&lt;0.05 vs. CTRL). ILP therapy resulted in stimulation of neoangiogenesis (capillary density=0.98±0.01 capillaries per myocyte; p&lt;0.05 vs. PH and RVF). ILP therapy rescues severe pre-existing PH and retards the development of RV failure possibly via stimulation of RV neoangiogenesis.