tbuckley/cabot-search huggingface dataset:
DIPG-17. TELOMERE-INDUCED DAMAGE AS A NOVEL APPROACH TO TREAT DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Satarupa Sengupta, Angela R. White, Shiva Senthil Kumar, Kyungwoo Lee, Christine Fuller, Mariko DeWire, Maryam Fouladi, Lionel M.L. Chow, Rachid Drissi
Journal: Neuro-Oncology (2017)

Diffuse intrinsic pontine glioma (DIPG) is one of the deadliest brain tumors in children. Hence, there is an urgent need to identify actionable therapeutic targets. We have previously shown that over 70% of DIPGs demonstrate telomerase activity and elevated hTERT mRNA levels are associated with shorter overall survival. Thus, telomeres and telomerase represent ideal targets to treat DIPG. We recently validated a novel approach consisting of the incorporation of 6-thio-dG, a telomerase substrate analogue, into telomeres to treat therapy-resistant pediatric brain tumor cells. 6-thio-dG treatment of high-risk group 3 medulloblastoma, pediatric GBM and DIPG patients-derived neurospheres caused telomere damage leading to dose-dependent cell growth inhibition and complete abolition of sphere formation ability. Here, we present our results of the in vivo effectiveness of 6-thio-dG in orthotopic DIPG mouse models. Primary DIPG neurospheres were derived post-autopsy from patients’ tumor tissue. Luciferase positive cells were implanted in the pons of two strains of mice. The generated tumors were highly aggressive and the histopathological characterization of the xenograft showed close similarity with the original patient tumor. Relative to the original patient tissue and the derived neurospheres, telomerase expression and activity were sustained in the xenografts. Tumor bearing mice were treated with 6-thio-dG or the vehicle upon tumor establishment. Molecular analyses of the tumors showed that 6-thio-dG generated significantly higher number of telomere dysfunction-induced foci (TIFs) compared to the untreated tumors, indicating that 6-thio-dG reached the tumor tissue in the pons. Of note, 6-thio-dG treatment had no detectable effect on normal brain tissue. Results regarding tumor regression/stabilization and survival will be discussed. Our data suggest that 6-thio-dG-induced telomere damage is a promising novel approach to treat DIPG.
BIOL-02. INTRACRANIAL TUMORS IN CHILDREN: A 10 YEAR REVIEW FROM A SINGLE TERTIARY HEALTH CARE CENTRE
Authors: Quratulain Riaz, Ehsan Naeem, Zehra Fadoo, Maha Dev, Naureen Mushtaq
Journal: Neuro-Oncology (2017)

OBJECTIVE: Brain tumors are the second most common malignancy in children and the most common cause of cancer related deaths. Major advances in management in terms of surgery, radiation and chemotherapy have led to better outcomes. Delayed diagnosis, advanced disease at presentation, late referrals, nosocomial infections, delays to radiotherapy and poor support services are the major reasons for poorer outcomes in developing countries. Little is known about the profile of brain tumors in Pakistan. This study aims to describe the clinical profile and outcome of primary brain tumors in children at a single tertiary center in Pakistan. METHODS/MATERIALS: All children (0 – 16 years) with primary CNS tumors from 2004 till 2014 at Aga Khan University Hospital were reviewed retrospectively for clinical data, demographics, radiological findings, management and outcome. RESULTS: 175 children were included in the study. Male to female ratio was 1.4:1. Most of the patients were in 5 -10 years age group (38.9%). Most common presenting complains were headache 115 (65.7%) & vomiting 100 (57.1%). Predominant site was supratentorial 91 (52%). Three patients (1.7%) had family history of cancers. Glial tumors were 93 (53.1%) followed by embryonal 40(22.9%), Craniopharyngiomas 25 (14.3%) & Germ cell 1 (0.6%). Low grade astrocytoma (23.4%) were the most common glial tumors while Medulloblastoma (15.4%) was the most common embryonal tumor. Majority of the patients underwent surgery only (53.7%). Radiation was given to 48 (27.4%) patients. Half of the patients 79 (45.1%) were lost to follow up. Patients expired were 41 (23.4%), 24 (13.7%) are alive with residual disease while 22 patients (12.6%) were cured. CONCLUSION: This is the only study from Pakistan showing demographics of the children with brain tumors. Significant improvement needs to be made for timely diagnosis, early referrals and collaborated team efforts with multidisciplinary tumor board to improve outcome.
The effect of persistent post-concussive symptoms on cognitive performance after sport concussion
Authors: Zhangjie Su, David Davies, Amar Bhavsar, Douglas Hammond, David Hacker, Shaun Evans, Michael Grey, Antonio Belli
Journal: British Journal of Sports Medicine (2017)

Objective We aim to study the effect of persistent post-concussive symptoms on cognitive performance of elite athletes, based on the hypothesis that persistent symptoms could impair athletes’ cognitive performances and functional outcomes. Design Prospective observational and longitudinal case control study. Setting University research centre, single centre. Participants 7 athletes with persistent symptoms (&gt;2 weeks, assessed at median 31 days post-concussion), 10 athletes with brief symptoms (&lt;3 days, assessed within a week, median 3.5 days), and 9 age-matched healthy volunteers. Inclusion criteria: male/female athletes (aged 18–40) in contact sports who sustained concussion(s) recently, being symptomatic with normal neuro-radiological findings at enrolment. Intervention Independent variables: post-concussive symptom scores and duration of symptoms. Outcome measures Multi-dimensional scores from Sport Concussion Assessment Tool III, Immediate Post-concussion Assessment and Cognitive Testing, WAIS symbol search and digit span backward tests. Main results Patients with persistent symptoms scored less in the symbol search test than those with brief symptoms and the healthy volunteers (grouping effect p=0.006; post hoc tests p=0.039 and 0.004, respectively). In all 17 patients, symptom scores correlated with reaction time (ρ=−0.61, p=0.009), and visual motor speed correlated with symbol search scores (ρ=0.59, p=0.013). 6 patients who completed follow-up assessments when symptom-free showed improvement in their symbol search scores (p=0.042) and visual memory (p=0.028). Conclusions Concussed athletes with persistent symptoms performed poorly in visual perception/analysis and information processing. Persistent post-concussive symptoms could affect athletes’ visual memory, perception/analysis, reaction time and information processing speed, thus precipitating them to further injuries should they return to play prematurely. Competing interests None.
Diabetic db/db mice do not develop heart failure upon pressure overload: a longitudinal in vivo PET, MRI, and MRS study on cardiac metabolic, structural, and functional adaptations
Authors: Desiree Abdurrachim, Miranda Nabben, Verena Hoerr, Michael T. Kuhlmann, Philipp Bovenkamp, Jolita Ciapaite, Ilvy M.E. Geraets, Will Coumans, Joost J.F.P. Luiken, Jan F.C. Glatz, Michael Schäfers, Klaas Nicolay, Cornelius Faber, Sven Hermann, Jeanine J. Prompers
Journal: Cardiovascular Research (2017)

Heart failure is associated with altered myocardial substrate metabolism and impaired cardiac energetics. Comorbidities like diabetes may influence the metabolic adaptations during heart failure development. We quantified to what extent changes in substrate preference, lipid accumulation, and energy status predict the longitudinal development of hypertrophy and failure in the non-diabetic and the diabetic heart.Transverse aortic constriction (TAC) was performed in non-diabetic (db/+) and diabetic (db/db) mice to induce pressure overload. Magnetic resonance imaging, 31P magnetic resonance spectroscopy (MRS), 1H MRS, and 18F-fluorodeoxyglucose-positron emission tomography (PET) were applied to measure cardiac function, energy status, lipid content, and glucose uptake, respectively. In vivo measurements were complemented with ex vivo techniques of high-resolution respirometry, proteomics, and western blotting to elucidate the underlying molecular pathways. In non-diabetic mice, TAC induced progressive cardiac hypertrophy and dysfunction, which correlated with increased protein kinase D-1 (PKD1) phosphorylation and increased glucose uptake. These changes in glucose utilization preceded a reduction in cardiac energy status. At baseline, compared with non-diabetic mice, diabetic mice showed normal cardiac function, higher lipid content and mitochondrial capacity for fatty acid oxidation, and lower PKD1 phosphorylation, glucose uptake, and energetics. Interestingly, TAC affected cardiac function only mildly in diabetic mice, which was accompanied by normalization of phosphorylated PKD1, glucose uptake, and cardiac energy status.The cardiac metabolic adaptations in diabetic mice seem to prevent the heart from failing upon pressure overload, suggesting that restoring the balance between glucose and fatty acid utilization is beneficial for cardiac function.
Multifunctional Effects of a Small-Molecule STAT3 Inhibitor on NASH and Hepatocellular Carcinoma in Mice
Authors: Kwang Hwa Jung, Wonbeak Yoo, Heather L. Stevenson, Dipti Deshpande, Hong Shen, Mihai Gagea, Suk-Young Yoo, Jing Wang, T. Kris Eckols, Uddalak Bharadwaj, David J. Tweardy, Laura Beretta
Journal: Clinical Cancer Research (2017)

Purpose: The incidence of hepatocellular carcinoma is increasing in the United States, and liver cancer is the second leading cause of cancer-related mortality worldwide. Nonalcoholic steatohepatitis (NASH) is becoming an important risk for hepatocellular carcinoma, and most patients with hepatocellular carcinoma have underlying liver cirrhosis and compromised liver function, which limit treatment options. Thus, novel therapeutic strategies to prevent or treat hepatocellular carcinoma in the context of NASH and cirrhosis are urgently needed.Experimental Design: Constitutive activation of STAT3 is frequently detected in hepatocellular carcinoma tumors. STAT3 signaling plays a pivotal role in hepatocellular carcinoma survival, growth, angiogenesis, and metastasis. We identified C188-9, a novel small-molecule STAT3 inhibitor using computer-aided rational drug design. In this study, we evaluated the therapeutic potential of C188-9 for hepatocellular carcinoma treatment and prevention.Results: C188-9 showed antitumor activity in vitro in three hepatocellular carcinoma cell lines. In mice with hepatocyte-specific deletion of Pten (HepPten- mice), C188-9 treatment blocked hepatocellular carcinoma tumor growth, reduced tumor development, and reduced liver steatosis, inflammation, and bile ductular reactions, resulting in improvement of the pathological lesions of NASH. Remarkably, C188-9 also greatly reduced liver injury in these mice as measured by serum aspartate aminotransferase and alanine transaminase levels. Analysis of gene expression showed that C188-9 treatment of HepPten- mice resulted in inhibition of signaling pathways downstream of STAT3, STAT1, TREM-1, and Toll-like receptors. In contrast, C188-9 treatment increased liver specification and differentiation gene pathways.Conclusions: Our results suggest that C188-9 should be evaluated further for the treatment and/or prevention of hepatocellular carcinoma. Clin Cancer Res; 23(18); 5537-46. ©2017 AACR.
Antibiotic prescription strategies and adverse outcome for uncomplicated lower respiratory tract infections: prospective cough complication cohort (3C) study
Authors: Paul Little, Beth Stuart, Sue Smith, Matthew J Thompson, Kyle Knox, Ann van den Bruel, Mark Lown, Michael Moore, David Mant
Journal: BMJ (2017)

<b>Objective</b>&nbsp;To assess the impact on adverse outcomes of different antibiotic prescribing strategies for lower respiratory tract infections in people aged 16 years or more. <b>Design</b>&nbsp;Prospective cohort study. <b>Setting</b>&nbsp;UK general practice. <b>Participants</b>&nbsp;28 883 patients with lower respiratory tract infection; symptoms, signs, and antibiotic prescribing strategies were recorded at the index consultation. <b>Main outcome measures</b>&nbsp;The main outcomes were reconsultation with symptoms of lower respiratory tract infection in the 30 days after the index consultation, hospital admission, or death. Multivariable analysis controlled for an extensive list of variables related to the propensity to prescribe antibiotics and for clustering by doctor. <b>Results</b>&nbsp;Of the 28 883 participants, 104 (0.4%) were referred to hospital for radiographic investigation or admission, or both on the day of the index consultation, or were admitted with cancer. Of the remaining 28 779, subsequent hospital admission or death occurred in 26/7332 (0.3%) after no antibiotic prescription, 156/17 628 (0.9%) after prescription for immediate antibiotics, and 14/3819 (0.4%) after a prescription for delayed antibiotics. Multivariable analysis documented no reduction in hospital admission and death after immediate antibiotics (multivariable risk ratio 1.06, 95% confidence interval 0.63 to 1.81, P=0.84) and a non-significant reduction with delayed antibiotics (0.81, 0.41 to 1.64, P=0.61). Reconsultation for new, worsening, or non-resolving symptoms was common (1443/7332 (19.7%), 4455/17 628 (25.3%), and 538/3819 (14.1%), respectively) and was significantly reduced by delayed antibiotics (multivariable risk ratio 0.64, 0.57 to 0.72, P&lt;0.001) but not by immediate antibiotics (0.98, 0.90 to 1.07, P=0.66). <b>Conclusion</b>&nbsp;Prescribing immediate antibiotics may not reduce subsequent hospital admission or death for young people and adults with uncomplicated lower respiratory tract infection, and such events are uncommon. If clinicians are considering antibiotics, a delayed prescription may be preferable since it is associated with a reduced number of reconsultations for worsening illness.
Cardiovascular Reactivity Among Surgeons: Not Music to Everyone's Ears
Authors: Leon Morgenstern
Journal: JAMA (1995)

<h3>To the Editor.</h3> —In nearly half a century spent in operating rooms, most of it as director of surgery in a large teaching hospital, I was convinced that music of any kind in the operating room detracted from the intensity of purpose and attentiveness mandatory in that setting. During my frequent operating room rounds, I would hear all types of music, ranging from rock to Bach. At times, the noise level emanating from the anesthetist's boom box was loud enough to drown out any meaningful communication between surgeon and scrub nurse. I forbade the playing of music during resident teaching, not only because I felt that it taught a bad habit, but also because it diluted the teaching experience. Music hath charms, but there should be no savage beasts in the operating rooms. I hope the article by Drs Allen and Blascovich,<sup>1</sup>whose tests were performed far from the
Italy recognises patient safety as a fundamental right
Authors: Tommaso Bellandi, Riccardo Tartaglia, Aziz Sheikh, Liam Donaldson
Journal: BMJ (2017)

A new law takes a bold step towards enhancing patient safety

On 8 March 2017 Italy enacted a new law on patient safety and health professionals’ responsibilities.1 It begins by recognising that “Patient safety is a fundamental right of each individual within any healthcare service and it is a primary goal of the national healthcare service.” This is a bold step, by a G8 country, towards the goal of reducing avoidable harm in healthcare.

National and regional patient safety programmes started in Italy around a decade ago. The first step towards the new law was an agreement between the national government and the regions in 2008, which required the establishment of a patient safety incident reporting system in each hospital; a local and regional clinical risk management function; and the creation of a national repository of safety practices. The second step, a year later, was the introduction of mandatory monitoring of sentinel events and claims, a key component of the legislation.

An assessment of the economic burden of unsafe care was another driver of the …
LEAVES FROM THE NOTE-BOOK OF A WEST INDIAN PRACTITIONER
Authors: L. Ashenheim
Journal: BMJ (1854)

jdat but snot thoept ayw6de }q.Hewas mm theo duie ot,eeeper.CA nn Jones, aged 11, wastted th ptoms about the inning of D mber 19. in three dys, lat leg became very much in- lamd sad swollen.This eZed in a formation of matter, whih was lanced at the end of three wees and a large atity of matter ea .It continued to dige freey for a long time, an upon e ining it with a probe, the tibia wa found diseed.About four months after wards, she fell and fractured the tibia, about an inch below its tuberosity.No union took place, nd the end of the lower portion became gradually exposed, prominent, and dis- coloured.It wa a compound facture.The patient's con- otitution was, about two months afte the accident, much weakened; and upon a consultation, amputation was thought the most advisable course, which was aeterminately efused, and the patient was placed under the care of a quackingroman The bone gradually became more ex- posed, and I was called in to remove the sequestrum, which Wa about six inches long; including the wole circumfer- once of the bone at its upper end, but tapered gradually to a point at the lower one.The wound gradually healed, and
Abstract 83: Modulation of Macrophage Function via Metabolism by Trypanosoma cruzi
Authors: Sue-Jie Koo, Nisha J Garg
Journal: Circulation Research (2015)

Chagas heart disease is an inflammatory cardiomyopathy which presents with mononuclear infiltrates in the interstitium and myocardial fibrosis in the chronic phase. Incomplete clearance by macrophages of the etiologic agent, Trypanosoma cruzi , is a significant cause of chronic disease development in approximately 30% of those serologically positive for the blood-borne parasite. The differential metabolic status, anaerobic glycolysis and mitochondria-dependent oxidative phosphorylation, are respectively associated with pro-inflammatory (M1) and anti-inflammatory (M2) functional activation of macrophages. Reactive oxygen species (ROS) have been shown to be an intracellular signal for glycolysis while peroxisome proliferator-activated receptors (PPARs) that enhance fatty acid oxidation provide transcription control of macrophage functional state. In our studies using diverse T. cruzi isolates, we showed that SylvioX10 (virulent), but not TCC (non-virulent), isolates are able to differentially control extracellular and intracellular ROS levels in macrophages. We found in macrophages infected with SylvioX10, the nuclear expression of PPAR-α was increased by 18 hours post-infection, and mitochondrial metabolic activity was similar to that of not-infected and M2 controls; which indicates anti-inflammatory function of macrophages, and therefore prohibiting T. cruzi clearance. In our ongoing studies, we are examining the impact of PPAR-α inhibitors in modulating the metabolic gene expression profile, functional phenotype and parasite survival in macrophages. Our data will provide the first indication that host macrophages have deficient pro-inflammatory capacity due to sub-optimal glucose oxidation, and enhancing the metabolism that supports T. cruzi clearance will provide a valuable basis for a strategy to arrest Chagas disease progression.
Pazopanib in soft tissue sarcoma: Experience from a U.K. expanded-access program.
Authors: Anna Maria Frezza, Charlotte Benson, Aisha Miah, Mark David Linch, Rolyn Alvarado, Scott Mitchell, Claire Esler, Helen Hatcher, Ian Robert Judson
Journal: Journal of Clinical Oncology (2013)

e21516 Background: Pazopanib has been recently proven to be a valuable treatment option for patients with metastatic non-adipocytic soft-tissue sarcoma (STS). We present our expanded-access experience to assess the safety and efficacy in routine clinical practice. Methods: Twenty-two patients were treated at 3 UK Sarcoma Centres between December 2011 and September 2012. Response was assessed according to RECIST 1.1 criteria and treatment toxicity graded. Results: Patients had a median age of 50 years (range-21-83), female (54%), 19 (86%) were metastatic. Primary sites were limb (27%), abdominal cavity (46%) and trunk (27%). Median number of previous chemotherapy lines was 2 and all patients were angiogenesis inhibitor naïve. Eighteen patients (82%) started pazopanib at 800 mg daily, 4 (18%) at 600 mg due to borderline PS. The most common side effects included fatigue (G1/2: 59%; G3/4: 9%), hypertension (G1/2: 5%, G3/4: 23%), liver function abnormalities (G1/2: 14%, G3/4: 9%) and diarrhoea (G1/2: 18%). Nine patients (41%) required a dose reduction and four (18%) discontinued the drug due to toxicity. One patient with metastatic pleomorphic sarcoma underwent RFA of the largest lung lesions and was started on pazopanib two weeks later. Despite achieving a partial response, pazopanib was discontinued due to the development of lung cavitation at the site of a previous RFA. Twenty-one patients were available for response evaluation. There were 7 (33%) partial responses (2 synovial sarcoma, 2 undifferentiated sarcoma, 1 fibromyxoid sarcoma, 1 fibromatosis and a 1 retroperitoneal leiomyosarcoma), 5 (24%) stable disease and 9 (43%) progressive disease. Clinical benefit rate (PR+SD) was 56%. Follow-up data were available for 18 patients. At a median follow-up of 25 weeks (range: 9-49), 8 patients (44%) were still alive and 5 (28%) were progression free. Median TTP was 11 weeks (95% CI 5.6-16.3). Conclusions: Pazopanib is effective in the treatment of STS progressing despite standard chemotherapy and has a manageable toxicity profile. However, due to its anti-angiogenic effect, it can interfere with the healing process and its use should be carefully considered in patients undergoing invasive procedures.
Efficacy and adverse events of oral isotretinoin for acne: a systematic review
Authors: I.A. Vallerand, R.T. Lewinson, M.S. Farris, C.D. Sibley, M.L. Ramien, A.G.M. Bulloch, S.B. Patten
Journal: British Journal of Dermatology (2017)

Despite many years of clinical use of isotretinoin, a comprehensive review of evidence for isotretinoin therapy in patients with acne is lacking. We searched MEDLINE, Embase, Cochrane Central, relevant web pages and bibliographies for randomized controlled trials in acne evaluating isotretinoin vs. control (placebo or other therapy). Data were extracted and summarized descriptively. Eleven trials were identified (total 760 patients randomized), containing mostly men. Mean treatment ages ranged from 18 to 47·9 years and participants generally had moderate‐to‐severe acne. Across all trials, isotretinoin therapy reduced acne lesion counts by a clinically relevant amount, and always by a greater amount than control, which was either placebo (two studies), oral antibiotics (seven studies) or other control (two studies). Across trials with an overall low risk of bias, two of three demonstrated statistically significant differences between isotretinoin and control. The frequency of adverse events was twice as high with isotretinoin (751 events) than with control (388 events). More than half of all adverse events were dermatological and related to dryness. Adverse events from isotretinoin causing participant withdrawal from trials (12 patients) included Stevens–Johnson syndrome, cheilitis, xerosis, acne flare, photophobia, elevated liver enzymes, decreased appetite, headaches and depressed mood. This review suggests that isotretinoin is effective in reducing acne lesion counts, but adverse events are common. This study was registered with PROSPERO number CRD42015025080.
Abstract 11432: Can the Functional Benefits of Cardiac Progenitor Cells Be Equaled by Their Secreted Extracellular Vesicles?
Authors: Nisa Renault, Anaïs Kervadec, Hadi Toeg, Xavier Loyer, Hany Nemetalla, Min Yin, Lousineh Arakélian, Marie-Cécile Périer, Valérie Bellamy, Nadia El Harane, Valérie Vanneaux, Jérôme Larghero, Albert A Hagège, Chantal Boulanger, Marc Ruel, Jean-Sébastien Silvestre, Philippe Menasché
Journal: Circulation (2014)

Introduction: Cell-derived extracellular vesicles ([EVs], i.e., exosomes and microparticles) have been reported to mediate the cardioprotective effects of stem cells. However, a head-to-head compar...