tbuckley/cabot-search huggingface dataset:
Syndecan‐1 limits the progression of liver injury and promotes liver repair in acetaminophen‐induced liver injury in mice
Authors: Eon Jeong Nam, Kazutaka Hayashida, Rafael S. Aquino, John R. Couchman, Rosemary A. Kozar, Jian Liu, Pyong Woo Park
Journal: Hepatology (2017)

Accidental or intentional misuse of acetaminophen (APAP) is the leading cause of acute liver failure in the Western world. Although mechanisms that trigger APAP‐induced liver injury (AILI) are well known, those that halt the progression of APAP liver disease and facilitate liver recovery are less understood. Heparan sulfate proteoglycans (HSPGs) bind to and regulate various tissue injury factors through their heparan sulfate (HS) chains, but the importance of HSPGs in liver injury in vivo remains unknown. Here, we examined the role of syndecan‐1, the major cell‐surface HSPG of hepatocytes, in AILI. Ablation of syndecan‐1 in mice led to unopposed progression of liver injury upon APAP overdose. However, direct APAP hepatoxicity and liver injury at early times post‐APAP overdose were unaffected by syndecan‐1, suggesting that syndecan‐1 influences later mechanisms that lead to liver repair. The exuberant liver injury phenotypes in syndecan‐1 null ( Sdc1−/− ) mice were traced to a deficiency in protein kinase B (Akt) activation in hepatocytes, which led to a delayed increase in glycogen synthase kinase‐3β (GSK‐3β)‐mediated hepatocyte apoptosis. Inhibition of Akt worsened, whereas inhibition of GSK‐3β and caspases protected mice from AILI. Moreover, administration of purified syndecan‐1, HS, or engineered heparan compounds containing 2‐ O ‐sulfate groups rescued Sdc1−/− mice from AILI by potentiating Akt signaling and inhibiting GSK‐3β‐mediated apoptosis in hepatocytes. In addition, HS showed a significantly prolonged therapeutic efficacy as compared to N ‐acetylcysteine. Conclusion : These results demonstrate that 2‐ O ‐sulfated domains in syndecan‐1 HS halt disease progression and promote liver repair by enhancing hepatocyte survival in AILI. We propose that syndecan‐1 is a critical endogenous factor that controls the balance between prosurvival signaling and apoptosis in hepatocytes in APAP liver disease. (H epatology 2017;66:1601–1615).
DIPG-14. EVALUATING THERAPEUTIC VULNERABILITIES IN DIPG TUMORS USING HIGH-THROUGHPUT SCREENING
Authors: Desmond Brown, David Daniels, Liang Zhang
Journal: Neuro-Oncology (2017)

INTRODUCTION: Pediatric high-grade gliomas including Diffuse Intrinsic Pontine Gliomas (DIPGs) are among the most lethal cancers known with no effective cure. Recently, somatic mutations in the H3F3A or HIST1H3B genes have been detected in the majority of midline high-grade pediatric glioma cases which leads to an amino acid change at lysine 27 of H3 to methionine. In an effort to identify drugs for rapid clinical translation, we performed a rigorous high-throughput in vitro drug screen of FDA approved chemotherapeutics and epigenetic regulators. METHODS: Over 200 drugs were tested including FDA approved cancer drugs and a comprehensive library of epigenetic regulators in 6 H3K27M tumors lines and 3 wild type (WT) cell lines using a HTS platform. RESULTS: We identified several major classes of drugs that potently reduce cell viability of DIPG tumors with the H3K27M mutation. Based on these results we uncovered a major signaling pathway that has not been previously reported as a therapeutic target for DIPG. We found proteins in this pathway that were overexpressed in H3K27M tumors compared to WT tumors and normal brain. Furthermore, depletion or inhibition of this pathway selectively inhibit the proliferation of H3K27M mutant DIPG cells, decreases cell colony formation, increases apoptosis compared to WT expressing tumors and restores H3K27 trimethylation patterns. These findings were validated in orthotopic xenografts. CONCLUSION: Malignant gliomas including DIPG, are one of the most aggressive primary malignant brain tumors with no effective therapies at this time. Using a HTS we identified a class of drugs that utilize a specific signaling pathway that is critical for H3K27M tumors. These studies pave the way for developing molecularly targeted therapies as our understanding how these mutations lead to tumorigenesis unfold.
Cardiovascular Reactivity Among Surgeons: Not Music to Everyone's Ears-Reply
Authors: Karen Allen
Journal: JAMA (1995)

<h3>In Reply.</h3> —We appreciate the insightful comments of the many physicians who took the time and trouble to comment on our study. Although we readily acknowledge the limitations of our methods, we would like to emphasize that this was our initial effort in a field that no one else has attempted to study. We plan to continue this line of research and would like to study a larger and more diverse sample of surgeons (including women as well as different surgical specialists). In addition, interactive videotapes that simulate surgery are now available to be used in place of the cognitive task we used. Whether or not music should be played during surgery is not a simple or clear issue to address. We developed our study because of anecdotal reports suggesting widespread use of music in a myriad of surgical applications. Since the publication of our article, we have received an
Iron status and inflammatory biomarkers in patients with acutely decompensated heart failure: early in‐hospital phase and 30‐day follow‐up
Authors: Lucas N.L. Van Aelst, Marjorie Abraham, Malha Sadoune, Thibaud Lefebvre, Philippe Manivet, Damien Logeart, Jean‐Marie Launay, Zoubida Karim, Hervé Puy, Alain Cohen‐Solal
Journal: European Journal of Heart Failure (2017)
Quelle est l'histoire naturelle du volvulus du sigmoïde? Résultats d'une étude sur 83 patients
Authors: C Dagouat, M Le Rhun, N Musquer, G Meurette, Y Touchefeu, S Bruley des varannes, E Coron
Journal: Endoscopy (2016)

Le Volvulus du sigmoïde (VS) est une occlusion mécanique par torsion de la boucle sigmoïdienne autour de Taxe de son méso. C'est la troisième cause d'occlusion colique chez l'adulte; la prise en charge thérapeutique immédiate reste mal codifiée, et l'histoire naturelle des patients non documentée. Le but de ce travail était d'analyser les modalités de prise en charge et le devenir des patients adressés pour VS au sein d'un même centre hospitalier universitaire.
Patient Experiences of Trauma Resuscitation
Authors: Elinore J. Kaufman, Therese S. Richmond, Douglas J. Wiebe, Sara F. Jacoby, Daniel N. Holena
Journal: JAMA Surgery (2017)

Patient satisfaction is an increasingly common feature of quality measurement, and patient-centered care is a key aspect of high-quality clinical care. Incorporating patient preferences in an acute context, such as trauma resuscitation, presents distinct challenges; however, to our knowledge, patients' experiences of trauma resuscitation have not been explored.To describe patient experiences of trauma resuscitation and to identify opportunities to improve patient experience without compromising speed or thoroughness.This qualitative, descriptive study was conducted at an urban, academic, level I trauma center. Semistructured interviews and video observations were conducted from May to December 2015. Interview participants were adult English-speaking patients who had experienced trauma resuscitation and were clinically stable with no alteration in consciousness. We recruited interview participants and conducted video observations until thematic saturation was reached, resulting in 30 interviews and 20 observations. Video observation patients did not overlap with interview participants. The purposive sample included equal numbers of violently and nonviolently injured patients. Data were analyzed for thematic content from June 2015 to April 2016.The main outcomes reported are themes of patient experience.Of 30 interview participants, 25 were men (83.3%), and 21 were black (70.0%). Of 20 video observation patients, 16 were men (80.0%), and 17 were black (85.0%). Salient aspects of patient experience of trauma resuscitation included emotional responses, physical experience, nonclinical concerns, treatment and procedures, trauma team members' interactions, communication, and comfort. Participants drew satisfaction from trauma team members' demeanor, expertise, and efficiency and valued clear clinical communication, as well as words of reassurance. Dissatisfaction stemmed from the perceived absence of these attributes and from participants' emotional or physical discomfort. Observation data added insight into the components of care that may have contributed to participants' responses and those aspects of care that were not salient to participants.Although the urgency of trauma care limits explicit discussion and consideration of patient priorities, we found that patient concerns corresponded well with trauma team goals. Patients perceived trauma team members as competent, efficient, and caring. Focusing on patient communication could further improve patient-centeredness in this setting.
C-MET mRNA expression in pancreatic ductal adenocarcinoma and stromal tissue: Prognostic and therapeutic implications.
Authors: Martin K. H. Maus, Craig Stephens, Dirk Waldschmidt, Anika Roll, Stephanie H. Astrow, Hans-Michael Steffen, Jack Hsiang, Gary Zeger, Arnulf H Hölscher, Peter Philipp Grimminger
Journal: Journal of Clinical Oncology (2014)

e15199 Background: Pancreatic ductal adenocarcinoma is one of the most aggressive solid malignancies. The c-MET oncogene plays a crucial role in mediating local invasion, systemic dissemination and resistance in this cancer. The genetic makeup of surrounding stromal tissue has shown to be relevant for drug delivery in pancreatic cancer as exemplified by nab-paclitaxel binding to the stromal protein SPARK. In this study we investigated c-MET mRNA expression patterns in pancreatic ductal adenocarcinoma and stromal tissue in patients with clinical outcome information. Methods: FFPE tumor specimens from patients with resectable pancreatic cancer that underwent surgery and adjuvant chemotherapy with gemcitabine were evaluated. C-MET mRNA expression results could be obtained for 25 cases in tumor and 19 cases in stromal tissue as not all samples were sufficient in quality and quantity for microdissection and mRNA analysis. Specifically designed primers and probes were used to detect mRNA c-MET expression levels by quantitative RT-PCR in reference to beta-actin. Results: c-MET mRNA expression was significantly divergent between pancreatic stromal (median 1.0, range 0.37-5.05) and tumor (median 3.8, range 0.78-12.27) tissue (p<0.0001). When statistically evaluated for the best cut-off, patients with high (>5.00) c-MET expression in the tumor tissue had a worse overall survival. (p<0.003). C-MET mRNA expression in stromal tissue did not correlate with outcome. Conclusions: According to this data high c-MET expression is a negative prognostic indicator for pancreatic cancer. Further studies have to evaluate if c-MET expression may predict response to new c-MET inhibitors like cabozantinib. The role of c-MET expression in pancreatic stromal tissue needs further investigation.
A 1980 Letter on the Risk of Opioid Addiction
Authors: Pamela T M Leung, Erin M Macdonald, Matthew B Stanbrook, Irfan A Dhalla, David N Juurlink
Journal: New England Journal of Medicine (2017)

A five-sentence letter published in the Journal in 1980 has been heavily cited as evidence that long-term opioid therapy has seldom been associated with addiction. Of the 608 citations, 72.2% used the letter uncritically as evidence that such addiction was rare.
Abstract P084: Cardiac-Specific Overexpression of Human Histidine-Rich Calcium Binding Protein (HRC-S96A) Genetic Variant Impairs Sarcoplasmic Ca <sup>2+</sup> Handling, Resulting in Arrhythmias
Authors: Vivek P Singh, Wenfeng Cai, Min Dong, Qian Liang, Chi Keung Lam, Xiaoqian Gao, Shan Chen, Demetrios A Arvanitis, Kobra Haghighi, Hong S Wang, Do H Kim, Chunghee Cho, Evangelia G Kranias
Journal: Circulation Research (2011)

Disturbed Ca-homeostasis in the cardiomyocyte is a hallmark of human and experimental heart failure. The histidine-rich Ca binding protein (HRC), an intraluminal SR protein is an additional regulator of SR Ca2+ cycling. Previous biochemical studies have shown that HRC can bind to triadin (a component of ryanodine receptors complex) and SERCA2a, suggesting that HRC may be involved in the regulation of SR Ca2+ release and Ca2+ uptake. We recently identified a human HRC genetic variant (S96A), which appears to correlate with ventricular arrhythmias and sudden death in dilated cardiomyopathy (DCM) patients. To gain insight into the physiological and pathological significance of the S96A-HRC variant, we generated transgenic mice with cardiac-specific overexpression of human HRC wild-type (HRC-WT) and S96A mutant (HRC-S96A) in the HRC null (HRC KO) background. We obtained lines with similar expression levels of HRC-S96A and HRC-WT for further characterization. Overexpression of human HRC-S96A resulted in decreased fractional shortening by 22% (7.7 ± 0.5% in HRC-WTs vs. 6.0 ± 0.4% in HRC-S96A), rates of contraction by 20% (75 ± 5 µm/sec in HRC-WTs vs. 60 ± 4 µm/sec in HRC-S96A) and rates of relaxation by 20% (87 ± 6 µm/sec in HRC-WTs vs. 70 ± 4.5 µm/sec in HRC-S96A) compared with HRC-WT. Myocytes isolated from HRC-S96A mice had diminished Ca2+ transient amplitude and delayed half-decay time of the Ca2+ transient. In addition, the frequency of Ca2+ sparks was significantly higher although caffeine-induced SR Ca2+ release (SR load) was reduced in HRC-S96A cells. To determine the effect of S96A-HRC under stress conditions, 5 Hz field stimulation in the presence of 1 µmol/L Isoproterenol was applied: after-contractions were developed in 46% (16 of 35) of HRC-S96A cardiomyocytes, compared to 12% (4 of 33) of HRC-WTs mice. The findings of the present study demonstrate that the human HRC-S96A variant results in impaired myocytes Ca2+ handling, associated with depressed SR Ca2+-uptake rate and increased rate of SR Ca2+ leak, which may destabilize the cells, promoting aftercontractions under stress conditions. Thus, there appears to be a link between this genetic variant and ventricular arrhythmias in DCM human carriers.
TRTH-11. EFFICACY OF ASPARAGINASE ERWINIA CHRYSANTHEMI WITH OR WITHOUT TEMOZOLOMIDE AGAINST GLIOMA CELLS AND INTRACRANIAL MOUSE MEDULLOBLASTOMA
Authors: Valentina Sanghez, Mengqing Chen, Tsui- Fen Chou, Michelina Iacovino, Henry Lin, Joseph Lasky, Eduard Panosyan
Journal: Neuro-Oncology (2017)

BACKGROUND: Anti-metabolites are less myelosuppressive than DNA-damaging drugs used for brain tumors, and can be tested for efficacy and less overlapping toxicity if combined. We studied if anti-leukemia agent Erwinaze (which depletes asparagine and glutamine) has antitumor effect with or without temozolomide (TMZ) against brain tumors. METHODS: Erwinaze, TMZ, and their combinations were tested against malignant glioma and medulloblastoma cells, neurospheres, and against SMO/SMO mouse model (typically succumbing from spontaneous medulloblastoma). MTT cell viability assays were used for dose-response curves. Mice survival and weight loss were used as efficacy and toxicity surrogates, respectively. RESULTS: Erwinaze monotherapy showed dose-dependent cytotoxicity against 4 tested cell lines with range of IC50s 0.1->10 IU/ml. Erwinaze at <1 IU/ml concentrations synergized with TMZ against cells with 1.5–4 fold decrease of TMZ IC50s (range 100-1000uM). Glutamine supplementation at 1 and 10 mmol/L concentrations counteracted Erwinaze cytotoxicity in dose-dependent manner. Neurospheres treated with Erwinaze also showed dose-dependent reduction (IC50s: 0.1–3 IU/ml). Four groups of 7 week-old SMO/SMO mice were treated with 3 cycles of 10 IP injections of DMSO (control), TMZ, Erwinaze, and combination (n=30, 6 in control and 8 in each of treatment groups). Preliminary analysis 17 weeks after initiation of therapy shows trends towards 35% survival advantage of mice receiving Erwinaze (with or without TMZ), compared to those that didn't (p=0.08). Temozolomide alone didn't improve survival of SMO/SMO mice (5/8 succumbed), and resulted in 10% less weight compared to other groups. Immunohistochemistry of brains and complete statistical analyses are pending. CONCLUSION: Erwinaze is effective against brain tumor cells in vitro and may enhance cytotoxicity of TMZ. Erwinaze may improve survival of SMO/SMO mice used with or without TMZ per preliminary data. The Erwinaze effect maybe due to glutamine depletion behind blood-brain barrier. Non-increased toxicity, as measured by weight, justifies further testing of conceptually similar combinations.
Genome-Wide Association Study to Identify Susceptibility Loci That Modify Radiation-Related Risk for Breast Cancer After Childhood Cancer
Authors: Lindsay M Morton, Joshua N Sampson, Gregory T Armstrong, Ting-Huei Chen, Melissa M Hudson, Eric Karlins, Casey L Dagnall, Shengchao Alfred Li, Carmen L Wilson, Deo Kumar Srivastava, Wei Liu, Guolian Kang, Kevin C Oeffinger, Tara O Henderson, Chaya S Moskowitz, Todd M Gibson, Diana M Merino, Jeannette R. Wong, Sue Hammond, Joseph P. Neglia, Lucie M. Turcotte, Jeremy Miller, Laura Bowen, William A. Wheeler, Wendy M. Leisenring, John A. Whitton, Laurie Burdette, Charles Chung, Belynda D. Hicks, Kristine Jones, Mitchell J. Machiela, Aurelie Vogt, Zhaoming Wang, Meredith Yeager, Geoffrey Neale, Matthew Lear, Louise C. Strong, Yutaka Yasui, Marilyn Stovall, Rita E. Weathers, Susan A. Smith, Rebecca Howell, Stella M. Davies, Gretchen A. Radloff, Kenan Onel, Berrington de González A, Peter D. Inskip, Preetha Rajaraman, Joseph F. Fraumeni, Smita Bhatia, Stephen J Chanock, Margaret A Tucker, Leslie L Robison
Journal: JNCI Journal of the National Cancer Institute (2017)

Childhood cancer survivors treated with chest-directed radiotherapy have substantially elevated risk for developing breast cancer. Although genetic susceptibility to breast cancer in the general population is well studied, large-scale evaluation of breast cancer susceptibility after chest-directed radiotherapy for childhood cancer is lacking. We conducted a genome-wide association study of breast cancer in female survivors of childhood cancer, pooling two cohorts with detailed treatment data and systematic, long-term follow-up: the Childhood Cancer Survivor Study and St. Jude Lifetime Cohort. The study population comprised 207 survivors who developed breast cancer and 2774 who had not developed any subsequent neoplasm as of last follow-up. Genotyping and subsequent imputation yielded 16 958 466 high-quality variants for analysis. We tested associations in the overall population and in subgroups stratified by receipt of lower than 10 and 10 or higher gray breast radiation exposure. We report P values and pooled per-allele risk estimates from Cox proportional hazards regression models. All statistical tests were two-sided. Among survivors who received 10 or higher gray breast radiation exposure, a locus on 1q41 was associated with subsequent breast cancer risk (rs4342822, nearest gene PROX1, risk allele frequency in control subjects [RAFcontrols] = 0.46, hazard ratio = 1.92, 95% confidence interval = 1.49 to 2.44, P = 7.09 × 10-9). Two rare variants also showed potentially promising associations (breast radiation ≥10 gray: rs74949440, 11q23, TAGLN, RAFcontrols = 0.02, P = 5.84 × 10-8; <10 gray: rs17020562, 1q32.3, RPS6KC1, RAFcontrols = 0.0005, P = 6.68 × 10-8). Associations were restricted to these dose subgroups, with consistent findings in the two survivor cohorts. Our study provides strong evidence that germline genetics outside high-risk syndromes could modify the effect of radiation exposure on breast cancer risk after childhood cancer.
Impact de l'endoscopie à 330 ° (full sprectrum endoscopy® FUSE®ENDOCHOICE®) dans la – détection des adénomes colorectaux: première étude française observationnelle
Authors: JP Ratone, E Bories, F Caillol, C Pesenti, S Godât, F Sellier, S Hoibian, M Landon, C Servajean, C De Cassan, M Giovannini
Journal: Endoscopy (2016)

Le cancer colorectal reste un problème majeur de santé publique. La coloscopie a prouvé lors de plusieurs études son utilité dans la prévention de son incidence notamment par l'ablation d'adénomes. Les sociétés savantes notamment l'american society of gastroenterology (ASGE) recommandent un taux de détection d'adénomes (TDA) supérieur à 25% chez l'homme et supérieur à 15% chez la femme. L'amélioration des techniques d'endoscopie diagnostique devrait permettre d'améliorer le TDA et donc diminuer l'incidence du «cancer d'intervalle». Le coloscope FUSE® a récemment prouvé son efficacité dans une étude randomisée multicentrique en détectant 41% d'adénomes supplémentaires. Nous rapportons ici la première étude française sur l'utilisation de ce coloscope. Le but principal était de déterminer le nombre d'adénomes potentiellement omis par un coloscope standard car non vus sur l'écran central (vision classique à 170 °). Les objectifs secondaires étaient d'évaluer le TDA de notre équipe avec ce coloscope, l'impact des écrans latéraux sur le TDA et le coloscope FUSE® via les temps de montées et descentes des médecins juniors et seniors.
Simulations of recently observed shear shock wave physics amplify local brain accelerations by a factor of 40 in head drop experiments – future implications for concussion
Authors: Kody R Campbell, Jason P Mihalik, Bharat B Tripathi, David Espindola, Gianmarco F Pinton
Journal: British Journal of Sports Medicine (2017)

Objective Shear waves that travel in the brain are highly nonlinear and can develop into shock waves. This newly observed phenomenon could have implications for concussion. Our objective was to determine the effect of the brain’s nonlinear shear wave propagation behaviour on laboratory acquired head impact kinematics through numerical simulations. Design Head impact kinematics, obtained from controlled laboratory drops to cadaveric human heads, provided inputs to a one dimensional simulation of a cubically nonlinear shear wave equation solved with a piecewise parabolic method. Of the 292 drops, 125 caused significant motion about one axis. We assumed this would provide optimal conditions to create shears waves. The nonlinear and attenuation properties for the simulation were experimentally measured in fresh porcine brains with high frame-rate ultrasound. Setting Labratory. Subjects None. Intervention Independent variable – Nonlinear and attenuating properties of the brain. Outcome measures Peak Linear Tangential Acceleration (PLTA) measured at the skull was compared to the max PLTA acquired from the simulation for each of the 125 trials. Results There were 17 cases where nonlinearity overcame attenuation and resulted in the PLTA amplifying as high as 40 times the initial PLTA at the skull. Conclusions Our models of previously unobserved shear shock wave physics strongly suggest that nonlinearity is a first order parameter in brain kinematics and may have a fundamental influence on brain injury. Expanding these nonlinear simulations to three dimensions could better link head impact kinematics collected in the field with concussion risk and other head injuries. Competing interests Head drop data were obtained in collaboration with Drs. Cameron “Dale” Bass and Jason F. Luck (Duke University, USA) and Dr. David B. Camarillo (Stanford University, USA) None.