tbuckley/cabot-search huggingface dataset:
Abstract 14729: Evaluation of the Combined Prehospital Hypoxia-Hypotension "Depth-Duration Dose" and Mortality in Major Traumatic Brain Injury
Authors: Daniel W Spaite, Chengcheng Hu, Bentley J Bobrow, Vatsal Chikani, Joshua B Gaither, Bruce J Barnhart, P. David Adelson, Kurt R Denninghoff, Amber D Rice, Chad Viscusi, Terry Mullins, Duane Sherrill, Samuel M Keim
Journal: Circulation (2017)

Objective:  Previous work has shown that, separately, the depth-duration doses of  prehospital  hypoxia (HO) and hypotension (HT) are strongly associated with mortality in Traumatic Brain Injury (TBI). However, because HO and HT are not mutually exclusive, we sought to evaluate the combined-dose effect of these physiological anomalies.   Methods:  We evaluated major TBI cases (CDC Barell Matrix Type 1) enrolled in the EPIC Study (NIH 1R01NS071049) before TBI guideline implementation (N = 16,711; 1/07-9/14). The HO dose was calculated as SpO2 depth    Results:  6682 cases were included [Exclusions: age  200 (2.1%), missing data (12.8%), only 1 recorded SBP or SpO2 (8.3%)]. Mortality rate increased consistently across the quartiles of the unadjusted dose score (Fig A). In the adjusted model, mortality increased monotonically (nearly linearly) with the dose score (B). This is consistent with the monotonically-increasing relationships between the HO and HT doses and their respective adjusted death rates (C, D with 95% bands). Across the entire range of dose, an increase of 1 standard deviation of adjusted dose score is associated with an OR of 1.63 for death among patients with  any  combination of HO, HT or both.   Conclusion:  Historically, HO and HT have been assessed dichotomously (present or not) in TBI. These data reveal that the depth-duration dose of  combined  prehospital HO/HT is strongly associated with increased mortality and that effects of HO and HT are  additive . The clinical effects of HO and HT may be significantly more complex than the current literature reflects.
Endothelial Nox2 overexpression potentiates vascular oxidative stress and hemodynamic response to angiotensin II: Studies in endothelial-targeted Nox2 transgenic mice (vol 100, pg 1016, 2007)
Authors: J K Bendall, R Rinze, D Adlam, A L Tatham, J de Bono, N Wilson, E Volpi, K M Channon
Journal: Circulation Research (2008)
The Addition of Sorafenib to Standard AML Treatment Results in a Substantial Reduction in Relapse Risk and Improved Survival. Updated Results from Long-Term Follow-up of the Randomized-Controlled Soraml Trial
Authors: Christoph Rollig, Hubert Serve, Andreas Hüttmann, Richard Noppeney, Carsten Müller-Tidow, Utz Krug, Claudia D. Baldus, Christian H. Brandts, Volker Kunzmann, Hermann Einsele, Alwin Krämer, Kerstin Schäfer-Eckart, Andreas Neubauer, Andreas Burchert, Aristoteles Giagounidis, Stefan W. Krause, Andreas Mackensen, Walter E. Aulitzky, Regina Herbst, Mathias Hänel, Alexander Kiani, Norbert Frickhofen, Johannes Kullmer, Ulrich Kaiser, Hartmut Link, Thomas Geer, Albrecht Reichle, Christian Junghanss, Roland Repp, Frank Heits, Heinz Albert Durk, Thomas Illmer, Martin Bornhäuser, Markus Schaich, Stefani Barbara Parmentier, Martin Goerner, Christian Thiede, Malte von Bonin, Johannes Schetelig, Michael Kramer, Wolfgang E. Berdel, Gerhard Ehninger
Journal: Blood (2017)
Access to emergency hospital care provided by the public sector in sub-Saharan Africa in 2015: a geocoded inventory and spatial analysis
Authors: Paul O Ouma, Joseph Maina, Pamela N Thuranira, Peter M Macharia, Victor A Alegana, Mike English, Emelda A Okiro, Robert W Snow
Journal: The Lancet Global Health (2018)

Timely access to emergency care can substantially reduce mortality. International benchmarks for access to emergency hospital care have been established to guide ambitions for universal health care by 2030. However, no Pan-African database of where hospitals are located exists; therefore, we aimed to complete a geocoded inventory of hospital services in Africa in relation to how populations might access these services in 2015, with focus on women of child bearing age.
A rare cause of small-bowel bleeding: haemorrhagic small-bowel lymphangioma diagnosed by antegrade double-balloon enteroscopy
Authors: Laura Gaeta, Alberto Murino, Nikolaos Koukias, Bu'Hussein Hayee, Amyn Haji, Andrea Telese, Edward Despott
Journal: Endoscopy (2018)

Small-bowel lymphangiomata (SBLs) are benign and relatively uncommon tumors of the lymphatic system [1]. Although SBLs are usually clinically silent, they may rarely present with significant small-bowel bleeding, protein-losing enteropathy, and intussusception [2] [3].
Toxicity of single-dose oral gemcitibine in mice.
Authors: Noel D. Horton, Jamie K. Young, Everett J. Perkins, Lewis L. Truex
Journal: Cancer Research (2004)

2115  The present study was conducted to determine the single-dose toxicity and toxicokinetics of gemcitabine when administered orally to mice. Gemcitabine hydrochloride, an intravenously administered chemotherapeutic antimetabolite, is a potent and specific oncolytic used for the treatment of cancer. The antiproliferative mechanism of the drug involves inhibition of DNA replication and repair by inhibiting DNA synthesis and by blocking repair mechanisms through masked chain termination. CD-1 mice (10/sex/group) were given a single oral (gavage) gemcitabine dose of 167, 333, or 500 mg/kg, and mice were euthanized 4 or 14 days postdose to determine the acute cytotoxic effects and the reversibility of compound-related effects, respectively. Data from this study were compared to data from previously conducted toxicology studies. Orally administered gemcitabine was rapidly absorbed with a time-to-peak plasma concentration of approximately 0.5 to 1.0 hours. Consistent with IV administration, metabolism of gemcitabine to difluorodeoxyuridine (dFdU) after a single-oral dose was extensive, with high plasma concentrations of dFdU relative to gemcitabine. There were no consistent gender-related differences in gemcitabine toxicokinetics. Exposure (area under the concentration vs. time curve) and maximum plasma concentration values for both gemcitabine and dFdU were not dose proportional in the dose range examined. Compound-related deaths in mice given 333 or 500 mg/kg occurred 3 to 5 days after dosing. The mortality seen in this study was attributed to adverse intestinal lesions characterized by moderate-to-marked loss of mucosal epithelium (atrophic enteropathy) throughout the entire length of the intestinal tract. Comparable exposures via IV dosing in previous mouse studies did not result in death or gastrointestinal toxicity. The enteropathy was dose-responsive in incidence and severity, but with marked variation among individual mice within compound-treated groups. In some mice that were euthanized and necropsied 4 days postdose, the intestinal changes were characterized by mucosal epithelial regeneration resulting in a normal mucosal thickness. Due to the severity of the intestinal lesions, suspected acute time of onset, and marked variation among individual mice within dose groups, it is likely that local effects due to the route of administration were important for development of the enteropathy. The systemic toxicities observed in this study were typical of those seen at these exposure levels. In summary, a single-oral dose of gemcitabine at 167, 333, or 500 mg/kg caused dose-responsive adverse intestinal lesions at exposures that were previously tolerated when the compound was adminstered IV. Toxicokinetics and systemic toxicity were consistent with data from earlier IV mouse studies.
A non-apoptotic cell death process, entosis, that occurs by cell-in-cell invasion.
Authors: Michael Overholtzer, Arnaud Mailleux, Ghassan Mouneimne, Guillaume Normand, Stuart Schnitt, Randall King, Edmund Cibas, Joan Brugge
Journal: Cancer Research (2008)

1560  Epithelial cells require attachment to extra-cellular matrix (ECM) to suppress an apoptotic cell death program termed anoikis. We describe a non-apoptotic cell death program in matrix-detached cells, termed entosis, that is initiated by a previously unrecognized and unusual process involving the invasion of one cell into another, leading to a transient state in which a live cell is contained within a neighboring host cell. These 9cell-in-cell9 structures closely resemble similar cytological features in human cancers. Although a small percentage of live internalized cells can be released, the majority of internalized cells undergo non-apoptotic cell death by lysosomal acidification. Based on these data, we present evidence for a tumor suppressive role of entosis in human breast cancer. Paradoxically, we have also found that entosis can promote the development of aneuploidy, as live internalized cells can disrupt cytokinesis of host cells leading to multinucleation in vitro and in vivo. Thus, entosis may be tumor suppressive in some contexts and paradoxically tumor promoting in others. Models to investigate the role of entosis in human tumors will be presented.
PD-1 through Asparaginyl Endopeptidase Regulates Foxp3 Stability in Induced Regulatory T Cells
Authors: Grace Mallett, Arun Gangaplara, Chaido Stathopolou, Francis Flomerfelt, Leigh Samsel, Tania Felizardo, Michael Eckhaus, Laura Edgington, Joshua Yim, Jonathan Martinez-Fabregas, Jinfang Zhu, Daniel H. Fowler, Matthew Bogyo, Sanders van-Kasteren, Colin Watts, Ethan Shevach, Arian Dominic John Laurence, Shoba Amarnath
Journal: Blood (2017)
Imatinib mesylate suppresses T-cell activation through inhibition of Lck/Zap-70 signaling: Evidence for a role in herpes zoster reactivation in CML patients
Authors: Nicholas J. Donato, Moshe Talpaz, Ji Y. Wu, Hui Gao, Bang-Ning Lee, Hagop Kantarjian, Daniel Lohse, Raymond Budde, James M. Reuben
Journal: Cancer Research (2004)

1241  Imatinib mesylate (IM) inhibits the BCR-ABL oncogene and effectively controls BCR-ABL (+) leukemias. This drug is one of the first and most successful applications of targeted therapy where minimal interference with unintended targets reduces drug toxicity. However, tyrosine kinases other than BCR-ABL are inhibited by IM; some exploited for therapeutic purposes in other disease. In CML patients receiving IM herpes zoster episodes were noted in a percentage of patients that had not been seen with other forms of CML therapy. The risk of herpes zoster reactivation in CML patient receiving IM was much higher than the general age-matched population, suggesting a link between IM therapy and herpes zoster episodes. In IM treated CML patients T-cell cytokine levels (IFN-gamma, IL-2) were significantly reduced, suggesting an impairment in T-cell function. Treatment of Jurkat T-cells with IM reduced tyrosine phosphorylation and cytokine expression without inducing apoptosis. In vitro studies with purified Lck and Zap-70 kinases demonstrated that Lck was inhibited at IM concentrations that are clinically achievable. Only Lck and Lyn kinase in the src family demonstrated sensitivity to IM-mediated kinase inhibition with IC50 values of 5.1 and 3.8 microM, respectively. In CML patients we detected suppression of Lck/Zap-70 signaling (p-LAT) following IM therapy. Signaling and cytokine expression were also inhibited by IM in T-cells derived from normal donors. These results suggest that IM suppresses T-cell activation through inhibition of Lck/Zap-70 signaling and may play a role in the inability of CML patients receiving IM to prevent the reactivation of varicella zoster virus infection
The Mutation Landscape of Follicular Lymphoma and Chronic Lymphocytic Leukemia Reveals a Distinctive Frequency and Composition of Aid-Related Mutation Signatures
Authors: Julieta Sepulveda, Cornelis A.M. van Bergen, Diego Alvarez, Szymon Kielbasa, Hailiang Mei, Hendrik Veelken, Marcelo Navarrete Signorile
Journal: Blood (2017)
Molecular surveillance of norovirus, 2005–16: an epidemiological analysis of data collected from the NoroNet network
Authors: Janko van Beek, Miranda de Graaf, Haider Al-Hello, David J Allen, Katia Ambert-Balay, Nadine Botteldoorn, Mia Brytting, Javier Buesa, Maria Cabrerizo, Martin Chan, Fiona Cloak, Ilaria Di Bartolo, Susana Guix, Joanne Hewitt, Nobuhiro Iritani, Miao Jin, Reimar Johne, Ingeborg Lederer, Janet Mans, Vito Martella, Leena Maunula, Georgina McAllister, Sandra Niendorf, Hubert G Niesters, Alexander T Podkolzin, Mateja Poljsak-Prijatelj, Lasse Dam Rasmussen, Gábor Reuter, Gráinne Tuite, Annelies Kroneman, Harry Vennema, Marion P G Koopmans
Journal: The Lancet Infectious Diseases (2018)
IgA Function in Relation to the Intestinal Microbiota
Authors: Andrew J. Macpherson, Bahtiyar Yilmaz, Julien P. Limenitakis, Stephanie C. Ganal-Vonarburg
Journal: Annual Review of Immunology (2018)

IgA is the dominant immunoglobulin isotype produced in mammals, largely secreted across the intestinal mucosal surface. Although induction of IgA has been a hallmark feature of microbiota colonization following colonization in germ-free animals, until recently appreciation of the function of IgA in host-microbial mutualism has depended mainly on indirect evidence of alterations in microbiota composition or penetration of microbes in the absence of somatic mutations in IgA (or compensatory IgM). Highly parallel sequencing techniques that enable high-resolution analysis of either microbial consortia or IgA sequence diversity are now giving us new perspectives on selective targeting of microbial taxa and the trajectory of IgA diversification according to induction mechanisms, between different individuals and over time. The prospects are to link the range of diversified IgA clonotypes to specific antigenic functions in modulating the microbiota composition, position and metabolism to ensure host mutualism.
Natural disease course of Crohn’s disease during the first 5 years after diagnosis in a European population-based inception cohort: an Epi-IBD study
Authors: Johan Burisch, Gediminas Kiudelis, Limas Kupcinskas, Hendrika Adriana Linda Kievit, Karina Winther Andersen, Vibeke Andersen, Riina Salupere, Natalia Pedersen, Jens Kjeldsen, Renata D’Incà, Daniela Valpiani, Doron Schwartz, Selwyn Odes, Jóngerð Olsen, Kári Rubek Nielsen, Zsuzsanna Vegh, Peter Laszlo Lakatos, Alina Toca, Svetlana Turcan, Konstantinos H Katsanos, Dimitrios K Christodoulou, Mathurin Fumery, Corinne Gower-Rousseau, Stefania Chetcuti Zammit, Pierre Ellul, Carl Eriksson, Jonas Halfvarson, Fernando Jose Magro, Dana Duricova, Martin Bortlik, Alberto Fernandez, Vicent Hernández, Sally Myers, Shaji Sebastian, Pia Oksanen, Pekka Collin, Adrian Goldis, Ravi Misra, Naila Arebi, Ioannis P Kaimakliotis, Inna Nikuina, Elena Belousova, Marko Brinar, Silvija Cukovic-Cavka, Ebbe Langholz, Pia Munkholm
Journal: Gut (2018)

The Epi-IBD cohort is a prospective population-based inception cohort of unselected patients with inflammatory bowel disease from 29 European centres covering a background population of almost 10 million people. The aim of this study was to assess the 5-year outcome and disease course of patients with Crohn's disease (CD).Patients were followed up prospectively from the time of diagnosis, including collection of their clinical data, demographics, disease activity, medical therapy, surgery, cancers and deaths. Associations between outcomes and multiple covariates were analysed by Cox regression analysis.In total, 488 patients were included in the study. During follow-up, 107 (22%) patients received surgery, while 176 (36%) patients were hospitalised because of CD. A total of 49 (14%) patients diagnosed with non-stricturing, non-penetrating disease progressed to either stricturing and/or penetrating disease. These rates did not differ between patients from Western and Eastern Europe. However, significant geographic differences were noted regarding treatment: more patients in Western Europe received biological therapy (33%) and immunomodulators (66%) than did those in Eastern Europe (14% and 54%, respectively, P<0.01), while more Eastern European patients received 5-aminosalicylates (90% vs 56%, P<0.05). Treatment with immunomodulators reduced the risk of surgery (HR: 0.4, 95% CI 0.2 to 0.6) and hospitalisation (HR: 0.3, 95% CI 0.2 to 0.5).Despite patients being treated early and frequently with immunomodulators and biological therapy in Western Europe, 5-year outcomes including surgery and phenotype progression in this cohort were comparable across Western and Eastern Europe. Differences in treatment strategies between Western and Eastern European centres did not affect the disease course. Treatment with immunomodulators reduced the risk of surgery and hospitalisation.
Golimumab and Methotrexate combinatation therapy significantly improves synovitis, osteitis and bone erosion compared to Methotrexate alone - A magnetic resonance imaging study of Methotrexate-naïve rheumatoid arthritis patients
Authors: Mikkel Østergaard, P. Emery, P.G. Conaghan, R. Fleischmann, W. Xu, E.C. Hsia, M.U. Rahman
Journal: Annals of the Rheumatic Diseases (2011)
Treatment Patterns and Survival Outcomes in Latin American Patients with Newly Diagnosed Multiple Myeloma: A Retrospective Medical Chart Review Study, 2008-2016
Authors: Vania T M Hungria, Deborah M. Martinez-Banos, Christian Ramos Penafiel, Carlos Eduardo Miguel, Jorge Vela-Ojeda, Guillermina Remaggi, Fernando Barroso Duarte, Carmen Cao, Maria Silvana Cugliari, Telma Santos, Eduardo Santos, Gerardo Machnicki, Jennifer Hsiang-Ling Lin, Yen-Wen Chen, Paula Barreyro
Journal: Blood (2017)
Abstract 19103: Tolvaptan Increases Urine Output Without Hemodynamic Impairment in Heart Failure Patients With Renal Dysfunction
Authors: Yuki Ikeda, Takayuki Inomata, Hisahito Shinagawa, Keisuke Kida, Yugo Shibagaki, Naoki Sato, Tohru Izumi, Junya Ako
Journal: Circulation (2015)

Introduction: There has been scant clinical evidence on whether the aquaretic effect of tolvaptan (TLV) contributes to decongestion without further renal impairment compared with furosemide (FUR). Methods: The Kanagawa Aquaresis Investigators Trial of TLV on Heart Failure Patients with Renal Impairment (K-STAR) is a multicenter, open-labeled, randomized, controlled prospective clinical study of 81 patients with heart failure (HF) in Japan. Patients with residual signs of congestion despite treatment with oral FUR at a dose of ≥40 mg/day with baseline estimated glomerular filtration rates of &lt;45 mL/min were randomly assigned to two groups for 7-day treatments with either ≤15 mg/day of additive TLV or ≤40 mg/day of FUR. Results: During the treatment period, a more significant increase from baseline in urine volume (%ΔUV) was seen in the TLV group than in the FUR group (+42 ± 43% in the TLV group vs. +15 ± 39% in the FUR group, p &lt; 0.01). Renal function was better preserved in the TLV group than in the FUR group [increase in serum creatinine (%ΔCr): +3 ± 13% in the TLV group vs. +10 ± 14% in the FUR group, p = 0.015]. Increases in the ratio of blood urea nitrogen to %ΔCr and %ΔUV were positively correlated in the FUR group (r = 0.33, p = 0.03) but were not significantly correlated in the TLV group (r = -0.15, p = 0.34). Moreover, an increase in pulse rate (%ΔPR: r = 0.31, p = 0.04) and decrease in stroke volume (%ΔSV: r = –0.35, p = 0.04) were positively correlated to the %ΔUV in the FUR group but not in the TLV group (%ΔPR: r = 0.10, p = 0.51; %ΔSV: r = –0.08, p = 0.65; respectively). Conclusions: TLV increases UV with less hemodynamic and renal impairment by maintaining adequate intravascular volume compared with FUR in HF patients with renal dysfunction.
Pimasertib plus gemcitabine in metastatic pancreatic adenocarcinoma: Results of a safety run-in part of a phase II trial.
Authors: Chris Verslype, Pascal Hammel, Manuel Hidalgo, Teresa Macarulla, Rocio Garcia-Carbonero, Thierry André, Marc Van Den Eynde, Berta Laquente Saez, Michele Milella, Eric Raymond, Thea Faivre, Alvin Milner, Dolores Tarabaric, Giuseppe Locatelli, Oliver von Richter, Bernard Laffranchi, Eric Van Cutsem
Journal: Journal of Clinical Oncology (2013)

4041 Background: Activating MAPK pathway mutations (predominantly RAS) occur with a high incidence in metastatic pancreatic adenocarcinoma (mPaCa). Pimasertib is a MEK1/2 inhibitor with potent activity in cell lines and xenografts with an activated MAPK pathway. This two-part trial in patients (pts) with mPaCa comprises a dose-escalation safety run-in and a randomized phase II part (EudraCT 2009-011992-61). We defined the maximum tolerated dose (MTD), safety, pharmacokinetics (PK) and antitumor activity of two pimasertib dosing schedules (S), and the recommended phase II dose (RP2D). Methods: Dose-escalation (3+3 design) in two dosing S of oral pimasertib: once-daily (qd) - 5 days on, 2 days off (S1); and twice-daily (bid) - continuous (S2) combined with the standard dose of gemcitabine (gem). Results: 53 pts (median age 61 years and ECOG performance status 0-1) have been treated at six dose levels in S1 (15 to 120 mg qd) and at 60 and 75 mg bid in S2. MTDs were defined as 120 mg qd and 75 mg bid. Two pts had a dose-limiting toxicity (DLT) in the DLT observation period: a grade (G) 3 confusion with ataxia and disorientation at 60 mg bid and a G4 suicidal ideation at 75 mg bid. G3-4 adverse events (AEs) in &gt;5% of pts were: neutropenia (32%), thrombocytopenia (25%), asthenia (19%), dyspnea (9%), transaminitis (9%), anemia (8%), and diarrhea, pulmonary embolism, pulmonary sepsis (6% each). Most common AEs were asthenia (70%), ocular AEs (68%), skin rash (62%), nausea (58%), diarrhea (58%), peripheral edema (51%), thrombocytopenia (49%), vomiting (45%), mucositis (43%), neutropenia (38%), decreased appetite (36%) and anemia (34%). The main ocular AE was serous retinal detachment (58%); manageable retinal vein occlusion occurred in five pts. PK data were comparable to pimasertib monotherapy and published gem data. Partial responses were noted in 10 pts and stabilisation ≥3 months in 13 pts. Hot spot mutations in genes activating the MAPK and PI3K/AKT pathway and correlation with clinical outcome are being investigated. Conclusions: Pimasertib MTDs were reached. The RP2D was defined as 60 mg bid. PK was dose proportional and associated with target inhibition. Sustained responses were seen in both dosing schedules. Clinical trial information: 2009-011992-61.