tbuckley/cabot-search huggingface dataset:
Hepatic function of FcRn revealed: Implications for overcoming drug‐mediated hepatotoxicity
Authors: E. Sally Ward, Raimund J. Ober
Journal: Hepatology (2017)

1Department of Molecular and Cellular MedicineTexas A&M University Health Science CenterCollege StationTX 2Department of Microbial Pathogenesis and ImmunologyTexas A&M University Health Science CenterBryanTX 3Department of Biomedical EngineeringTexas A&M UniversityCollege StationTX
Abstract 351: Nonlinear Dynamics in Long-Term Left Ventricular Remodeling in Chagas Heart Disease and Adverse Outcomes: SEARCH-Rio Substudy
Authors: Paulo R Benchimol-Barbosa, Bharat K Kantharia, Claudio G Carvalhaes
Journal: Circulation Research (2012)

Introduction: Left ventricular (LV) remodeling in Chagas heart disease (CHD) depends on the severity of the initial insult and may have clinical implication. SEARCH-Rio study investigated nonlinear dynamics in long-term LV remodeling in CHD. Methods: Fifty stable outpatients with CHD were enrolled and followed at scheduled visits. Cardiac death (sudden, arrhythmic or heart failure) was ascertained by review of medical records. LV dimension was assessed by echocardiogram, and mass estimated by Devereux. Subjects were distributed in four equally spaced groups according to initial mass. Intra-group standard deviation (SD) was calculated throughout follow-up. A plot of LV mass (corrected to initial value) vs recurrences during follow-up assessed non-linear relationship. Lyapunov exponent (LE) assessed LV mass dynamics during follow-up. Results: Median follow-up was 95 months; 10 subjects died. LV mass groups were [mean; Figure 1]: I-110g, II-140g, III-170g, IV-200g. No inter-group SD differences at baseline were observed (p=NS; table inset). At end of follow-up, intra-group SD increased roughly proportional to initial mean LV mass (Figure 1; p=0.01). A logistic parabolic-shaped equation was fit to corrected LV mass data in the plot (r²=0.98) and alpha coefficient was 3.9 (p&lt;0.01; Figure 2). In groups, median LE was: I: 0.22; II: 0.17; III: 0.22; IV: 0.15. Median LE was 0.7 for survivors and -0.45 for nonsurvivors. LE cutoff at 0.26 yielded 100% sensitivity and 88% specificity for cardiac death (AUC=0.89; p&lt;0.01). Conclusion: In CHD, LV remodeling exhibits complex nonlinear dynamics. LV remodeling dynamics has prognostic implication in this population.
テロメラーゼの触媒サブユニットの神経保護作用:中枢神経系における潜在的な治療標的【Powered by NICT】
Authors: Gonzalez-Giraldo Yeimy, A Forero Diego, Echeverria Valentina, Gonzalez Janneth, Avila-Rodriguez Marco, Garcia-Segura Luis Miguel, E Barreto George
Journal: Ageing Research Reviews (2016)
Margaret McCartney: The cult of CPR
Authors: Margaret McCartney
Journal: BMJ (2017)

CPR, again.The cultural significance we afford cardiopulmonary resuscitation has reached the status of a cult.No other medical intervention that we don't recommend on the basis of efficacy and adverse effects provokes such angst.It was acceptable 20 years ago to tell patients and families that dying was inevitable and imminent.Side wards were organised, if possible.Families were called to bedsides at home.Syringe drivers with generous morphine were obtained.Relatives often stayed with their dying family member at all hours.A discreet entry was made in the notes: not for resuscitation.The nurse in charge of the ward, or the district nurse, ensured that this was honoured.In hospital, cardiac monitors were removed, to avoid distress and panic from seeing irregular beats, or none at all.Blood tests were done only if they would provide information to relieve symptoms.Fluid was given if the patient wished, even if swallowing was difficult.In short, the medical care was gentle and respectful, though often imperfect.
重い金属を含まない量子ドットを用いたin vivo生体内分布研究とex vivoリンパ節イメージング【Powered by NICT】
Authors: Yaghini Elnaz, D Turner Helen, M Le Marois Alix, Suhling Klaus, Naasani Imad, J MacRobert Alexander
Journal: Biomaterials (2016)
血管新生のための蛋白質デリバリーのためのプロテアーゼ分解性ミクロゲル【Powered by NICT】
Authors: A Foster Greg, M Headen Devon, Gonzalez-Garcia Cristina, Salmeron-Sanchez Manuel, Shirwan Haval, J Garcia Andres
Journal: Biomaterials (2017)
A phase II/III, multicenter, open-label, 3-arm study of gilteritinib, gilteritinib plus azacitidine, or azacitidine alone in the treatment of newly diagnosed FLT3 mutation-positive acute myeloid leukemia (AML) patients ineligible for intensive induction chemotherapy.
Authors: Jorge E. Cortes, Jessica Altman, Ellen K. Ritchie, Richard A. Larson, David Claxton, Mark D. Minden, Alec Goldenberg, Tomoki Naoe, Sung-Soo Yoon, Philippe H. Rousselot, Carsten Mueller-Tidow, Teresa Bernal del Castillo, Violaine Havelange, Fabio Ciceri, Wanda Knopinska-Posluszny, Shufang Liu, Archita Shrivastava, Angela Joubert James, Elizabeth Shima Rich, Erkut Bahceci
Journal: Journal of Clinical Oncology (2017)

TPS7068 Background: Gilteritinib, a highly selective, potent FLT3/AXL inhibitor, showed antileukemic activity with favorable tolerability in a Phase 1/2 trial of FLT3 mutation-positive (FLT3 mut+ ) relapsed/refractory AML. In FLT3 mut+ AML cell lines, gilteritinib plus azacitidine (AZA) inhibited growth, and induced apoptosis and differentiation. This ongoing Phase 2/3 trial will examine the efficacy, safety, and tolerability of gilteritinib alone, gilteritinib plus AZA or AZA alone in newly diagnosed FLT3 mut+ AML patients ineligible for intensive induction chemotherapy. Methods: This open-label, 3-arm, 2-stage randomized trial (NCT02752035) will enroll ~540 newly diagnosed adults with FLT3 mut+ (FLT3-ITD or -TKD) AML; those with APL, BCR-ABL + , or active CNS leukemia will be excluded. Before initiation, the safety and tolerability of gilteritinib plus AZA will be assessed in a Safety Cohort to establish the appropriate gilteritinib dose for combination therapy. Subjects will then be randomized 1:1:1 to receive oral gilteritinib alone (120 mg daily; Days 1–28), AZA alone (75 mg/m 2 by subcutaneous injection or intravenous infusion on Days 1–7), or AZA (75 mg/m 2 ; Days 1–7) plus oral gilteritinib (daily on Days 1–28 at the dose determined from the Safety Cohort), and stratified by age ( &lt; 75 vs ≥75 years). Subjects will continue treatment until a discontinuation event occurs. The primary endpoint is overall survival of subjects receiving gilteritinib or gilteritinib plus AZA versus AZA alone; the key secondary endpoint is event-free survival. Additional secondary endpoints: complete remission rate, leukemia-free survival, remission duration, composite remission rate, tolerability, and fatigue. Dose changes and interruptions are allowed in all treatment arms. A formal interim futility analysis by an Independent Data Monitoring Committee is planned when ~50 subjects in each treatment arm have either discontinued therapy or completed 2 treatment cycles. Enrollment began on November 21, 2016; as of January 31, 2017, the Safety Cohort is ongoing. Clinical trial information: NCT02752035.
Clinical Outcomes of Phase I/II Clinical Trials for Patients with Relapsed/Refractory Haematological Malignancies: Experience of an Early Phase Clinical Trials Unit
Authors: Chin-Hin Ng, Dima El-Sharkawi, Elspeth M Payne, Kwee L Yong, Kirit M Ardeshna, Asim Khwaja, Rakesh Popat
Journal: Blood (2016)
Incidence and Outcomes of Repositioning Surgery to Correct Misalignment of Toric Intraocular Lenses
Authors: Tetsuro Oshika, Mikio Inamura, Yasushi Inoue, Tsutomu Ohashi, Toru Sugita, Yoshifumi Fujita, Kazunori Miyata, Shinichiro Nakano
Journal: Ophthalmology (2017)
Development and analytical performance of a molecular diagnostic for anti-PD1 response on the nCounter Dx Analysis System.
Authors: Brett Wallden, Irena Pekker, Simina Popa, Naeem Dowidar, Amy Sullivan, Tressa Hood, Patrick Danaher, Afshin Mashadi-Hossein, Jared K. Lunceford, Matthew John Marton, Ken C. N. Chang, Sean Ferree, James Justin Storhoff
Journal: Journal of Clinical Oncology (2016)

3034 Background: Pembrolizumab is a humanized anti-PD1 antibody that is FDA approved for use in patients with advanced melanoma and in selected patients with metastatic non-small-cell lung cancer. It has also shown clinical activity in a number of other tumor types in clinical trials, but there is need for a precise and accurate test that can identify patients most likely to benefit from therapy. Several immune-related gene expression (Gx) signatures in formalin fixed, paraffin embedded (FFPE) tissue were previously reported to enrich for responders to pembrolizumab across different tumor types. We have developed a clinical trial assay, referred to here as the anti-PD1 Gx test, based on genes repeatedly found to be associated with improved response to pembrolizumab in a number of cancers. Here we describe the development and analytical performance of the anti-PD1 Gx test in multiple tumor types. Methods: The anti-PD1 Predictor Score (PS) algorithm was trained using RNA from FFPE specimens from all cancer types in the KEYNOTE-012 trial and several cancer types in the KEYNOTE-028 trial (anal canal, biliary tract, colorectal, esophageal, and ovarian) to determine the final genes and weightings. Analytical precision from RNA, reproducibility from multiple tissue blocks, impact of intra-tumor heterogeneity, and sensitivity to RNA input amount were measured across operators using samples from multiple tumor types. The robustness of the assay was evaluated with the inclusion of adjacent non-tumor tissue. Results: The total standard deviation in anti-PD1 PS was < 5% of the score range with random error being the major source of variance. The assay was robust across the specified RNA input range and against the inclusion of non-tumor tissue. The major source of variability in Gx across multiple tumor types was associated with the tumors’ immune Gx signature rather than intra-tumor variability or even tumor type. Conclusions: The NanoString anti-PD1 Gx test is a robust assay, which profiles immune related Gx across multiple cancer types. The assay is well suited to clinical applications and its ability to identify responders to anti-PD1 therapy is being investigated in multiple indications in several studies.
Response to Comment on Gagnum et al. Long-term Mortality and End-Stage Renal Disease in a Type 1 Diabetes Population Diagnosed at Age 15–29 Years in Norway. Diabetes Care 2017;40:38–45
Authors: Vibeke Gagnum, Lars C. Stene, Torbjørn Leivestad, Geir Joner, Torild Skrivarhaug
Journal: Diabetes Care (2017)

We thank Sun et al. (1) for their comments on our article on mortality, causes of death, and end-stage renal disease in patients with type 1 diabetes (T1D) (2). We reported that deaths related to alcohol, suicide, and violence (intoxications or accidents) occurred at higher rates in people with T1D compared with the general population in Norway. Sun et al. (1) highlight the importance of paying attention to psychological issues in diabetes care. They …
緑内障治療に対するブリモニジン負荷ポリ(乳酸)マイクロスフェアの毛様体上デリバリーによる眼内圧の持続した低下
Authors: B Chiang, Y C Kim, A C Doty, H E Grossniklaus, S P Schwendeman, M R Prausnitz
Journal: Journal of Controlled Release (2016)
低接着線維性微小環境における細胞形態,速度と方向性の包括的調節因子としての収縮性【Powered by NICT】
Authors: L Schuster Simon, J Segerer Felix, A Gegenfurtner Florian, Kick Kerstin, Schreiber Christoph, Albert Max, M Vollmar Angelika, O Raedler Joachim, Zahler Stefan
Journal: Biomaterials (2016)
Terminal weaning or immediate extubation for withdrawing mechanical ventilation in critically ill patients (the ARREVE observational study)
Authors: René Robert, Amélie Le Gouge, Nancy Kentish-Barnes, Alice Cottereau, Bruno Giraudeau, Mélanie Adda, Djillali Annane, Juliette Audibert, François Barbier, Patrick Bardou, Simon Bourcier, Jeremy Bourenne, Alexandre Boyer, François Brenas, Vincent Das, Arnaud Desachy, Jérôme Devaquet, Marc Feissel, Frédérique Ganster, Maïté Garrouste-Orgeas, Guillaume Grillet, Olivier Guisset, Rebecca Hamidfar-Roy, Anne-Claire Hyacinthe, Sebastien Jochmans, Mercé Jourdain, Alexandre Lautrette, Nicolas Lerolle, Olivier Lesieur, Fabien Lion, Philippe Mateu, Bruno Megarbane, Sybille Merceron, Emmanuelle Mercier, Jonathan Messika, Paul Morin-Longuet, Bénédicte Philippon-Jouve, Jean-Pierre Quenot, Anne Renault, Xavier Repesse, Jean-Philippe Rigaud, Ségolène Robin, Antoine Roquilly, Amélie Seguin, Didier Thevenin, Patrice Tirot, Isabelle Vinatier, Elie Azoulay, Jean Reignier
Journal: Intensive Care Medicine (2017)
Clinical Summaries
Journal: Circulation (2010)

Fractures of pace-sense electrodes in implantable cardioverterdefibrillator patients are a common cause of inappropriate shocks.To reduce inappropriate shocks, we developed a lead-integrity alert (LIA) triggered by either oversensing or high impedance that can be downloaded into previously implanted implantable cardioverterdefibrillators.This prospective study tested the hypothesis that the LIA would reduce the percentage of patients who receive inappropriate shocks compared with a concurrent control group monitored by impedance only.Each group included a prospectively determined sample size of 213 consecutive patients with fractures confirmed by structural analysis of explanted leads.The LIA group had a 46% relative reduction (95% confidence interval 34% to 55%) in the percentage of patients with Ն1 inappropriate shock (LIA 38% versus control 70%, PϽ0.001) and a 50% relative reduction (95% confidence interval 33% to 61%) in the percentage with Ն5 shocks (25% versus 50%, PϽ0.001).These data show that a software download that upgrades previously implanted implantable cardioverterdefibrillators without surgical revision reduces inappropriate shocks caused by lead fractures.See p 1449.
OP0312 A proteomic signature of fatigue in primary sjÖgren's syndrome
Authors: R Omdal, E Larssen, C Brede, A Hjelle, AB Tjensvoll, KB Norheim, K Bårdsen, K Jonsdottir, P Ruoff, MM Nilsen
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Fatigue is a frequent and often disabling phenomenon in patients with chronic inflammatory and immunological diseases, neurodegenerative diseases, and cancer. The underlying biological mechanisms of fatigue are largely unknown and hypotheses are conflicting. It is important to uncover the pathophysiology and identify signalling pathways that generate and regulate this substantial phenomenon. <h3>Objectives</h3> Based on the hypothesis that fatigue originates from cerebral processes, we investigated whether relevant proteins and/or signaling pathways for fatigue could be revealed in the cerebrospinal fluid (CSF) of patients with primary Sjögren9s syndrome. <h3>Methods</h3> Label-free shotgun mass spectrometry was performed to analyze the CSF proteome of 20 patients with primary Sjögren9s syndrome. Fatigue was measured with the fatigue Visual Analogue Scale (fVAS). <h3>Results</h3> After depletion of high-abundance proteins, more than 800 proteins were identified and quantitated. Multivariate analyses showed that patients with low and high fatigue could be separated based on their CSF protein profiles, and 15 proteins were selected as top discriminatory proteins. Among these were apolipoprotein A4, hemopexin, pigment epithelium derived factor, secretogranin-1, secretogranin-3, selenium-binding protein 1, and complement factor B. The figure shows the top network from Ingenuity Pathway Analysis (IPA) with 14 of the differentially expressed proteins (red = upregulated, green = downregulated) and proteins that are directly associated to them (white molecules). <h3>Conclusions</h3> Most of the discriminatory proteins have important roles in regulation of innate immunity, cellular stress defense, and/or functions in the central nervous system. Some have been associated with severe depression and loss of appetite, which are important features of chronic fatigue. These proteins and their interacting protein networks may therefore have central roles in the generation and regulation of fatigue, and the findings add new, relevant, and important evidence to the concept of fatigue as a biological phenomenon signaled through specific molecular pathways. <h3>References</h3> Norheim KB, Jonsson G, Omdal R. Biological mechanisms of chronic fatigue. Rheumatology (Oxford). 2011;50:1009–18. Dantzer R, O9Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nature reviews Neuroscience. 2008;9:46–56. Schutzer SE, Angel TE, Liu T, Schepmoes AA, Clauss TR, Adkins JN, et al. Distinct cerebrospinal fluid proteomes differentiate post-treatment lyme disease from chronic fatigue syndrome. PloS one. 2011;6:e17287. <h3>Disclosure of Interest</h3> None declared
Abstract P108: Direct Evidence of Postnatal Cardiomyocyte Generation in Murine Models of Aging and Cardiac Injury
Authors: Shah R Ali, Reza Ardehali, Simon Hippenmeyer, Liqun Luo, Irving Weissman
Journal: Circulation Research (2011)

The dogma of the adult mammalian heart as a post-mitotic organ has recently come under question. Radiolabeled isotope studies have demonstrated that the human heart exhibits a low rate of renewal of cardiomyocytes throughout one’s lifespan. Furthermore, a recent study has elegantly shown that a neonatal mouse can regenerate its ventricle if the chamber is resected within the first week of birth. However, a number of questions remain unanswered about the nature of the cell type that gives rise to cardiomyocytes postnatally. The field has yet to clonally address whether cardiomyocytes divide symmetrically upon birth, or if a resident progenitor differentiates into cardiomyocytes. Rather than rely on proxies for cell division (e.g. BrdU incorporation studies), we use genetic mouse models in which cell division results in asymmetric, indelible labeling of the daughter cells (“Mosaic analysis of double markers” (MADM)) and a stochastic multi-color Cre reporter in the Rosa26 locus akin to the “Brainbow” mouse to investigate postnatal cell division clonally in order to identify which cell type(s) generate cardiomyocytes. Our studies have demonstrated limited symmetric division of cardiomyocytes during normal aging up to six weeks, with a significantly high rate of cardiomyocyte division during the first postnatal week. While we provide evidence for limited cell division in the peri-infarct region of a myocardial infarction model in the 24 hours after the infarct, the extent of cell division and proliferation over a longer time frame after the infarct remains to be explored.
Pyrrolo[2,3‐<i>d</i>]pyrimidine (7‐deazapurine) as a privileged scaffold in design of antitumor and antiviral nucleosides
Authors: Pavla Perlíková, Michal Hocek
Journal: Medicinal Research Reviews (2017)

Abstract 7‐Deazapurine (pyrrolo[2,3‐ d ]pyrimidine) nucleosides are important analogues of biogenic purine nucleosides with diverse biological activities. Replacement of the N7 atom with a carbon atom makes the five‐membered ring more electron rich and brings a possibility of attaching additional substituents at the C7 position. This often leads to derivatives with increased base‐pairing in DNA or RNA or better binding to enzymes. Several types of 7‐deazapurine nucleosides with potent cytostatic or cytotoxic effects have been identified. The most promising are 7‐hetaryl‐7‐deazaadenosines, which are activated in cancer cells by phosphorylation and get incorporated both to RNA (causing inhibition of proteosynthesis) and to DNA (causing DNA damage). Mechanism of action of other types of cytostatic nucleosides, 6‐hetaryl‐7‐deazapurine and thieno‐fused deazapurine ribonucleosides, is not yet known. Many 7‐deazaadenosine derivatives are potent inhibitors of adenosine kinases. Many types of sugar‐modified derivatives of 7‐deazapurine nucleosides are also strong antivirals. Most important are 2′‐ C ‐methylribo‐ or 2′‐ C ‐methyl‐2′‐fluororibonucleosides with anti‐HCV activities (several compounds underwent clinical trials). Some underexplored areas of potential interest are also outlined.
Longitudinal assessment of late-onset neurologic conditions in survivors of childhood central nervous system tumors: a Childhood Cancer Survivor Study report
Authors: Elizabeth M Wells, Nicole J Ullrich, Kristy Seidel, Wendy Leisenring, Charles A Sklar, Gregory T Armstrong, Lisa Diller, Allison King, Kevin R Krull, Joseph P Neglia, Marilyn Stovall, Kimberly Whelan, Kevin C Oeffinger, Leslie L Robison, Roger J Packer
Journal: Neuro-Oncology (2017)

Survivors of childhood central nervous system (CNS) tumors experience high rates of treatment-related neurologic sequelae. Whether survivors continue to be at increased risk for new events as they age is unknown. Adverse neurologic health conditions in 5-year survivors of CNS tumors from the Childhood Cancer Survivor Study (n = 1876) were evaluated longitudinally at a median 23.0 years from diagnosis (range, 5.1–38.9), median age at last evaluation 30.3 years (range, 6.1–56.4). Multivariable regression estimated hazard ratios (HRs) and 95% CIs. From 5 to 30 years post diagnosis, cumulative incidence increased for seizures from 27% to 41%, motor impairment 21% to 35%, and hearing loss 9% to 23%. Risks were elevated compared with siblings (eg, seizures HR: 12.7; 95% CI: 9.6–16.7; motor impairment HR: 7.6; 95% CI: 5.8–9.9; hearing loss HR: 18.4; 95% CI: 13.1–25.9). Regional brain doses of radiation therapy were associated with development of new deficits (eg, frontal ≥50 Gy and motor impairment HR: 2.0; 95% CI: 1.2–3.4). Increased risk for motor impairment was also associated with tumor recurrence (HR: 2.6; 95% CI: 1.8–3.8), development of a meningioma (HR: 2.3; 95% CI: 0.9–5.4), and stroke (HR: 14.9; 95% CI: 10.4–21.4). Seizure risk was doubled by recurrence (HR: 2.3; 95% CI: 1.6–3.2), meningioma (HR: 2.6; 95% CI: 1.1–6.5), and stroke (HR: 2.0; 95% CI: 1.1–3.4). CNS tumor survivors remain at risk for new-onset adverse neurologic events across their lifespans at a rate greater than siblings. Cranial radiation, stroke, tumor recurrence, and development of meningioma were independently associated with late-onset adverse neurologic sequelae.