tbuckley/cabot-search huggingface dataset:
Abstract 11742: Moderate to Severe Acute Kidney Injury Provides the Additional Long-Term Prognostic Information to ADHERE Risk Level in Patients Admitted With Acute Decompensated Heart Failure
Authors: Takahisa Yamada, Takashi Morita, Yoshio Furukawa, Shunsuke Tamaki, Yusuke Iwasaki, Masato Kawasaki, Atsushi Kikuchi, Takumi Kondo, Masashi Ishimi, Hideyuki Hakui, Tatsuhisa Ozaki, Yoshihiro Satoh, Masahiro Seo, Masatake Fukunami
Journal: Circulation (2015)

Backgrounds: The Acute Decompensated Heart Failure National Registry (AHDERE) risk levels are a validated tool to assess the risk of in-hospital mortality in patients (pts) with acute decompensated heart failure (ADHF). Acute kidney injury (AKI) during heart failure treatment is also associated with poor outcome in ADHF pts. However, there is no information available on the long-term prognostic significance of AKI, relating to ADHERE risk levels in ADHF pts. Methods and Results: We studied 305 consecutive ADHF pts discharged with survival. ADHERE risk levels were assigned, as previously described, baseline BUN(≥43 vs &lt;43 mg/dl), systolic BP (&lt;115 vs ≥115 mmHg), and creatinine(Cr≥2.75 vs &lt;2.75 mg/dl). AKI during ADHF treatment was defined according to AKI Network criteria (stage 1, ≥0.3mg/dl absolute or 1.5- to 2.0-fold relative increase in Cr; stage 2, &gt;2- to 3-fold increase in Cr; stage 3, &gt;3-fold increase in Cr or Cr≥4.0mg/dl with an acute rise of ≥0.5mg/dl). During a follow-up period of 4.1±3.2 yrs, 81 pts had cardiovascular-renal poor outcome, defined as cardiovascular death and the development of end-stage renal disease requiring renal replacement therapy. At multivariate Cox analysis, ADHERE risk levels (p&lt;0.0001) and AKI (p&lt;0.0001) were significantly associated with cardiovascular-renal poor outcome, independently of age, serum sodium and hemoglobin levels. Irrespective of high/intermediate or low ADHERE risk levels, pts with stage 2 or 3 AKI (adjusted HR: 5.9[1.8-19.2] in high/intermediate riskgroup, 4.9[2.1-11.3] in low risk group) had a significant increased risk of cardiovascular-renal poor outcome, compared to pts with no AKI. On the other hand, there were no significant differences in the risk between pts with stage 1 AKI and no AKI in both groups. Conclusion: Moderate to severe AKI during heart failure treatment would provide the additional long-term prognostic information to ADHERE risk levels in ADHF pts.
Intrusive memories of trauma: A target for research bridging cognitive science and its clinical application
Authors: Lalitha Iyadurai, Renée M. Visser, Alex Lau-Zhu, Kate Porcheret, Antje Horsch, Emily A. Holmes, Ella L. James
Journal: Clinical Psychology Review (2018)

Intrusive memories of a traumatic event can be distressing and disruptive, and comprise a core clinical feature of post-traumatic stress disorder (PTSD). Intrusive memories involve mental imagery-based impressions that intrude into mind involuntarily, and are emotional. Here we consider how recent advances in cognitive science have fueled our understanding of the development and possible treatment of intrusive memories of trauma. We conducted a systematic literature search in PubMed, selecting articles published from 2008 to 2018 that used the terms "trauma" AND ("intrusive memories" OR "involuntary memories") in their abstract or title. First, we discuss studies that investigated internal (neural, hormonal, psychophysiological, and cognitive) processes that contribute to intrusive memory development. Second, we discuss studies that targeted these processes using behavioural/pharmacological interventions to reduce intrusive memories. Third, we consider possible clinical implications of this work and highlight some emerging research avenues for treatment and prevention, supplemented by new data to examine some unanswered questions. In conclusion, we raise the possibility that intrusive memories comprise an alternative, possibly more focused, target in translational research endeavours, rather than only targeting overall symptoms of disorders such as PTSD. If so, relatively simple approaches could help to address the need for easy-to-deliver, widely-scalable trauma interventions.
Prognostic factors of disease severity in infants with sickle cell anemia: A comprehensive longitudinal cohort study
Authors: Valentine Brousse, Sara El Hoss, Naïm Bouazza, Cécile Arnaud, Francoise Bernaudin, Béatrice Pellegrino, Corinne Guitton, Marie‐Hélène Odièvre‐Montanié, David Mames, Chantal Brouzes, Véronique Picard, Thao Nguyen‐Khoa, Catia Pereira, Claudine Lapouméroulie, Serge Pissard, Kate Gardner, Stephan Menzel, Caroline Le Van Kim, Yves Colin‐Aronovicz, Pierre Buffet, Narla Mohandas, Caroline Elie, Micheline Maier‐Redelsperger, Wassim El Nemer, Mariane de Montalembert
Journal: American Journal of Hematology (2018)

Abstract In order to identify very early prognostic factors that can provide insights into subsequent clinical complications, we performed a comprehensive longitudinal multi‐center cohort study on 57 infants with sickle cell anemia (55 SS; 2 Sβ°) during the first 2 years of life ( ClinicalTrials.gov : NCT01207037). Time to first occurrence of a severe clinical event—acute splenic sequestration (ASS), vaso‐occlusive (VOC) event requiring hospitalization, transfusion requirement, conditional/ abnormal cerebral velocities, or death—was used as a composite endpoint. Infants were recruited at a mean age of 4.4 ±1 months. Median follow‐up was 19.4 months. During the study period, 38.6% of infants experienced ≥1 severe event: 14% ASS, 22.8% ≥ 1 VOC (median age: 13.4 and 12.8 months, respectively) and 33.3% required transfusion. Of note, 77% of the cohort was hospitalized, with febrile illness being the leading cause for admission. Univariate analysis of various biomarkers measured at enrollment showed that fetal hemoglobin (HbF) was the strongest prognostic factor of subsequent severe outcome. Other biomarkers measured at enrolment including absolute neutrophil or reticulocyte counts, expression of erythroid adhesion markers, % of dense red cells, cellular deformability or ϒ‐globin genetic variants, failed to be associated with severe clinical outcome. Multivariate analysis demonstrated that higher Hb concentration and HbF level are two independent protective factors (adjusted HRs (95% CI) 0.27 (0.11‐0.73) and 0.16 (0.06‐0.43), respectively). These findings imply that early measurement of HbF and Hb levels can identify infants at high risk for subsequent severe complications, who might maximally benefit from early disease modifying treatments.
First-in-Human Phase I Trial of a Tumor-Targeted Cytokine (NHS-IL12) in Subjects with Metastatic Solid Tumors
Authors: Julius Strauss, Christopher R. Heery, Joseph W. Kim, Caroline Jochems, Renee N. Donahue, Agnes S. Montgomery, Sheri McMahon, Elizabeth Lamping, Jennifer L. Marté, Ravi A. Madan, Marijo Bilusic, Matthew R. Silver, Elisa Bertotti, Jeffrey Schlom, James L. Gulley
Journal: Clinical Cancer Research (2018)

The NHS-IL12 immunocytokine is composed of two IL12 heterodimers fused to the NHS76 antibody. Preclinical studies have shown that this antibody targets IL12 to regions of tumor necrosis by binding histones on free DNA fragments in these areas, resulting in enhanced antitumor activity. The objectives of this phase I study were to determine the maximum tolerated dose (MTD) and pharmacokinetics of NHS-IL12 in subjects with advanced solid tumors.Subjects (n = 59) were treated subcutaneously with NHS-IL12 in a single ascending-dose cohort followed by a multiple ascending-dose cohort (n = 37 with every 4-week dosing).The most frequently observed treatment-related adverse events (TRAE) included decreased circulating lymphocytes, increased liver transaminases, and flu-like symptoms. Of the grade ≥3 TRAEs, all were transient and only one was symptomatic (hyperhidrosis). The MTD is 16.8 μg/kg. A time-dependent rise in IFNγ and an associated rise in IL10 were observed following NHS-IL12. Of peripheral immune cell subsets evaluated, most noticeable were increases in frequencies of activated and mature natural killer (NK) cells and NKT cells. Based on T-cell receptor sequencing analysis, increases in T-cell receptor diversity and tumor-infiltrating lymphocyte density were observed after treatment where both biopsies and peripheral blood mononuclear cells were available. Although no objective tumor responses were observed, 5 subjects had durable stable disease (range, 6-30+ months).NHS-IL12 was well tolerated up to a dose of 16.8 μg/kg, which is the recommended phase II dose. Early clinical immune-related activity warrants further studies, including combination with immune checkpoint inhibitors.See related commentary by Lyerly et al., p. 9.
TLR3 agonist and CD40-targeting vaccination induces immune responses and reduces HIV-1 reservoirs
Authors: Liang Cheng, Qi Wang, Guangming Li, Riddhima Banga, Jianping Ma, Haisheng Yu, Fumihiko Yasui, Zheng Zhang, Giuseppe Pantaleo, Matthieu Perreau, Sandra Zurawski, Gerard Zurawski, Yves Levy, Lishan Su
Journal: Journal of Clinical Investigation (2018)

Activation of HIV-1 reservoirs and induction of anti–HIV-1 T cells are critical to control HIV-1 rebound after combined antiretroviral therapy (cART). Here we evaluated in humanized mice (hu-mice) with persistent HIV-1 infection the therapeutic effect of TLR3 agonist and a CD40-targeting HIV-1 vaccine, which consists of a string of 5 highly conserved CD4+ and CD8+ T cell epitope-rich regions of HIV-1 Gag, Nef, and Pol fused to the C-terminus of a recombinant anti-human CD40 antibody (αCD40.HIV5pep). We show that αCD40.HIV5pep vaccination coadministered with poly(I:C) adjuvant induced HIV-1–specific human CD8+ and CD4+ T cell responses in hu-mice. Interestingly, poly(I:C) treatment also reactivated HIV-1 reservoirs. When administrated in therapeutic settings in HIV-1–infected hu-mice under effective cART, αCD40.HIV5pep with poly(I:C) vaccination induced HIV-1–specific CD8+ T cells and reduced the level of cell-associated HIV-1 DNA (or HIV-1 reservoirs) in lymphoid tissues. Most strikingly, the vaccination significantly delayed HIV-1 rebound after cART cessation. In summary, the αCD40.HIV5pep with poly(I:C) vaccination approach both activates replication of HIV-1 reservoirs and enhances the anti–HIV-1 T cell response, leading to a reduced level of cell-associated HIV-1 DNA or reservoirs. Our proof-of-concept study has significant implication for the development of CD40-targeting HIV-1 vaccine to enhance anti–HIV-1 immunity and reduce HIV-1 reservoirs in patients with suppressive cART.
Abstract 14420: MicroRNA-214 Regulates Stem Cell Differentiation Into Smooth Muscle Cells by Targeting Quaking
Authors: Ting Chen, Hui Yan, Yutao Wu, Jianhua Zhu, Qingbo Xu, Li Zhang
Journal: Circulation (2013)

Background: Smooth muscle cell (SMC) differentiation is a critical process during vascular development and SMC proliferative related vascular disease. Several microRNAs have been reported to be involved in SMC differentiation. Recently, the microRNA-214 (miR-214) was shown to regulate cell cycle progression and apoptosis. However, very little is known about the functional role of miR-214 in SMC differentiation. The present study investigated the role of miR-214 during SMC differentiation from stem cells and verified its targets. Methods and results: Mouse embryonic stem cells (ES cells) were seeded on collagen IV-coated flasks and cultured in the absence of Leukemia Inhibitory Factor (LIF) in differentiation medium for 4 to 8 days in order to induce SMC differentiation. We found that miR-214 was significantly upregulated during SMC differentiation by using real-time RT-PCR analysis. Furthermore, enforced expression of miR-214 by its mimic in differentiating ES cells was found to induce expression of SMC-s...
Baseline patient factors impact on the clinical efficacy of benralizumab for severe asthma
Authors: Eugene R. Bleecker, Michael E. Wechsler, J. Mark FitzGerald, Andrew Menzies-Gow, Yanping Wu, Ian Hirsch, Mitchell Goldman, Paul Newbold, James G. Zangrilli
Journal: European Respiratory Journal (2018)

Benralizumab is an anti-eosinophilic monoclonal antibody that reduces exacerbations and improves lung function for patients with severe, uncontrolled asthma with eosinophilic inflammation. We evaluated the impact of baseline factors on benralizumab efficacy for patients with severe asthma. This analysis used pooled data from the SIROCCO ( ClinicalTrials.gov identifier NCT01928771 ) and CALIMA ( ClinicalTrials.gov identifier NCT01914757 ) Phase III studies. Patients aged 12–75 years with severe, uncontrolled asthma receiving high-dosage inhaled corticosteroids plus long-acting β 2 -agonists received benralizumab 30 mg subcutaneously every 8 weeks (Q8W, first three doses every 4 weeks (Q4W)), Q4W or placebo. Baseline factors that influenced benralizumab efficacy were evaluated, including oral corticosteroid (OCS) use, nasal polyposis, pre-bronchodilator forced vital capacity (FVC), prior year exacerbations and age at diagnosis. Efficacy outcomes included annual exacerbation rate and change in pre-bronchodilator forced expiratory volume in 1 s at treatment end relative to placebo. Benralizumab Q8W treatment effect was enhanced with each baseline factor for all patients and those with ≥300 eosinophils·μL −1 relative to the overall population. OCS use, nasal polyposis and FVC &lt;65% of predicted were associated with greater benralizumab Q8W responsiveness for reduced exacerbation rate for patients with &lt;300 eosinophils·μL −1 . Baseline clinical factors and blood eosinophil counts can help identify patients potentially responsive to benralizumab.
Tumor Antigen Escape from CAR T-cell Therapy
Authors: Robbie G. Majzner, Crystal L. Mackall
Journal: Cancer Discovery (2018)

Abstract Emerging data from chimeric antigen receptor (CAR) T-cell trials in B-cell malignancies demonstrate that a common mechanism of resistance to this novel class of therapeutics is the emergence of tumors with loss or downregulation of the target antigen. Antigen loss or antigen-low escape is likely to emerge as an even greater barrier to success in solid tumors, which manifest greater heterogeneity in target antigen expression. Potential approaches to overcome this challenge include engineering CAR T cells to achieve multispecificity and to respond to lower levels of target antigen and more efficient induction of natural antitumor immune responses as a result of CAR-induced inflammation. In this article, we review the evidence to date for antigen escape and downregulation and discuss approaches currently under study to overcome these obstacles. Significance: Antigen escape and downregulation have emerged as major issues impacting the durability of CAR T-cell therapy. Here, we explore their incidence and ways to overcome these obstacles in order to improve clinical outcomes. Cancer Discov; 8(10); 1219–26. ©2018 AACR.
Factors associated with health-related quality of life 6 years after ICU discharge in a Finnish paediatric population: a cohort study
Authors: Elina Kyösti, Tero I. Ala-Kokko, Pasi Ohtonen, Outi Peltoniemi, Paula Rautiainen, Janne Kataja, Hanna Ebeling, Janne H. Liisanantti
Journal: Intensive Care Medicine (2018)
Abstract 15775: The Impact of B-type Natriuretic Peptide Activation on the Association of Left Ventricular Longitudinal Strain With All-cause Mortality
Authors: Zi Ye, Maurice Enriquez-Sarano, Joseph Malouf, Hector I Michelena, Allan S Jaffe, Rakesh M Suri, Marie-Annick Clavel
Journal: Circulation (2015)

Introduction: Left ventricular longitudinal strain (LV-LS) 1) predicts mortality in patients with aortic stenosis (AS) and 2) is highly correlated to type-B natriuretic peptide (BNP) values. The BNP ratio (measured BNP/maximal expected BNP value specific for age and sex) is a powerful independent predictor of death in patients with AS. Hypothesis: we hypothesize that BNP activation (i.e. BNP ratio &gt;1) affects the association between LV-LS and mortality in patients with asymptomatic AS and preserved LV ejection fraction (EF ≥50%). Methods: 315 patients (age 74±12 years, 56% men and mean aortic valve area = 1.02±0.15cm2) underwent simultaneous Doppler echocardiographic and BNP measurements. LV-LS was calculated as the average of 12 LV segments from apical 2- and 4-chamber views using Velocity Vector Imaging. Results: Mean LV-LS was -16.8±3.2%, LV EF 66±7%, median BNP level 121 (interquartile 48-320) pg/ml. 58% of patients had BNP activation. Better LV-LS was associated with lower log BNPratio (regression coefficient 0.10, p&lt;0.001). After a median follow-up of 6.5 yrs (interquartile: 3.6-8.2), 119 deaths occurred. After adjustment for age, sex, Charlson score index, hemoglobin level, aortic valve replacement (as a time dependent variable), LV-LS and log BNPratio were separately associated with increased risk for death (all p&lt;0.01). Further adjustment for predictors of mortality, LV-LS and log-BNP ratio remained associated with increased risk for death (hazard ratio HR [95%CI]: 1.09 [1.03-1.15]; p=0.003 and 1.82 [1.52-2.19]; p&lt;0.0001 respectively). In patients without BNP activation (i.e. normal BNP), LV-LS was associated with mortality (HR: 1.22 [1.04-1.43]; p=0.01) while it was not in patients with BNP activation (p=0.22). Conclusions: In patients with asymptomatic AS, without clinically obvious myocardial impairment (i.e. normal LVEF), a notable proportion of patients present with myocardial alterations detected by an elevated BNPratio or reduced LV-LS. These signs of myocardial alterations were predictive of mortality after diagnosis. Thus both BNP and LV-LS should be assessed in the clinical setting to provide complementary information on prognosis in patients with asymptomatic AS and preserved LV EF.
Abstract 14587: Different Sequence of Fractionated Proton and Single Low Dose Iron Radiation Induce Divergent Biological Responses in the Heart
Authors: Sharath P Sasi, Xinhua Yan, Juyong Lee, Kenneth Walsh, Raj Kishore, David A Goukassian
Journal: Circulation (2016)

Astronauts will be exposed to ionizing radiation (IR) composed of a spectrum of low-fluence protons (1H) and high charge and energy (HZE) nuclei iron (e.g., 56Fe). During GCR each cell in the body will be traversed by 1H every 3-4 days and HZE nuclei every few months. The effects of sequential/fractionated low doses of 1H or HZE on cardiovascular system are unknown. Male C57BL/6NT mice of 8-9 month old were evaluated over 3 months: Group 1- control; Group 2 - 1H 17 cGy every 2 days/3 doses; Group 3 - 1H 17 cGy every 2 days/3 doses followed by a single dose of 56Fe 15 cGy 2 days after the last dose of 1H; Group 4 - a single dose of 56Fe 15 cGy/followed by fractionated 1H 17 cGy every 2 days/3 doses 2 days after a single 56Fe-IR; at 1 GeV energy for both ions. Cardiac function, cardiac fibrosis and cardiac remodeling were assessed by echocardiography, hemodynamic measurements, H&E and Trichrome staining. In IR + Aging group, over 3 months, 1H+1H+1H-IR alone or 1H+1H+1H/56Fe-IR did not induce negative effect...
<i>RAB37</i> Hypermethylation Regulates Metastasis and Resistance to Docetaxel-Based Induction Chemotherapy in Nasopharyngeal Carcinoma
Authors: Yingqin Li, Xiaojing Yang, Xiaojing Du, Yuan Lei, Qingmei He, Xiaohong Hong, Xinran Tang, Xin Wen, Panpan Zhang, Ying Sun, Jian Zhang, Yaqin Wang, Jun Ma, Na Liu
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Epigenetic alterations play important roles in metastasis and drug resistance through gene regulation. However, the functional features and molecular mechanisms of epigenetic changes remain largely unclear in nasopharyngeal carcinoma (NPC) metastasis. Experimental Design: Gene regulatory network analysis was used to identify metastatic-specific dysregulated genes between normal and NPC tissues and the expression was validated in published Gene-Expression Omnibus data set. The regulatory and functional role of RAB37 downregulation was examined in NPC and was validated in vitro and in vivo, and downstream target of RAB37 was explored. The clinical value of RAB37 methylation was evaluated in NPC metastasis and chemosensitivity. Results: We identified RAB37 as a specific hypermethylated gene that is most commonly downregulated in NPC. Moreover, RAB37 downregulation was attributed to hypermethylation of its promoter and was significantly associated with metastasis- and docetaxel chemoresistance-related features in NPC. Ectopic RAB37 overexpression suppressed NPC cell metastasis and enhanced chemosensitivity to docetaxel. Mechanistically, RAB37 colocalized with TIMP2, regulated TIMP2 secretion, inhibited downstream MMP2 activity, and consequently altered NPC cell metastasis. Furthermore, RAB37 hypermethylation was correlated with poor clinical outcomes in patients with NPC. We developed a prognostic model based on RAB37 methylation and N stage that effectively predicted an increased risk of distant metastasis and a favorable response to docetaxel-containing induction chemotherapy (IC) in NPC patients. Conclusions: This study shows that RAB37 hypermethylation is involved in NPC metastasis and chemoresistance, and that our prognostic model can identify patients who are at a high risk of distant metastasis and might benefit from for docetaxel IC.
Oral vancomycin induces clinical and mucosal remission of colitis in children with primary sclerosing cholangitis–ulcerative colitis
Authors: Li-Zsa Tan, Claire R Reilly, Lana C Steward-Harrison, Fariha Balouch, Richard Muir, Peter J Lewindon
Journal: Gut (2018)

The report by Kummen et al 1 describing differences in gut microbial profile in patients with primary sclerosing cholangitis (PSC) and primary sclerosing cholangitis–ulcerative colitis (PSC–UC) compared with healthy controls and patients with UC without liver disease supports the tantalising prospect of microbiome manipulation as therapy for these conditions. The role of antibiotics in this setting, particularly in UC, is of great current interest2; The use of oral vancomycin (OV) for treatment of PSC was first reported by Cox and Cox3 in 1998, the focus then was treatment of liver disease, although it remains unclear if OV affects liver outcomes in PSC. We did, however, become interested in the description of improved clinical and endoscopic colitis in children with UC associated with PSC.Although typically mild, the colitis of PSC–UC or autoimmune sclerosing cholangitis–ulcerative colitis (ASC–UC) can be severe …
c-MET Overexpression as a Poor Predictor of MET Amplifications or Exon 14 Mutations in Lung Sarcomatoid Carcinomas
Authors: Xavier Mignard, Anne-Marie Ruppert, Martine Antoine, Julie Vasseur, Nicolas Girard, Julien Mazières, Denis Moro-Sibilot, Vincent Fallet, Nathalie Rabbe, Françoise Thivolet-Bejui, Isabelle Rouquette, Sylvie Lantuejoul, Alexis Cortot, Raphaël Saffroy, Jacques Cadranel, Antoinette Lemoine, Marie Wislez
Journal: Journal of Thoracic Oncology (2018)
Identification of gut microbiome signatures associated with longevity provides a promising modulation target for healthy aging
Authors: Fanli Kong, Feilong Deng, Ying Li, Jiangchao Zhao
Journal: Gut Microbes (2018)

The world population is aging, which poses a significant burden to the economy and health care system. As people age, so do their gut microbiomes. Age-related changes in gut microbiome have been reported, including decreased microbial diversity and increased Proteobacteria. Recently, we characterized the gut microbiome of a group of long-living (≥ 90 years old) Chinese people. Interestingly, the diversity of their gut microbiome was greater than that of a young adult control group. We also identified several potentially beneficial bacteria enriched in the long-living Chinese group. These results were validated using data from an independent Italian cohort that included a group of long-living individuals. Other recent studies have found similar results. Here, we provide a summary of these discoveries and discuss their implications in healthy aging.