tbuckley/cabot-search huggingface dataset:
HIV Superinfection Drives De Novo Antibody Responses and Not Neutralization Breadth
Authors: Daniel J. Sheward, Jinny Marais, Valerie Bekker, Ben Murrell, Kemal Eren, Jinal N. Bhiman, Molati Nonyane, Nigel Garrett, Zenda L. Woodman, Quarraisha Abdool Karim, Salim S. Abdool Karim, Lynn Morris, Penny L. Moore, Carolyn Williamson
Journal: Cell Host & Microbe (2018)

Eliciting antibodies that neutralize a broad range of circulating HIV strains (broadly neutralizing antibodies [bnAbs]) represents a key priority for vaccine development. HIV superinfection (re-infection with a second strain following an established infection) has been associated with neutralization breadth, and can provide insights into how the immune system responds to sequential exposure to distinct HIV envelope glycoproteins (Env). Characterizing the neutralizing antibody (nAb) responses in four superinfected women revealed that superinfection does not boost memory nAb responses primed by the first infection or promote nAb responses to epitopes conserved in both infecting viruses. While one superinfected individual developed potent bnAbs, superinfection was likely not the driver as the nAb response did not target an epitope conserved in both viruses. Rather, sequential exposure led to nAbs specific to each Env but did not promote bnAb development. Thus, sequential immunization with heterologous Envs may not be sufficient to focus the immune response onto conserved epitopes.
Abstract 17019: Mitochondrial Biogenesis in Myocardial Ischemia/Reperfusion Injury is Controlled by Parkin-dependent Elimination of PARIS, Which is Also Regulated by Sumoylation & SENP5
Authors: Chengqun Huang, Moutusee Islam, Allen M Andres, Aleksandr Stotland, Roberta Gottlieb
Journal: Circulation (2016)

Background: PARIS (Parkin Interacting Substrate) is a recently identified zinc finger protein acting as a transcriptional inhibitor for PGC-1α. Previous studies showed that Parkin ubiquitinates PAR...
Epidemiology of Bladder Cancer: A Systematic Review and Contemporary Update of Risk Factors in 2018
Authors: Marcus George Kwesi Cumberbatch, Ibrahim Jubber, Peter C. Black, Francesco Esperto, Jonine D. Figueroa, Ashish M. Kamat, Lambertus Kiemeney, Yair Lotan, Karl Pang, Debra T. Silverman, Ariana Znaor, James W.F. Catto
Journal: European Urology (2018)
Genetic Tools for Coronary Risk Assessment in Type 2 Diabetes: A Cohort Study From the ACCORD Clinical Trial
Authors: Mario Luca Morieri, He Gao, Marie Pigeyre, Hetal S. Shah, Jennifer Sjaarda, Christine Mendonca, Timothy Hastings, Patinut Buranasupkajorn, Alison A. Motsinger-Reif, Daniel M. Rotroff, Ronald J. Sigal, Santica M. Marcovina, Peter Kraft, John B. Buse, Michael J. Wagner, Hertzel C. Gerstein, Josyf C. Mychaleckyj, Guillaume Parè, Alessandro Doria
Journal: Diabetes Care (2018)

OBJECTIVE We evaluated whether the increasing number of genetic loci for coronary artery disease (CAD) identified in the general population could be used to predict the risk of major CAD events (MCE) among participants with type 2 diabetes at high cardiovascular risk. RESEARCH DESIGN AND METHODS A weighted genetic risk score (GRS) derived from 204 variants representative of all the 160 CAD loci identified in the general population as of December 2017 was calculated in 5,360 and 1,931 white participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Outcome Reduction With Initial Glargine Intervention (ORIGIN) studies, respectively. The association between GRS and MCE (combining fatal CAD events, nonfatal myocardial infarction, and unstable angina) was assessed by Cox proportional hazards regression. RESULTS The GRS was associated with MCE risk in both ACCORD and ORIGIN (hazard ratio [HR] per SD 1.27, 95% CI 1.18–1.37, P = 4 × 10−10, and HR per SD 1.35, 95% CI 1.16–1.58, P = 2 × 10−4, respectively). This association was independent from interventions tested in the trials and persisted, though attenuated, after adjustment for classic cardiovascular risk predictors. Adding the GRS to clinical predictors improved incident MCE risk classification (relative integrated discrimination improvement +8%, P = 7 × 10−4). The performance of this GRS was superior to that of GRS based on the smaller number of CAD loci available in previous years. CONCLUSIONS When combined into a GRS, CAD loci identified in the general population are associated with CAD also in type 2 diabetes. This GRS provides a significant improvement in the ability to correctly predict future MCE, which may increase further with the discovery of new CAD loci.
A randomized phase II clinical trial of dendritic cell vaccination following complete resection of colon cancer liver metastasis
Authors: Javier Rodriguez, Eduardo Castañón, Jose Luis Perez-Gracia, Inmaculada Rodriguez, Antonio Viudez, Carlos Alfaro, Carmen Oñate, Guiomar Perez, Fernando Rotellar, Susana Inogés, Ascensión López-Diaz de Cerio, Leyre Resano, Mariano Ponz-Sarvise, Maria E. Rodriguez-Ruiz, Ana Chopitea, Ruth Vera, Ignacio Melero
Journal: Journal for ImmunoTherapy of Cancer (2018)

Surgically resectable synchronic and metachronic liver metastases of colon cancer have high risk of relapse in spite of standard-of-care neoadjuvant and adjuvant chemotherapy regimens. Dendritic cell vaccines loaded with autologous tumor lysates were tested for their potential to avoid or delay disease relapses (NCT01348256). Patients with surgically amenable liver metastasis of colon adenocarcinoma (<i>n</i> = 19) were included and underwent neoadjuvant chemotherapy, surgery and adjuvant chemotherapy. Fifteen patients with disease-free resection margins were randomized 1:1 to receive two courses of four daily doses of dendritic cell intradermal vaccinations versus observation. The trial had been originally designed to include 56 patients but was curtailed due to budgetary restrictions. Follow-up of the patients indicates a clear tendency to fewer and later relapses in the vaccine arm (median disease free survival –DFS-) 25.26&nbsp;months, 95% CI 8.74-n.r) versus observation arm (median DFS 9.53&nbsp;months, 95% CI 5.32–18.88).
AMG 176, a Selective MCL1 Inhibitor, Is Effective in Hematologic Cancer Models Alone and in Combination with Established Therapies
Authors: Sean Caenepeel, Sean P. Brown, Brian Belmontes, Gordon Moody, Kathleen S. Keegan, Danny Chui, Douglas A. Whittington, Xin Huang, Leszek Poppe, Alan C. Cheng, Mario Cardozo, Jonathan Houze, Yunxiao Li, Brian Lucas, Nick A. Paras, Xianghong Wang, Joshua P. Taygerly, Marc Vimolratana, Manuel Zancanella, Liusheng Zhu, Elaina Cajulis, Tao Osgood, Jan Sun, Leah Damon, Regina K. Egan, Patricia Greninger, Joseph D. McClanaghan, Jianan Gong, Donia Moujalled, Giovanna Pomilio, Pedro Beltran, Cyril H. Benes, Andrew W. Roberts, David C. Huang, Andrew Wei, Jude Canon, Angela Coxon, Paul E. Hughes
Journal: Cancer Discovery (2018)

Abstract The prosurvival BCL2 family member MCL1 is frequently dysregulated in cancer. To overcome the significant challenges associated with inhibition of MCL1 protein–protein interactions, we rigorously applied small-molecule conformational restriction, which culminated in the discovery of AMG 176, the first selective MCL1 inhibitor to be studied in humans. We demonstrate that MCL1 inhibition induces a rapid and committed step toward apoptosis in subsets of hematologic cancer cell lines, tumor xenograft models, and primary patient samples. With the use of a human MCL1 knock-in mouse, we demonstrate that MCL1 inhibition at active doses of AMG 176 is tolerated and correlates with clear pharmacodynamic effects, demonstrated by reductions in B cells, monocytes, and neutrophils. Furthermore, the combination of AMG 176 and venetoclax is synergistic in acute myeloid leukemia (AML) tumor models and in primary patient samples at tolerated doses. These results highlight the therapeutic promise of AMG 176 and the potential for combinations with other BH3 mimetics. Significance: AMG 176 is a potent, selective, and orally bioavailable MCL1 inhibitor that induces a rapid commitment to apoptosis in models of hematologic malignancies. The synergistic combination of AMG 176 and venetoclax demonstrates robust activity in models of AML at tolerated doses, highlighting the promise of BH3-mimetic combinations in hematologic cancers. See related commentary by Leber et al., p. 1511. This article is highlighted in the In This Issue feature, p. 1494
Abstract 12471: CHA2DS2VASc Score Predicts Future Development of Atrial Fibrillation After Successful Catheter Ablation of Typical Atrial–Flutter
Authors: Adarsh Bhan, Paula Dunskis, Jeffrey S Neiger, Christopher Blair, Manoj Duggal
Journal: Circulation (2016)

Introduction: After successful catheter ablation (CA) for typical atrial flutter (AFL), long term development of atrial fibrillation (AF) is common. No definitive predictive models currently exist to identify patients who are likely to develop AF. The aim of this study was to evaluate whether CHA2DS2VASc score can predict future occurrence of AF after successful CA of AFL. Methods: We conducted a retrospective chart review of 171 consecutive patients with isolated AFL who underwent successful CA between years 2007-2014 at a teaching community hospital. Patients with at least 2 years of follow-up were included for analysis. 40 patients were lost to follow-up. CHA2DS2VASc scores were calculated at the time of CA. Follow up consisted of in-office electrocardiograms, and (when available) in-office and remote device interrogation. Patients were anticoagulated at the discretion of their treating physician. The endpoint was time to first occurrence of AF. Data was analyzed using appropriate descriptive and univa...
Financial toxicity among patients with lung cancer in a publicly funded health care system.
Authors: Doreen Anuli Ezeife, Joshua Morganstein, Sally C Lau, Lisa Le, David Cella, Penelope Ann Bradbury, Geoffrey Liu, Adrian G. Sacher, Frances A. Shepherd, Natasha B. Leighl
Journal: Journal of Clinical Oncology (2018)

192 Background: Financial distress has been established as a clinically relevant patient-reported outcome (PRO) associated with worse mortality and quality of life, but remains under-recognized by health care providers. Our goal was to define factors associated with financial toxicity (FT) in a public healthcare system. Methods: Patients with advanced lung cancer were recruited from outpatient clinics at the Princess Margaret Cancer Centre (Toronto, Canada). FT was measured with the validated Comprehensive Score for Financial Toxicity (COST) instrument, a 12-item survey scored from 0-44 with lower scores reflecting worse financial well-being. Data on patient and treatment characteristics, total out-of-pocket costs (OOP) and extended insurance coverage (EIC) were collected. Multivariable logistic regression models were fit for COST score and each variable, to determine factors associated with greater FT (COST &lt; 21). Results: Of 251 patients approached, 200 (80%) participated. Median age of the cohort was 65 years; 56% were female, 64% immigrants and 77% employed or on pension. Median total OOP while on treatment ranged between $1000-5000 CAD. Median COST score was 21 (range 0-44). FT was associated with age, with patients &lt; 65 years reporting greater FT than older patients (COST 18.0 vs. 24.0, p &lt; 0.0001). In multivariable logistic regression analysis, younger age was associated with greater FT, when adjusting for income, employment status, OOP and EIC (OR 3.6, [95% CI, 1.5-9.1]; p &lt; 0.0001). Total OOP &gt; $1000 and EIC also were associated with greater FT (adjusted OR 5.0 [95% CI, 2.0-12.1] and 3.7 [95% CI, 1.5-9.1], respectively). Conclusions: Age is significantly associated with FT in the Canadian (Ontario) public healthcare system, with younger lung cancer patients reporting greater financial distress. This study highlights priority patient populations where FT should be routinely assessed and appropriate resources for support offered.
Impact of early-life events on the susceptibility to <i>Clostridium difficile</i> colonisation and infection in the offspring of the pig
Authors: Łukasz M. Grześkowiak, Robert Pieper, Hong A. Huynh, Simon M. Cutting, Wilfried Vahjen, Jürgen Zentek
Journal: Gut Microbes (2018)

Clostridium difficile has been documented as a major cause of uncontrolled outbreaks of enteritis in neonatal pigs and antibiotic-associated infections in clinical settings. It belongs to the natural cohort of early colonisers of the gastrointestinal tract of pigs and can be detected in faeces up to two weeks post-partum. In older pigs, it often remains under the detection limit. Most neonatal pigs show no clinical signs of disease although C. difficile and its toxins can be detected at high levels in faeces. Increased mortality rates associated with C. difficile on pig farms are, so far, considered "spontaneous" and the predisposing factors are mostly not defined. The infection caused by C. difficile is multifactorial and it is likely that the repertoire of maternal factors, host physiology, the individually developing gut microbiota, co-infections and environmental stress define the conditions for disease development. In this addendum to our recently published work on CDI in neonatal piglets, we discuss the "early-life events" that influence C. difficile spread and infection in neonatal piglets.
IL-33 drives the antitumor effects of dendritic cells via the induction of Tc9 cells
Authors: Ning Liu, Yuxue Jiang, Jintong Chen, He Nan, Yinghua Zhao, Xiao Chu, Alison Wang, Dongjiao Wang, Tianxue Qin, Sujun Gao, Qing Yi, Ying Yue, Siqing Wang
Journal: Cellular and Molecular Immunology (2018)
Poor Metabolic Control in Children and Adolescents With Type 1 Diabetes and Psychiatric Comorbidity
Authors: Stine M. Sildorf, Nina Breinegaard, Emilie B. Lindkvist, Janne S. Tolstrup, Kirsten A. Boisen, Grete K. Teilmann, Anne Mette Skovgaard, Jannet Svensson
Journal: Diabetes Care (2018)

Type 1 diabetes is associated with an increased risk of psychiatric morbidities. We investigated predictors and diabetes outcomes in a pediatric population with and without psychiatric comorbidities.Data from the Danish Registry of Childhood and Adolescent Diabetes (DanDiabKids) and National Patient Register were collected (1996-2015) for this population-based study. We used Kaplan-Meier plots to investigate whether age at type 1 diabetes onset and average glycated hemoglobin (HbA1c) levels during the first 2 years after onset of type 1 diabetes (excluding HbA1c at debut) were associated with the risk of being diagnosed with a psychiatric disorder. Mixed-effects linear and logistic regression models were used to analyze HbA1c, BMI, severe hypoglycemia (SH), or ketoacidosis as outcomes, with psychiatric comorbidities as explanatory factor.Among 4,725 children and adolescents with type 1 diabetes identified in both registers, 1,035 were diagnosed with at least one psychiatric disorder. High average HbA1c levels during the first 2 years predicted higher risk of psychiatric diagnoses. Patients with psychiatric comorbidity had higher HbA1c levels (0.22% [95% CI 0.15; 0.29]; 2.40 mmol/mol [1.62; 3.18]; P < 0.001) and an increased risk of hospitalization with diabetic ketoacidosis (1.80 [1.18; 2.76]; P = 0.006). We found no associations with BMI or SH.High average HbA1c levels during the first 2 years after onset of type 1 diabetes might indicate later psychiatric comorbidities. Psychiatric comorbidity in children and adolescents with type 1 diabetes increases the risk of poor metabolic outcomes. Early focus on the disease burden might improve outcomes.
Indoles derived from intestinal microbiota act via type I interferon signaling to limit graft-versus-host disease
Authors: Alyson Swimm, Cynthia R. Giver, Zachariah DeFilipp, Sravanti Rangaraju, Akshay Sharma, Alina Ulezko Antonova, Robert Sonowal, Christopher Capaldo, Domonica Powell, Muna Qayed, Daniel Kalman, Edmund K. Waller
Journal: Blood (2018)
Financial toxicity of cancer treatment at a diverse county hospital.
Authors: Divya Ahuja Parikh, Meera Vimala Ragavan, Debeshi Maitra, Sangeeta Aggarwal, Manali I. Patel
Journal: Journal of Clinical Oncology (2018)

76 Background: The rising costs of cancer care increasingly results in financial distress for patients and their families. Low-income patients face a greater burden of financial toxicity, but few studies have characterized what factors contribute to this, and what interventions can relieve toxicity. Methods: From October 2017 to December 2017, we used a validated COST survey tool to understand the extent of financial burden that patients with cancer experience. We surveyed patients who receive their oncology care in a medical system that serves predominantly minority and low-income patients in Santa Clara County. We collected demographic information including sex, education level, ethnicity, income, insurance status, monthly out of pocket costs (OOPC) and employment status prior to diagnosis. We used a multivariable linear regression to study the association between the patient factors and financial burden as demonstrated by the COST score. All data were analyzed using Stata 14. Results: Demographic information is presented in Table 1. A total of 152 patients completed all 11 items of the COST survey. In the multivariate model, there was no significant difference in COST score by sex, education level, or ethnicity. However, income ≤$25,000 was associated with higher COST scores (p = 0.019), as was higher monthly OOPC (p = 0.003). Medicare patients and patients who were employed prior to diagnosis tended to have higher COST scores although not quite statistically significant (p = 0.057, p = 0.083). Conclusions: Patient-reported financial toxicity is an unmet concern among patients in this single institution study with a high proportion of underinsured patients. Higher OOPC and low income was associated with a higher financial burden. These findings suggest that patients would benefit from targeted interventions to mediate out of pocket costs of cancer care.[Table: see text]
Prenatal Household Air Pollution Is Associated with Impaired Infant Lung Function with Sex-Specific Effects. Evidence from GRAPHS, a Cluster Randomized Cookstove Intervention Trial
Authors: Alison G. Lee, Seyram Kaali, Ashlinn Quinn, Rupert Delimini, Katrin Burkart, Jones Opoku-Mensah, Blair J. Wylie, Abena Konadu Yawson, Patrick L. Kinney, Kenneth A. Ae-Ngibise, Steven Chillrud, Darby Jack, Kwaku Poku Asante
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Approximately 2.8 billion people are exposed daily to household air pollution from polluting cookstoves. The effects of prenatal household air pollution on lung development are unknown.To prospectively examine associations between prenatal household air pollution and infant lung function and pneumonia in rural Ghana.Prenatal household air pollution exposure was indexed by serial maternal carbon monoxide personal exposure measurements. Using linear regression, we examined associations between average prenatal carbon monoxide and infant lung function at age 30 days, first in the entire cohort (n = 384) and then stratified by sex. Quasi-Poisson generalized additive models explored associations between infant lung function and pneumonia.Multivariable linear regression models showed that average prenatal carbon monoxide exposure was associated with reduced time to peak tidal expiratory flow to expiratory time (β = -0.004; P = 0.01), increased respiratory rate (β = 0.28; P = 0.01), and increased minute ventilation (β = 7.21; P = 0.05), considered separately, per 1 ppm increase in average prenatal carbon monoxide. Sex-stratified analyses suggested that girls were particularly vulnerable (time to peak tidal expiratory flow to expiratory time: β = -0.003, P = 0.05; respiratory rate: β = 0.36, P = 0.01; minute ventilation: β = 11.25, P = 0.01; passive respiratory compliance normalized for body weight: β = 0.005, P = 0.01). Increased respiratory rate at age 30 days was associated with increased risk for physician-assessed pneumonia (relative risk, 1.02; 95% confidence interval, 1.00-1.04) and severe pneumonia (relative risk, 1.04; 95% confidence interval, 1.00-1.08) in the first year of life.Increased prenatal household air pollution exposure is associated with impaired infant lung function. Altered infant lung function may increase risk for pneumonia in the first year of life. These findings have implications for future respiratory health. Clinical trial registered with www.clinicaltrials.gov (NCT 01335490).
Learning from the research on amebiasis and gut microbiome: Is stimulation by gut flora essential for effective neutrophil mediated protection from external pathogens?
Authors: Koji Watanabe, William A. Petri
Journal: Gut Microbes (2018)

Amebiasis, caused by intestinal infection with Entamoeba histolytica, is one of the leading causes of parasite infection-related mortality and morbidity globally. Although its pathogenesis, including determinant factors of infection outcome, remains unclear, recent clinical data indicate that the gut microbiome plays a role in determining the severity of amebiasis. Recently, we investigated the effects of the gut microbiome on neutrophil mediated protection from E. histolytica infection using a mouse model. We identified that surface expression of CXCR2 on neutrophils was diminished in mice with dysbiosis, which resulted in decreased neutrophil recruitment to the infection site, allowing more aggressive intestinal tissue damage by E. histolytica. Our results indicated that oxidase activity during E. histolytica infection was also diminished after dysbiosis, consistent with the results from prior research. Thus, the gut microbiome plays an important role in regulating neutrophil phenotype when fighting against external pathogens.
Neutrophils in tPA-induced hemorrhagic transformations: Main culprit, accomplice or innocent bystander?
Authors: Thavarak Ouk, Camille Potey, Ilaria Maestrini, Maud Petrault, Anne-Marie Mendyk, Didier Leys, Regis Bordet, Sophie Gautier
Journal: Pharmacology & Therapeutics (2018)
Machine learning for real-time prediction of complications in critical care: a retrospective study
Authors: Alexander Meyer, Dina Zverinski, Boris Pfahringer, Jörg Kempfert, Titus Kuehne, Simon H Sündermann, Christof Stamm, Thomas Hofmann, Volkmar Falk, Carsten Eickhoff
Journal: The Lancet Respiratory Medicine (2018)