tbuckley/cabot-search huggingface dataset:
Cytokine Profiling of Primary Human Macrophages Exposed to Endotoxin‐Free Graphene Oxide: Size‐Independent NLRP3 Inflammasome Activation
Authors: Sourav P. Mukherjee, Kostas Kostarelos, Bengt Fadeel
Journal: Advanced Healthcare Materials (2017)

Abstract Graphene‐based materials including graphene oxide (GO) are envisioned for a variety of biomedical applications. However, there are conflicting results concerning the biocompatibility of these materials. Here, a question is raised whether GO with small or large lateral dimensions triggers cytotoxicity and/or cytokine responses in primary human monocyte‐derived macrophages. GO sheets produced under sterile conditions by a modified Hummers' method are found to be taken up by macrophages without signs of cytotoxicity. Then, multiplex arrays are used for profiling of proinflammatory and anti‐inflammatory responses. Notably, GO suppresses the lipopolysaccharide (LPS)‐triggered induction of several chemokines and cytokines, including the anti‐inflammatory cytokine, interleukin‐10 (IL‐10). No production of proinflammatory TNF‐ α is observed. However, GO elicits caspase‐dependent IL‐1 β expression, a hallmark of inflammasome activation, in LPS‐primed macrophages. Furthermore, GO‐triggered IL‐1 β production requires NADPH oxidase‐generated reactive oxygen species and cellular uptake of GO and is accompanied by cathepsin B release and K+ efflux. Using THP‐1 knockdown cells, a role for the inflammasome sensor, NLRP3, the adaptor protein, ASC, and caspase‐1 for GO‐induced IL‐1 β secretion is demonstrated. Finally, these studies show that inflammasome activation is independent of the lateral dimensions of the GO sheets. These studies provide novel insights regarding the immunomodulatory properties of endotoxin‐free GO.
Brief Report: Genetic Variation of the α<sub>1</sub>‐Antitrypsin Gene Is Associated With Increased Autoantibody Production in Rheumatoid Arthritis
Authors: Cormac McCarthy, Carl Orr, Laura T. Fee, Tomás P. Carroll, Danielle M. Dunlea, David J. L. Hunt, Eimear Dunne, Paul O'Connell, Geraldine McCarthy, Dermot Kenny, Ursula Fearon, Douglas J. Veale, Emer P. Reeves, Noel G. McElvaney
Journal: Arthritis & Rheumatology (2017)

To examine the prevalence of α1 -antitrypsin deficiency (AATD) in rheumatoid arthritis (RA), and to determine whether AATD is associated with higher levels of rheumatoid factor (RF), antinuclear antibodies (ANAs), and anti-citrullinated peptide autoantibodies (ACPAs).RF, ANAs, and ACPAs were measured by standard immunoturbidimetry, immunofluorescence assay, and enzyme-linked immunosorbent assay, respectively. Characterization of AAT phenotypes was performed by isoelectric focusing and immunofixation. The chi-square test with Yates' correction and the Mann-Whitney U test were used to assess the prevalence of alleles associated with AATD in RA and to compare mean antibody titers, respectively.Of 246 patients with RA, 24 who were heterozygous for AATD were identified, with no statistically significant difference in the prevalence of AATD between RA patients and the general population (P = 0.39). A positive association between heterozygosity for AATD and the production of ACPAs was observed (P < 0.0001), with increased ACPA titers recorded in the AATD RA cohort compared with the general population (P = 0.01).AAT heterozygous status in RA is strongly associated with positive ACPAs and may define a distinct subset of patients with increased disease severity.
Atorvastatin enhances bone marrow endothelial cell function in corticosteroid-resistant immune thrombocytopenia patients
Authors: Yuan Kong, Xie-Na Cao, Xiao-Hui Zhang, Min-Min Shi, Yue-Yun Lai, Yu Wang, Lan-Ping Xu, Ying-Jun Chang, Xiao-Jun Huang
Journal: Blood (2017)
Overall Survival (OS) of Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Treated with Carfilzomib, Lenalidomide, and Dexamethasone (KRd) Versus Lenalidomide and Dexamethasone (Rd): Final Analysis from the Randomized Phase 3 Aspire Trial
Authors: A. Keith Stewart, David Siegel, Heinz Ludwig, Thierry Facon, Hartmut Goldschmidt, Andrzej J. Jakubowiak, Jesus F. San Miguel, Mihaela Obreja, Julie Blaedel, Meletios A. Dimopoulos
Journal: Blood (2017)
Right Lower Quadrant Pain in Early Pregnancy
Authors: Salomone Di Saverio, Clarissa Ann Elisabeth Gelmi, Antonino Perrone
Journal: JAMA Surgery (2017)

A woman in her mid-20s who was 8 weeks pregnant presented to the emergency department for abdominal pain localized in the right iliac fossa, sense of numbness in the right lower limb, and nausea and vomiting. What is your diagnosis?
2016 Lucian Award
Authors: Susan Ince
Journal: Circulation Research (2016)

pursued specialty training in cardiology at Duke University in a program that encouraged fellows to pursue basic research.While working in the laboratory of Robert Lefkowitz, MD, he was part of the team that cloned the gene for the β 2 -adrenergic receptor, finding its sequence to be strikingly similar to rhodopsin, a seemingly unrelated receptor.This research led to the recognition of the 7 transmembrane structure shared by rhodopsin and a large number of other G protein-coupled receptors.
An APRIL-based chimeric antigen receptor for dual targeting of BCMA and TACI in multiple myeloma
Authors: Lydia Lee, Benjamin Draper, Neil Chaplin, Brian Philip, Melody Chin, Daria Galas-Filipowicz, Shimobi Onuoha, Simon Thomas, Vania Baldan, Reyisa Bughda, Paul Maciocia, Eva Kokalaki, Margarida P. Neves, Dominic Patel, Manuel Rodriguez-Justo, James Francis, Kwee Yong, Martin Pule
Journal: Blood (2017)
Circulating Tumor Cell Number as a Response Measure of Prolonged Survival for Metastatic Castration-Resistant Prostate Cancer: A Comparison With Prostate-Specific Antigen Across Five Randomized Phase III Clinical Trials
Authors: Glenn Heller, Robert McCormack, Thian Kheoh, Arturo Molina, Matthew R. Smith, Robert Dreicer, Fred Saad, Ronald de Wit, Dana T. Aftab, Mohammad Hirmand, Ana Limon, Karim Fizazi, Martin Fleisher, Johann S. de Bono, Howard I. Scher
Journal: Journal of Clinical Oncology (2017)

Purpose Measures of response that are clinically meaningful and occur early are an unmet need in metastatic castration-resistant prostate cancer clinical research and practice. We explored, using individual patient data, week 13 circulating tumor cell (CTC) and prostate-specific antigen (PSA) response end points in five prospective randomized phase III trials that enrolled a total of 6,081 patients-COU-AA-301, AFFIRM, ELM-PC-5, ELM-PC-4, and COMET-1- ClinicalTrials.Gov identifiers: NCT00638690, NCT00974311, NCT01193257, NCT01193244, and NCT01605227, respectively. Methods Eight response end points were explored. CTC nonzero at baseline and 0 at 13 weeks (CTC0); CTC conversion (≥ 5 CTCs at baseline, ≤ 4 at 13 weeks-the US Food and Drug Administration cleared response measure); a 30%, 50%, and 70% decrease in CTC count; and a 30%, 50%, and 70% decrease in PSA level. Patients missing week-13 values were considered nonresponders. The discriminatory strength of each end point with respect to overall survival in each trial was assessed using the weighted c-index. Results Of the eight response end points, CTC0 and CTC conversion had the highest weighted c-indices, with smaller standard deviations. For CTC0, the mean (standard deviation) was 0.81 (0.04); for CTC conversion, 0.79 (0.03); for 30% decrease in CTC count, 0.72 (0.06); for 50% decrease in CTC count, 0.72 (0.06); for 70% decrease in CTC count, 0.73 (0.05); for 30% decrease in PSA level, 0.71 (0.03); for 50% decrease in PSA level, 0.72 (0.06); and for 70% decrease in PSA level, 0.74 (0.05). Seventy-five percent of eligible patients could be evaluated with the CTC0 end point, compared with 51% with the CTC conversion end point. Conclusion The CTC0 and CTC conversion end points had the highest discriminatory power for overall survival. Both are robust and meaningful response end points for early-phase metastatic castration-resistant prostate cancer clinical trials. CTC0 is applicable to a significantly higher percentage of patients than CTC conversion.
Phase I Study of ATR Inhibitor M6620 in Combination With Topotecan in Patients With Advanced Solid Tumors
Authors: Anish Thomas, Christophe E. Redon, Linda Sciuto, Emerson Padiernos, Jiuping Ji, Min-Jung Lee, Akira Yuno, Sunmin Lee, Yiping Zhang, Lan Tran, William Yutzy, Arun Rajan, Udayan Guha, Haobin Chen, Raffit Hassan, Christine C. Alewine, Eva Szabo, Susan E. Bates, Robert J. Kinders, Seth M. Steinberg, James H. Doroshow, Mirit I. Aladjem, Jane B. Trepel, Yves Pommier
Journal: Journal of Clinical Oncology (2017)

Purpose Our preclinical work identified depletion of ATR as a top candidate for topoisomerase 1 (TOP1) inhibitor synthetic lethality and showed that ATR inhibition sensitizes tumors to TOP1 inhibitors. We hypothesized that a combination of selective ATR inhibitor M6620 (previously VX-970) and topotecan, a selective TOP1 inhibitor, would be tolerable and active, particularly in tumors with high replicative stress. Patients and Methods This phase I study tested the combination of M6620 and topotecan in 3-week cycles using 3 + 3 dose escalation. The primary end point was the identification of the maximum tolerated dose of the combination. Efficacy and pharmacodynamics were secondary end points. Results Between September 2016 and February 2017, 21 patients enrolled. The combination was well tolerated, which allowed for dose escalation to the highest planned dose level (topotecan 1.25 mg/m
Counterfactual Reasoning Underlies the Learning of Priors in Decision Making
Authors: Ariel Zylberberg, Daniel M. Wolpert, Michael N. Shadlen
Journal: Neuron (2018)

Accurate decisions require knowledge of prior probabilities (e.g., prevalence or base rate), but it is unclear how prior probabilities are learned in the absence of a teacher. We hypothesized that humans could learn base rates from experience making decisions, even without feedback. Participants made difficult decisions about the direction of dynamic random dot motion. Across blocks of 15–42 trials, the base rate favoring left or right varied. Participants were not informed of the base rate or choice accuracy, yet they gradually biased their choices and thereby increased accuracy and confidence in their decisions. They achieved this by updating knowledge of base rate after each decision, using a counterfactual representation of confidence that simulates a neutral prior. The strategy is consistent with Bayesian updating of belief and suggests that humans represent both true confidence, which incorporates the evolving belief of the prior, and counterfactual confidence, which discounts the prior.
Associations of Four Community Factors With Longitudinal Change in Hemoglobin A1c Levels in Patients With Type 2 Diabetes
Authors: Annemarie G. Hirsch, T. Elizabeth Durden, Cara Nordberg, Andrea Berger, Brian S. Schwartz
Journal: Diabetes Care (2017)

OBJECTIVE To evaluate associations of community factors with glycated hemoglobin (HbA1c). RESEARCH DESIGN AND METHODS We identified patients with type 2 diabetes who had an HbA1c ≥7.5% (58 mmol/mol) and subsequent HbA1c testing within 90–270 days. We used mixed-effect models to assess whether treatment intensification (TI) and community domains (community socioeconomic deprivation [CSD], food availability, fitness assets, and utilitarian physical activity favorability [quartiled]) were associated with HbA1c change over 6 and 24 months, controlling for demographics, HbA1c, BMI, and time with evidence of type 2 diabetes. We evaluated whether community domains modified associations of TI with HbA1c change using cross product terms. RESULTS There were 15,308 patients with 69,818 elevated HbA1c measures. The average reduction in HbA1c over 6 months was 0.07% less in townships with a high level of CSD (third quartile versus the first). Reductions were 0.10% greater for HbA1c in townships with the best food availability (versus worst). HbA1c reductions were 0.17–0.19% greater in census tracts in the second and third quartiles of utilitarian physical activity favorability versus the first. The association of TI with 6-month HbA1c change was weaker in townships and boroughs with the worst CSD (versus best) and in boroughs with the best fitness assets (versus worst). The association of TI with 24-month HbA1c change was weaker in census tracts with the worst CSD (versus third quartile) and strongest in census tracts most favorable for utilitarian physical activity (versus worst). CONCLUSIONS Community domains were associated with HbA1c change and blunted TI effectiveness.
Association of Childhood Blood Lead Levels With Criminal Offending
Authors: Amber L. Beckley, Avshalom Caspi, Jonathan Broadbent, Honalee Harrington, Renate M. Houts, Richie Poulton, Sandhya Ramrakha, Aaron Reuben, Terrie E. Moffitt
Journal: JAMA Pediatrics (2017)

Lead is a neurotoxin with well-documented effects on health. Research suggests that lead may be associated with criminal behavior. This association is difficult to disentangle from low socioeconomic status, a factor in both lead exposure and criminal offending.To test the hypothesis that a higher childhood blood lead level (BLL) is associated with greater risk of criminal conviction, recidivism (repeat conviction), conviction for violent offenses, and variety of self-reported criminal offending in a setting where BLL was not associated with low socioeconomic status.A total of 553 individuals participated in a prospective study based on a population-representative cohort born between April 1, 1972, and March 31, 1973, from New Zealand; the Dunedin Multidisciplinary Health and Development Study observed participants to age 38 years (December 2012). Statistical analysis was performed from November 10, 2016, to September 5, 2017.Blood lead level measured at age 11 years.Official criminal conviction cumulative to age 38 years (data collected in 2013), single conviction or recidivism, conviction for nonviolent or violent crime, and self-reported variety of crime types at ages 15, 18, 21, 26, 32, and 38 years.Participants included 553 individuals (255 female and 298 male participants) who had their blood tested for lead at age 11 years. The mean (SD) BLL at age 11 years was 11.01 (4.62) μg/dL. A total of 154 participants (27.8%) had a criminal conviction, 86 (15.6%) had recidivated, and 53 (9.6%) had a violent offense conviction. Variety scores for self-reported offending ranged from 0 to 10 offense types at each assessment; higher numbers indicated greater crime involvement. Self-reported offending followed the well-established age-crime curve (ie, the mean [SD] variety of self-reported offending increased from 1.99 [2.82] at age 15 years to its peak of 4.24 [3.15] at age 18 years and 4.22 [3.02] at age 21 years and declined thereafter to 1.10 [1.59] at age 38 years). Blood lead level was a poor discriminator between no conviction and conviction (area under the curve, 0.58). Overall, associations between BLL and conviction outcomes were weak. The estimated effect of BLL was lower for recidivism than for single convictions and lower for violent offending than for nonviolent offending. Sex-adjusted associations between BLL reached statistical significance for only 1 of the 6 self-reported offending outcomes at age 15 years (r = 0.10; 95% CI, 0.01-0.18; P = .02).This study overcomes past limitations of studies of BLL and crime by studying the association in a place and time where the correlation was not confounded by childhood socioeconomic status. Findings failed to support a dose-response association between BLL and consequential criminal offending.
Starting Out After Rail
Authors: Virginia Neal Hinze
Journal: JAMA (1980)

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False-Positive Heat-Damaged RBC Scan for Splenosis
Authors: Joseph S. Donald, Delphine L. Chen, Jessica Peterson, Mark Perry
Journal: Clinical Nuclear Medicine (2017)

Extramedullary hematopoiesis (EMH) is a well-known compensatory response to severe anemia, most commonly due to a chronic hemolytic anemia such as thalassemia or sickle cell disease. We present a case of a 72-year-old man with autoimmune hemolytic anemia refractory to steroids and splenectomy. An incidental retroperitoneal mass on CT was suggestive of ectopic splenic tissue. However, an alternative diagnosis of EMH was considered, given an atypical appearance on heat-damaged Tc-RBC scan, and was confirmed with biopsy. The case report illustrates the imaging characteristics of EMH, widely known to have increased activity on Tc-sulfur colloid scans.
Association of Elevated NT-proBNP With Myocardial Fibrosis in the Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Chia-Ying Liu, Susan R. Heckbert, Shenghan Lai, Bharath Ambale-Venkatesh, Mohammad R. Ostovaneh, Robyn L. McClelland, João A.C. Lima, David A. Bluemke
Journal: Journal of the American College of Cardiology (2017)
Impact of Staphylococcus aureus phenotype and genotype on the clinical characteristics and outcome of infective endocarditis. A multicentre, longitudinal, prospective, observational study
Authors: N. Fernández-Hidalgo, A. Ribera, M.N. Larrosa, E. Viedma, J. Origüen, A. de Alarcón, M.C. Fariñas, C. Sáez, C. Peña, E. Múñez, M.V. García López, J. Gavaldà, D. Pérez-Montarelo, F. Chaves, B. Almirante
Journal: Clinical Microbiology and Infection (2017)
Combined delivery of sorafenib and a MEK inhibitor using CXCR4-targeted nanoparticles reduces hepatic fibrosis and prevents tumor development
Authors: Yun-Chieh Sung, Ya-Chi Liu, Po-Han Chao, Chih-Chun Chang, Pei-Ru Jin, Ts-Ting Lin, Ja-An Lin, Hui-Teng Cheng, Jane Wang, Charles P. Lai, Ling-Hsuan Chen, Anthony Y. Wu, Ting-Lun Ho, Tsaiyu Chiang, Dong-Yu Gao, Dan G. Duda, Yunching Chen
Journal: Theranostics (2017)

Liver damage and fibrosis are precursors of hepatocellular carcinoma (HCC). In HCC patients, sorafenib-a multikinase inhibitor drug-has been reported to exert anti-fibrotic activity. However, incomplete inhibition of RAF activity by sorafenib may also induce paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in malignant cells. The consequence of this effect in non-malignant disease (hepatic fibrosis) remains unknown. This study aimed to examine the effects of sorafenib on activated hepatic stellate cells (HSCs), and develop effective therapeutic approaches to treat liver fibrosis and prevent cancer development.
Genomic response to DNA damage agents in A549 human adenocarcinoma cells
Authors: Huijun Zhu, Nigel J. Gooderham
Journal: Cancer Research (2004)

2636  Numerous anticancer drugs and chemical carcinogens interact with DNA, provoking cellular responses. We have studied the genomic reaction evoked by four different DNA damaging agents in A549 human lung adenocarcinoma cells to understand the molecular pathways involved in orchestrating cellular responses. The topoisomerase II inhibitor etoposide is a cancer chemotherapeutic agent that induces DNA double strand breaks. Cryptolepine (CLP), a plant-derived alkaloid, is a potential anticancer drug that interferes with topoisomerase II and inhibits DNA synthesis. Benzo(a)pyrene (BaP), one of the polycyclic aromatic hydrocarbons found in cigarette smoke, is a suspected human lung carcinogen that induces cytochrome P450s (CYPs), namely CYP1A1 and CYP1B1, which in turn metabolize BaP to electrophiles that covalently bind to DNA. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a carcinogenic diet-derived heterocyclic amine, is metabolised chiefly by CYP1A2 to form DNA damaging electrophiles. Cells were treated with DMSO or a non-lethal dose of etoposide (10 μM), CLP (2.5 μM), BaP (25 μM) or PhIP (50 μM) for 6-72 h when mRNAs were extracted for gene expression profiling using Affymetrix human genome U-95Av2 array. Compared with DMSO control, etoposide induced a time-dependent decrease in the expression of genes controlling mitosis and G2/M transition. CLP, like etoposide, affected the expression of genes controlling G2/M transition, although the temporal aspect of the effect differed in the expression of genes involved in mitosis. Nevertheless, etoposide and CLP appear to share similar molecular pathways of action in alteration of cell cycle. BaP and PhIP treatment, on the other hand, had little effect on the expression of genes required for cell cycle progression at early times (up to 24 h), although BaP induced time dependent expression of CYP1B1 mRNA. After prolonged treatment, BaP downregulated genes involved in normal cell cycle progression. In contrast, PhIP upregulated genes responsible for cell cycle progression. These results indicate different mechanisms in relation to the genomic response to these DNA damaging carcinogens. Thus the ability to induce the expression of CYP1B1 may be important in cellular response to BaP treatment, whilst promoting cell growth may contribute to PhIP toxicity. Examining cell cycle profiles revealed that after 24 h, etoposide and CLP induced similar effects on cell cycle distribution, causing delay in S phase and G2/M phase progression. Yet cells treated with BaP and PhIP showed near normal cell cycle distribution. Our data demonstrate that monitoring gene network response to DNA damaging agents provides biomarkers for outcome that can be missed by more conventional whole cell approaches.