tbuckley/cabot-search huggingface dataset:
CLO19-051: CDK 4/6 Inhibitor-Associated Hematologic Toxicities and Febrile Neutropenia in Patients With Hormone Receptor-Positive HER2-Negative Metastatic Breast Cancer
Authors: Sriman Swarup, Anita Sultan, Somedeb Ball, Francis Mogollon-Duffo, Nimesh Adhikari, Yin M. Myat, Myo H. Zaw, Catherine Jones, Kyaw Z. Thein
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: Breast cancer is the most common cancer in women, and the majority of breast cancers express the estrogen receptor or progesterone receptor. Inhibition of CDK4/6 signaling pathway has shown survival benefit in advanced breast cancer by overcoming endocrine therapy resistance. Yet, there are considerable hematologic toxicities associated with CDK 4/6 inhibitors and hence, we performed a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk. Methods: MEDLINE, EMBASE databases, and meeting abstracts from inception through September 2018 were queried. RCTs that mention anemia, thrombocytopenia, leukopenia, neutropenia, and neutropenic fever as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) and risk difference (RD) with 95% CI. Random effects model was applied. Results: 8 RCTs (7 phase III and 1 phase II studies) with a total of 4,557 patients were eligible. The study arms used palbociclib/ribociclib/abemaciclib with letrozole or anastrozole or fulvestrant or other hormonal agent while the control arms utilized placebo in combination with letrozole or anastrozole or fulvestrant or other hormonal agent. The RR of all-grade side effects were as follows: anemia, 3.494 (95% CI: 2.535–4.814; P &lt;.0001); thrombocytopenia, 6.066 (95% CI: 3.055–12.046; P &lt;.0001); leukopenia, 10.376(95% CI: 7.236–14.879; P &lt;.0001); and neutropenia, 14.387 (95% CI: 10.877–19.031; P &lt;.0001). The RR of high-grade adverse effects were as follows: anemia, 2.251 (95% CI: 1.393–3.637; P =.001); thrombocytopenia, 3.696 (95% CI: 1.417–9.642; P =.008); leukopenia, 22.083(95% CI: 12.126–40.217; P &lt;.0001); neutropenia, 33.527(95% CI: 17.271–65.082; P &lt;.001). Neutropenic fever was noted in 71 (3.73%) in CDK 4/6 inhibitors group vs 28 (2.18%) in control arm. The pooled RR was statistically significant at 12.056 (95% CI: 1. 352–3.127; P =.001) and RD was 0.014 (95% CI: −0.002–0.029; P =.078) Conclusion: CDK 4/6 inhibitors–based regimen significantly contributed to all hematologic toxicities as well as febrile neutropenia. The improved efficacy outcomes and manageable toxicities with CDK 4/6 inhibitors are observed with proper supportive care and close monitoring.
Abstract 16082: Plin2 Attenuates Cardiomyocyte Lipotoxicity
Authors: Felix-Antoine Berube-Simard, Taha Haffar, Nicolas Bousette
Journal: Circulation (2015)

Diabetic cardiomyopathy is associated with excess lipid accumulation in the heart. We previously showed that oleate, a non-toxic mono-unsaturated fatty acid causes the formation of abundant lipid droplets in cardiomyocytes that were lined with Plin2, an important lipid droplet binding protein. In contrast, palmitate, a toxic saturated fatty acid, led to the formation of aberrant lipid droplets which lacked Plin2 immunoreactivity. Hypothesis: We hypothesized that Plin2 overexpression may protect against palmitate mediated lipotoxicity. Methods: We overexpressed and silenced Plin2 in rat neonatal cardiomyocytes (NCMs) by LentiVector mediated overexpression of Plin2 cDNA and shRNAs, respectively. We treated these NCMs with bovine serum albumin (51μM, vehicle control), 100-300μM oleate, or 100-300μM palmitate for 4-24 hours. We evaluated viability with the propidium iodide exclusion assay and measured gene expression by qRT-PCR. Results: Plin2 overexpression protected NCMs from the lipotoxic effects of palmitate. Conversely, silencing of Plin2 sensitized NCMs to the effects of palmitate and caused oleate, which is normally non-toxic, to induce cell death in NCMs. Interestingly, we found that Plin2 overexpression had a marked stimulatory effect on several PPAR target genes including Carnitine palmitoyl transferase 1b (Cpt1b), the rate limiting enzyme in β-oxidation. In contrast, Plin2 silencing led to a significant decrease in oleate induced expression of PPAR target genes, including Cpt1b. Conclusion: Here we showed that overexpression of Plin2, a key lipid droplet binding protein protected against lipotoxicity, while silencing it caused lipotoxicity. We show that this may be due to alterations in lipid metabolism, since Plin2 overexpression led to increased expression of key β-oxidation genes. This is important because we have previously shown that palmitate impairs β-oxidation capacity in cardiomyocytes. Therefore enhancing β-oxidation may attenuate lipotoxicity by limiting the build-up of lipid metabolites. The mechanism of Plin2 mediated effects on PPAR target gene expression, as well as the effect on lipid droplet formation are the subject of on-going studies.
Will we reach the Sustainable Development Goals target for tuberculosis in the European Union/European Economic Area by 2030?
Authors: Hanna Merk, Csaba Ködmön, Marieke J van der Werf
Journal: Eurosurveillance (2019)

We assessed progress towards the Sustainable Development Goals target for tuberculosis in the European Union/European Economic Area using the latest tuberculosis (TB) surveillance and Eurostat data. Both the TB notification rate and the number of TB deaths were decreasing before 2015 and the TB notification rate further declined between 2015 and 2017. With the current average decline in notification rate and number of TB deaths however, the EU/EEA will not reach the targets by 2030.
The Transcription Factor ERG Regulates Super-Enhancers Associated With an Endothelial-Specific Gene Expression Program
Authors: Viktoria Kalna, Youwen Yang, Claire R. Peghaire, Karen Frudd, Rebecca Hannah, Aarti V. Shah, Lourdes Osuna Almagro, Joseph J. Boyle, Berthold Göttgens, Jorge Ferrer, Anna M. Randi, Graeme M. Birdsey
Journal: Circulation Research (2019)

Rationale: The ETS (E-26 transformation-specific) transcription factor ERG (ETS-related gene) is essential for endothelial homeostasis, driving expression of lineage genes and repressing proinflammatory genes. Loss of ERG expression is associated with diseases including atherosclerosis. ERG’s homeostatic function is lineage-specific, because aberrant ERG expression in cancer is oncogenic. The molecular basis for ERG lineage-specific activity is unknown. Transcriptional regulation of lineage specificity is linked to enhancer clusters (super-enhancers). Objective: To investigate whether ERG regulates endothelial-specific gene expression via super-enhancers. Methods and Results: Chromatin immunoprecipitation with high-throughput sequencing in human umbilical vein endothelial cells showed that ERG binds 93% of super-enhancers ranked according to H3K27ac, a mark of active chromatin. These were associated with endothelial genes such as DLL4 (Delta-like protein 4), CLDN5 (claudin-5), VWF (von Willebrand factor), and CDH5 (VE-cadherin). Comparison between human umbilical vein endothelial cell and prostate cancer TMPRSS2 (transmembrane protease, serine-2):ERG fusion-positive human prostate epithelial cancer cell line (VCaP) cells revealed distinctive lineage-specific transcriptome and super-enhancer profiles. At a subset of endothelial super-enhancers (including DLL4 and CLDN5), loss of ERG results in significant reduction in gene expression which correlates with decreased enrichment of H3K27ac and MED (Mediator complex subunit)-1, and reduced recruitment of acetyltransferase p300. At these super-enhancers, co-occupancy of GATA2 (GATA-binding protein 2) and AP-1 (activator protein 1) is significantly lower compared with super-enhancers that remained constant following ERG inhibition. These data suggest distinct mechanisms of super-enhancer regulation in endothelial cells and highlight the unique role of ERG in controlling a core subset of super-enhancers. Most disease-associated single nucleotide polymorphisms from genome-wide association studies lie within noncoding regions and perturb transcription factor recognition sequences in relevant cell types. Analysis of genome-wide association studies data shows significant enrichment of risk variants for cardiovascular disease and other diseases, at ERG endothelial enhancers and super-enhancers. Conclusions: The transcription factor ERG promotes endothelial homeostasis via regulation of lineage-specific enhancers and super-enhancers. Enrichment of cardiovascular disease-associated single nucleotide polymorphisms at ERG super-enhancers suggests that ERG-dependent transcription modulates disease risk.
<i>Helicobacter pylori</i> Infection
Authors: Sheila E. Crowe
Journal: New England Journal of Medicine (2019)

Testing for H. pylori, either directly on biopsy specimens or by means of stool antigen or urea breath testing, is recommended in persons at increased risk for this infection. Treatment choice depends on whether there is penicillin allergy, previous exposure to macrolides, and macrolide resistance. Testing for cure is recommended after treatment.
Childhood Lead Exposure May Affect Personality, Mental Health in Adulthood
Authors: Feyza Sancar
Journal: JAMA (2019)

Aaron Reuben, MEM; Jonathan D. Schaefer, MA; Terrie E. Moffitt, PhD; Jonathan Broadbent, PhD; Honalee Harrington, BA; Renate M. Houts, PhD; Sandhya Ramrakha, PhD; Richie Poulton, PhD; Avshalom Caspi, PhD
Abstract 1875: Early Strain Rate Impairment During Epirubicin Treatment Correlates With Markers Of Inflammation And Oxidative Stress
Authors: Christian Cadeddu, Alessandra Piras, Mariele Dessi, Martino Deidda, Elena Massa, Clelia Madeddu, Giovanni Mantovani, Giuseppe Mercuro
Journal: Circulation (2007)

INTRODUCTION Epirubicin (EPI) cardiotoxicity (CTX) is associated with progressive impairment of cardiac function, which proceeds slowly and continues irreversible for years after treatment cessatio...
Macrophage p38α promotes nutritional steatohepatitis through M1 polarization
Authors: Xiang Zhang, Lina Fan, Jianfeng Wu, Hongzhi Xu, Wing Yan Leung, Kaili Fu, Jingtong Wu, Ken Liu, Kwan Man, Xiaoyong Yang, Jiahuai Han, Jianlin Ren, Jun Yu
Journal: Journal of Hepatology (2019)

p38 mitogen-activated protein kinases are important inflammatory factors. p38α alteration has been implicated in both human and mouse inflammatory disease models. Therefore, we aimed to characterize the cell type-specific role of p38α in non-alcoholic steatohepatitis (NASH).Human liver tissues were obtained from 27 patients with non-alcoholic fatty liver disease (NAFLD) and 20 control individuals. NASH was established and compared between hepatocyte-specific p38α knockout (p38αΔHep), macrophage-specific p38α knockout (p38αΔMΦ) and wild-type (p38αfl/fl) mice fed with high-fat diet (HFD), high-fat/high-cholesterol diet (HFHC), or methionine-and choline-deficient diet (MCD). p38 inhibitors were administered to HFHC-fed wild-type mice for disease treatment.p38α was significantly upregulated in the liver tissues of patients with NAFLD. Compared to p38αfl/fl littermates, p38αΔHep mice developed significant nutritional steatohepatitis induced by HFD, HFHC or MCD. Meanwhile, p38αΔMΦ mice exhibited less severe steatohepatitis and insulin resistance than p38αfl/fl mice in response to a HFHC or MCD. The effect of macrophage p38α in promoting steatohepatitis was mediated by the induction of pro-inflammatory factors (CXCL2, IL-1β, CXCL10 and IL-6) secreted by M1 macrophages and associated signaling pathways. p38αΔMΦ mice exhibited M2 anti-inflammatory polarization as demonstrated by increased CD45+F4/80+CD11b+CD206+ M2 macrophages and enhanced arginase activity in liver tissues. Primary hepatocytes from p38αΔMΦ mice showed decreased steatosis and inflammatory damage. In a co-culture system, p38α deleted macrophages attenuated steatohepatitic changes in hepatocytes through decreased secretion of pro-inflammatory cytokines (TNF-α, CXCL10 and IL-6), which mediate M1 macrophage polarization in p38αΔMΦ mice. Restoration of TNF-α, CXCL10 or IL-6 induced lipid accumulation and inflammatory responses in p38αfl/fl hepatocytes co-cultured with p38αΔMΦ macrophages. Moreover, pharmacological p38 inhibitors suppressed HFHC-induced steatohepatitis.Macrophage p38α promotes the progression of steatohepatitis by inducing pro-inflammatory cytokine secretion and M1 polarization. p38 inhibition protects against steatohepatitis. LAY SUMMARY: p38 mitogen-activated protein kinases are important inflammatory factors. In the present study, we demonstrated that p38α is upregulated in liver tissues of patients with non-alcoholic fatty liver diseases. Genetic deletion of p38α in macrophages led to ameliorated nutritional steatohepatitis in mice through decreased pro-inflammatory cytokine secretion and increased M2 macrophage polarization.
CLO19-053: Incidence of Cabozantinib-Associated Palmar-Plantar Erythrodysesthesia and Hypertension in Patients With Metastatic Solid Tumors: A Combined Analysis of 4 Phase III Randomized Controlled Trials
Authors: Kyaw Z. Thein, Sriman Swarup, Anita Sultan, Subhanudh Thavaraputta, Myo H. Zaw, Nicholas D’Cunha, Sanjay Awasthi, Fred Hardwicke, Lukman Tijani
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: Tyrosine kinases such as VEGFR, KIT, RET, MET are implicated in development and progression of several solid tumors. Cabozantinib is an oral multiple tyrosine kinase inhibitor and has shown survival benefits in several solid tumors. Yet, there are notable toxicities. We performed a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of palmar-plantar erythrodysesthesia (PPE) and hypertension in patients with metastatic solid tumors treated with cabozantinib. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases, and meeting abstracts through September 2018. Phase III RCTs that mention PPE and hypertension as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% CI. Random effects model was applied. Heterogeneity was assessed using I 2 statistic. Results: 4 phase III RCTs with total of 2,703 patients, comparing cabozantinib (C) vs everolimus, C vs placebo, C vs prednisone, were included. I 2 statistic was 70.70, suggesting some heterogeneity among RCTs. All grade-PPE incidence was 666 (39.3%) in cabozantinib arm vs 38 (3.76%) in control arm with a RR of 11.378 (95% CI: 6.545–19.782; P &lt;.0001). The absolute RD was 0.383 (95% CI: 0.294–0.473; P &lt;.0001). High-grade PPE was reported in 172 (10.15%) in cabozantinib group vs 3 (0.29%) in control group with a RR of 19.077 (95% CI: 5.733–63.476; P &lt;.0001). The RD was 0.105 (95% CI: 0.049–0.160; P &lt;.0001). The overall incidence of hypertension was noted at 524 (30.95%) in cabozantinib arm vs 84 (8.31%) in control arm. The pooled RR of hypertension was 4.131 (95% CI: 2.656–6.425; P &lt;.0001) and RD was 0.240 (95% CI: 0.186–0.295; P &lt;.0001). High-grade hypertension was reported in 276 (16.30%) in cabozantinib group vs 41 (4.05%) in control group with a RR of 4.324 (95% CI: 2.484–7.525; P &lt;.0001) and RD was 0.115 (95% CI: 0.085–0.144; P &lt;.0001). Conclusion: Our meta-analysis demonstrated that cabozantinib contributed to significant toxicity of any-grade and high-grade PPE as well as hypertension, with a RR of 19.07 for grade 3 and 4 PPE. Recognizing these toxicities and prompt intervention with proper supportive care may enhance patients’ quality of life, ultimately leading to better compliance.
Inflaming the Brain
Authors: Hyung Jin Ahn, Sarah K. Baker, Erin H. Norris, Sidney Strickland
Journal: Neuron (2019)

Exactly how cerebrovascular alterations contribute to Alzheimer's disease (AD) is still unknown. Merlini et al. (2019) show that blood-derived fibrinogen leads to dendritic spine elimination and cognitive deficit via microglial CD11b/CD18. Fibrinogen may be a significant contributor to AD pathogenesis.
Mechanistic models must link the field and the lab
Authors: Alasdair I. Houston, Gaurav Malhotra
Journal: Behavioral and Brain Sciences (2019)

Abstract In the theory outlined in the target article, an animal forages continuously, making sequential decisions in a world where the amount of food and its uncertainty are fixed, but delays are variable. These assumptions contrast with the risk-sensitive foraging theory and create a problem for comparing the predictions of this model with many laboratory experiments that do not make these assumptions.
Brian Wolstan Dixie Crawford
Authors: David Crawford
Journal: BMJ (2019)

My father, Brian Wolstan Dixie Crawford, was born in Washington, County Durham, the son of a history teacher. He attended King’s College (Newcastle Medical School) at Durham University. After house officer posts in the infectious diseases ward at Queen Elizabeth Hospital in Gateshead, where he remembered administering intrathecal streptomycin to patients with tuberculous meningitis, he did national service in Hong Kong. He married …
CRISPR/Cas9-Mediated Disruption of PD-L1 Reduces the T Cell Suppressive Effect of Wharton's Jelly Mesenchymal Stromal Cells and Their Extracellular Vesicles
Authors: Neil Dunavin, Meizhang Li, Safinur Atay, Jim Mitchell, Rupal Soder, Sunil Abhyankar, Joseph P. McGuirk, Andrew K Godwin, Buddhadeb Dawn
Journal: Blood (2018)
Abstract 21098: Variables From the CMS Heart Failure Readmission Model Poorly Predict 30-Day Rehospitalization Risk in Heart Failure Patients From a Large Academic Hospital System
Authors: Antonio L Perez, Kevin Chagin, Alex Milinovich, W.H. Wilson Tang, Michael Kattan, Randall C Starling
Journal: Circulation (2017)

Introduction: Predicting 30 day readmission risk in patients with acute heart failure (HF) remains challenging. As part of the Hospital Readmissions Reduction Program, the Centers for Medicare and Medicaid Services (CMS) has implemented a claims-based 30 day readmission risk model to stratify US hospitals for its HF penalty algorithm, with a reported c-statistic of 0.61. The variables used in this model may be useful in hospitals for predicting readmission risk and informing population health efforts. Methods: We evaluated the discriminatory power of variables from the CMS HF readmission risk model to predict 30 day readmission in patients part of the Cleveland Clinic Heart Failure Registry (n=29,749 hospitalizations), which contains data from all admissions from 2010 to present with a primary diagnosis of HF to all Cleveland Clinic Health System hospitals. The CMS model contains 37 variables including history of HF, ACS, COPD, renal failure (RF) and drug/alcohol abuse. Results: Twenty one percent of our cohort experienced all cause 30 day readmission (n=5109). The median age was 74 (IQR 63-84) and 48% were female. Based on billing codes from the year prior to a HF admission, there was no significant difference in the rates of ACS, RF, active cancer, CVA, dementia and COPD between patients who did and did not experience a 30 day readmission (p&gt;0.05). Using 2010-13 admissions (n=19,904) and 37 variables from the CMS HF readmission model, we derived a 30 day all cause readmission predictive model. We validated this model using 2014-15 admissions (n=9,845). This model had poor discriminatory power in the derivation and validation cohorts (c-statistic=0.51 for both). In a parallel analysis, a bootstrapped model using the entire cohort was created, with a c-statistic of 0.53. The discriminatory power did not improve when the cohort was limited to patients ≥ 65 years (validation c-statistic=0.51). Conclusion: A prediction model derived using claims-based variables from the CMS HF readmission model poorly predicts 30 day all cause readmission in a large hospital system-based cohort, with a validated c-statistic of 0.51. The applicability of CMS’ readmission risk stratification approach to clinical care and local population management efforts in HF is likely limited.
A Comprehensive Review of Overactive Bladder Pathophysiology: On the Way to Tailored Treatment
Authors: Benoit Peyronnet, Emma Mironska, Christopher Chapple, Linda Cardozo, Matthias Oelke, Roger Dmochowski, Gérard Amarenco, Xavier Gamé, Roger Kirby, Frank Van Der Aa, Jean-Nicolas Cornu
Journal: European Urology (2019)
A Delayed Innate T Cell Reconstitution Is Associated with Epstein-Barr Virus Reactivation after Haploidentical Hematopoietic Stem Cell Transplantation Using Anti-Thymoglobulin and High-Dose Post-Transplant Cyclophosphamide
Authors: Nicolas Stocker, Agathe Farge, Laure Ricard, Vincent Jachiet, Clemence Mediavilla, Eolia Brissot, Giorgia Battipaglia, Remy Duléry, Simona Sestili, Annalisa Ruggeri, Razan Mohty, Mohamad Mohty, Béatrice Gaugler, Florent Malard
Journal: Blood (2018)
The D-State
Authors: Ernest L. Hartmann
Journal: New England Journal of Medicine (1965)

THROUGHOUT recorded history man has been fascinated by his dreams, whether he considered them the voyages of his soul, the conveyors of messages from the gods, the perverse products of a poorly oxygenated brain, the psychoses of the sane man or the via regia to the unconscious. Even after Freud's1 great work on dreams, and after it had been accepted that dreams had a meaning in terms of the unconscious wishes of the dreamer, dreaming was considered a fleeting, probably instantaneous phenomenon superimposed on the solid physiologic state of sleep; likewise, the various properties of dreaming, in almost all psychologic . . .
Neutrophil Extracellular Traps Promote Hypercoagulability in ST-Elevated Myocardial Infarction Following Fibrinolytic Administration
Authors: Lili Zou, Hui Liang, LI Hou, Tao Li, Yan Zhang, Baorong LI, Yingmiao LIU, Cong Zhang, Yan Kou, Xinyi Zhao, Ruipeng Liu, Ying Wang, Peng Zhou, Yayan Bi, Jialan Shi, Junjie Kou
Journal: Blood (2018)