tbuckley/cabot-search huggingface dataset:
A curative‐intent endoscopic surgery for postradiation nasopharyngeal necrosis in patients with nasopharyngeal carcinoma
Authors: Xiong Zou, Shun‐Lan Wang, You‐Ping Liu, Yan‐Ling Liu, Ru‐Hai Zou, Yi‐Nuan Zhang, Rui You, Qi Yang, Yu‐Long Xie, Mei Lin, Pei‐Yu Huang, Rou Jiang, Meng‐Xia Zhang, Chao‐Nan Qian, Hai‐Qiang Mai, Ling Guo, Ming‐Huang Hong, Ming‐Yuan Chen
Journal: Cancer Communications (2018)

Abstract Background Postradiation nasopharyngeal necrosis (PRNN) is a severe complication after radiotherapy in patients with nasopharyngeal carcinoma (NPC), which can severely affect the quality of life and threaten the patient's life. Only 13.4%–28.6% of patients can be cured by traditional repeated endoscopic debridement. Here, we introduced an innovative curative‐intent endoscopic surgery for PRNN patients and evaluated its clinical efficacy. Methods Clinical data of 72 PRNN patients who underwent radical endoscopic necrectomy, followed by reconstruction using a posterior pedicle nasal septum and floor mucoperiosteum flap were analyzed to determine the efficacy of this surgery. The endpoints were complete re‐epithelialization of the nasopharyngeal defect, relief of headache, and overall survival (OS). Results All surgeries were successfully performed without any severe postoperative complications or death. The median value of numeric rating scales of pain decreased from 8 before surgery to 0 after surgery ( P &lt; 0.001). Fifty‐one patients (70.8%) achieved complete re‐epithelialization of the nasopharyngeal defect. The number of cycles of radiotherapy (odds ratio [OR], 7.254; 95% confidence interval [CI] 1.035–50.821; P = 0.046), postoperative pathological result (OR, 34.087; 95% CI 3.168–366.746; P = 0.004), and survival status of flap (OR, 261.179; 95% CI 17.176–3971.599; P &lt; 0.001) were independent risk factors of re‐epithelialization of the nasopharyngeal defects. Postoperative pathological result (hazard ratio [HR], 5.018; 95% CI 1.970–12.782; P = 0.001) was an independent prognostic factor for OS. The 2‐year OS rate of the entire cohort was 77.9%. Conclusion Curative‐intent endoscopic necrectomy followed by construction using the posterior pedicle nasal septum and floor mucoperiosteum flap is a novel, safe, and effective treatment of PRNN in patients with NPC.
Drug and Opioid-Involved Overdose Deaths — United States, 2013–2017
Authors: Lawrence Scholl, Puja Seth, Mbabazi Kariisa, Nana Wilson, Grant Baldwin
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

The 63,632 drug overdose deaths in the United States in 2016 represented a 21.4% increase from 2015; two thirds of these deaths involved an opioid (1). From 2015 to 2016, drug overdose deaths increased in all drug categories examined; the largest increase occurred among deaths involving synthetic opioids other than methadone (synthetic opioids), which includes illicitly manufactured fentanyl (IMF) (1). Since 2013, driven largely by IMF, including fentanyl analogs (2-4), the current wave of the opioid overdose epidemic has been marked by increases in deaths involving synthetic opioids. IMF has contributed to increases in overdose deaths, with geographic differences reported (1). CDC examined state-level changes in death rates involving all drug overdoses in 50 states and the District of Columbia (DC) and those involving synthetic opioids in 20 states, during 2013-2017. In addition, changes in death rates from 2016 to 2017 involving all opioids and opioid subcategories,* were examined by demographics, county urbanization levels, and by 34 states and DC. Among 70,237 drug overdose deaths in 2017, 47,600 (67.8%) involved an opioid.† From 2013 to 2017, drug overdose death rates increased in 35 of 50 states and DC, and significant increases in death rates involving synthetic opioids occurred in 15 of 20 states, likely driven by IMF (2,3). From 2016 to 2017, overdose deaths involving all opioids and synthetic opioids increased, but deaths involving prescription opioids and heroin remained stable. The opioid overdose epidemic continues to worsen and evolve because of the continuing increase in deaths involving synthetic opioids. Provisional data from 2018 indicate potential improvements in some drug overdose indicators;§ however, analysis of final data from 2018 is necessary for confirmation. More timely and comprehensive surveillance data are essential to inform efforts to prevent and respond to opioid overdoses; intensified prevention and response measures are urgently needed to curb deaths involving prescription and illicit opioids, specifically IMF.
Abstract 18512: Exercise Test Predicts Non-Cardiovascular Death in a Low Risk Population
Authors: Nóra Sydó, Tibor Sydó, Karina Gonzalez Karta, Béla Merkely, Joseph G Murphy, Francisco Lopez-Jimenez, Thomas G Allison
Journal: Circulation (2017)

Introduction: Total mortality can be predicted by exercise test variables such as functional aerobic capacity (FAC) and heart rate (HR) recovery. The ability of exercise test variables to predict r...
Chemoimmunotherapy for Triple-Negative Breast Cancer
Authors: Anita Slomski
Journal: JAMA (2018)

A chemoimmunotherapy combination with the programmed death ligand 1 (PD-L1) inhibitor atezolizumab prolonged progression-free survival in women with metastatic triple-negative breast cancer, an aggressive cancer with poor outcomes, according to a trial in the New England Journal of Medicine.
Dual‐Specificity Phosphatase 9 Protects Against Nonalcoholic Fatty Liver Disease in Mice Through ASK1 Suppression
Authors: Ping Ye, Mei Xiang, Hua Liao, Jijun Liu, Hongbo Luo, Yayun Wang, Ling Huang, Manhua Chen, Jiahong Xia
Journal: Hepatology (2018)

Nonalcoholic fatty liver disease (NAFLD), ranging from nonalcoholic fatty liver to nonalcoholic steatohepatitis (NASH), is the leading cause of chronic liver diseases. Until now, no medications for NAFLD have been approved by relevant governmental agencies. Dual-specificity phosphatase 9 (Dusp9) is a member of the DUSP protein family. Dusp9 is expressed in insulin-sensitive tissues, and its expression may be modified with the development of insulin resistance (IR). However, the molecular targets and mechanisms of Dusp9 action on NAFLD and NASH remain poorly understood. In this study, using conditional liver-specific Dusp9-knockout (Dusp9-CKO) mice and Dusp9-transgenic mice, we showed that Dusp9 was a key suppressor of high-fat diet–induced hepatic steatosis and inflammatory responses and that Dusp9 deficiency aggravated high-fat high-cholesterol diet–induced liver fibrosis. Dusp9 was shown to exert its effects by blocking apoptosis signal–regulating kinase 1 (ASK1) phosphorylation and the subsequent activation of p38 and c-Jun NH2-terminal kinase signaling. Conclusion: Hepatocyte Dusp9 prevents NAFLD and NASH progression in mice, including lipid accumulation, glucose metabolism disorders, and enhanced inflammation and liver fibrosis, in an ASK1-dependent manner; these findings suggest that Dusp9 may be a promising therapeutic target for the treatment of NAFLD and NASH.
Dose-Response-Time Data Analysis: An Underexploited Trinity
Authors: Johan Gabrielsson, Robert Andersson, Mats Jirstrand, Stephan Hjorth
Journal: Pharmacological Reviews (2018)

The most common approach to in vivo pharmacokinetic and pharmacodynamic analyses involves sequential analysis of the plasma concentration<i>-</i> and response<i>-</i>time data, such that the plasma kinetic model provides an independent function, driving the dynamics. However, in situations when plasma sampling may jeopardize the effect measurements or is scarce, nonexistent, or unlinked to the effect (e.g., in intensive care units, pediatric or frail elderly populations, or drug discovery), focusing on the response-time course alone may be an adequate alternative for pharmacodynamic analyses. Response-time data inherently contain useful information about the turnover characteristics of response (target turnover rate, half-life of response), as well as the drug's biophase kinetics (biophase availability, absorption half-life, and disposition half-life) pharmacodynamic properties (potency, efficacy). The use of pharmacodynamic time-response data circumvents the need for a direct assay method for the drug and has the additional advantage of being applicable to cases of local drug administration close to its intended targets in the immediate vicinity of target, or when target precedes systemic plasma concentrations. This review exemplifies the potential of biophase functions in pharmacodynamic analyses in both preclinical and clinical studies, with the purpose of characterizing response data and optimizing subsequent study protocols. This article illustrates crucial determinants to the success of modeling dose-response-time (DRT) data, such as the dose selection, repeated dosing, and different input rates and routes. Finally, a literature search was also performed to gauge how frequently this technique has been applied in preclinical and clinical studies. This review highlights situations in which DRT should be carefully scrutinized and discusses future perspectives of the field.
Abstract 15312: Predictors for Defibrillator Therapy in Modern Urban Cohort of Patients With Heart Failure
Authors: Christian Abrahim, Jesse Kane, Jack Kurtz, Sridesh Nath, Granit Veseli, Adam Budzikowski
Journal: Circulation (2018)

Introduction: African Americans (AA) have been under-represented in landmark ICD trials and the impact of co-morbidities and medications on sudden cardiac death (SCD) and ventricular arrhythmias is...
Non-Effectiveness of Using RICE Post RDHAP or RDHAP Post RICE after Failure of First Line Salvage Therapy in DLBCL Patients Who Are Eligible for ASCT
Authors: Tony Ibrahim, Tarek Assi, Julien Lazarovici, Maxime Annereau, David Ghez, Jean-Marie Michot, Julia Arfi-Rouche, Julien Rossignol, Veronique Vergé, Jacques Bosq, Peggy Dartigues-Cuillères, Alina Danu, Vincent Ribrag
Journal: Blood (2018)
Effect of green tea catechins in prostate cancer chemoprevention.
Authors: Nagi B. Kumar, Julio Pow-Sang, Kathleen Egan, Philippe E. Spiess, Shohreh I Dickinson, Raoul Salup, Mohamed Helal, Jerry McLarty, Christopher R Williams, Fred James Schreiber, Howard Parnes, Said Sebti, Aslam Kazi, Loveleen Kang, Gwendolyn P. Quinn, Tiffany Smith, Binglin Yue, Ganna Chornokur, Theresa Crocker, Michael J. Schell
Journal: Journal of Clinical Oncology (2015)

1572 Background: Preclinical, epidemiological and prior clinical trial data suggest that green tea catechins may reduce prostate cancer (PCa) risk. Methods: We, therefore, conducted a placebo-controlled, randomized clinical trial of one year of Polyphenon E (PolyE), a proprietary mixture of green tea catechins containing 400 mgs of epigallocatechin-3-gallate (EGCG) per day, in 97 men with high-grade prostatic intraepithelial neoplasia (HGPIN) or atypical small acinar proliferstion (ASAP) on prostate biopsy. The primary study endpoint was the total number of PCa diagnoses on the PolyE versus placebo arm at one year. Results: No differences in prostate cancer rates were observed in the two groups (4/49 PolyE vs 6/48 placebo, P = 0.25). A prespecified analysis comparing the combined rates of PCa + ASAP in the subgroup of men with HGPIN-only at baseline, showed a decrease in this composite endpoint (3/26 PolyE vs 10/25 placebo, P < 0.024). This was largely driven by a reduction in ASAP (0/26 PolyE vs 5/25 placebo). In another prespecified analysis, a decrease in serum PSA was observed the PolyE arm.(-0.90 ng/mL; 95% CI:-1.67, -0.12; P < 0.05). Adverse events related to the study agent did not significantly differ between the two study groups. Conclusions: Daily intake of a standardized, decaffeinated catechin mixture containing 400 mgs EGCG per day for 1 year accumulated in plasma and was well tolerated, but did not reduce the likelihood of a subsequent PCa diagnosis in men with baseline HGPIN or ASAP over this period of time. Clinical trial information: NCT00596011.
FUNDC2 regulates platelet activation through AKT/GSK-3β/cGMP axis
Authors: Qi Ma, Weilin Zhang, Chongzhuo Zhu, Junling Liu, Quan Chen
Journal: Cardiovascular Research (2018)

AKT kinase is vital for regulating signal transduction in platelet aggregation. We previously found that mitochondrial protein FUNDC2 mediates phosphoinositide 3-kinase (PI3K)/phosphatidylinositol-3,4,5-trisphosphate (PIP3)-dependent AKT phosphorylation and regulates platelet apoptosis. The aim of this study was to evaluate the role of FUNDC2 in platelet activation and aggregation.We demonstrated that FUNDC2 deficiency diminished platelet aggregation in response to a variety of agonists, including adenosine 5'-diphosphate (ADP), collagen, ristocetin/VWF, and thrombin. Consistently, in vivo assays of tail bleeding and thrombus formation showed that FUNDC2-knockout mice displayed deficiency in haemostasis and thrombosis. Mechanistically, FUNDC2 deficiency impairs the phosphorylation of AKT and downstream GSK-3β in a PI3K-dependent manner. Moreover, cGMP also plays an important role in FUNDC2/AKT-mediated platelet activation. This FUNDC2/AKT/GSK-3β/cGMP axis also regulates clot retraction of platelet-rich plasma.FUNDC2 positively regulates platelet functions via AKT/GSK-3β/cGMP signalling pathways, which provides new insight for platelet-related diseases.
Direct Targeting of <i>MYCN</i> Gene Amplification by Site-Specific DNA Alkylation in Neuroblastoma
Authors: Hiroyuki Yoda, Takahiro Inoue, Yoshinao Shinozaki, Jason Lin, Takayoshi Watanabe, Nobuko Koshikawa, Atsushi Takatori, Hiroki Nagase
Journal: Cancer Research (2018)

Abstract Amplification of MYCN plays a pivotal role in multiple types of tumors and correlates with poor prognosis in high-risk neuroblastoma. Despite recent advances in the treatment of neuroblastoma, no approaches directly target the master oncogene MYCN. Difficulties in targeting the MYCN protein inspired us to develop a new gene-level–inhibitory strategy using a sequence-specific gene regulator. Here, we generated a MYCN-targeting pyrrole-imidazole (PI) polyamide, MYCN-A3, which directly binds to and alkylates DNA at homing motifs within the MYCN transcript. Pharmacologic suppression of MYCN inhibited the proliferation of cancer cells harboring MYCN amplification compared with MYCN nonamplified cancer cells. In neuroblastoma xenograft mouse models, MYCN-A3 specifically downregulated MYCN expression and suppressed tumor progression with no detectable adverse effects and resulted in prolonged overall survival. Moreover, treatment with MYCN-A3, but not MYCN nontargeting PI polyamide, precipitated a copy number reduction of MYCN in neuroblastoma cells with MYCN amplification. These findings suggest that directly targeting MYCN with MYCN-A3 is a novel therapeutic approach to reduce copy number of the MYCN gene for MYCN-amplified neuroblastoma. Significance: This study presents a novel approach to drugging an amplified oncogene by showing that targeting gene amplification of MYCN suppresses MYCN expression and neuroblastoma growth.
Open-Label, Phase 2 Study of Blinatumomab As Second Salvage Therapy in Adults with Relapsed/Refractory Aggressive B-Cell Non-Hodgkin Lymphoma
Authors: Luke Coyle, Nicholas J. Morley, Alessandro Rambaldi, Kylie D. Mason, Gregor Verhoef, Caroline Furness, Alicia Zhang, A. Scott Jung, Janet L. Franklin
Journal: Blood (2018)
Response to: ‘OCTA, a sensitive screening for asymptomatic retinopathy, raises alarm over systemic involvements in patients with SLE’ by Mizuno et <i>al</i>
Authors: Paola Conigliaro, Massimo Cesareo, Maria Sole Chimenti, Paola Triggianese, Claudia Canofari, Gianluca Aloe, Carlo Nucci, Roberto Perricone
Journal: Annals of the Rheumatic Diseases (2018)

We read with interest the letter titled ‘OCTA, a sensitive screening for asymptomatic retinopathy, raises alarm over systemic involvements in patients with SLE’ by Mizuno et al published in the Annals of the Rheumatic Diseases .1 In the letter, the authors pointed out that retinal vasculitis is an important manifestation of systemic lupus erythematosus (SLE), even if the patient is asymptomatic. Furthermore, they claim that patients with abnormal eye findings should be closely followed. We agree with Mizuno et al considering the non-invasive nature of optical coherence tomography angiography (OCTA), the reliability, and that high-resolution images of the retinal vasculature can be obtained approaching histology-level resolution. OCTA seems to …
Reply to Chandrasekhar: Socioeconomic Disparities and Health Outcomes
Authors: Sarath Raju, Corinne A. Keet, Laura M. Paulin, Elizabeth C. Matsui, Roger D. Peng, Nadia N. Hansel, Meredith C. McCormack
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

area-based measures.Although the availability of public datasets such as that provided by the U.S. Census make such investigations possible, it must be emphasized that their implementation is challenging.Several resources, such as the Public Health Disparities Geocoding Project (6), are available to provide guidance on techniques to conduct research on socioeconomic gradients in health.
Origin, Organization, Dynamics, and Function of Actin and Actomyosin Networks at the T Cell Immunological Synapse
Authors: John A. Hammer, Jia C. Wang, Mezida Saeed, Antonio T. Pedrosa
Journal: Annual Review of Immunology (2018)

The engagement of a T cell with an antigen-presenting cell (APC) or activating surface results in the formation within the T cell of several distinct actin and actomyosin networks. These networks reside largely within a narrow zone immediately under the T cell's plasma membrane at its site of contact with the APC or activating surface, i.e., at the immunological synapse. Here we review the origin, organization, dynamics, and function of these synapse-associated actin and actomyosin networks. Importantly, recent insights into the nature of these actin-based cytoskeletal structures were made possible in several cases by advances in light microscopy.
Lifestyle modifications: coordinating the tRNA epitranscriptome with codon bias to adapt translation during stress responses
Authors: Cheryl Chan, Phuong Pham, Peter C. Dedon, Thomas J. Begley
Journal: Genome biology (2018)

Cells adapt to stress by altering gene expression at multiple levels. Here, we propose a new mechanism regulating stress-dependent gene expression at the level of translation, with coordinated interplay between the tRNA epitranscriptome and biased codon usage in families of stress-response genes. In this model, auxiliary genetic information contained in synonymous codon usage enables regulation of codon-biased and functionally related transcripts by dynamic changes in the tRNA epitranscriptome. This model partly explains the association between synchronous stress-dependent epitranscriptomic marks and significant multi-codon usage skewing in families of translationally regulated transcripts. The model also predicts translational adaptation during viral infections.
Abstract 19830: Role of Nlrp3 Inflammasomes in Aggravation of Atherosclerosis and Xanthoma in Hyperlipidemic Mice Lacking Acyl Coa Cholesterol Acyltransferase 1 (acat1) in Bone Marrow
Authors: Tetsuji Wakabayashi, Manabu Takahashi, Shuichi Nagashima, Ken Ebihara, Masafumi Takahashi, Shun Ishibashi
Journal: Circulation (2017)

Background: ACAT1 catalyzes esterification of cellular free cholesterol, thereby converting macrophages to lipid-laden foam cells in atherosclerotic lesions and xanthoma. We reported that ACAT1 def...
Translational assessment of the efficacy of CPI-613 against pancreatic cancer in animal models versus patients with stage IV disease.
Authors: Avi S. Retter
Journal: Journal of Clinical Oncology (2012)

3075 Background: CPI-613 is a novel agent that selectively targets the altered mitochondrial enzymes of tumor cells, causing apoptosis, necrosis, and autophagia. Results assessing clinical efficacy of CPI-613 translated from animal tumor xenograft models to patients with stage IV pancreatic cancer are presented. Methods: Efficacy of CPI-613 was tested in mice with pancreatic tumor xenografts generated by inoculation of BxPC-3 human pancreatic tumor cells. The safety and efficacy of CPI-613 (70-320 mg/m 2 ), when used in combination with gemcitabine (1,000 mg/m 2 ), was assessed in patients with stage IV pancreatic cancer. Results: In the animal pancreatic tumor xenograft model (n=10/grp), CPI-613 (25 mg/kg, IV, 1x weekly for 4 weeks) suppressed tumor growth by ~100%, when compared to vehicle. The positive control, gemcitabine (50 mg/kg, IV, 1x weekly for 4 weeks), suppressed tumor growth by only ~50%. Median overall survival in tumor-bearing mice treated with CPI-613 was ~240 days, which was significantly longer than those with gemcitabine or vehicle treatments (~65 and ~50 days, respectively). In 6 humans with stage IV pancreatic cancer (Table), the CPI-613+gemcitabine combination was well-tolerated. In those without prior chemotherapy before participating in the clinical trial (first three patients in the table), the CPI-613+gemcitabine combination prolonged survival that correlated with the dose of CPI-613. Conclusions: CPI-613 exhibits efficacy against pancreatic cancer in animal models, which is translational to patients with stage IV disease. [Table: see text]
Abstract 16785: Atrial Fibrillation Clinical Phenotypes: A Cluster Analysis
Authors: Taku Inohara, Peter Shrader, Karen Pieper, Rosalia G Blanco, Laine Thomas, Daniel E Singer, James V Freeman, Larry A Allen, Gregg C Fonarow, Bernard J Gersh, Michael D Ezekowitz, Peter R Kowey, James A Reiffel, Gerald V Naccarelli, Paul S Chan, Benjamin A Steinberg, Eric D Peterson, Jonathan P Piccini
Journal: Circulation (2017)

Background: — Atrial fibrillation (AF) is usually classified on the basis of duration and frequency, however these may not capture the heterogeneity of AF. We sought to derive a cluster analysis-ba...
Phenotype and function of HBV-specific T cells is determined by the targeted epitope in addition to the stage of infection
Authors: Ruben C Hoogeveen, Maxwell P Robidoux, Tatjana Schwarz, Laura Heydmann, James A Cheney, Daniel Kvistad, Jasneet Aneja, Juliana G Melgaço, Carlos A Fernandes, Raymond T Chung, Andre Boonstra, Arthur Y Kim, Thomas F Baumert, Jörg Timm, Lia L Lewis-Ximenez, Pierre Tonnerre, Georg M Lauer
Journal: Gut (2018)

Objective Chronic HBV infection affects more than 250 million people worldwide and remains a global healthcare problem in part because we lack curative treatment. Sustained viral control requires HBV-specific T cells, but these become functionally impaired in chronic infection. Clinical evidence indicates that functional cure of HBV infection by the host immune response is feasible. Developing T cell-based therapies able to achieve functional cure will require identification of the requirements for a successful T cell response against HBV and the relative contribution of individual T cell specificities to HBV control. Design The phenotype and function of HBV-specific T cells were studied directly ex vivo using fluorochrome-labelled multimers. We studied multiple HBV-specific T cell specificities targeting different HBV proteins in individuals with either an acute self-limiting or chronic HBV infection. Results We detected strong T cell responses targeting multiple HBV viral proteins in acute self-limiting and low-frequency core and polymerase-specific T cells in chronic infection. Expression of the T cell inhibitory receptor PD-1, as well as T cell differentiation, T cell function and T cell regulation differed by stages and outcomes of infection. In addition, these features differed significantly between T cells targeting different HBV specificities. Conclusion HBV-specific T cells with different target specificities are characterised by distinct phenotypical and functional profiles. These results have direct implications for the design of immunological studies in HBV infection, and are potentially relevant for informing immunotherapeutic approaches to induce functional cure.