tbuckley/cabot-search huggingface dataset:
Epigenetic regulation in human cancer: the potential role of epi-drug in cancer therapy
Authors: Yuanjun Lu, Yau-Tuen Chan, Hor-Yue Tan, Sha Li, Ning Wang, Yibin Feng
Journal: Molecular Cancer (2020)

Abstract Epigenetics is dynamic and heritable modifications to the genome that occur independently of DNA sequence. It requires interactions cohesively with various enzymes and other molecular components. Aberrant epigenetic alterations can lead to inappropriate onset of genetic expressions and promote tumorigenesis. As the epigenetic modifiers are susceptible to extrinsic factors and reversible, they are becoming promising targets in multiple cancer therapies. Recently, various epi-drugs have been developed and implicated in clinical use. The use of epi-drugs alone, or in combination with chemotherapy or immunotherapy, has shown compelling outcomes, including augmentation of anti-tumoral effects, overcoming drug resistance, and activation of host immune response.
Factors associated with complete clearance of difficult common bile duct stones after temporary biliary stenting followed by a second ERCP: a multicenter, retrospective, cohort study
Authors: Dong Kee Jang, Sang Hyub Lee, Dong Won Ahn, Woo Hyun Paik, Jae Min Lee, Jun Kyu Lee, Ji Kon Ryu, Yong-Tae Kim
Journal: Endoscopy (2020)

Abstract Background Although temporary endoscopic biliary stenting is considered effective for difficult common bile duct (CBD) stones, few studies have investigated the optimal conditions for complete stone clearance at the second endoscopic retrograde cholangiopancreatography (ERCP) after temporary biliary stenting. We aimed to evaluate factors associated with complete clearance. Methods Patients with difficult CBD stones (a large [≥ 20 mm] or multiple [≥ 3 sized ≥ 15 mm] CBD stones) were retrospectively enrolled from three institutions. Patients who underwent temporary biliary stenting at the first ERCP were analyzed. Double-pigtail plastic stents (7 or 10 Fr) were placed with the proximal ends above the stones. Complete clearance rate and stone size reduction at the second ERCP, and factors associated with complete clearance were evaluated using univariate and multivariate analyses. Results 85 patients were enrolled (mean age 74.5 years [SD 11.3]; 47 women). Stone size and CBD diameter significantly decreased during the interval. The overall complete stone clearance rate was 64.7 % (55/85) at the second ERCP. The mean stone size reduction was 5.6 mm (SD 6.8). In multivariate analysis, complete clearance rate was significantly lower in male patients, in patients aged &gt; 80 years, and in stones &gt; 25 mm initially, but was significantly higher when 7-Fr stents were placed and stone size was reduced by &gt; 5 mm. Conclusion Use of 7-Fr rather than 10-Fr plastic stents was beneficial for complete clearance of difficult CBD stones after temporary biliary stenting; older male patients as well as patients with initial stones &gt; 25 mm had a lower clearance rate.
Listeria Phages Induce Cas9 Degradation to Protect Lysogenic Genomes
Authors: Beatriz A. Osuna, Shweta Karambelkar, Caroline Mahendra, Kathleen A. Christie, Bianca Garcia, Alan R. Davidson, Benjamin P. Kleinstiver, Samuel Kilcher, Joseph Bondy-Denomy
Journal: Cell Host & Microbe (2020)
KCNQ1 Antibodies for Immunotherapy of Long QT Syndrome Type 2
Authors: Ange Maguy, Jan P. Kucera, Jonas P. Wepfer, Virginie Forest, Flavien Charpentier, Jin Li
Journal: Journal of the American College of Cardiology (2020)

Patients with long QT syndrome (LQTS) are predisposed to life-threatening arrhythmias. A delay in cardiac repolarization is characteristic of the disease. Pharmacotherapy, implantable cardioverter-defibrillators, and left cardiac sympathetic denervation are part of the current treatment options, but no targeted therapy for LQTS exists to date. Previous studies indicate that induced autoimmunity against the voltage-gated KCNQ1 K+ channels accelerates cardiac repolarization.However, a causative relationship between KCNQ1 antibodies and the observed electrophysiological effects has never been demonstrated, and thus presents the aim of this study.The authors purified KCNQ1 antibodies and performed whole-cell patch clamp experiments as well as single-channel recordings on Chinese hamster ovary cells overexpressing IKs channels. The effect of purified KCNQ1 antibodies on human cardiomyocytes derived from induced pluripotent stem cells was then studied.The study demonstrated that KCNQ1 antibodies underlie the previously observed increase in repolarizing IKs current. The antibodies shift the voltage dependence of activation and slow the deactivation of IKs. At the single-channel level, KCNQ1 antibodies increase the open time and probability of the channel. In models of LQTS type 2 (LQTS2) using human induced pluripotent stem cell-derived cardiomyocytes, KCNQ1 antibodies reverse the prolonged cardiac repolarization and abolish arrhythmic activities.Here, the authors provide the first direct evidence that KCNQ1 antibodies act as agonists on IKs channels. Moreover, KCNQ1 antibodies were able to restore alterations in cardiac repolarization and most importantly to suppress arrhythmias in LQTS2. KCNQ1 antibody therapy may thus present a novel promising therapeutic approach for LQTS2.
Increased activation of HDAC1/2/6 and Sp1 underlies therapeutic resistance and tumor growth in glioblastoma
Authors: Wen-Bin Yang, Che-Chia Hsu, Tsung-I Hsu, Jing-Ping Liou, Kwang-Yu Chang, Pin-Yuan Chen, Jr-Jiun Liu, Shung-Tai Yang, Jia-Yi Wang, Shiu-Hwa Yeh, Ruei-Ming Chen, Wen-Chang Chang, Jian-Ying Chuang
Journal: Neuro-Oncology (2020)

Glioblastoma is associated with poor prognosis and high mortality. Although the use of first-line temozolomide can reduce tumor growth, therapy-induced stress drives stem cells out of quiescence, leading to chemoresistance and glioblastoma recurrence. The specificity protein 1 (Sp1) transcription factor is known to protect glioblastoma cells against temozolomide; however, how tumor cells hijack this factor to gain resistance to therapy is not known.Sp1 acetylation in temozolomide-resistant cells and stemlike tumorspheres was analyzed by immunoprecipitation and immunoblotting experiments. Effects of the histone deacetylase (HDAC)/Sp1 axis on malignant growth were examined using cell proliferation-related assays and in vivo experiments. Furthermore, integrative analysis of gene expression with chromatin immunoprecipitation sequencing and the recurrent glioblastoma omics data were also used to further determine the target genes of the HDAC/Sp1 axis.We identified Sp1 as a novel substrate of HDAC6, and observed that the HDAC1/2/6/Sp1 pathway promotes self-renewal of malignancy by upregulating B cell-specific Mo-MLV integration site 1 (BMI1) and human telomerase reverse transcriptase (hTERT), as well as by regulating G2/M progression and DNA repair via alteration of the transcription of various genes. Importantly, HDAC1/2/6/Sp1 activation is associated with poor clinical outcome in both glioblastoma and low-grade gliomas. However, treatment with azaindolyl sulfonamide, a potent HDAC6 inhibitor with partial efficacy against HDAC1/2, induced G2/M arrest and senescence in both temozolomide-resistant cells and stemlike tumorspheres.Our study uncovers a previously unknown regulatory mechanism in which the HDAC6/Sp1 axis induces cell division and maintains the stem cell population to fuel tumor growth and therapeutic resistance.
Abstract MP07: Parathyroid Hormone is Associated with Higher Risk of Cardiovascular Diseases: A Systematic Review and Meta-analysis
Authors: Adriana J van Ballegooijen, Ilse Reinders, Marjolein Visser, Ingeborg A Brouwer
Journal: Circulation (2013)

Introduction Parathyroid hormone (PTH) excess might play a role in cardiovascular health and is associated with cardiovascular disease (CVD) events. We conducted a systematic review to synthesize a...
Caution Needed on the Use of Chloroquine and Hydroxychloroquine for Coronavirus Disease 2019
Authors: Stephan D. Fihn, Eli Perencevich, Steven M. Bradley
Journal: JAMA Network Open (2020)

Mayla Gabriela Silva Borba, MD; Fernando Fonseca Almeida Val, PhD; Vanderson Souza Sampaio, PhD; Marcia Almeida Araújo Alexandre, MD; Gisely Cardoso Melo, PhD; Marcelo Brito, MSc; Maria Paula Gomes Mourão, MD; José Diego Brito-Sousa, MSc; Djane Baía-da-Silva, PhD; Marcus Vinitius Farias Guerra, MD; Ludhmila Abrahão Hajjar, MD; Rosemary Costa Pinto, BSc; Antonio Alcirley Silva Balieiro, MSc; Antônio Guilherme Fonseca Pacheco, MD; James Dean Oliveira Santos Jr, PhD; Felipe Gomes Naveca, PhD; Mariana Simão Xavier, MSc; André Machado Siqueira, MD; Alexandre Schwarzbold, MD; Júlio Croda, MD; Maurício Lacerda Nogueira, MD; Gustavo Adolfo Sierra Romero, MD; Quique Bassat, MD; Cor Jesus Fontes, MD; Bernardino Cláudio Albuquerque, MD; Cláudio-Tadeu Daniel-Ribeiro, MD; Wuelton Marcelo Monteiro, PhD; Marcus Vinícius Guimarães Lacerda, MD; for the CloroCovid-19 Team
Association Between Spatial Heterogeneity Within Nonmetastatic Gastroesophageal Adenocarcinomas and Survival
Authors: Joseph Chao, Victoria Bedell, Jeeyun Lee, Min Sierra Li, Peiguo Chu, Yate-Ching Yuan, Dan Zhao, Samuel J. Klempner, Ren-Jang Lin
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Intratumoral heterogeneity has been recognized as a significant barrier in successfully developing targetable biomarkers for gastroesophageal adenocarcinoma (GEA) and may affect neoadjuvant precision medicine approaches. <h3>Objective</h3> To describe intratumoral spatial heterogeneity of tumor cell populations in nonmetastatic GEA and its association with survival. <h3>Design, Setting, and Participants</h3> This case series retrospectively identified 41 patients with GEA who underwent up-front surgical resection at a tertiary referral cancer center from January 1, 1989, through December 31, 2013. Survival was calculated from date of surgery to date of death through June 1, 2017. Data were analyzed from June 2, 2017, to March 1, 2019. <h3>Main Outcomes and Measures</h3> Overall survival, intratumoral clonal composition determined by genomic single-nucleotide variation array and bioinformatic analysis, and intercellular tumoral distances determined by multiprobe fluorescence in situ hybridization. <h3>Results</h3> Among the 41 patients included in the analysis (22 men [54%]; mean [SD] age, 63 [12] years), a high proportion (19 [46%]) presented with tumors possessing high intratumoral heterogeneity. Kaplan-Meier analysis demonstrated that cases with an intratumoral clonal composition count of at least 2 exhibited worse survival compared with cases with a clonal composition count of 0 to 1 (univariate hazard ratio, 3.92; 95% CI, 1.27-12.08;<i>P</i> = .02). This finding remained significant on multivariate analysis controlling for stage, Lauren histologic subtype, receipt of adjuvant therapy, and age (multivariate hazard ratio, 4.55; 95% CI, 1.09-19.04;<i>P</i> = .04). Multiprobe fluorescence in situ hybridization demonstrated intratumoral clonal populations coexisting at submillimeter distances with differing relevant oncogenic copy number alterations, such as<i>EGFR</i>,<i>JAK2</i>,<i>FGFR2</i>,<i>MET</i>,<i>CCND1</i>,<i>KRAS</i>,<i>MYC</i>,<i>PIK3CA</i>,<i>CD274</i>, and<i>PDCD1LG2</i>. <h3>Conclusions and Relevance</h3> This study found that spatial intratumoral heterogeneity of oncogenic copy number alterations exists before metastatic dissemination, and increased heterogeneity was associated with worse outcomes in resected GEA. Baseline heterogeneity illustrates the challenges in GEA targeted therapy. Further study may offer insight into strategies on combinatorial and/or sequential targeted and immunotherapeutic approaches.
Targeting the HTLV-I-Regulated BATF3/IRF4 Transcriptional Network in Adult T-Cell Leukemia/Lymphoma
Authors: Masao Nakagawa, Arthur L Shaffer, Michele Ceribelli, Meili Zhang, George Wright, Da Wei Huang, Wenming Xiao, John Powell, Michael N Petrus, Yibin Yang, James D Phelan, Holger Kohlhammer, Hee Min Yoo, Yandan Yang, Weihong Xu, Xin Yu, Hong Zhao, Bonita R Bryant, Michiyuki Maeda, Thomas A Waldmann, Lou Staudt
Journal: Blood (2017)
Deletions within the LMP1 oncogene of Epstein-Barr virus are clustered in Hodgkin's disease and identical to those observed in nasopharyngeal carcinoma
Authors: H Knecht, E Bachmann, P Brousset, K Sandvej, D Nadal, F Bachmann, BF Odermatt, G Delsol, G Pallesen
Journal: Blood (1993)
Orthotopic Bone Regeneration within 3D Printed Bioceramic Scaffolds with Region‐Dependent Porosity Gradients in an Equine Model
Authors: Paweena Diloksumpan, Rafael Vindas Bolaños, Stefan Cokelaere, Behdad Pouran, Janny de Grauw, Mattie van Rijen, René van Weeren, Riccardo Levato, Jos Malda
Journal: Advanced Healthcare Materials (2020)

The clinical translation of three-dimensionally printed bioceramic scaffolds with tailored architectures holds great promise toward the regeneration of bone to heal critical-size defects. Herein, the long-term in vivo performance of printed hydrogel-ceramic composites made of methacrylated-oligocaprolactone-poloxamer and low-temperature self-setting calcium-phosphates is assessed in a large animal model. Scaffolds printed with different internal architectures, displaying either a designed porosity gradient or a constant pore distribution, are implanted in equine tuber coxae critical size defects. Bone ingrowth is challenged and facilitated only from one direction via encasing the bioceramic in a polycaprolactone shell. After 7 months, total new bone volume and scaffold degradation are significantly greater in structures with constant porosity. Interestingly, gradient scaffolds show lower extent of remodeling and regeneration even in areas having the same porosity as the constant scaffolds. Low regeneration in distal regions from the interface with native bone impairs ossification in proximal regions of the construct, suggesting that anisotropic architectures modulate the cross-talk between distant cells within critical-size defects. The study provides key information on how engineered architectural patterns impact osteoregeneration in vivo, and also indicates the equine tuber coxae as promising orthotopic model for studying materials stimulating bone formation.
Comparative Analysis of Osteoclast Lineage Cre-Drivers and Identification of Novel Osteoclast Lineage Selective Genes
Authors: Megan M Weivoda, Katharina Jaehn, Matthew Prideaux, Ming Ruant, Christine Hachfeldt, Larry Pederson, Rachel Ann Davey, Sundeep Khosla, Lynda F Bonewald, Merry Jo Oursler
Journal: Endocrine Reviews (2014)
Thyroid Hormone Signaling and the Liver
Authors: Megan J. Ritter, Izuki Amano, Anthony N. Hollenberg
Journal: Hepatology (2020)

Thyroid hormone (TH) plays a critical role in maintaining metabolic homeostasis throughout life. It is well known that the liver and thyroid are intimately linked, with TH playing important roles in de novo lipogenesis, beta‐oxidation (fatty acid oxidation), cholesterol metabolism, and carbohydrate metabolism. Indeed, patients with hypothyroidism have abnormal lipid panels with higher levels of low‐density lipoprotein levels, triglycerides (triacylglycerol; TAG), and apolipoprotein B levels. Even in euthyroid patients, lower serum‐free thyroxine levels are associated with higher total cholesterol levels, LDL, and TAG levels. In addition to abnormal serum lipids, the risk of nonalcoholic fatty liver disease (NAFLD) increases with lower free thyroxine levels. As free thyroxine rises, the risk of NAFLD is reduced. This has led to numerous animal studies and clinical trials investigating TH analogs and TH receptor agonists as potential therapies for NAFLD and hyperlipidemia. Thus, TH plays an important role in maintaining hepatic homeostasis, and this continues to be an important area of study. A review of TH action and TH actions on the liver will be presented here.
Effective coverage measurement in maternal, newborn, child, and adolescent health and nutrition: progress, future prospects, and implications for quality health systems
Authors: Andrew D Marsh, Moise Muzigaba, Theresa Diaz, Jennifer Requejo, Debra Jackson, Doris Chou, Jenny A Cresswell, Regina Guthold, Allisyn C Moran, Kathleen L Strong, Anshu Banerjee, Agnès Soucat
Journal: The Lancet Global Health (2020)

Intervention coverage—the proportion of the population with a health-care need who receive care—does not account for intervention quality and potentially overestimates health benefits of services provided to populations. Effective coverage introduces the dimension of quality of care to the measurement of intervention coverage. Many definitions and methodological approaches to measuring effective coverage have been developed, resulting in confusion over definition, calculation, interpretation, and monitoring of these measures. To develop a consensus on the definition and measurement of effective coverage for maternal, newborn, child, and adolescent health and nutrition (MNCAHN), WHO and UNICEF convened a group of experts, the Effective Coverage Think Tank Group, to make recommendations for standardising the definition of effective coverage, measurement approaches for effective coverage, indicators of effective coverage in MNCAHN, and to develop future effective coverage research priorities. Via a series of consultations, the group recommended that effective coverage be defined as the proportion of a population in need of a service that resulted in a positive health outcome from the service. The proposed effective coverage measures and care cascade steps can be applied to further develop effective coverage measures across a broad range of MNCAHN services. Furthermore, advances in measurement of effective coverage could improve monitoring efforts towards the achievement of universal health coverage.
Effect of Dexrazoxane on Left Ventricular Systolic Function and Treatment Outcomes in Patients With Acute Myeloid Leukemia: A Report From the Children’s Oncology Group
Authors: Kelly D. Getz, Lillian Sung, Todd A. Alonzo, Kasey J. Leger, Robert B. Gerbing, Jessica A. Pollard, Todd Cooper, E. Anders Kolb, Alan S. Gamis, Bonnie Ky, Richard Aplenc
Journal: Journal of Clinical Oncology (2020)

PURPOSE To determine whether dexrazoxane provides effective cardioprotection during frontline treatment of pediatric acute myeloid leukemia (AML) without increasing relapse risk or noncardiac toxicities of the chemotherapy regimens. PATIENTS AND METHODS This was a multicenter study of all pediatric patients with AML without high allelic ratio FLT3/ITD treated in the Children’s Oncology Group trial AAML1031 between 2011 and 2016. Median follow-up was 3.5 years. Dexrazoxane was administered at the discretion of treating physicians and documented at each course. Ejection fraction (EF) and shortening fraction (SF) were recorded after each course and at regular intervals in follow-up. Per protocol, anthracyclines were to be withheld if there was evidence of left ventricular systolic dysfunction (LVSD) defined as SF &lt; 28% or EF &lt; 55%. Occurrence of LVSD, trends in EF and SF, 5-year event-free survival (EFS) and overall survival (OS), and treatment-related mortality (TRM) were compared by dexrazoxane exposure. RESULTS A total of 1,014 patients were included in the analyses; 96 were exposed to dexrazoxane at every anthracycline course, and 918 were never exposed. Distributions of sex, age, race, presenting WBC count, risk group, treatment arm, and compliance with cardiac monitoring were similar for dexrazoxane-exposed and -unexposed patients. Dexrazoxane-exposed patients had significantly smaller EF and SF declines than unexposed patients across courses and a lower risk for LVSD (26.5% v 42.2%; hazard ratio, 0.55; 95% CI, 0.36 to 0.86; P = .009). Dexrazoxane-exposed patients had similar 5-year EFS (49.0% v 45.1%; P = .534) and OS (65.0% v 61.9%; P = .613) to those unexposed; however, there was a suggestion of lower TRM with dexrazoxane (5.7% v 12.7%; P = .068). CONCLUSION Dexrazoxane preserved cardiac function without compromising EFS and OS or increasing noncardiac toxicities. Dexrazoxane should be considered for cardioprotection during frontline treatment of pediatric AML.
Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with hormone receptor-positive, HER2-positive advanced breast cancer (monarcHER): a randomised, open-label, phase 2 trial
Authors: Sara M Tolaney, Andrew M Wardley, Stefania Zambelli, John F Hilton, Tiffany A Troso-Sandoval, Francesco Ricci, Seock-Ah Im, Sung-Bae Kim, Stephen RD Johnston, Arlene Chan, Shom Goel, Kristen Catron, Sonya C Chapman, Gregory L Price, Zhengyu Yang, M Corona Gainford, Fabrice André
Journal: The Lancet Oncology (2020)
Early T cell infiltration is modulated by programed cell death-1 protein and its ligand (PD-1/PD-L1) interactions in murine kidney transplants
Authors: Young Jun Shim, Raneem Khedraki, Jayeeta Dhar, Ran Fan, Nina Dvorina, Anna Valujskikh, Robert L. Fairchild, William M. Baldwin
Journal: Kidney International (2020)
A quantitative framework for modeling COVID-19 risk during adjuvant therapy using published randomized trials of glioblastoma in the elderly
Authors: Shervin Tabrizi, Lorenzo Trippa, Daniel Cagney, Shyam Tanguturi, Steffen Ventz, Geoffrey Fell, Patrick Y Wen, Brian M Alexander, Rifaquat Rahman
Journal: Neuro-Oncology (2020)

Abstract Background During the ongoing COVID-19 pandemic, contact with the health care system for cancer treatment can increase risk of infection and associated mortality. Treatment recommendations must consider this risk for elderly and vulnerable cancer patients. We reanalyzed trials in elderly glioblastoma (GBM) patients, incorporating COVID-19 risk, in order to provide a quantitative framework for comparing different radiation (RT) fractionation schedules on patient outcomes. Methods We extracted individual patient-level data for 1321 patients from Kaplan–Meier curves from 5 randomized trials on treatment of elderly GBM patients including available subanalyses based on O6-methylguanine-DNA methyltransferase (MGMT) methylation status. We simulated trial data with incorporation of COVID-19–associated mortality risk in several scenarios (low, medium, and high infection and mortality risks). Median overall survival and hazard ratios were calculated for each simulation replicate. Results Our simulations reveal how COVID-19–associated risks affect survival under different treatment regimens. Hypofractionated RT with concurrent and adjuvant temozolomide (TMZ) demonstrated the best outcomes in low and medium risk scenarios. In frail elderly patients, shorter courses of RT are preferable. In patients with methylated MGMT receiving single modality treatment, TMZ-alone treatment approaches may be an option in settings with high COVID-19–associated risk. Conclusions Incorporation of COVID-19–associated risk models into analysis of randomized trials can help guide clinical decisions during this pandemic. In elderly GBM patients, our results support prioritization of hypofractionated RT and highlight the utility of MGMT methylation status in decision making in pandemic scenarios. Our quantitative framework can serve as a model for assessing COVID-19 risk associated with treatment across neuro-oncology. Key Points • Re-analysis of randomized controlled trials in COVID-19 era gives insight on optimal treatment of GBM. • Hypofractionated RT or temozolomide alone may be reasonable options in high risk pandemic settings. • A quantitative framework incorporating COVID-19 risks can be applied across neuro-oncology.
An international cohort study of birth outcomes associated with hospitalized acute respiratory infection during pregnancy
Authors: Annette K. Regan, Becca S. Feldman, Eduardo Azziz-Baumgartner, Allison L. Naleway, Jennifer Williams, Brandy E. Wyant, Kim Simmonds, Paul V. Effler, Stephanie Booth, Sarah W. Ball, Mark A. Katz, Rebecca V. Fink, Mark G. Thompson, Hannah Chung, Jeffrey C. Kwong, Deshayne B. Fell
Journal: Journal of Infection (2020)