tbuckley/cabot-search huggingface dataset:
SNHG6 Acts as a Genome-Wide Hypomethylation Trigger via Coupling of miR-1297–Mediated S-Adenosylmethionine–Dependent Positive Feedback Loops
Authors: Tao Guo, Hongling Wang, Pengpeng Liu, Yushao Xiao, Ping Wu, Yitao Wang, Baiyang Chen, Qiu Zhao, Zhisu Liu, Quanyan Liu
Journal: Cancer Research (2018)

Abstract Aberrant genome-wide hypomethylation and long noncoding RNA (lncRNA) dysregulation are associated with hepatocarcinogenesis. However, whether a relationship between the two exists remains largely unknown. S-adenosylmethionine (SAMe)-dependent methylation is a critical factor in genomic methylation. We previously found that SNHG6 lncRNA acted as an oncogene in hepatocarcinogenesis and could be considered a potential prognostic indicator for hepatocellular carcinoma (HCC). Here we verify that SNHG6 leads to genome-wide hypomethylation in hepatoma cells and that SNHG6 negatively correlates with the steady-state SAMe concentration in vivo and in vitro. SNHG6 suppressed MAT1A protein expression by activating the miR-1297/FUS pathway to regulate nucleocytoplasmic shuttling of MAT1A mRNA. In addition, SNHG6 promoted expression of MAT2A by suppressing direct binding of miR-1297 to the MAT2A 3′UTR. SNHG6 regulated steady-state SAMe levels via coupling of two miR-1297–mediated SAMe-dependent positive feedback loops. Interestingly, the effect of SNHG6 on genome-wide methylation was inhibited by exogenous SAMe within a certain concentration range. These results suggest that single lncRNA dysregulation can lead to aberrant genome-wide hypomethylation by inhibiting SAMe production in HCC and that exogenous SAMe may be beneficial in the treatment of HCC. Significance: These findings explore the role of SNHG6 lncRNA in suppressing production of the universal methyl donor SAMe and its impact on global DNA methylation levels in liver cancer and highlight the potential benefit of SAMe for the treatment of liver cancer. Cancer Res; 78(14); 3849–64. ©2018 AACR.
Rapid Response to Vedolizumab Therapy in Biologic-Naive Patients With Inflammatory Bowel Diseases
Authors: Brian G. Feagan, Karen Lasch, Trevor Lissoos, Charlie Cao, Abigail M. Wojtowicz, Javaria Mona Khalid, Jean-Frédéric Colombel
Journal: Clinical Gastroenterology and Hepatology (2018)

Vedolizumab, a humanized monoclonal antibody against α4β7 integrin, is used to treat adults with moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD). We investigated the time course of clinical response to vedolizumab in patients who were and were not previously treated with tumor necrosis factor (TNF) antagonists.We performed a post-hoc analysis of data from phase 3, randomized, controlled trials of vedolizumab vs placebo in adult patients with UC (N = 374) or CD (N = 784). We collected data on patient-reported symptoms (rectal bleeding and stool frequency for patients with UC, abdominal pain and loose stool frequency for patients with CD) reported at weeks 2, 4, and 6 of treatment. We reported mean percentage score changes from baseline and proportions of patients who achieved predefined scores. We performed multivariate logistic regression analysis to identify factors associated with an early response (at week 2).In patients with UC (overall or naive to TNF antagonist therapy), a significantly greater percentage of patients given vedolizumab achieved the predefined composite symptom score at weeks 2, 4, and 6 compared to those given placebo. In patients with CD who were naive to TNF antagonists, a significantly greater percentage of patients given vedolizumab achieved the predefined score at weeks 2 and 4 compared to those given placebo. Among patients with UC given vedolizumab, 19.1% (overall) and 22.3% (TNF antagonist naive) achieved a composite score of rectal bleeding of 0 and stool frequency ≤1 at week 2 compared to 10% (overall) and 6.6% (TNF antagonist naive) of those receiving placebo. Among TNF antagonist-naive patients with CD, 15.0% of those given vedolizumab achieved an average daily composite score of abdominal pain ≤1 and loose stool frequency ≤3 at week 2 (compared to 7.9% given placebo), and 23.8% of those given vedolizumab achieved these by week 4 (compared to 10.3% given placebo).In a post-hoc analysis of data from phase 3 clinical trials, vedolizumab significantly improved patient-reported symptoms of UC and CD as early as week 2 of treatment, continuing through the first 6 weeks-especially when given as first-line biologic therapy. ClinicalTrials.gov no: NCT00783718, NCT00783692, NCT01224171.
A phase II clinical trial to analyze olaparib response in patients with <i>BRCA1</i> and/or <i>BRCA</i>2 promoter methylation with advanced breast cancer (GEICAM/2015-06 COMETA-Breast study).
Authors: Juan De La Haba, Angel Guerrero-Zotano, Jose Alejandro Perez-Fidalgo, Santiago Gonzalez Santiago, Montserrat Muñoz, Raquel Andres, Cristina Cruz Zambrano, Sebastian Moran Salama, Sara Lopez-Tarruella, Vanesa Quiroga Garcia, Sonia Servitja, Mireia Mele, Sonia Alonso Soler, Barbara Adamo, Maria Jose Escudero, Nuria Martin, Susana Bezares, Rosalia Caballero, Manel Esteller, Federico Rojo
Journal: Journal of Clinical Oncology (2018)

TPS1114 Background: Identification of targeted therapies for advanced triple negative breast cancer (TNBC) remains as an important clinical challenge. TNBC frequently shows BRCA dysfunction and 80% of germline BRCA1 mutation (gBRCAm) carriers with BC diagnosis are TNBC patients (pts). In addition to germline mutations, epigenetic silencing by aberrant methylation of BRCA1/2 promoters can be responsible for a dysfunctional BRCA protein. Methylation of BRCA1 promoter occurs in 15-57% of TNBCs. Interestingly, BRCA1-methylated sporadic breast tumors display pathologic features and gene expression profiles similar to those of gBRCAm carriers, a phenotype called “BRCAness”. Olaparib (O) is an oral poly (ADP-ribose) polymerase (PARP) inhibitor approved by the FDA for treatment of gBRCA-mutated HER2-negative metastatic BC. Tutt et al. have shown antitumor activity in gBRCA-mutated advanced TNBC (54% Objective Response Rate [ORR]). We report an ongoing phase II clinical trial to analyze the O efficacy in advanced TNBC pts with BRCA1/2 promoter methylation (NCT03205761). Methods: Eligible pts are advanced TNBC cases with ≥ 1 prior treatment for advanced disease, without germline BRCA1/2 mutations and centrally confirmed somatic BRCA1/2 promoter methylation in metastatic lesions. Pts receive O 300 mg b.i.d. orally. Primary objective is to analyze O efficacy in terms of ORR according to RECIST 1.1 by investigator assessment. Secondary objectives include safety, other efficacy endpoints, and biomarker analyses. Sequential tumor and blood samples are collected to a) explore changes in methylation status, b) correlate BRCA-methylation status both in blood vs. tumor and in primary vs. metastatic counterpart lesions, and c) correlate methylation status with BRCA1/2 expression and outcome. Thirty-four evaluable pts are required based on an optimal two-stage Simon model (α error = 0.05, power = 80%, dropout rate = 10%). Recruitment started in October 2017, with 17 pts screened for methylation status, 3 pts enrolled by 31th January 2018, and 14 active sites out of 16 participants. Primary endpoint analysis is planned for Q2 2020. Clinical trial information: NCT03205761.
Electrical Stimulation for Epilepsy
Authors: Rebecca Voelker
Journal: JAMA (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
SINC-seq: correlation of transient gene expressions between nucleus and cytoplasm reflects single-cell physiology
Authors: Mahmoud N. Abdelmoez, Kei Iida, Yusuke Oguchi, Hidekazu Nishikii, Ryuji Yokokawa, Hidetoshi Kotera, Sotaro Uemura, Juan G. Santiago, Hirofumi Shintaku
Journal: Genome biology (2018)

We report a microfluidic system that physically separates nuclear RNA (nucRNA) and cytoplasmic RNA (cytRNA) from a single cell and enables single-cell integrated nucRNA and cytRNA-sequencing (SINC-seq). SINC-seq constructs two individual RNA-seq libraries, nucRNA and cytRNA, per cell, quantifies gene expression in the subcellular compartments, and combines them to create novel single-cell RNA-seq data. Leveraging SINC-seq, we discover distinct natures of correlation among cytRNA and nucRNA that reflect the transient physiological state of single cells. These data provide unique insights into the regulatory network of messenger RNA from the nucleus toward the cytoplasm at the single-cell level.
Mechanisms of Crystalloid versus Colloid Osmosis across the Peritoneal Membrane
Authors: Johann Morelle, Amadou Sow, Charles-André Fustin, Catherine Fillée, Elvia Garcia-Lopez, Bengt Lindholm, Eric Goffin, Fréderic Vandemaele, Bengt Rippe, Carl M. Öberg, Olivier Devuyst
Journal: Journal of the American Society of Nephrology (2018)

Background Osmosis drives transcapillary ultrafiltration and water removal in patients treated with peritoneal dialysis. Crystalloid osmosis, typically induced by glucose, relies on dialysate tonicity and occurs through endothelial aquaporin-1 water channels and interendothelial clefts. In contrast, the mechanisms mediating water flow driven by colloidal agents, such as icodextrin, and combinations of osmotic agents have not been evaluated. Methods We used experimental models of peritoneal dialysis in mouse and biophysical studies combined with mathematical modeling to evaluate the mechanisms of colloid versus crystalloid osmosis across the peritoneal membrane and to investigate the pathways mediating water flow generated by the glucose polymer icodextrin. Results In silico modeling and in vivo studies showed that deletion of aquaporin-1 did not influence osmotic water transport induced by icodextrin but did affect that induced by crystalloid agents. Water flow induced by icodextrin was dependent upon the presence of large, colloidal fractions, with a reflection coefficient close to unity, a low diffusion capacity, and a minimal effect on dialysate osmolality. Combining crystalloid and colloid osmotic agents in the same dialysis solution strikingly enhanced water and sodium transport across the peritoneal membrane, improving ultrafiltration efficiency over that obtained with either type of agent alone. Conclusions These data cast light on the molecular mechanisms involved in colloid versus crystalloid osmosis and characterize novel osmotic agents. Dialysis solutions combining crystalloid and colloid particles may help restore fluid balance in patients treated with peritoneal dialysis.
Abstract 17608: Identification of a Tissue-specific Very Long-chain Acyl-CoA Synthetase Involved in the Inhibition of ATP-Citrate Lyase (ACL) by ETC-1002: A Novel Mechanism for Cholesterol Biosynthesis Inhibition in the Liver
Authors: Stephen L Pinkosky, Roger S Newton, Carolyn M Birch, Sergey Filippov, Pieter H Groot, Narendra D Lalwani
Journal: Circulation (2015)

ETC-1002 is a first-in-class oral small molecule that significantly lowers levels of low- density lipoprotein-cholesterol (LDL-C) by 30-40% in hypercholesterolemic patients with reduced potential for muscle-related adverse events. Our previous investigations into the mechanism of action demonstrated a requirement for acyl-CoA synthetase- (ACS) dependent coenzyme A (CoA) activation of ETC-1002 (ETC-1002-CoA) to inhibit its molecular target, ATP-citrate lyase (ACL), an enzyme upstream of HMG-CoA reductase in the cholesterol biosynthesis pathway. In the present study, we have elucidated a mechanistic basis for tissue-specific inhibition of ACL by providing evidence that ACSVL1 is the ACS isoform that catalyzes the CoA activation of ETC-1002. Genetic silencing of ACSVL1 in McArdle cells prevented the CoA activation of ETC-1002 and consequently its inhibition of de novo cholesterol synthesis. We demonstrate that ACSVL1 is highly expressed in primary human hepatocytes and human liver microsomes. Furthermore, we establish a statin-like regulatory link between ACL activity and cholesterol metabolism by showing that ACL siRNA silencing or pharmacological inhibition by ETC-1002-CoA, leads to increased LDLR expression and activity. Using primary human hepatocytes, we demonstrate the concentration-dependent inhibition of cholesterol synthesis by ETC-1002, an associated increase in mRNA expression of the sterol responsive genes srebp2, hmgr, pcsk9, and ldlr mRNA, and increased LDLR activity. In addition, we demonstrate that ACSVL1 is not expressed in L6 myotubes, primary human skeletal muscle cells, or human skeletal muscle microsomes. Unlike statins, ETC-1002 did not inhibit the de novo synthesis of sterols in skeletal muscle cell cultures, nor promote caspase 3/7 activation. Therefore, by establishing a regulatory link between ACL inhibition and LDLR up-regulation, and by identifying ACSVL1 as the ACS isoform that catalyzes the CoA activation of ETC-1002, we provide evidence for the tissue-specific inhibition of ACL by ETC-1002-CoA that results in LDL-C-lowering without activity in skeletal muscle or associated side effects.
Effects of frequency, intensity, duration and volume of walking interventions on CVD risk factors: a systematic review and meta-regression analysis of randomised controlled trials among inactive healthy adults
Authors: Pekka Oja, Paul Kelly, Elaine M Murtagh, Marie H Murphy, Charlie Foster, Sylvia Titze
Journal: British Journal of Sports Medicine (2018)

Objective Walking interventions in healthy populations show clinically relevant improvements for many cardiovascular disease (CVD) risk factors. We aimed to assess the changes in CVD risk factors and the dose–response relationship between frequency, intensity, duration and volume of walking and cardiovascular risk factors based on randomised controlled trials (RCTs). Design A systematic review with meta-analysis and meta-regression. Data sources Four electronic databases searched from January 1971 to April 2017. Eligibility criteria Walking RCTs reporting one or more CVD risk factor outcomes; trials including at least one group with walking intervention and a no-walking control group; duration ≥8 weeks; participants ≥18 years old, inactive but healthy; risk factors assessed preintervention and postintervention; English-language articles in peer-reviewed journals. Results Thirty-seven RCTs, involving 2001 participants (81% women) and assessing 13 CVD risk factors, were identified. Pooled meta-analysis showed favourable effects (P≤0.05) of walking intervention for seven CVD risk factors (body mass, body mass index, body fat, systolic and diastolic blood pressure, fasting glucose and VO 2 max). T here were no significant effects (P&gt;0.05) for waist circumference, waist-to-hip ratio and four blood lipid variables. Despite testing 91 possible dose–response relationships, linear meta-regression analysis adjusted for age indicated just 7 (or 7.7%) statistically significant findings. Summary/conclusion Walking interventions benefit a number of CVD risk factors. Despite multiple studies and tested metrics, only a few dose–response relationships were identified and the possibility of chance findings cannot be ruled out. There is insufficient evidence to quantify the frequency, length, bout duration, intensity and volume of the walking required to improve CVD risk factors. PROSPERO registration number CRD42016039409.
Methylated circulating tumor DNA as a potential marker of PARP inhibitor efficiency in BRCA mutated ovarian cancer patients.
Authors: Karina Dahl Steffensen, Rikke Fredslund Andersen, Anders Kristian Moeller Jakobsen
Journal: Journal of Clinical Oncology (2018)

5540 Background: The liquid biopsy has proven to be an excellent material for analysis of different circulating tumor markers, among which mutated tumor DNA (ctDNA) ranks high. Cancer specific ctDNA methylation can be used to quantitate tumor DNA and is a promising new approach for monitoring changes in tumor burden in response to therapy. Homeobox genes (HOX) constitute a family of transcription factors that involved in regulating differentiation and are expressed in normal adult reproductive tissue and methylation of the HOXA9 gene has been observed in 95% of patients with high grade serous ovarian carcinoma. Treatment with PARP inhibitors has demonstrated considerable benefit in ovarian cancer (OC) patients but stratification of patients for PARP inhibitor (PARPi) treatment by BRCA status has proved suboptimal. The primary aim of the present study was to investigate if methylated HOXA9 already at baseline, before initiation of single agent PARPi treatment could predict treatment efficacy in OC patients with platinum resistant or intermediate resistant relapse. Methods: Plasma from OC patients were retrieved at baseline before initiation of daily oral single agent Veliparib as part of a phase II investigator initiated trial. DNA was purified from 4 ml plasma, bisulfite converted and analysed by droplet digital PCR with methylation specific assay for HOXA9 and Albumin as reference. The fractional abundance of methylated HOXA9 was calculated. CA125 was analysed according to international standard. Results: The phase II trial enrolled 32 patients of which 23 patients had methylated HOXA9 at baseline. Patients with methylated HOXA9 showed a worse progression-free survival (p = 0.046) compared to patients with non-methylated HOXA9. In multivariate analysis HOXA9 showed borderline significance (p = 0.056, HR 2.53 (95%CI: [0.98-6.54]) when correcting for age, performance status and platinum sensitivity. Baseline CA125 was not a predictor of PFS. Conclusions: The data presented suggests circulating methylated HOXA9 as a potential marker for prediction of efficacy of PARPi treatment. Clinical trial information: NCT01472783.
Reproductive Function and Outcomes in Female Survivors of Childhood, Adolescent, and Young Adult Cancer: A Review
Authors: Wendy van Dorp, Riccardo Haupt, Richard A. Anderson, Renee L. Mulder, Marry M. van den Heuvel-Eibrink, Eline van Dulmen-den Broeder, H. Irene Su, Jeanette F. Winther, Melissa M. Hudson, Jennifer M. Levine, W. Hamish Wallace
Journal: Journal of Clinical Oncology (2018)

Some survivors of childhood, adolescent, and young adult cancer are at increased risk of gonadal dysfunction and adverse pregnancy outcomes. We reviewed currently available literature that evaluated reproductive function and pregnancy outcomes of female cancer survivors diagnosed before the age of 25 years. High-dose alkylating agent chemotherapy and abdominal/pelvic radiotherapy adversely affect gonadal function in a dose-related fashion, with older age at exposure conferring greater risk as a result of the age-related decline in ovarian reserve. Gonadal injury clinically manifests as ovarian hormone insufficiency (delayed or arrested puberty, premature ovarian insufficiency, or premature menopause) and infertility. The effect of molecular-targeted agents on ovarian function has not been established. For female cancer survivors who maintain fertility, overall pregnancy (relative risk, 0.67 to 0.81) and live birth rates (hazard ratio, 0.79 to 0.82) are lower than those in the general public. Pregnancy in cancer survivors also may be associated with risks to both the mother and the fetus related to miscarriage; preterm birth; and, rarely, cardiomyopathy. Women at risk for these complications require preconception assessment and counseling from both obstetricians and oncology providers. The risk for inherited genetic disease in offspring conceived after cancer treatment exposure is not increased. The optimization of reproductive outcomes and minimization of risks of pregnancy complications in survivors requires informed, risk-based assessment and monitoring.
Low Levels of Evidence for Neoadjuvant Chemotherapy to Treat Soft-Tissue Sarcoma
Authors: Suzanne George, Andrew J. Wagner
Journal: JAMA Oncology (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
KLRD1-expressing natural killer cells predict influenza susceptibility
Authors: Erika Bongen, Francesco Vallania, Paul J. Utz, Purvesh Khatri
Journal: Genome Medicine (2018)

Influenza infects tens of millions of people every year in the USA. Other than notable risk groups, such as children and the elderly, it is difficult to predict what subpopulations are at higher risk of infection. Viral challenge studies, where healthy human volunteers are inoculated with live influenza virus, provide a unique opportunity to study infection susceptibility. Biomarkers predicting influenza susceptibility would be useful for identifying risk groups and designing vaccines. We applied cell mixture deconvolution to estimate immune cell proportions from whole blood transcriptome data in four independent influenza challenge studies. We compared immune cell proportions in the blood between symptomatic shedders and asymptomatic nonshedders across three discovery cohorts prior to influenza inoculation and tested results in a held-out validation challenge cohort. Natural killer (NK) cells were significantly lower in symptomatic shedders at baseline in both discovery and validation cohorts. Hematopoietic stem and progenitor cells (HSPCs) were higher in symptomatic shedders at baseline in discovery cohorts. Although the HSPCs were higher in symptomatic shedders in the validation cohort, the increase was statistically nonsignificant. We observed that a gene associated with NK cells, KLRD1, which encodes CD94, was expressed at lower levels in symptomatic shedders at baseline in discovery and validation cohorts. KLRD1 expression in the blood at baseline negatively correlated with influenza infection symptom severity. KLRD1 expression 8 h post-infection in the nasal epithelium from a rhinovirus challenge study also negatively correlated with symptom severity. We identified KLRD1-expressing NK cells as a potential biomarker for influenza susceptibility. Expression of KLRD1 was inversely correlated with symptom severity. Our results support a model where an early response by KLRD1-expressing NK cells may control influenza infection.