tbuckley/cabot-search huggingface dataset:
Selection on Accessible Chromatin Regions in<i>Capsella grandiflora</i>
Authors: Robert Horvath, Emily B Josephs, Edouard Pesquet, John R Stinchcombe, Stephen I Wright, Douglas Scofield, Tanja Slotte
Journal: Molecular Biology and Evolution (2021)

Abstract Accurate estimates of genome-wide rates and fitness effects of new mutations are essential for an improved understanding of molecular evolutionary processes. Although eukaryotic genomes generally contain a large noncoding fraction, functional noncoding regions and fitness effects of mutations in such regions are still incompletely characterized. A promising approach to characterize functional noncoding regions relies on identifying accessible chromatin regions (ACRs) tightly associated with regulatory DNA. Here, we applied this approach to identify and estimate selection on ACRs in Capsella grandiflora, a crucifer species ideal for population genomic quantification of selection due to its favorable population demography. We describe a population-wide ACR distribution based on ATAC-seq data for leaf samples of 16 individuals from a natural population. We use population genomic methods to estimate fitness effects and proportions of positively selected fixations (α) in ACRs and find that intergenic ACRs harbor a considerable fraction of weakly deleterious new mutations, as well as a significantly higher proportion of strongly deleterious mutations than comparable inaccessible intergenic regions. ACRs are enriched for expression quantitative trait loci (eQTL) and depleted of transposable element insertions, as expected if intergenic ACRs are under selection because they harbor regulatory regions. By integrating empirical identification of intergenic ACRs with analyses of eQTL and population genomic analyses of selection, we demonstrate that intergenic regulatory regions are an important source of nearly neutral mutations. These results improve our understanding of selection on noncoding regions and the role of nearly neutral mutations for evolutionary processes in outcrossing Brassicaceae species.
Refractive Outcomes of the Yamane Flanged Intrascleral Haptic Fixation Technique
Authors: John R. Rocke, Myra B. McGuinness, William K. Atkins, Lewis E. Fry, Jack X. Kane, David C.A. Fabinyi, Jonathan Yeoh, Daniel Chiu, Rohan W. Essex MBiostat, Edward Roufail, Amy M. Sheridan, Penelope J. Allen, Thomas L. Edwards
Journal: Ophthalmology (2020)
Circulating Retinol-Binding Protein 4 Is Inversely Associated With Pancreatic β-Cell Function Across the Spectrum of Glycemia
Authors: Rong Huang, Songping Yin, Yongxin Ye, Nixuan Chen, Shiyun Luo, Min Xia, Lina Zhao
Journal: Diabetes Care (2020)

OBJECTIVE The aim of this study was to examine the association of circulating retinol-binding protein 4 (RBP4) levels with β-cell function across the spectrum of glucose tolerance from normal to overt type 2 diabetes. RESEARCH DESIGN AND METHODS A total of 291 subjects aged 35–60 years with normal glucose tolerance (NGT), newly diagnosed impaired fasting glucose or glucose tolerance (IFG/IGT), or type 2 diabetes were screened by a standard 2-h oral glucose tolerance test (OGTT) with the use of traditional measures to evaluate β-cell function. From these participants, 74 subjects were recruited for an oral minimal model test, and β-cell function was assessed with model-derived indices. Circulating RBP4 levels were measured by a commercially available ELISA kit. RESULTS Circulating RBP4 levels were significantly and inversely correlated with β-cell function indicated by the Stumvoll first-phase and second-phase insulin secretion indices, but not with HOMA of β-cell function, calculated from the 2-h OGTT in 291 subjects across the spectrum of glycemia. The inverse association was also observed in subjects involved in the oral minimal model test with β-cell function assessed by both direct measures and model-derived measures, after adjustment for potential confounders. Moreover, RBP4 emerged as an independent factor of the disposition index-total insulin secretion. CONCLUSIONS Circulating RBP4 levels are inversely and independently correlated with β-cell function across the spectrum of glycemia, providing another possible explanation of the linkage between RBP4 and the pathogenesis of type 2 diabetes.
Infection and Rapid Transmission of SARS-CoV-2 in Ferrets
Authors: Young-Il Kim, Seong-Gyu Kim, Se-Mi Kim, Eun-Ha Kim, Su-Jin Park, Kwang-Min Yu, Jae-Hyung Chang, Eun Ji Kim, Seunghun Lee, Mark Anthony B. Casel, Jihye Um, Min-Suk Song, Hye Won Jeong, Van Dam Lai, Yeonjae Kim, Bum Sik Chin, Jun-Sun Park, Ki-Hyun Chung, Suan-Sin Foo, Haryoung Poo, In-Pil Mo, Ok-Jun Lee, Richard J. Webby, Jae U. Jung, Young Ki Choi
Journal: Cell Host & Microbe (2020)
Abstract P318: Wide State-By-State Variation in Maternal Mortality and Chronic Diseases That Contribute to Pregnancy Complications
Authors: Sarah Milder, Jamie Kenealy, Mary Ann Honors, Thomas Eckstein
Journal: Circulation (2017)

Background: Among developed countries, the United States has the highest maternal mortality rate. Between 1987 and 2011, the US maternal mortality rate more than doubled from 7.2 to 17.8 deaths per 100,000 live births. More than 1,300 pregnancy-related deaths occurred in the United States in 2011-2012. Additionally, an increasing number of women have chronic health conditions, such as hypertension, diabetes, and chronic heart disease, that increase their risk of pregnancy complications, including maternal mortality. Reducing the prevalence of these diseases may be an important step toward reducing maternal mortality. To examine the current state of maternal mortality and chronic diseases in the United States, the geographical variation of these factors was examined. Methodology: State-level prevalence estimates were calculated for diabetes, heart disease, and hypertension awareness among women of reproductive age (18 to 44 years) using data from the 2013-2014 Behavioral Risk Factor Surveillance System. State-level maternal mortality rates were calculated using CDC’s 2010-2014 National Vital Statistics System. Maternal mortality was defined as the number of deaths from any cause related to or aggravated by pregnancy or its management (excluding accidental or incidental causes) during pregnancy and childbirth or within 42 days of termination of pregnancy, irrespective of the duration and site of the pregnancy, per 100,000 live births. Results: The maternal mortality rate is 6.8 times higher in Georgia (39.3 deaths per 100,000 live births) than in Massachusetts (5.8 deaths per 100,000 live births). Nationally, there are an estimated 19.9 maternal deaths per 100,000 live births. The prevalence of chronic diseases that increase risk of pregnancy complications also vary by state. For example, diabetes (excluding gestational diabetes) ranges from a low of 1.9% of women aged 18 to 44 in Alaska, Minnesota, and Wisconsin to a high of 4.8% in Alabama. Nationally, an estimated 3.1% of women aged 18 to 44 have been told by a doctor that they have diabetes. Conclusion: The prevalence of chronic diseases in women of reproductive age vary based on state of residence, as does the maternal mortality rate. Raising awareness about the variation in these measures is an important step toward identifying what strategies are being utilized in states with a low prevalence of diabetes, heart disease, and hypertension, and determining how their public health efforts may help those states facing challenges in these areas.
Editor's Note: p73 and p63 Sustain Cellular Growth by Transcriptional Activation of Cell Cycle Progression Genes
Authors: Konstantinos Lefkimmiatis, Mariano Francesco Caratozzolo, Paola Merlo, Anna Maria D'Erchia, Beatriz Navarro, Massimo Levrero, Elisabetta Sbisa', Apollonia Tullo
Journal: Cancer Research (2020)

The editors are publishing this note to alert readers to a concern about [this article][1] ([1][2]). The authors made the editors aware of duplicated Western blot bands in Fig. 3. Specifically, the same image was used for the actin loading control Western blot bands for the ADA and FASN experiments
E-Cigarette or Vaping Product Use–associated Lung Injury: Developing a Research Agenda. An NIH Workshop Report
Authors: Laura E. Crotty Alexander, Lorraine B. Ware, Carolyn S. Calfee, Sean J. Callahan, Thomas Eissenberg, Carol Farver, Maciej L. Goniewicz, Ilona Jaspers, Farrah Kheradmand, Talmadge E. King, Nuala J. Meyer, Vladimir B. Mikheev, Peter G. Shields, Alan Shihadeh, Robert Strongin, Robert Tarran
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

The NHLBI convened a working group on October 23, 2019, to identify the most relevant and urgent research priorities and prevailing challenges in e-cigarette or vaping product use-associated lung injury (EVALI). Experts across multiple disciplines discussed the complexities of the EVALI outbreak, identified research priorities, and recommended strategies to address most effectively its causal factors and improve diagnosis, treatment, and prevention of this disease. Many research priorities were identified, including the need to create national and international registries of patients with EVALI, to track accurately those affected and assess outcomes. The group concluded that biospecimens from subjects with EVALI are urgently needed to help define EVALI pathogenesis and that vaping has disease risks that are disparate from smoking, with the occurrence of EVALI highlighting the importance of broadening e-cigarette research beyond comparators to smoking-related diseases.
Excellent outcomes following hematopoietic cell transplantation for Wiskott-Aldrich syndrome: a PIDTC report
Authors: Lauri M. Burroughs, Aleksandra Petrovic, Ruta Brazauskas, Xuerong Liu, Linda M. Griffith, Hans D. Ochs, Jack J. Bleesing, Stephanie Edwards, Christopher C. Dvorak, Sonali Chaudhury, Susan E. Prockop, Ralph Quinones, Frederick D. Goldman, Troy C. Quigg, Shanmuganathan Chandrakasan, Angela R. Smith, Suhag Parikh, Blachy J. Dávila Saldaña, Monica S. Thakar, Rachel Phelan, Shalini Shenoy, Lisa R. Forbes, Caridad Martinez, Deepak Chellapandian, Evan Shereck, Holly K. Miller, Neena Kapoor, Jessie L. Barnum, Hey Chong, David C. Shyr, Karin Chen, Rolla Abu-Arja, Ami J. Shah, Katja G. Weinacht, Theodore B. Moore, Avni Joshi, Kenneth B. DeSantes, Alfred P. Gillio, Geoffrey D. E. Cuvelier, Michael D. Keller, Jacob Rozmus, Troy Torgerson, Michael A. Pulsipher, Elie Haddad, Kathleen E. Sullivan, Brent R. Logan, Donald B. Kohn, Jennifer M. Puck, Luigi D. Notarangelo, Sung-Yun Pai, David J. Rawlings, Morton J. Cowan
Journal: Blood (2020)
Perspective evaluation of emotional state of oncological patients in the waiting rooms
Authors: N. M. La Verde, R. Resega, C. Lurati, M. C. Garassino, V. Torri, M. Cinquini, G. Buffa, Mrs J. Landi, M. Riva, K. Borgonovo, G. Farina
Journal: Journal of Clinical Oncology (2009)

e20693 Background: The waiting room is one of the most emotional place in oncological divisions; indeed, it's presumed that the waiting moment makes increase thoughts most related to the experience of disease and its treatment, making them sometimes unbearable. At present, any evaluation of the emotional states in the waiting room doesn't exist, therefore we analyzed the most prevailing emotions and feelings for patients in this context. The identification of them should address also ways to improve patients well being in these moments. Primary objective was to prospectively evaluate the prevailing emotional state patients and feelings in oncological waiting rooms; secondary endpoint is to develop a questionnaire to be further validated and useful to quantify how changes in the environment, as people and furnishings, could reduce prevailing emotional intensity. Methods: A committee of psychoncologists, oncologists, psychiatrists, volunteers, nurses, past patients, and statisticians identified the emotional states considered most important (relationship with environment, surrounding people and treatment, recurrent thoughts about disease and life, fears and things that could ease the wait and prevailing emotions) and developed a questionnaire. In May 2008 for two consecutive weeks this questionnaire was administered by the same dedicated nurse to all the outpatients afferred to our Oncology Department. The compilation of questionnaire was spontaneous and anonymous and it collected also age, sex, whether the patient was under treatment or in follow up and whether was accompanied. Results: In two consecutive weeks 300 questionnaires have been collected in the waiting rooms. Statistical analysis showed that the most prevailing emotions are sadness (51%), fear (29%), anger (17%) and joy (7%). A positive disposition (Cronbach alpha 0.60) and anxiety (Cronbach alpha 0.64) were also assessed. No differences in answers were revealed among patients waiting for follow up and patients waiting for chemotherapy and among different ages. Conclusions: The level of negative feelings seems higher than in other conditions and suggests that active intervention to improve the waiting in waiting rooms is warranted. A further validated questionnaire is ongoing also to evaluate emotions intensity. No significant financial relationships to disclose.
Successful generation of epigenetic disease model mice by targeted demethylation of the epigenome
Authors: Takuro Horii, Sumiyo Morita, Shinjiro Hino, Mika Kimura, Yuko Hino, Hiroshi Kogo, Mitsuyoshi Nakao, Izuho Hatada
Journal: Genome biology (2020)

Abstract Background Epigenetic modifications, including DNA methylation, play an important role in gene silencing and genome stability. Consequently, epigenetic dysregulation can cause several diseases, such as cancer, obesity, diabetes, autism, and imprinting disorders. Results We validate three methods for the generation of epigenome-edited mice using the dCas9-SunTag and single-chain variable fragment-TET1 catalytic domain. We generate model mice for Silver-Russell syndrome (SRS), an imprinting disorder, by target-specific DNA demethylation in the H19 differentially methylated region. Like SRS patients, these mice show H19 upregulation and Igf2 downregulation, leading to severe intrauterine and postnatal growth retardation. Conclusion This is the first report of an imprinting disease model animal generated by targeted demethylation of specific loci of the epigenome in fertilized eggs. Epigenome-edited animals are also useful for exploring the causative epimutations in epigenetic diseases.
Eplerenone prevents an increase in serum carboxy‐terminal propeptide of procollagen type I after myocardial infarction complicated by left ventricular dysfunction and/or heart failure
Authors: Susan Stienen, João Pedro Ferreira, Bertram Pitt, John G. Cleland, Pierpaolo Pellicori, Nicolas Girerd, Patrick Rossignol, Faiez Zannad
Journal: European Journal of Heart Failure (2020)
Will children reveal their secret? The coronavirus dilemma
Authors: Fabio Midulla, Luca Cristiani, Enrica Mancino
Journal: European Respiratory Journal (2020)

We thank G.J. Porter for his comments on our recently published editorial: "Will children reveal their secret? The coronavirus dilemma" [1]. In the editorial, we reviewed some of the strongest evidence that may support our perspective. It was beyond the purpose of our manuscript to provide a full description of the renin–angiotensin–aldosterone system (RAAS) and angiotensin-converting enzyme 2 (ACE2) receptor. We strongly agree that evidence about the role of ACE2 in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is conflicting and our putative perspective was clearly pointed out in the paper. The debate around the role of ACE2 in SARS-CoV-2 infection is ongoing and we appreciate the chance that G.J. Porter has given us to better elucidate some of its main aspects. The role of ACE2 receptor in SARS-CoV-2 infection and in COVID-19 outcomes is still debated, especially in children <https://bit.ly/35ZLf7V>
A Randomized, Open-label, Presurgical, Window-of-Opportunity Study Comparing the Pharmacodynamic Effects of the Novel Oral SERD AZD9496 with Fulvestrant in Patients with Newly Diagnosed ER+ HER2− Primary Breast Cancer
Authors: John F.R. Robertson, Abigail Evans, Stephan Henschen, Cliona C. Kirwan, Ali Jahan, Laura M. Kenny, J. Michael Dixon, Peter Schmid, Ashutosh Kothari, Omar Mohamed, Peter A. Fasching, Kwok-Leung Cheung, Rachel Wuerstlein, Danielle Carroll, Teresa Klinowska, Justin P.O. Lindemann, Alexander MacDonald, Richard Mather, Rhiannon Maudsley, Michele Moschetta, Myria Nikolaou, Martine P. Roudier, Tinnu Sarvotham, Gaia Schiavon, Diansong Zhou, Li Zhou, Nadia Harbeck
Journal: Clinical Cancer Research (2020)

Fulvestrant, the first-in-class selective estrogen receptor (ER) degrader (SERD), is clinically effective in patients with ER+ breast cancer, but it has administration and pharmacokinetic limitations. Pharmacodynamic data suggest complete ER degradation is not achieved at fulvestrant's clinically feasible dose. This presurgical study (NCT03236974) compared the pharmacodynamic effects of fulvestrant with AZD9496, a novel, orally bioavailable, nonsteroidal, potent SERD, in treatment-naïve patients with ER+ HER2- primary breast cancer awaiting curative intent surgery.Patients were randomized 1:1 to receive AZD9496 250 mg twice daily from day 1 for 5-14 days, or fulvestrant 500 mg on day 1. On-treatment imaging-guided core tumor biopsies were taken between day 5 and 14 and compared with pretreatment diagnostic biopsies. The primary objective was to compare the effects of AZD9496 and fulvestrant on ER expression. Secondary objectives included changes in progesterone receptor (PR) and Ki-67 pharmacokinetic/pharmacodynamic relationships and safety.Forty-six women received treatment (AZD9496 n = 22; fulvestrant n = 24); 35 paired biopsies were evaluable (AZD9496 n = 15; fulvestrant n = 20). The least square mean estimate for ER H-score reduction was 24% after AZD9496 versus 36% after fulvestrant treatment (P = 0.86). AZD9496 also reduced PR H-scores (-33.3%) and Ki-67 levels (-39.9%) from baseline, but was also not superior to fulvestrant (PR: -68.7%, P = 0.97; Ki-67: -75.4%, P = 0.98). No new safety findings were identified.This was the first presurgical study to demonstrate that an oral SERD affects its key biological targets. However, AZD9496 was not superior to fulvestrant at the dose tested.
Noneffectiveness of scopolamine for facilitating detection of upper gastrointestinal neoplasia during screening esophagogastroduodenoscopy: propensity score-matched study
Authors: Fumio Omata, Yasuhisa Kumakura, Naoki Ishii, Gautam A. Deshpande, Kohei Matoba, Akemi Ohmuro, Fumie Rai, Misako Takashima, Akira Kato, Katsunori Masuda
Journal: Endoscopy (2020)

Antispasmodics, such as scopolamine, are widely used in several countries prior to diagnostic and screening esophagogastroduodenoscopy (EGD), with the goal of optimizing the detection of minute lesions, typically early gastric cancer (T1 lesions). The aim of this study was to determine whether scopolamine facilitates detection of gastric cancer in the screening setting.A propensity score-matched retrospective study was conducted in a tertiary referral medical center in Tokyo, Japan. Consecutive individuals (n = 40 776) underwent screening EGD between January 2011 and May 2016. All outcome lesions were diagnosed with histopathological confirmation. Detection of esophageal cancer, gastric adenoma, duodenal adenoma, and upper gastrointestinal neoplasia (UGIN) were investigated as secondary outcomes.Scopolamine was used in 31 130 patients (76.3 %) and propensity score matching yielded 6625 pairs. Bivariate analysis revealed no significant association between possible confounders (age, sex, overweight, atrophic gastritis, alcohol history, smoking history, midazolam use, endoscopist biopsy rate grade, and gastric cancer in first-degree relatives) and scopolamine use. Lesions detected were 18 gastric cancers, 11 esophageal cancers, 19 gastric adenomas, 6 duodenal adenomas, and 54 UGINs, with no significant association between scopolamine use and lesion detection.Scopolamine use did not appear to effectively facilitate detection of gastric or esophageal cancer, gastric or duodenal adenoma, and UGIN during screening EGD. Scopolamine should be avoided until its efficacy is confirmed by a randomized controlled trial.
Abstract 13815: Effect of S-Nitrosoglutathione on Cardiovascular Dysfunction in a Paediatric Animal Model of Cardiopulmonary Bypass
Authors: Roberto Chiletti, Kelly Kenna, Joe Smolich, Martin Bennett, Perrier Stephanie, Johann Brink, Diana Zannino, Julie Angerosa, Salvatore Pepe, Michael Cheung
Journal: Circulation (2019)

Introduction: Myocardial dysfunction remains a major contributor of morbidity and mortality in children after cardiopulmonary bypass (CPB). During hypoxia or acidosis, S-nitrosoglutathione (GSNO) h...
Abstract 14165: The Prevalence of Frailty Among Older Adults With Acute Myocardial Infarction
Authors: Abdulla A Damluji, Jin Huang, Jodi B Segal
Journal: Circulation (2018)

Introduction: Frailty is an independent predictor of all-cause and cardiac mortality, non-fatal myocardial infarction, and major bleeding after acute myocardial infarction (AMI) admission. The obje...
A phase II study of continuous oral mTOR inhibitor everolimus for recurrent, radiographic-progressive neurofibromatosis type 1–associated pediatric low-grade glioma: a Neurofibromatosis Clinical Trials Consortium study
Authors: Nicole J Ullrich, Sanjay P Prabhu, Alyssa T Reddy, Michael J Fisher, Roger Packer, Stewart Goldman, Nathan J Robison, David H Gutmann, David H Viskochil, Jeffrey C Allen, Bruce Korf, Alan Cantor, Gary Cutter, Coretta Thomas, John P Perentesis, Tomoyuki Mizuno, Alexander A Vinks, Peter E Manley, Susan N Chi, Mark W Kieran
Journal: Neuro-Oncology (2020)

Activation of the mammalian target of rapamycin (mTOR) pathway is observed in neurofibromatosis type 1 (NF1) associated low-grade gliomas (LGGs), but agents that inhibit this pathway, including mTOR inhibitors, have not been studied in this population. We evaluate the efficacy of the orally administered mTOR inhibitor everolimus for radiographically progressive NF1-associated pediatric LGGs.Children with radiologic-progressive, NF1-associated LGG and prior treatment with a carboplatin-containing chemotherapy were prospectively enrolled on this phase II clinical trial to receive daily everolimus. Whole blood was analyzed for everolimus and markers of phosphatidylinositol-3 kinase (PI3K)/mTOR pathway inhibition. Serial MRIs were obtained during treatment. The primary endpoint was progression-free survival at 48 weeks.Twenty-three participants (median age, 9.4 y; range, 3.2-21.6 y) were enrolled. All participants were initially evaluable for response; 1 patient was removed from study after development of a malignant peripheral nerve sheath tumor. Fifteen of 22 participants (68%) demonstrated a response, defined as either shrinkage (1 complete response, 2 partial response) or arrest of tumor growth (12 stable disease). Of these, 10/15 remained free of progression (median follow-up, 33 mo). All remaining 22 participants were alive at completion of therapy. Treatment was well tolerated; no patient discontinued therapy due to toxicity. Pharmacokinetic parameters and pre-dose concentrations showed substantial between-subject variability. PI3K/mTOR pathway inhibition markers demonstrating blood mononuclear cell mTOR pathway inactivation was achieved in most participants.Individuals with recurrent/progressive NF1-associated LGG demonstrate significant disease stability/shrinkage during treatment with oral everolimus with a well-tolerated toxicity profile. Everolimus is well suited for future consideration as upfront or combination therapy in this patient population.
Myeloid-specific IRE1alpha deletion reduces tumour development in a diabetic, non-alcoholic steatohepatitis-induced hepatocellular carcinoma mouse model
Authors: Sanne Van Campenhout, Laurentijn Tilleman, Sander Lefere, Astrid Vandierendonck, Sarah Raevens, Xavier Verhelst, Anja Geerts, Filip Van Nieuwerburgh, Hans Van Vlierberghe, Lindsey Devisscher
Journal: Metabolism (2020)