bluuebunny/crossref_metadata_2025_split huggingface dataset:
Valproic acid, in combination with all-trans retinoic acid and 5-aza-2′-deoxycytidine, restores expression of silenced RARβ2 in breast cancer cells
Authors: Mongan Nigel P. , Gudas Lorraine J. 
Published: February 2021

Abstract
Epigenetic silencing of tumor suppressor genes has been established as an important process of carcinogenesis. The retinoic acid (RA) receptor β2 (RARβ2) gene is one such tumor suppressor gene often silenced during carcinogenesis. The combined use of histone deacetylase and DNA methyltransferase inhibitors has been shown to reverse the epigenetic silencing of numerous growth regulatory genes. Valproic acid (VPA), which has long been used in the treatment of epilepsy, was shown recently to be an effective histone deacetylase inhibitor that can induce differentiation of neoplastically transformed cells. In this study, we show for the first time that VPA, in combination with RA and the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (Aza-dC), can overcome the epigenetic barriers to transcription of a prototypical silenced tumor suppressor gene, RARβ2, in human breast cancer cells. Chromatin immunoprecipitation assays show that the combination of VPA, RA, and Aza-dC increases histone acetylation at the silenced RARβ2 promoter of MCF-7 breast cancer cells. Furthermore, reverse transcription-PCR analyses reveal cell type–specific effects in the actions of VPA on RARβ2 expression in cultured human breast cancer cells. Finally, we show that VPA, in combination with RA and Aza-dC, inhibits the proliferation of both estrogen receptor α-positive (MCF-7) and estrogen receptor α-negative (MDA-MB-231) breast cancer cell lines. These data suggest that VPA may ultimately be useful in combination therapies in the treatment of human breast cancers.
Gene expression profiling revealed novel molecular targets of docetaxel and estramustine combination treatment in prostate cancer cells
Authors: Li Yiwei , Hong Xin , Hussain Maha , Sarkar Sarah H. , Li Ran , Sarkar Fazlul H. 
Published: February 2021

Abstract
Both docetaxel and estramustine are antimicrotubule agents with antitumor activity in various cancers including prostate cancer. Clinical trials for docetaxel and estramustine combination treatment have suggested improved antitumor activity in hormone-refractory prostate cancer. However, the molecular mechanisms involved in the combination treatment with docetaxel and estramustine have not been fully elucidated. In order to establish such molecular mechanisms in both hormone insensitive (PC-3) and sensitive (LNCaP) prostate cancer cells, gene expression profiles of docetaxel- and estramustine-treated prostate cancer cells were obtained by using Affymetrix Human Genome U133A Array. Total RNA from PC-3 and LNCaP cells untreated and treated with 2 nmol/L docetaxel, 4 μmol/L estramustine, or 1 nmol/L docetaxel plus 2 μmol/L estramustine for 6, 36, and 72 hours was subjected to microarray analysis. Real-time PCR and Western blot analysis were conducted to confirm the microarray data. Clustering analysis based on biological function showed that docetaxel and estramustine combination treatment down-regulated some genes that are known to regulate cell proliferation, transcription, translation, and oncogenesis. In contrast, docetaxel and estramustine combination treatment up-regulated some genes related to induction of apoptosis, cell cycle arrest, and tumor suppression. Docetaxel and estramustine also showed differential effects on gene expression between mono- and combination treatment. Combination treatment with docetaxel and estramustine caused alternations of a large number of genes, many of which may contribute to the molecular mechanisms by which docetaxel and estramustine inhibit the growth of prostate cancer cells. These results provide novel molecular targets of docetaxel and estramustine combination treatment in prostate cancer cells. This information could be utilized for further mechanistic research and for devising optimized therapeutic strategies against prostate cancer.
Health and Fitness at the Single-Cell Level
Authors: Green Douglas R. 
Published: February 2021

Abstract
Genetically identical cells in a tissue can respond differently to perturbations in their environment or “stress.” Such stresses can be physicochemical, mechanical, or infectious or may come from competition with other cells in the tissue. Here, I discuss how the varying responses to stress influence the decision of a cell to repair or die, and how one cell's response can have effects on surrounding cells. Such responses control the health and fitness of single cells and how they compete with other genetically identical cells.
See related article on p. 129
Abstract PO083: Treatment of CEA-positive solid tumors with anti-CEA chimeric antigen receptor T-cells in CEA transgenic mice
Authors: Cha Seung , Yazaki Paul , Brown Christine , Shively John 
Published: February 2021

Abstract
Chimeric antigen receptors (CARs) combine specificity of antibody to target antigen on cancer cells with the potent cytotoxic activity of T-cells without the need for MHC recognition. Chimeric antigen receptor (CAR) T-cells that were designed to express the single chain variable fragment binding domain of human anti-CEA antibody BW431/26 on mouse splenocytes were able to reduce CEA-expressing pancreatic adenocarcinoma tumor in CEA-transgenic (CEAtg) mice without significant off-target effects (Chmielewski et al., 2012). In this study, an anti-CEA CAR construct derived from murine anti-CEA antibody (T84.66) expressed on human T-cells targeted CEA+ colon carcinoma cells (LS174T/CEA and MC38CEA) with high specificity in vitro. When co-incubated with CEA-positive or CEA-negative mouse cancer cells, anti-CEA CAR expressed on mouse T-cells also specifically targeted CEA-positive cancer cells in vitro. Compared to mock T-cells control, anti-CEA CAR T-cells injected intravenously delayed subcutaneous MC38CEA tumor growth in CEA-transgenic mice (CEAtg). Lymphodepletion via cyclophosphamide injected before anti-CEA T-cells injection further delayed subcutaneous MC38CEA tumor growth and delayed orthotopic CEA+ breast carcinoma (E0771CEA) tumor growth in CEAtg mice. To improve the therapeutic potential of anti-CEA CAR T-cells, IL2 conjugated to humanized anti-CEA antibody (M5A-IL2, ICK) was interperitoneally injected after anti-CEA CAR T-cells into lymphodepleted CEAtg mice. A single injection of ICK after anti-CEA CAR T-cells delayed subcutaneous MC38CEA tumor growth even further. Two injections of ICK after anti-CEA T-cells delayed orthotopic E0771CEA tumor growth. Four injections of ICK after anti-CEA CAR T-cells eradicated subcutaneous MC38CEA tumors. These data show the therapeutic potential of anti-CEA CAR T-cells to target CEA-positive tumors.
Citation Format: Seung Cha, Paul Yazaki, Christine Brown, John Shively. Treatment of CEA-positive solid tumors with anti-CEA chimeric antigen receptor T-cells in CEA transgenic mice [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO083.
Efficacy and Safety of Sacubitril/Valsartan in High-Risk Patients in the PIONEER-HF Trial
Authors: Berg David D. , Samsky Marc D. , Velazquez Eric J. , Duffy Carol I. , Gurmu Yared , Braunwald Eugene , Morrow David A. , DeVore Adam D. 
Published: February 2021

Background:
In patients stabilized during hospitalization for acute decompensated heart failure (HF), initiation of sacubitril/valsartan compared with enalapril decreased the risk of cardiovascular death or rehospitalization for HF without increasing the risk of adverse events. It is unknown whether potentially high-risk subpopulations have a similar risk-benefit profile.

Methods:

PIONEER-HF (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP [N-terminal pro-B type natriuretic peptide] in Patients Stabilized From an Acute HF Episode) was a multicenter, randomized, double-blind trial of in-hospital initiation of sacubitril/valsartan (n=440) versus enalapril (n=441) in patients stabilized during hospitalization for acute decompensated HF. The composite of cardiovascular death or rehospitalization for HF was adjudicated. Safety outcomes included worsening renal function, symptomatic hypotension, and hyperkalemia. We evaluated heterogeneity in the effect of sacubitril/valsartan on these efficacy and safety outcomes in selected subgroups of clinical concern: patients with baseline systolic blood pressure ≤118 mm Hg (median; n=448), baseline NT-proBNP >2701 pg/mL (median; n=395), estimated glomerular filtration rate <60 mL/minute per 1.73 m
2
(n=455), ≥1 additional hospitalization for HF within the prior year (n=343), admission to the ICU during the index hospitalization (n=96), inotrope use during the index hospitalization (n=68), and severe congestion (n=219).

Results:

The relative risk reduction in cardiovascular death or rehospitalization for HF with sacubitril/valsartan versus enalapril was consistent across all high-risk subgroups (
P
interaction=non-significant [NS] for each). The risks of worsening renal function, symptomatic hypotension, and hyperkalemia with sacubitril/valsartan versus enalapril were also consistent in each high- versus low-risk subgroup (
P
interaction=NS for each).

Conclusions:
In high-risk subpopulations admitted for acute decompensated HF, treatment with sacubitril/valsartan after initial stabilization conferred a consistent reduction in cardiovascular death or rehospitalization for HF and was well tolerated.
MK2‐Deficient Mice Are Bradycardic and Display Delayed Hypertrophic Remodeling in Response to a Chronic Increase in Afterload
Authors: Ruiz Matthieu , Khairallah Maya , Dingar Dharmendra , Vaniotis George , Khairallah Ramzi J. , Lauzier Benjamin , Thibault Simon , Trépanier Joëlle , Shi Yanfen , Douillette Annie , Hussein Bahira , Nawaito Sherin Ali , Sahadevan Pramod , Nguyen Albert , Sahmi Fatiha , Gillis Marc‐Antoine , Sirois Martin G. , Gaestel Matthias , Stanley William C. , Fiset Céline , Tardif Jean‐Claude , Allen Bruce G. 
Published: February 2021

Background

Mitogen‐activated protein kinase–activated protein kinase‐2 (MK2) is a protein serine/threonine kinase activated by p38α/β. Herein, we examine the cardiac phenotype of pan MK2‐null (MK2
−/−
) mice.

Methods and Results

Survival curves for male MK2
+/+
and MK2
−/−
mice did not differ (Mantel‐Cox test,
P
=0.580). At 12 weeks of age, MK2
−/−
mice exhibited normal systolic function along with signs of possible early diastolic dysfunction; however, aging was not associated with an abnormal reduction in diastolic function. Both R‐R interval and P‐R segment durations were prolonged in MK2‐deficient mice. However, heart rates normalized when isolated hearts were perfused ex vivo in working mode. Ca
2+
transients evoked by field stimulation or caffeine were similar in ventricular myocytes from MK2
+/+
and MK2
−/−
mice. MK2
−/−
mice had lower body temperature and an age‐dependent reduction in body weight. mRNA levels of key metabolic genes, including
Ppargc1a
,
Acadm
,
Lipe
, and
Ucp3,
were increased in hearts from MK2
−/−
mice. For equivalent respiration rates, mitochondria from MK2
−/−
hearts showed a significant decrease in Ca
2+
sensitivity to mitochondrial permeability transition pore opening. Eight weeks of pressure overload increased left ventricular mass in MK2
+/+
and MK2
−/−
mice; however, after 2 weeks the increase was significant in MK2
+/+
but not MK2
−/−
mice. Finally, the pressure overload–induced decrease in systolic function was attenuated in MK2
−/−
mice 2 weeks, but not 8 weeks, after constriction of the transverse aorta.

Conclusions
Collectively, these results implicate MK2 in (1) autonomic regulation of heart rate, (2) cardiac mitochondrial function, and (3) the early stages of myocardial remodeling in response to chronic pressure overload.
Risk of QTc Interval Prolongation Associated With Circulating Anti‐Ro/SSA Antibodies Among US Veterans: An Observational Cohort Study
Authors: Lazzerini Pietro Enea , Cevenini Gabriele , Qu Yongxia Sarah , Fabris Frank , El‐Sherif Nabil , Acampa Maurizio , Cartocci Alessandra , Laghi‐Pasini Franco , Capecchi Pier Leopoldo , Boutjdir Mohamed , Lazaro Deana 
Published: February 2021

Background
Anti‐Sjögren's syndrome‐related antigen A‐antibodies (anti‐Ro/SSA‐antibodies) are responsible for a novel form of acquired long‐QT syndrome, owing to autoimmune‐mediated inhibition of cardiac human ether‐a‐go‐go‐related gene‐potassium channels. However, current evidence derives only from basic mechanistic studies and relatively small sample‐size clinical investigations. Hence, the aim of our study is to estimate the risk of QTc prolongation associated with the presence of anti‐Ro/SSA‐antibodies in a large population of unselected subjects.

Methods and Results
This is a retrospective observational cohort study using the Veterans Affairs Informatics and Computing Infrastructure. Participants were veterans who were tested for anti‐Ro/SSA status and had an ECG. Descriptive statistics and univariate and multivariate logistic regression analyses were performed to identify risk factors for heart rate‐corrected QT interval (QTc) prolongation. The study population consisted of 7339 subjects (61.4±12.2 years), 612 of whom were anti‐Ro/SSA‐positive (8.3%). Subjects who were anti‐Ro/SSA‐positive showed an increased prevalence of QTc prolongation, in the presence of other concomitant risk factors (crude odds ratios [OR], 1.67 [1.26–2.21] for QTc >470/480 ms; 2.32 [1.54–3.49] for QTc >490 ms; 2.77 [1.66–4.60] for QTc >500 ms), independent of a connective tissue disease history. Adjustments for age, sex, electrolytes, cardiovascular risk factors/diseases, and medications gradually attenuated QTc prolongation estimates, particularly when QT‐prolonging drugs were added to the model. Nevertheless, stepwise‐fully adjusted OR for the higher cutoffs remained significantly increased in anti‐Ro/SSA‐positive subjects, particularly for QTc >500 ms (2.27 [1.34–3.87]).

Conclusions
Anti‐Ro/SSA‐antibody positivity was independently associated with an increased risk of marked QTc prolongation in a large cohort of US veterans. Our data suggest that within the general population individuals who are anti‐Ro/SSA‐positive may represent a subgroup of patients particularly predisposed to ventricular arrhythmias/sudden cardiac death.
COVID-19: Companion Animals Help People Cope during Government-Imposed Social Isolation
Authors: Johnson Elizabeth , Volsche Shelly 
Published: February 2021

Abstract
This research explores the impact of government-imposed social isolation orders on homes with companion animals. Data were collected April through May 2020, the onset of the COVID-19 pandemic. A survey of 234 Americans observing social isolation orders included demographic questions; questions about relationships to other persons and companion animals within the home; and Likert-scale questions designed to probe the complexities of these relationships and their influences on perceived stress and isolation. We hypothesized that the presence of companion animals helps to mitigate stressors related to observing social isolation orders, with those living alone experiencing more benefit and homes with children experiencing less. The results suggest that the presence of companion animals alleviates stress and isolation by providing attachment figures and activities on which to focus one’s energy. These results support that companion animals are increasingly viewed as members of one’s family and provide social support during stressful life events.
Preventing Zoonotic Emerging Disease Outbreaks: The Need to Complement One Health with Ethical Considerations
Authors: Martin Angela K. , Dürr Salome 
Published: February 2021

Abstract
Human encroachment on the habitats of wild animals and the dense living conditions of farmed animals increase spill-over risk of emerging infectious diseases from animals to humans (such as COVID-19). In this article, we defend two claims: First, we argue that in order to limit the risk of emerging infectious disease outbreaks in the future, a One Health approach is needed, which focuses on human, animal, and environmental health. Second, we claim that One Health should not solely be grounded in collaborations between veterinary, medical, and environmental scientists, but should also involve more dialogue with animal and environmental ethicists. Such an interdisciplinary approach would result in epidemiology-driven measures that are ethically legitimate.
A 23-Year Severe Hail Climatology Using GridRad MESH Observations
Authors: Murillo Elisa M. , Homeyer Cameron R. , Allen John T. 
Published: February 2021

AbstractAssessments of spatiotemporal severe hailfall characteristics using hail reports are plagued by serious limitations in report databases, including biases in reported sizes, occurrence time, and location. Multiple studies have used Next Generation Weather Radar (NEXRAD) network observations or environmental hail proxies from reanalyses. Previous work has specifically utilized the single-polarization radar parameter maximum expected size of hail (MESH). In addition to previous work being temporally limited, updates are needed to include recent improvements that have been made to MESH. This study aims to quantify severe hailfall characteristics during a 23-yr period, markedly longer than previous studies, using both radar observations and reanalysis data. First, the improved MESH configuration is applied to the full archive of gridded hourly radar observations known as GridRad (1995–2017). Next, environmental constraints from the Modern-Era Retrospective Analysis for Research and Applications, version 2, are applied to the MESH distributions to produce a corrected hailfall climatology that accounts for the reduced likelihood of hail reaching the ground. Spatial, diurnal, and seasonal patterns show that in contrast to the report climatology indicating one high-frequency hail maximum centered on the Great Plains, the MESH-only method characterizes two regions: the Great Plains and the Gulf Coast. The environmentally filtered MESH climatology reveals improved agreement between report characteristics (frequency, location, and timing) and the recently improved MESH calculation methods, and it reveals an overall increase in diagnosed hail days and westward broadening in the spatial maximum in the Great Plains than that seen in reports.
The importance of interventional timing in the bleomycin model of pulmonary fibrosis
Authors: Kolb Philipp , Upagupta Chandak , Vierhout Megan , Ayaub Ehab , Bellaye Pierre Simon , Gauldie Jack , Shimbori Chiko , Inman Mark , Ask Kjetil , Kolb Martin R.J. 
Published: February 2021

Idiopathic pulmonary fibrosis (IPF) is a complex disease of unknown aetiology, which makes drug development challenging. Single administration of bleomycin directly to the lungs of mice is a widely used experimental model for studying pulmonary fibrogenesis and evaluating the effect of therapeutic antifibrotic strategies. The model works by inducing an early inflammatory phase, which transitions into fibrosis after 5–7 days. This initial inflammation makes therapeutic timing crucial. To accurately assess antifibrotic efficacy, the intervention should inhibit fibrosis without impacting early inflammation.Studies published between 2008 and 2019 using the bleomycin model to investigate pulmonary fibrosis were retrieved from PubMed, and study characteristics were analysed. Intervention-based studies were classified as either preventative (starting <7 days after bleomycin installation) or therapeutic (>7 days). In addition, studies were cross-referenced with current major clinical trials to assess the availability of preclinical rationale.A total of 976 publications were evaluated. 726 investigated potential therapies, of which 443 (61.0%) were solely preventative, 166 (22.9%) were solely therapeutic and 105 (14.5%) were both. Of the 443 preventative studies, only 70 (15.8%) characterised inflammation during the model's early inflammatory phase. In the reported 145 IPF clinical trials investigating 93 compounds/combinations, only 25 (26.9%) interventions had any preclinical data on bleomycin available on PubMed.Since 2008, we observed a shift (from <5% to 37.4%) in the number of studies evaluating drugs in the therapeutic setting in the bleomycin model. While this shift is encouraging, further characterisation of early inflammation and appropriate preclinical therapeutic testing are still needed. This will facilitate fruitful drug development in IPF, and more therapeutic strategies for patients with this devastating disease.
Comparing transcriptional responses to Fusarium crown rot in wheat and barley identified an important relationship between disease resistance and drought tolerance
Authors: Su Z. Y. , Powell J. J. , Gao S. , Zhou M. , Liu C. 
Published: February 2021

Abstract
Background
Fusarium crown rot (FCR) is a chronic disease in cereal production worldwide. The impact of this disease is highly environmentally dependant and significant yield losses occur mainly in drought-affected crops.

Results
In the study reported here, we evaluated possible relationships between genes conferring FCR resistance and drought tolerance using two approaches. The first approach studied FCR induced differentially expressed genes (DEGs) targeting two barley and one wheat loci against a panel of genes curated from the literature based on known functions in drought tolerance. Of the 149 curated genes, 61.0% were responsive to FCR infection across the three loci. The second approach was a comparison of the global DEGs induced by FCR infection with the global transcriptomic responses under drought in wheat. This analysis found that approximately 48.0% of the DEGs detected one week following drought treatment and 74.4% of the DEGs detected three weeks following drought treatment were also differentially expressed between the susceptible and resistant isolines under FCR infection at one or more timepoints. As for the results from the first approach, the vast majority of common DEGs were downregulated under drought and expressed more highly in the resistant isoline than the sensitive isoline under FCR infection.

Conclusions
Results from this study suggest that the resistant isoline in wheat was experiencing less drought stress, which could contribute to the stronger defence response than the sensitive isoline. However, most of the genes induced by drought stress in barley were more highly expressed in the susceptible isolines than the resistant isolines under infection, indicating that genes conferring drought tolerance and FCR resistance may interact differently between these two crop species. Nevertheless, the strong relationship between FCR resistance and drought responsiveness provides further evidence indicating the possibility to enhance FCR resistance by manipulating genes conferring drought tolerance.