bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pan-cancer distribution of cleaved cell-surface amphiregulin, the target of the GMF-1A3 antibody drug conjugate
Authors: Lofgren Kristopher A , Reker Nicolette C , Sreekumar Sreeja , Kenny Paraic A 
Published: August 2022

Abstract
Amphiregulin is a transmembrane protein which, when cleaved by the TACE/ADAM17 protease, releases a soluble epidermal growth factor receptor ligand domain that promotes proliferation of normal and malignant cells. We previously described a rabbit monoclonal antibody, GMF-1A3, that selectively recognizes the cell-associated cleaved amphiregulin epitope. Antibody-drug conjugates had anti-tumor activity against human breast cancer xenografts. Several tumor types express amphiregulin, but evidence for a functional requirement for amphiregulin in these malignancies is limited. By directly evaluating amphiregulin cleavage with immunohistochemistry, GMF-1A3 provides a more direct measure of amphiregulin activity. Using 370 specimens from 10 tumor types (as well as normal controls), we demonstrate that cleaved amphiregulin is widely expressed in solid tumors and is especially common (&gt; 50% of cases) in breast, prostate, liver and lung cancer. As a potential companion diagnostic for this antibody-drug conjugate, this assay allows identification of tumors with high levels of the cleaved amphiregulin target.
Spatiotemporal Trends in Norovirus Outbreaks in the United States, 2009–2019
Authors: Kambhampati Anita K , Calderwood Laura , Wikswo Mary E , Barclay Leslie , Mattison Claire P , Balachandran Neha , Vinjé Jan , Hall Aron J , Mirza Sara A 
Published: August 2022

AbstractBackgroundGlobally, noroviruses cause infections year-round but have recognized winter seasonality in the Northern Hemisphere and yearly variations in incidence. With candidate norovirus vaccines in development, understanding temporal and geographic trends in norovirus disease is important to inform potential vaccination strategies and evaluate vaccine impact.MethodsWe analyzed data from the National Outbreak Reporting System (NORS) and CaliciNet on single-state norovirus outbreaks that occurred during August 2009–July 2019 in the contiguous United States. We defined norovirus season onset and offset as the weeks by which 10% and 90% of norovirus outbreaks in a surveillance year occurred, respectively, and duration as the difference in weeks between onset and offset. We compared norovirus seasons across surveillance years and geographic regions.ResultsDuring August 2009–July 2019, 24 995 single-state norovirus outbreaks were reported to NORS and/or CaliciNet. Nationally, the median norovirus season duration was 24 weeks, with onset occurring between October and December and offset occurring between April and May. Across all years combined, we observed a west-to-east trend in seasonality, with the earliest onset (October) and latest offset (May) occurring in western regions and the latest onset (December) and earliest offset (April) occurring in northeastern regions.ConclusionsTiming and duration of the US norovirus season varied annually but generally occurred during October–May. Norovirus wintertime seasonality was less distinct in western regions and was progressively more pronounced moving east. Further understanding the drivers of spatiotemporal dynamics of norovirus could provide insights into factors that promote virus transmission and help guide future interventions.
Validity of Self-testing at Home With Rapid Severe Acute Respiratory Syndrome Coronavirus 2 Antibody Detection by Lateral Flow Immunoassay
Authors: Atchison Christina J , Moshe Maya , Brown Jonathan C , Whitaker Matthew , Wong Nathan C K , Bharath Anil A , McKendry Rachel A , Darzi Ara , Ashby Deborah , Donnelly Christl A , Riley Steven , Elliott Paul , Barclay Wendy S , Cooke Graham S , Ward Helen 
Published: August 2022

AbstractBackgroundWe explore severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody lateral flow immunoassay (LFIA) performance under field conditions compared to laboratory-based electrochemiluminescence immunoassay (ECLIA) and live virus neutralization.MethodsIn July 2021, 3758 participants performed, at home, a self-administered Fortress LFIA on finger-prick blood, reported and submitted a photograph of the result, and provided a self-collected capillary blood sample for assessment of immunoglobulin G (IgG) antibodies using the Roche Elecsys® Anti-SARS-CoV-2 ECLIA. We compared the self-reported LFIA result to the quantitative ECLIA and checked the reading of the LFIA result with an automated image analysis (ALFA). In a subsample of 250 participants, we compared the results to live virus neutralization.ResultsAlmost all participants (3593/3758, 95.6%) had been vaccinated or reported prior infection. Overall, 2777/3758 (73.9%) were positive on self-reported LFIA, 2811/3457 (81.3%) positive by LFIA when ALFA-reported, and 3622/3758 (96.4%) positive on ECLIA (using the manufacturer reference standard threshold for positivity of 0.8 U mL–1). Live virus neutralization was detected in 169 of 250 randomly selected samples (67.6%); 133/169 were positive with self-reported LFIA (sensitivity 78.7%; 95% confidence interval [CI]: 71.8, 84.6), 142/155 (91.6%; 95% CI: 86.1, 95.5) with ALFA, and 169 (100%; 95% CI: 97.8, 100.0) with ECLIA. There were 81 samples with no detectable virus neutralization; 47/81 were negative with self-reported LFIA (specificity 58.0%; 95% CI: 46.5, 68.9), 34/75 (45.3%; 95% CI: 33.8, 57.3) with ALFA, and 0/81 (0%; 95% CI: 0, 4.5) with ECLIA.ConclusionsSelf-administered LFIA is less sensitive than a quantitative antibody test, but the positivity in LFIA correlates better than the quantitative ECLIA with virus neutralization.
Reduced Incidence of Long Coronavirus Disease Referrals to the Cambridge University Teaching Hospital Long Coronavirus Disease Clinic
Authors: Krishna Benjamin A , Metaxaki Marina , Wills Mark R , Sithole Nyaradzai 
Published: August 2022

AbstractLong coronavirus disease (COVID [LC]) constitutes a potential health emergency as millions of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections lead to chronic symptoms. We must understand whether vaccines reduce LC because this has major implications for health policy. We report a 79% reduction in LC referrals correlating with vaccination in the United Kingdom.
Riociguat in pulmonary hypertension and heart failure with preserved ejection fraction: the haemoDYNAMIC trial
Authors: Dachs Theresa Marie , Duca Franz , Rettl René , Binder-Rodriguez Christina , Dalos Daniel , Ligios Luciana Camuz , Kammerlander Andreas , Grünig Ekkehard , Pretsch Ingrid , Steringer-Mascherbauer Regina , Ablasser Klemens , Wargenau Manfred , Mascherbauer Julia , Lang Irene M , Hengstenberg Christian , Badr-Eslam Roza , Kastner Johannes , Bonderman Diana 
Published: August 2022

Abstract

Aims
The presence of pulmonary hypertension (PH) severely aggravates the clinical course of heart failure with preserved ejection fraction (HFpEF). To date, neither established heart failure therapies nor pulmonary vasodilators proved beneficial. This study investigated the efficacy of chronic treatment with the oral soluble guanylate cyclase stimulator riociguat in patients with PH-HFpEF.

Methods and Results
The phase IIb, randomized, double-blind, placebo-controlled, parallel-group, multicentre DYNAMIC trial assessed riociguat in PH-HFpEF. Patients were recruited at five hospitals across Austria and Germany. Key eligibility criteria were mean pulmonary artery pressure ≥25 mmHg, pulmonary arterial wedge pressure &gt;15 mmHg, and left ventricular ejection fraction ≥50%. Patients were randomized to oral treatment with riociguat or placebo (1:1). Patients started at 0.5 mg three times daily (TID) and were up-titrated to 1.5 mg TID. The primary efficacy endpoint was change from baseline to week 26 in cardiac output (CO) at rest, measured by right heart catheterization. Primary efficacy analyses were performed on the full analysis set. Fifty-eight patients received riociguat and 56 patients placebo. After 26 weeks, CO increased by 0.37 ± 1.263 L/min in the riociguat group and decreased by −0.11 ± 0.921 L/min in the placebo group (least-squares mean difference: 0.54 L/min, 95% confidence interval 0.112, 0.971; P = 0.0142). Five patients dropped out due to riociguat-related adverse events but no riociguat-related serious adverse event or death occurred.

Conclusion
The vasodilator riociguat improved haemodynamics in PH-HFpEF. Riociguat was safe in most patients but led to more dropouts as compared to placebo and did not change clinical symptoms within the study period.
Repeat expansions nested within tandem CNVs: a unique structural change in GLS exemplifies the diagnostic challenges of non-coding pathogenic variation
Authors: Fazal Sarah , Danzi Matt C , van Kuilenburg André B P , Reich Selina , Traschütz Andreas , Bender Benjamin , Leen René , Toro Camilo , Usdin Karen , Hayward Bruce , Adams David R , van Karnebeek Clara D M , Ferreira Carlos R , D’Sousa Precilla , Network Undiagnosed Diseases , Tekin Mustafa , Züchner Stephan , Synofzik Matthis 
Published: August 2022

Abstract
Glutaminase deficiency has recently been associated with ataxia and developmental delay due to repeat expansions in the 5′UTR of the glutaminase (GLS) gene. Patients with the described GLS repeat expansion may indeed remain undiagnosed due to the rarity of this variant, the challenge of its detection and the recency of its discovery. In this study, we combined advanced bioinformatics screening of ~3000 genomes and ~1500 exomes with optical genome mapping and long-read sequencing for confirmation studies. We identified two GLS families, previously intensely and unsuccessfully analyzed. One family carries an unusual and complex structural change involving a homozygous repeat expansion nested within a quadruplication event in the 5′UTR of GLS. Glutaminase deficiency and its metabolic consequences were validated by in-depth biochemical analysis. The identified GLS patients showed progressive early-onset ataxia, cognitive deficits, pyramidal tract damage and optic atrophy, thus demonstrating susceptibility of several specific neuron populations to glutaminase deficiency. This large-scale screening study demonstrates the ability of bioinformatics analysis—validated by latest state-of-the-art technologies (optical genome mapping and long-read sequencing)—to effectively flag complex repeat expansions using short-read datasets and thus facilitate diagnosis of ultra-rare disorders.
Thermal stress and selection for growth affect myogenic satellite cell lipid accumulation and adipogenic gene expression through mechanistic target of rapamycin pathway
Authors: Xu Jiahui , Strasburg Gale M , Reed Kent M , Velleman Sandra G 
Published: August 2022

Abstract
Satellite cells (SCs) are multipotential stem cells having the plasticity to convert to an adipogenic lineage in response to thermal stress during the period of peak mitotic activity (the first week after hatch in poultry). The mechanistic target of rapamycin (mTOR) pathway, which regulates cellular function and fate of SCs, is greatly altered by thermal stress in turkey pectoralis major muscle SCs. The objective of the present study was to determine the effects of thermal stress, selection for growth, and the role of the mTOR pathway on SC intracellular lipid accumulation and expression of adipogenic regulatory genes. These effects were analyzed using SCs isolated from the pectoralis major muscle of 1-wk-old modern faster-growing commercial turkey line (NC) selected for increased growth and breast muscle yield as compared with SCs of a historic slower-growing Randombred Control Line 2 (RBC2) turkey. Heat stress (43 °C) of SCs during proliferation increased intracellular lipid accumulation (P &lt; 0.001), whereas cold stress (33 °C) showed an inhibitory effect (P &lt; 0.001) in both lines. Knockdown of mTOR reduced the intracellular lipid accumulation (P &lt; 0.001) and suppressed the expression of several adipogenic regulatory genes: peroxisome proliferator-activated receptor-γ (PPARγ; P &lt; 0.001), CCAAT/enhancer-binding protein-β (C/EBPβ; P &lt; 0.001), and neuropeptide-Y (NPY; P &lt; 0.001) during both proliferation and differentiation. The NC line SCs showed fewer reductions in lipid accumulation compared with the RBC2 line independent of temperature. Both intracellular lipid accumulation (P &lt; 0.001) and PPARγ expression (P &lt; 0.001) were greater at 72 h of proliferation than at 48 h of differentiation in both the RBC2 and NC lines independent of temperature. Thus, hot and cold thermal stress affected intracellular lipid accumulation in the pectoralis major muscle SCs, in part, through the mTOR pathway in wea growth-dependent manner. Altered intracellular lipid accumulation could eventually affect intramuscular fat deposition, resulting in a long-lasting effect on the structure and protein to fat ratio of the poultry pectoralis major muscle.
Supplementation with artificial sweetener and capsaicin alters metabolic flexibility and performance in heat-stressed and feed-restricted pigs
Authors: Kroscher Kellie A , Fausnacht Dane W , McMillan Ryan P , El-Kadi Samer W , Wall Emma H , Bravo David M , Rhoads Robert P 
Published: August 2022

Abstract
Substantial economic losses in animal agriculture result from animals experiencing heat stress (HS). Pigs are especially susceptible to HS, resulting in reductions in growth, altered body composition, and compromised substrate metabolism. In this study, an artificial high-intensity sweetener and capsaicin (CAPS-SUC; Pancosma, Switzerland) were supplemented in combination to mitigate the adverse effects of HS on pig performance. Forty cross-bred barrows (16.2 ± 6 kg) were assigned to one of five treatments: thermal neutral controls (TN) (22 ± 1.2 °C; 38%–73% relative humidity) with ad libitum feed, HS conditions with ad libitum feed with (HS+) or without (HS−) supplementation, and pair-fed to HS with (PF+) or without supplementation (PF−). Pigs in heat-stressed treatments were exposed to a cyclical environmental temperature of 12 h at 35 ± 1.2 °C with 27%–45% relative humidity and 12 h at 30 ± 1.1 °C with 24%–35% relative humidity for 21 d. Supplementation (0.1 g/kg feed) began 7 d before and persisted through the duration of environmental or dietary treatments (HS/PF), which lasted for 21 d. Rectal temperatures and respiration rates (RR; breaths/minute) were recorded thrice daily, and feed intake (FI) was recorded daily. Before the start and at the termination of environmental treatments (HS/PF), a muscle biopsy of the longissimus dorsi was taken for metabolic analyses. Blood samples were collected weekly, and animals were weighed every 3 d during treatment. Core temperature (TN 39.2 ± 0.02 °C, HS− 39.6 ± 0.02 °C, and HS+ 39.6 ± 0.02 °C, P &lt; 0.001) and RR (P &lt; 0.001) were increased in both HS− and HS+ groups, but no difference was detected between HS− and HS+. PF− pigs exhibited reduced core temperature (39.1 ± 0.02 °C, P &lt; 0.001), which was restored in PF+ pigs (39.3 ± 0.02 °C) to match TN. Weight gain and feed efficiency were reduced in PF− pigs (P &lt; 0.05) but not in the PF+ or the HS− or HS+ groups. Metabolic flexibility was decreased in the HS− group (−48.4%, P &lt; 0.05) but maintained in the HS+ group. CAPS-SUC did not influence core temperature or weight gain in HS pigs but did restore core temperature, weight gain, and feed efficiency in supplemented PF pigs. In addition, supplementation restored metabolic flexibility during HS and improved weight gain and feed efficiency during PF, highlighting CAPS-SUC’s therapeutic metabolic effects.
Cattle breed type and anabolic implants impact calpastatin expression and abundance of mRNA associated with protein turnover in the longissimus thoracis of feedlot steers
Authors: Reichhardt Caleb C , Stafford Chandler D , Cuthbert Jocelyn M , Dang David S , Motsinger Laura A , Taylor Mackenzie J , Briggs Reganne K , Brady Tevan J , Thomas Aaron J , Garcia Matthew D , Matarneh Sulaiman K , Thornton Kara J 
Published: August 2022

Abstract
Two methods that the beef cattle industry can use to improve efficiency, sustainability, and economic viability are growth promotants and crossbreeding cattle of different breed types. In the United States, over 90% of cattle receive an anabolic implant at some point during production resulting in an overall increase in skeletal muscle growth. Recent research suggests that the two main cattle breed types, Bos indicus and Bos taurus, respond differently to anabolic implants. The objective of this study was to characterize changes that occur in skeletal muscle following implanting in Bos indicus influenced steers or Bos taurus steers. Twenty steers were stratified by initial weight in a 2 × 2 factorial design examining two different breeds: Angus (AN; n = 10) or Santa Gertrudis influenced (SG; n = 10), and two implant strategies: no implant (CON; n = 10) or a combined implant containing 120 mg TBA and 24 mg E2 (IMP; n = 10; Revalor-S, Merck Animal Health). Skeletal muscle biopsies were taken from the longissimus thoracis (LT) 2 and 10 d post-implantation. The mRNA abundance of 24 genes associated with skeletal muscle growth were examined, as well as the protein expression of µ-calpain and calpastatin. Succinate dehydrogenase mRNA abundance was impacted (P = 0.05) by a breed × treatment interaction 2 d post-implanting, with SG-CON having a greater increased abundance than all other steers. A tendency for a breed × treatment interaction was observed for calpain-6 mRNA (P = 0.07), with SG-CON having greater abundance than AN-CON and SG-IMP. Additionally, calpastatin protein expression was altered (P = 0.01) by a breed × treatment interaction, with SG-CON and SG-IMP steers having increased expression (P = 0.01) compared with AN-CON steers. At 2 d post-implanting, a breed × treatment interaction was observed with SG-CON steers having greater (P = 0.05) mRNA abundance of mitogen-activated protein kinase compared with AN-CON steers. Furthermore, breed affected (P = 0.05) calpastatin abundance with AN steers having increased (P = 0.05) abundance 2 d post-implanting compared with SG steers. Meanwhile, implants tended to affect (P = 0.09) muscle RING finger protein-1 mRNA abundance, with CON steers having increased (P = 0.09) abundance compared with that of IMP steers. These findings suggest that cattle breed type and anabolic implants impact calpastatin expression and mRNA abundance associated with protein turnover in the LT of feedlot steers 2 and 10 d post-implantation.
Short Communication: Beta-adrenergic agonists alter oxidative phosphorylation in primary myoblasts
Authors: Sieck Renae L , Treffer Leah K , Fuller Anna M , Ponte Viana Martonio , Khalimonchuk Oleh , Schmidt Ty B , Yates Dustin T , Petersen Jessica L 
Published: August 2022

Abstract
Beta-adrenergic agonists (β-AAs) are widely used supplements in beef and pork production to improve feed efficiency and increase lean muscle mass, yet little is known about the molecular mechanism by which β-AAs achieve this outcome. Our objective was to identify the influence of ractopamine HCl and zilpaterol HCl on mitochondrial respiratory activity in muscle satellite cells isolated from crossbred beef steers (N = 5), crossbred barrows (N = 2), Yorkshire-cross gilts (N = 3), and commercial weather lambs (N = 5). Real-time measurements of oxygen consumption rates (OCRs) were recorded using extracellular flux analyses with a Seahorse XFe24 analyzer. After basal OCR measurements were recorded, zilpaterol HCl, ractopamine HCl, or no β-AA was injected into the assay plate in three technical replicates for each cell isolate. Then, oligomycin, carbonyl cyanide-p-trifluoromethoxyphenylhydrazone, and rotenone were injected into the assay plate sequentially, each inducing a different cellular state. This allowed for the measurement of OCR at these states and for the calculation of the following measures of mitochondrial function: basal respiration, non-mitochondrial respiration, maximal respiration, proton leak, adenosine triphosphate (ATP)-linked respiration, and spare respiratory capacity. Incubation of bovine cells with either zilpaterol HCl or ractopamine HCl increased maximal respiration (P = 0.046) and spare respiratory capacity (P = 0.035) compared with non-supplemented counterparts. No difference (P &gt; 0.05) was observed between zilpaterol HCl and ractopamine HCl for maximal respiration and spare respiratory capacity in bovine cell isolates. No measures of mitochondrial function (basal respiration, non-mitochondrial respiration, maximal respiration, proton leak, ATP-linked respiration, and spare respiratory capacity) were altered by β-AA treatment in ovine or porcine cells. These findings indicate that β-AAs in cattle may improve the efficiency of oxidative metabolism in muscle satellite cells by modifying mitochondrial respiratory activity. The lack of response by ovine and porcine cells to β-AA incubation also demonstrates differing physiological responses to β-AA across species, which helps to explain the variation in its effectiveness as a growth supplement.
Impact of the COVID-19 pandemic on the diagnosis of cancer in Japan: analysis of hospital-based cancer registries
Authors: Okuyama Ayako , Watabe Mari , Makoshi Riko , Takahashi Hirokazu , Tsukada Yoichiro , Higashi Takahiro 
Published: August 2022

Abstract

Background
There is significant concern that cancer care is adversely impacted due to the coronavirus disease pandemic. Using the national database, we document the impact of the pandemic on cancer diagnosis in Japan.

Methods
Data from 735 hospital-based cancer registries, covering &gt;70% of newly diagnosed cases, were analysed. We compared trends during 2016–2019 and those in 2020 by the type of cancer, diagnostic process, stage and 13 prefectures as requiring special precautions to prevent the spread of infection.

Results
Overall, the number of patients who began treatment decreased by 1.9% in 2020 as compared with the average number during 2016–2019. A sharp decline of 13.8% was observed for stomach cases. The decline in cases (22.0% decrease for all cancers) was more pronounced in May. Cancer screening and resulting detection decreased significantly in 2020 (8.1–24.3%). Case registrations of stage I and II gastric cancer, stage II intrahepatic cholangiocarcinoma, stage II oesophageal cancer, stage 0 and I laryngeal cancer and stage II gallbladder cancer decreased by &gt;10% compared with those in 2018 and 2019. The trends in cancer cases by area of residence indicated a decline in 13 prefectures in May 2020 compared with other areas.

Conclusions
The number of cancer diagnoses decreased during the year 2020 under coronavirus pandemic, especially right after the Japanese government declared the first state of emergency in April. We need to carefully observe the consequences of these decrease in diagnosis, or perhaps the delay in care, on patient survival or population mortality.