bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neoadjuvant Nivolumab for Patients With Resectable Merkel Cell Carcinoma in the CheckMate 358 Trial
Authors: Topalian Suzanne L. , Bhatia Shailender , Amin Asim , Kudchadkar Ragini R. , Sharfman William H. , Lebbé Celeste , Delord Jean-Pierre , Dunn Lara A. , Shinohara Michi M. , Kulikauskas Rima , Chung Christine H. , Martens Uwe M. , Ferris Robert L. , Stein Julie E. , Engle Elizabeth L. , Devriese Lot A. , Lao Christopher D. , Gu Junchen , Li Bin , Chen Tian , Barrows Adam , Horvath Andrea , Taube Janis M. , Nghiem Paul 
Published: April 2020

PURPOSE Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer commonly driven by the Merkel cell polyomavirus (MCPyV). The programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immunosuppressive pathway is often upregulated in MCC, and advanced metastatic MCC frequently responds to PD-1 blockade. We report what we believe to be the first trial of anti–PD-1 in the neoadjuvant setting for resectable MCC. METHODS In the phase I/II CheckMate 358 study of virus-associated cancer types, patients with resectable MCC received nivolumab 240 mg intravenously on days 1 and 15. Surgery was planned on day 29. Tumor regression was assessed radiographically and microscopically. Tumor MCPyV status, PD-L1 expression, and tumor mutational burden (TMB) were assessed in pretreatment tumor biopsies. RESULTS Thirty-nine patients with American Joint Committee on Cancer stage IIA-IV resectable MCC received ≥ 1 nivolumab dose. Three patients (7.7%) did not undergo surgery because of tumor progression (n = 1) or adverse events (n = 2). Any-grade treatment-related adverse events occurred in 18 patients (46.2%), and grade 3-4 events in 3 patients (7.7%), with no unexpected toxicities. Among 36 patients who underwent surgery, 17 (47.2%) achieved a pathologic complete response (pCR). Among 33 radiographically evaluable patients who underwent surgery, 18 (54.5%) had tumor reductions ≥ 30%. Responses were observed regardless of tumor MCPyV, PD-L1, or TMB status. At a median follow-up of 20.3 months, median recurrence-free survival (RFS) and overall survival were not reached. RFS significantly correlated with pCR and radiographic response at the time of surgery. No patient with a pCR had tumor relapse during observation. CONCLUSION Nivolumab administered approximately 4 weeks before surgery in MCC was generally tolerable and induced pCRs and radiographic tumor regressions in approximately one half of treated patients. These early markers of response significantly predicted improved RFS. Additional investigation of these promising findings is warranted.
LncRNA-Malat1 is Involved in Lipotoxicity-Induced ß-cell Dysfunction and the Therapeutic Effect of Exendin-4 via Ptbp1
Authors: Xiong Li , Gong Yingying , Wu Liting , Li Jin , He Weiman , Zhu Xiaonan , Xiao Haipeng 
Published: April 2020

Abstract
Increasing evidence indicates that long noncoding RNAs (lncRNAs) have crucial roles in various biological processes. However, the contribution of lncRNAs to β-cell dysfunction and their roles in diabetes therapeutics remain poorly understood. The aim of this study was to identify the lncRNAs dysregulated in diabetic islets and to explore the lncRNAs involved in β-cell function as potential therapeutic targets. By using RNA sequencing and real-time PCR, we identified thousands of lncRNAs in the islets of db/db mice and db/m littermate mice. Among the differentially expressed lncRNAs, lncRNA-Malat1 (metastasis-associated lung adenocarcinoma transcript 1) was reduced in the islets of db/db mice and palmitate-treated MIN6 cells. The results of TUNEL, Western blot and flow cytometric analyses, and GSIS assays revealed that Malat1 knockdown significantly induced β-cell apoptosis and inhibited insulin secretion. Mechanistically, RNA immunoprecipitation showed that Malat1 enhanced polypyrimidine tract-binding protein 1 (Ptbp1) protein stability by direct interaction, thereby adjusting the ratio of pyruvate kinase muscle (PKM) isoforms 1 and 2 (PKM1/PKM2). Moreover, luciferase assay and chromatin immunoprecipitation indicated that Malat1 was transcriptionally activated by pancreatic and duodenal homeobox 1 (Pdx1), through which exendin-4 alleviated lipotoxicity-induced β-cell damage. In summary, our findings suggested the involvement of Malat1 in β-cell dysfunction under diabetic conditions via the Malat1/Ptbp1/PKM2 pathway. In addition, exendin-4 ameliorated β-cell impairment by Pdx1-mediated Malat1 upregulation. Hence, Malat1 may serve as a therapeutic target for the treatment of type 2 diabetes.
Osh6 requires Ist2 for localization to ER–PM contacts and efficient phosphatidylserine transport in budding yeast
Authors: D'Ambrosio Juan Martín , Albanèse Véronique , Lipp Nicolas-Frédéric , Fleuriot Lucile , Debayle Delphine , Drin Guillaume , Čopič Alenka 
Published: April 2020

ABSTRACT
Osh6 and Osh7 are lipid transfer proteins (LTPs) that move phosphatidylserine (PS) from the endoplasmic reticulum (ER) to the plasma membrane (PM). High PS levels at the PM are key for many cellular functions. Intriguingly, Osh6 and Osh7 localize to ER–PM contact sites, although they lack membrane-targeting motifs, in contrast to multidomain LTPs that both bridge membranes and convey lipids. We show that Osh6 localization to contact sites depends on its interaction with the cytosolic tail of the ER–PM tether Ist2, a homolog of TMEM16 proteins. We identify a motif in the Ist2 tail, conserved in yeasts, as the Osh6-binding region, and we map an Ist2-binding surface on Osh6. Mutations in the Ist2 tail phenocopy osh6Δ osh7Δ deletion: they decrease cellular PS levels and block PS transport to the PM. Our study unveils an unexpected partnership between a TMEM16-like protein and a soluble LTP, which together mediate lipid transport at contact sites.
This article has an associated First Person interview with the first author of the paper.
Seeing the rainbow: mechanisms underlying spectral sensitivity in teleost fishes
Authors: Carleton Karen L. , Escobar-Camacho Daniel , Stieb Sara M. , Cortesi Fabio , Marshall N. Justin 
Published: April 2020

ABSTRACT
Among vertebrates, teleost eye diversity exceeds that found in all other groups. Their spectral sensitivities range from ultraviolet to red, and the number of visual pigments varies from 1 to over 40. This variation is correlated with the different ecologies and life histories of fish species, including their variable aquatic habitats: murky lakes, clear oceans, deep seas and turbulent rivers. These ecotopes often change with the season, but fish may also migrate between ecotopes diurnally, seasonally or ontogenetically. To survive in these variable light habitats, fish visual systems have evolved a suite of mechanisms that modulate spectral sensitivities on a range of timescales. These mechanisms include: (1) optical media that filter light, (2) variations in photoreceptor type and size to vary absorbance and sensitivity, and (3) changes in photoreceptor visual pigments to optimize peak sensitivity. The visual pigment changes can result from changes in chromophore or changes to the opsin. Opsin variation results from changes in opsin sequence, opsin expression or co-expression, and opsin gene duplications and losses. Here, we review visual diversity in a number of teleost groups where the structural and molecular mechanisms underlying their spectral sensitivities have been relatively well determined. Although we document considerable variability, this alone does not imply functional difference per se. We therefore highlight the need for more studies that examine species with known sensitivity differences, emphasizing behavioral experiments to test whether such differences actually matter in the execution of visual tasks that are relevant to the fish.
Hourly 4-s Sprints Prevent Impairment of Postprandial Fat Metabolism from Inactivity
Authors: WOLFE ANTHONY S. , BURTON HEATH M. , VARDARLI EMRE , COYLE EDWARD F. 
Published: April 2020

ABSTRACT
High postprandial plasma lipids (PPL; i.e., triglycerides) are a risk factor for cardiovascular disease. Physical inactivity, characterized by prolonged sitting and a low step count, elevates PPL and thus risk of disease.

Purpose
This study determined if the interruption of prolonged sitting (i.e., 8 h of inactivity) with hourly cycling sprints of only 4-s duration each (i.e., 4 s × 5 per hour × 8 h = 160 s·d−1 SPRINTS) improves PPL. The 4-s sprints used an inertial load ergometer and were followed by 45 s of seated rest.

Methods
Four men and four women participated in two trials. Interventions consisted of an 8-h period of sitting (SIT), or a trial with equal sitting time interrupted with five SPRINTS every hour. The morning after the interventions, PPL and fat oxidation were measured over a 6-h period. Plasma glucose, insulin, and triglyceride concentrations were measured bihourly and incremental area under the curve (AUC) was calculated.

Results
No differences (P > 0.05) between interventions were found for plasma insulin or glucose AUC. However, SPRINTS displayed a 31% (408 ± 119 vs 593 ± 88 mg·dL−1 per 6 h; P = 0.009) decrease in plasma triglyceride incremental AUC and a 43% increase in whole-body fat oxidation (P = 0.001) when compared with SIT.

Conclusions
These data indicate that hourly very short bouts (4 s) of maximal intensity cycle sprints interrupting prolonged sitting can significantly lower the next day’s postprandial plasma triglyceride response and increase fat oxidation after a high-fat meal in healthy young adults. Given that these improvements were elicited from only 160 s of nonfatiguing exercise per day, it raises the question as to what is the least amount of exercise that can acutely improve fat metabolism and other aspects of health.
Exercise Training Impacts Skeletal Muscle Clock Machinery in Prediabetes
Authors: ERICKSON MELISSA L. , ZHANG HUI , MEY JACOB T. , KIRWAN JOHN P. 
Published: April 2020

ABSTRACT

Purpose
Disruption of the skeletal muscle molecular clock leads to metabolic disease, whereas exercise may be restorative, leading to improvements in metabolic health. The purpose of this study was to evaluate the effects of a 12-wk exercise intervention on skeletal muscle molecular clock machinery in adults with obesity and prediabetes, and determine whether these changes were related to exercise-induced improvements in metabolic health.

Methods
Twenty-six adults (age, 66 ± 4.5 yr; body mass index (BMI), 34 ± 3.4 kg·m−2; fasting plasma glucose, 105 ± 15 mg·dL−1) participated in a 12-wk exercise intervention and were fully provided isoenergetic diets. Body composition (dual x-ray absorptiometry), abdominal adiposity (computed tomography scans), peripheral insulin sensitivity (euglycemic–hyperinsulinemic clamp), exercise capacity (maximal oxygen consumption), and skeletal muscle molecular clock machinery (vastus lateralis biopsy) were assessed at baseline and after intervention. Gene and protein expression of skeletal muscle BMAL1, CLOCK, CRY1/2, and PER 1/2 were measured by quantitative real-time polymerase chain reaction and Western blot, respectively.

Results
Body composition (BMI, dual x-ray absorptiometry, computed tomography), peripheral insulin sensitivity (glucose disposal rate), and exercise capacity (maximal oxygen consumption) all improved (P < 0.005) with exercise training. Skeletal muscle BMAL1 gene (fold change, 1.62 ± 1.01; P = 0.027) and PER2 protein expression (fold change, 1.35 ± 0.05; P = 0.02) increased, whereas CLOCK, CRY1/2, and PER1 were unchanged. The fold change in BMAL1 correlated with post–glucose disposal rate (r = 0.43, P = 0.044), BMI (r = −0.44, P = 0.042), and body weight changes (r = −0.44, P = 0.039) expressed as percent delta.

Conclusions
Exercise training impacts skeletal muscle molecular clock machinery in a clinically relevant cohort of adults with obesity and prediabetes. Skeletal muscle BMAL1 gene expression may improve insulin sensitivity. Future studies are needed to determine the physiological significance of exercise-induced alterations in skeletal muscle clock machinery.
Microvascular Function Is Impaired after Short-Term Immobilization in Healthy Men
Authors: RYTTER NICOLAI , PIIL PETER , CARTER HOWARD , NYBERG MICHAEL , HELLSTEN YLVA , GLIEMANN LASSE 
Published: April 2020

ABSTRACT

Purpose
We examined whether 2 wk of one-leg immobilization would impair leg microvascular function and to what extent a subsequent period of intense aerobic cycle training could restore function.

Methods
Study participants were healthy young men (n = 12; 20–24 yr of age). Leg microvascular function was determined before the intervention, after the immobilization period, and after a 4-wk exercise training period. Microvascular function was assessed as the vasodilator response to intra-arterial infusion of acetylcholine and sodium nitroprusside and as the vasoconstrictor response to endogenous noradrenaline release induced by tyramine infusion. Vasodilator enzymes as well as prooxidant and antioxidant enzymes were assessed by protein analysis in skeletal muscle samples: endothelial nitric oxide synthase, NADPH oxidase (NOX p67phox and NOX gp91phox), and superoxide dismutase 2 (SOD2).

Results
The acetylcholine-induced change in vascular conductance was reduced after the 2 wk of immobilization (P = 0.003), tended to increase (P = 0.061), and was back to baseline levels after the subsequent 4 wk of exercise training. Plasma prostacyclin levels in response to acetylcholine infusion were lower after immobilization than before (P = 0.041). The changes in vascular conductance with sodium nitroprusside and tyramine were similar during all conditions. Skeletal muscle protein levels of endothelial nitric oxide synthase in the experimental leg were unchanged with immobilization and subsequent training but increased 47% in the control leg with training (P = 0.002). NOX p67phox, NOX gp91phox, and SOD2 in the experimental leg remained unaltered with immobilization, and SOD2 was higher than preimmobilization after 4 wk of training (P < 0.001).

Conclusions
The study shows that 2 wk of immobilization impairs leg microvascular endothelial function and prostacyclin formation but that 4 wk of intense aerobic exercise training restores the function. The underlying mechanism may reside in the prostacyclin system.
Muscle Metabolism and Fatigue during Simulated Ice Hockey Match-Play in Elite Players
Authors: VIGH-LARSEN JEPPE F. , ERMIDIS GEORGIOS , RAGO VINCENZO , RANDERS MORTEN B. , FRANSSON DAN , NIELSEN JAKOB L. , GLIEMANN LASSE , PIIL JACOB F. , MORRIS NATHAN B. , DE PAOLI FRANK V. , OVERGAARD KRISTIAN , ANDERSEN THOMAS B. , NYBO LARS , KRUSTRUP PETER , MOHR MAGNI 
Published: April 2020

ABSTRACT

Purpose
The present study investigated muscle metabolism and fatigue during simulated elite male ice hockey match-play.

Methods
Thirty U20 male national team players completed an experimental game comprising three periods of 8 × 1-min shifts separated by 2-min recovery intervals. Two vastus lateralis biopsies were obtained either during the game (n = 7) or pregame and postgame (n = 6). Venous blood samples were drawn pregame and at the end of the first and last periods (n = 14). Activity pattern and physiological responses were continuously monitored using local positioning system and heart rate recordings. Further, repeated-sprint ability was tested pregame and after each period.

Results
Total distance covered was 5980 ± 199 m with almost half the distance covered at high skating speeds (>17 km·h−1). Average and peak on-ice heart rate was 84% ± 2% and 97% ± 2% of maximum heart rate, respectively. Muscle lactate increased (P ≤ 0.05) more than fivefold and threefold, whereas muscle pH decreased (P ≤ 0.05) from 7.31 ± 0.04 pregame to 6.99 ± 0.07 and 7.13 ± 0.11 during the first and last periods, respectively. Muscle glycogen decreased by 53% postgame (P ≤ 0.05) with ~65% of fast- and slow-twitch fibers depleted of glycogen. Blood lactate increased sixfold (P ≤ 0.05), whereas plasma free fatty acid levels increased 1.5-fold and threefold (P ≤ 0.05) after the first and last periods. Repeated-sprint ability was impaired (~3%; P ≤ 0.05) postgame concomitant with a ~10% decrease in the number of accelerations and decelerations during the second and last periods (P ≤ 0.05).

Conclusions
Our findings demonstrate that a simulated ice hockey match-play scenario encompasses a high on-ice heart rate response and glycolytic loading resulting in a marked degradation of muscle glycogen, particularly in specific sub-groups of fibers. This may be of importance both for fatigue in the final stages of a game and for subsequent recovery.
Exercise Training Improves Microvascular Function in Burn Injury Survivors
Authors: ROMERO STEVEN A. , MORALEZ GILBERT , JAFFERY MANALL F. , HUANG MU , ENGELLAND RACHEL E. , CRAMER MATTHEW N. , CRANDALL CRAIG G. 
Published: April 2020

ABSTRACT

Introduction
Vasodilator function is impaired in individuals with well-healed burn injuries; however, therapeutic interventions that lessen or reverse this maladaptation are lacking. The purpose of this study was to test the hypothesis that a 6-month community-based exercise training program would increase microvascular dilator function in individuals with well-healed burn injuries, irrespective of the magnitude of the injured body surface area. Further, we hypothesize that macrovascular dilator function would remain unchanged posttraining.

Methods
Microvascular function (forearm reactive hyperemia), macrovascular function (brachial artery flow-mediated dilation), and the maximal vasodilatory response after ischemic handgrip exercise (an estimate of microvascular remodeling) were assessed before and after exercise training in nonburned control subjects (n = 11) and individuals with burn injuries covering a moderate body surface area (26% ± 7%; n = 13) and a high body surface area (59% ± 15%; n = 19).

Results
Peak vascular conductance and area under the curve during postocclusive reactive hyperemia increased from pretraining to posttraining in control and burn injury groups (both P < 0.05), the magnitude of which did not differ between groups (both P = 0.6). Likewise, the maximal vasodilatory response after ischemic handgrip exercise increased in all groups after exercise training (P < 0.05). Macrovascular dilator function did not differ across time or between groups (P = 0.8).

Conclusions
These data suggest that a community-based exercise training program improves microvascular function in individuals with well-healed burn injuries, which may be due in part to vascular remodeling.
Accuracy of the Region of Limb Stability in Predicting Risk for Lower Limb Injury
Authors: FEIGENBAUM LUIS A. , GAUNAURD IGNACIO A. , KIM KYOUNG JAE , RAYA MICHELE A. , RUIZ JEFFREY T. , RAPICAVOLI JULIA , BEST THOMAS M. , KAPLAN LEE , GAILEY ROBERT S. 
Published: April 2020

ABSTRACT

Purpose
This study aimed to determine whether a measure of lower limb segment stability derived from body-worn inertial measurement units can predict risk for lower limb musculoskeletal injury in Division I Collegiate Football Players (D1CFP).

Methods
The region of limb stability (ROLS) values were collected in a cohort of D1CFP during preseason. ROLS is a measure of knee joint stability, defined by thigh and shank excursion (cm2) in the anterior–posterior and medial–lateral direction during single limb stance. The ROLS symmetry index (SI) (%) is the ratio between lower limb ROLS values where 100% suggests absolute symmetry.

Results
One-hundred and four D1CFP participated in this study and were divided into two groups: 1) no previous lower limb injury or no in-season injury (n = 70, “noninjured group”) and 2) no previous lower limb injury, but in-season injury requiring surgery (n = 34, “injured group” group). The mean ± SD ROLS SI was 82.86% ± 14.75% and 65.58% ± 16.46% for the noninjured and injured group, respectively. Significant differences in ROLS SI were found between groups (P < 0.001). The ROLS SI demonstrated an area under the curve of 0.8 (P < 0.001; 95% confidence interval = 0.71–0.88) with an SE of 0.04, indicating that the ROLS SI has good predictive accuracy in detecting those healthy D1CFP at risk for lower limb injury resulting in surgery.

Conclusion
The ROLS SI was found to have good predictive accuracy in detecting individuals at risk for injury that were healthy and asymptomatic during preseason testing. Increase in thigh and shank excursions and/or decrease in SI between lower limbs may be a predictor of risk for future injury.
Effects of Cognitive Training and Exergaming in Pediatric Cancer Survivors—A Randomized Clinical Trial
Authors: BENZING VALENTIN , SPITZHÜTTL JANINE , SIEGWART VALERIE , SCHMID JÜRG , GROTZER MICHAEL , HEINKS THEDA , ROEBERS CLAUDIA M. , STEINLIN MAJA , LEIBUNDGUT KURT , SCHMIDT MIRKO , EVERTS REGULA 
Published: April 2020

ABSTRACT

Purpose
Although most pediatric cancer patients survive, those who undergo anticancer treatments like chemotherapy and/or radiotherapy are at a high risk for late effects, such as cognitive deficits. To counteract these deficits, feasible and effective interventions are needed. The aim of this study was to compare the effects of working memory training, exergaming, and a wait-list control condition on cognitive functions in pediatric cancer survivors.

Methods
In a parallel-group randomized trial, 69 pediatric cancer survivors aged 7–16 yr (mean = 11.35, SD = 3.53) were randomly assigned to 8-wk working memory training, exergaming, or a wait-list control group. Each training course consisted of three 45-min training sessions per week. The primary outcome comprised the core executive functions (visual working memory, inhibition, switching), and the secondary outcomes included other cognitive domains (intelligence, planning, memory, attention, processing speed), motor abilities, and parent rating on their children’s executive functions. Assessments were conducted both before and immediately after the interventions, and at 3-month follow-up.

Results
Linear mixed models revealed that participants in the working memory training group showed a linear improvement in visual working memory after training and at follow-up compared with the control group. No other intervention effects of either type of training could be detected.

Conclusion
This study presents evidence that working memory training improves visual working memory in pediatric cancer survivors. Results show that near-transfer, but no far-transfer effects can be expected from working memory training. Multiple-component interventions tailored to fit the individual’s cognitive profile are needed to best support cognitive development after cancer and its treatment.
STUDY OF NUCLEON CORRELATIONS IN HEAVY NUCLEI WITH HIGH ENERGY ELASTIC ELECTRON SCATTERING
Authors: Vellidis C. E. , Frois B. , Goutte D. , Papadakis N. , Papanicolas C. N. , Vodinas N. , Williamson S. E. 
Published: April 2020

During the last decade the detailed analysis of several observables and especially of electron scattering data has shown conclusively the presence of short-range nucleon correlations. As a result the degree to which the shape and amplitude of a correlated wave function can be approximated by an independent particle wave function has emerged as a question of fundamental importance. A presentation will be given below of an experiment that will be performed at the Bates Linear Accelerator Center attempting to study this question. The elastic cross-section ratios from 208,207,206Pb,205Ti(e,e) will be measured with high accuracy up to momentum transfers of 3.4 fm^-1 in order to study the influence of correlations on the shape of the 3s1/2 proton wave function. The purpose, motivation and main aspects of the new research will be explained and the experimental considerations together with the running scenario for the experiment will be presented.