bluuebunny/crossref_metadata_2025_split huggingface dataset:
High CXCR4 expression in adenoid cystic carcinoma of the head and neck is associated with increased risk of locoregional recurrence
Authors: Klein Nulent Thomas J W , van Es Robert J J , Valstar Matthijs H , Smeele Ludwig E , Smit Laura A , Klein Gunnewiek Raquel , Zuithoff Nicolaas P A , de Keizer Bart , de Bree Remco , Willems Stefan M 
Published: January 2020

AimTreatment options for head and neck adenoid cystic carcinoma (AdCC) are limited in advanced disease. Chemokine receptor type 4 (CXCR4) is present in various tumour types, including AdCC. Upregulation is associated with tumour recurrence and metastasis. New CXCR4-specific diagnostic and therapeutic target agents have recently been available. This study aimed to analyse CXCR4 expression in a cohort of primary head and neck AdCC.MethodsAfter histopathological revision, tumour tissues of 73 consecutive patients with AdCC over 1990–2016 were sampled on a tissue microarray. Slides were immunohistochemically stained for CXCR4 and semiquantitatively scored. Associations between protein expression and cliniopathological parameters were tested. HRs were calculated using a Cox proportional hazard model.ResultsSixty-six tumours could be analysed. CXCR4 expression was present in 81% of the tumours with a median of 29% (IQR 1–70) positive cells. Expression was univariately correlated to perineural growth (Spearman ρ .26, p=0.04) and bone invasion (Spearman ρ .32, p=0.01), but not with tumour grade.CXCR4 expression in the primary tumour was significantly higher in tumours that recurred as compared with those that did not recur (median 60%, IQR 33–72 vs 12%, IQR 1–70, Kruskal-Wallis p=0.01). After dichotomisation, >25% of CXCR4 expressions proved an independent prognosticator for a reduced recurrence-free survival (RFS) (HR 7.2, 95% CI 1.5 to 72.4, p=0.04).ConclusionCXCR4 is expressed in the majority of primary AdCCs and independently correlated to worse RFS, suggesting CXCR4 as a target for imaging and therapy purposes in patients with advanced AdCC.
Defining current gaps in quality measures for cancer immunotherapy: consensus report from the Society for Immunotherapy of Cancer (SITC) 2019 Quality Summit
Authors: Pai Sara , Blaisdell David , Brodie Rachel , Carlson Robert , Finnes Heidi , Galioto Michele , Jensen Roxanne E , Valuck Tom , Sepulveda Antonia R , Kaufman Howard L 
Published: January 2020

BackgroundQuality measures are important because they can help improve and standardize the delivery of cancer care among healthcare providers and across tumor types. In an environment characterized by a rapidly shifting immunotherapeutic landscape and lack of associated long-term outcome data, defining quality measures for cancer immunotherapy is a high priority yet fraught with many challenges.MethodsThus, the Society for Immunotherapy of Cancer convened a multistakeholder expert panel to,first, identify the current gaps in measures of quality cancer care delivery as it relates to immunotherapy and to,second, advance priority concepts surrounding quality measures that could be developed and broadly adopted by the field.ResultsAfter reviewing the existing quality measure landscape employed for immunotherapeutic-based cancer care, the expert panel identified four relevant National Quality Strategy domains (patient safety, person and family-centered care, care coordination and communication, appropriate treatment selection) with significant gaps in immunotherapy-based quality cancer care delivery. Furthermore, these domains offer opportunities for the development of quality measures as they relate to cancer immunotherapy. These four quality measure concepts are presented in this consensus statement.ConclusionsThis work represents a first step toward defining and standardizing quality delivery of cancer immunotherapy in order to realize its optimal application and benefit for patients.
Regulatory T-cell depletion in the setting of autologous stem cell transplantation for multiple myeloma: pilot study
Authors: Derman Benjamin A , Zha Yuanyuan , Zimmerman Todd M , Malloy Rebecca , Jakubowiak Andrzej , Bishop Michael R , Kline Justin 
Published: January 2020

BackgroundProgression after high-dose melphalan with autologous stem cell transplantation (ASCT) in multiple myeloma (MM) may be due in part to immune dysfunction. Regulatory T (Treg) cells reconstitute rapidly after ASCT and inhibit immune responses against myeloma cells.MethodsWe performed a randomized study to evaluate two methods of Treg depletion in patients with MM undergoing ASCT. No Treg depletion was performed in the control ASCT arm. An anti-CD25 monoclonal antibody (basiliximab 20 mg IV) was administered on day +1 post-ASCT in the in vivo Treg depletion (IVTRD) arm. Tregs were depleted from autologous stem cell (ASC) grafts with anti-CD25 microbeads and the CliniMACS device in the ex vivo Treg depletion (EVTRD) arm.ResultsFifteen patients were enrolled, five in each arm. The conditioning regimen was melphalan 200 mg/m2. Primary objectives included assessments of efficiency of IVTRD/EVTRD, kinetics of Treg depletion and recovery following ASCT, and safety. EVTRD removed 90% of CD4+CD25+cells from ASC grafts. IVTRD and EVTRD led to reductions in Treg frequency between days +7 and +90 post-transplant compared with the control (p=0.007 and p<0.001, respectively).ConclusionsIVTRD and EVTRD are feasible and significantly reduce and delay Treg recovery post-ASCT for MM, and serve as a platform for using post-transplant immunotherapies to improve post-ASCT outcomes.Trial registration numberNCT01526096.
Analysis of the non-linear beam dynamics at top energy for the CERN Large Hadron Collider by means of a diffusion model
Authors: Bazzani A. , Giovannozzi M. , Maclean E. H. 
Published: January 2020

AbstractIn this paper, the experimental results of the recent dynamic aperture at top energy for the CERN Large Hadron Collider are analysed by means of a diffusion model whose novelty consists of deriving the functional form of the diffusion coefficient from Nekhoroshev theorem. This theorem provides an optimal estimate of the remainder of perturbative series for Hamiltonian systems. As a consequence, a three-parameter diffusion model is built that reproduces the experimental results with a high level of accuracy. A detailed discussion of the physical interpretation of the proposed model is also presented.
Differential regulation of mTORC1 activation by leucine and β-hydroxy-β-methylbutyrate in skeletal muscle of neonatal pigs
Authors: Suryawan Agus , Rudar Marko , Fiorotto Marta L. , Davis Teresa A. 
Published: January 2020

Leucine (Leu) and its metabolite β-hydroxy-β-methylbutyrate (HMB) stimulate mechanistic target of rapamycin (mTOR) complex 1 (mTORC1)-dependent protein synthesis in the skeletal muscle of neonatal pigs. This study aimed to determine whether HMB and Leu utilize common nutrient-sensing mechanisms to activate mTORC1. In study 1, neonatal pigs were fed one of five diets for 24 h: low protein (LP), high protein (HP), or LP supplemented with 4 (LP+HMB4), 40 (LP+HMB40), or 80 (LP+HMB80) μmol HMB·kg body wt−1·day−1. In study 2, neonatal pigs were fed for 24 h: LP, LP supplemented with Leu (LP+Leu), or HP diets delivering 9, 18, and 18 mmol Leu·kg body wt−1·day−1, respectively. The upstream signaling molecules that regulate mTORC1 activity were analyzed. mTOR phosphorylation on Ser2448 and Ser2481 was greater in LP+HMB40, LP+HMB80, and LP+Leu than in LP and greater in HP than in HMB-supplemented groups ( P < 0.05), whereas HP and LP+Leu were similar. Rheb-mTOR complex formation was lower in LP than in HP ( P < 0.05), with no enhancement by HMB or Leu supplementation. The Sestrin2-GATOR2 complex was more abundant in LP than in HP and was reduced by Leu ( P < 0.05) but not HMB supplementation. RagA-mTOR and RagC-mTOR complexes were higher in LP+Leu and HP than in LP and HMB groups ( P < 0.05). There were no treatment differences in RagB-SH3BP4, Vps34-LRS, and RagD-LRS complex abundances. Phosphorylation of Erk1/2 and TSC2, but not AMPK, was lower in LP than HP ( P < 0.05) and unaffected by HMB or Leu supplementation. Our results demonstrate that HMB stimulates mTORC1 activation in neonatal muscle independent of the leucine-sensing pathway mediated by Sestrin2 and the Rag proteins. NEW & NOTEWORTHY Dietary supplementation with either leucine or its metabolite β-hydroxy-β-methylbutyrate (HMB) stimulates protein synthesis in skeletal muscle of the neonatal pig. Our results demonstrate that both leucine and HMB stimulate mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) phosphorylation in neonatal muscle. This leucine-stimulated process involves dissociation of the Sestrin2-GATOR2 complex and increased binding of Rag A/C to mTOR. However, HMB’s activation of mTORC1 is independent of this leucine-sensing pathway.
Exercise effects on γ3-AMPK activity, phosphorylation of Akt2 and AS160, and insulin-stimulated glucose uptake in insulin-resistant rat skeletal muscle
Authors: Pataky Mark W. , Arias Edward B. , Wang Haiyan , Zheng Xiaohua , Cartee Gregory D. 
Published: January 2020

One exercise session can increase subsequent insulin-stimulated glucose uptake (ISGU) by skeletal muscle. Prior research on healthy muscle suggests that enhanced postexercise ISGU depends on elevated γ3-AMPK activity leading to greater phosphorylation of Akt substrate of 160 kDa (pAS160) on an AMPK-phosphomotif (Ser704). Phosphorylation of AS160Ser704, in turn, may favor greater insulin-stimulated pAS160 on an Akt-phosphomotif (Thr642) that regulates ISGU. Accordingly, we tested if exercise-induced increases in γ3-AMPK activity and pAS160 on key regulatory sites accompany improved ISGU at 3 h postexercise (3hPEX) in insulin-resistant muscle. Rats fed a high-fat diet (HFD; 2-wk) that induces insulin resistance either performed acute swim-exercise (2 h) or were sedentary (SED). SED rats fed a low-fat diet (LFD; 2 wk) served as healthy controls. Isolated epitrochlearis muscles from 3hPEX and SED rats were analyzed for ISGU, pAS160, pAkt2 (Akt-isoform that phosphorylates pAS160Thr642), and γ1-AMPK and γ3-AMPK activity. ISGU was lower in HFD-SED muscles versus LFD-SED, but this decrement was eliminated in the HFD-3hPEX group. γ3-AMPK activity, but not γ1-AMPK activity, was elevated in HFD-3hPEX muscles versus both SED controls. Furthermore, insulin-stimulated pAS160Thr642, pAS160Ser704, and pAkt2Ser474 in HFD-3hPEX muscles were elevated above HFD-SED and equal to values in LFD-SED muscles, but insulin-independent pAS160Ser704 was unaltered at 3hPEX. These results demonstrated, for the first time in an insulin-resistant model, that the postexercise increase in ISGU was accompanied by sustained enhancement of γ3-AMPK activation and greater pAkt2Ser474. Our working hypothesis is that these changes along with enhanced insulin-stimulated pAS160 increase ISGU of insulin-resistant muscles to values equaling insulin-sensitive sedentary controls. NEW & NOTEWORTHY Earlier research focusing on signaling events linked to increased insulin sensitivity in muscle has rarely evaluated insulin resistant muscle after exercise. We assessed insulin resistant muscle after an exercise protocol that improved insulin-stimulated glucose uptake. Prior exercise also amplified several signaling steps expected to favor enhanced insulin-stimulated glucose uptake: increased γ3-AMP-activated protein kinase activity, greater insulin-stimulated Akt2 phosphorylation on Ser474, and elevated insulin-stimulated Akt substrate of 160 kDa phosphorylation on Ser588, Thr642, and Ser704.
Absence of dynamic hyperinflation during exhaustive exercise in severe COPD reflects submaximal IC maneuvers rather than a nonhyperinflator phenotype
Authors: Luo Yuan-Ming , Qiu Zhi-Hui , Wang Yuan , He Bai-Ting , Qin Hua , Xiao Si-chang , Luo Ying-mei , Steier Joerg , Moxham John , Polkey Michael I 
Published: January 2020

Approximately 20% of chronic obstructive pulmonary disease (COPD) patients have been considered to have a “nonhyperinflator phenotype.” However, this judgment depends on patients making a fully maximal inspiratory capacity (IC) maneuver at rest, since the IC during exercise is compared with this baseline measurement. We hypothesized that IC maneuvers at rest are sometimes submaximal and tested this hypothesis by measuring IC and associated neural respiratory drive at rest and during inhalation of CO2 and exercise in patients with COPD. Twenty-six COPD patients [age 66 ± 6 yr, mean forced expiratory volume in 1 s (FEV1) 40 ± 11% predicted] and 39 healthy subjects (age 39 ± 14 yr, FEV1 98 ± 12% predicted) were studied. IC and the diaphragm electromyogram (EMGdi) associated with it (EMGdi-IC) and forced inspiratory vital capacity (FIVC) and its corresponding EMGdi (EMGdi-FIVC) were measured during inhalation of 8% CO2 (8% CO2-92% O2) and room air. Incremental exhaustive cycle ergometer exercise was also performed in both patients with COPD and healthy subjects. IC, EMGdi-IC, FIVC, and EMGdi-FIVC during breathing 8% CO2 were significantly greater than those during breathing room air in both patients with COPD and healthy subjects (all P < 0.001). EMGdi-IC in patients with COPD constantly increased during exercise from 145 ± 40 µV at rest to 185 ± 52 µV at the end of exercise but change in IC was variable. Neural respiratory drive and its relevant IC increased during hypercapnia. Exercise-related hypercapnia in patients with COPD raises neural respiratory drives, which compensate for IC reduction, leading to underestimation of dynamic hyperinflation measured by IC at rest breathing room air. NEW & NOTEWORTHY Inspiratory capacity measured during hypercapnia is higher than that during eucapnia. Thus total lung capacity is not always be achieved by a standard inspiratory capacity maneuver, leading to risk of underestimation of dynamic hyperinflation in patients with severe chronic obstructive pulmonary disease after exhaustive exercise.
Linking Transcriptomic and Imaging Data Defines Features of a Favorable Tumor Immune Microenvironment and Identifies a Combination Biomarker for Primary Melanoma
Authors: Gartrell-Corrado Robyn D. , Chen Andrew X. , Rizk Emanuelle M. , Marks Douglas K. , Bogardus Margaret H. , Hart Thomas D. , Silverman Andrew M. , Bayan Claire-Audrey Y. , Finkel Grace G. , Barker Luke W. , Komatsubara Kimberly M. , Carvajal Richard D. , Horst Basil A. , Chang Rui , Monod Anthea , Rabadan Raul , Saenger Yvonne M. 
Published: January 2020

Abstract

Patients with resected stage II-III melanoma have approximately a 35% chance of death from their disease. A deeper understanding of the tumor immune microenvironment (TIME) is required to stratify patients and identify factors leading to therapy resistance. We previously identified that the melanoma immune profile (MIP), an IFN-based gene signature, and the ratio of CD8+ cytotoxic T lymphocytes (CTL) to CD68+ macrophages both predict disease-specific survival (DSS). Here, we compared primary with metastatic tumors and found that the nuclei of tumor cells were significantly larger in metastases. The CTL/macrophage ratio was significantly different between primary tumors without distant metastatic recurrence (DMR) and metastases. Patients without DMR had higher degrees of clustering between tumor cells and CTLs, and between tumor cells and HLA-DR+ macrophages, but not HLA-DR− macrophages. The HLA-DR− subset coexpressed CD163+CSF1R+ at higher levels than CD68+HLA-DR+ macrophages, consistent with an M2 phenotype. Finally, combined transcriptomic and multiplex data revealed that densities of CD8 and M1 macrophages correlated with their respective cell phenotype signatures. Combination of the MIP signature with the CTL/macrophage ratio stratified patients into three risk groups that were predictive of DSS, highlighting the potential use of combination biomarkers for adjuvant therapy.

Significance:
These findings provide a deeper understanding of the tumor immune microenvironment by combining multiple modalities to stratify patients into risk groups, a critical step to improving the management of patients with melanoma.
Suporte nutricional no recém-nascido doente ou prematuro
Authors: Falcão Mário Cícero 
Published: January 2020

Ao nascimento, o recém-nascido tem que se adaptar a uma nova maneira de nutrição, passando de um afluxo constante de praticamente todos os nutrientes, para uma alimentação intermitente, tendo que utilizar suas funções digestórias. Recém-nascidos de termo normais rapidamente superam essas barreiras. No entanto, recém-nascidos pré-termo ou mesmo recém-nascidos de temo doentes normalmenteapresentam condições adversas que dificultam a sua nutrição plena. Nestes casos, um suporte nutricional deve ser instituído para que se possa promover uma nutrição adequada. Este suporte normalmente consiste na avaliação nutricional, no cálculo das necessidades nutricionais e na monitorização da terapia nutricional individualizada.
High Brown Fat Activity Correlates With Cardiovascular Risk Factor Levels Cross-Sectionally and Subclinical Atherosclerosis at 5-Year Follow-Up
Authors: Raiko Juho , Orava Janne , Savisto Nina , Virtanen Kirsi A. 
Published: January 2020

Objective:
Brown adipose tissue (BAT) activity correlates negatively with obesity and insulin resistance, and BAT has been suggested to act as a protective factor against atherogenesis. We aimed to examine subclinical atherosclerosis and risk factor levels in a group of individuals who had 5 years earlier participated in positron-emission tomography studies with measurements of BAT activity.

Approach and Results:

Study cohort (males/females=5/26, baseline age 41.4±7.9 years; body mass index, 26.8±6.3 kg/m
2
) underwent positron-emission tomography imaging at baseline with [
18
F] FDG (glucose uptake) and [
15
O] H
2
O (perfusion) to measure BAT activity during cold exposure. At 5-year follow-up, ultrasound was performed to measure carotid intima-media thickness, carotid distensibility (a marker of arterial elasticity), and brachial flow-mediated dilation (an estimate of endothelial function). Fasting plasma lipids and hemoglobin A1c were measured from venous samples at baseline and at follow-up. Median values were used as cut points for high cold-induced BAT activity (BAT glucose uptake >2.40 μmoL/100 g per minute and perfusion >8.4 mL/100 g per minute). Baseline cold-induced BAT glucose uptake and perfusion correlated directly with carotid distensibility and inversely with mean bulbus intima-media thickness and maximum intima-media thickness (
P
always ≤0.02). Baseline body mass index, plasma triglycerides, and HbA1c correlated negatively with BAT glucose uptake and perfusion in cold (
P
always ≤0.048). Correlations between cold-induced BAT activity, cardiovascular risk factors, and atherosclerosis were attenuated with corrections for multiple comparisons.

Conclusions:
Cold-induced BAT activity at baseline seems to correlate with lower levels of conventional cardiovascular risk factors at baseline and with lower carotid intima-media thickness and higher carotid elasticity at 5-year follow-up.
Importance of Diastolic Function for the Prediction of Arrhythmic Death
Authors: Pezawas Thomas , Burger Achim Leo , Binder Thomas , Diedrich André 
Published: January 2020

Background:
Patients with ischemic or dilated cardiomyopathy and reduced left ventricular ejection fraction (LVEF) face a high risk for ventricular arrhythmias. Exact grading of diastolic function might improve risk stratification for arrhythmic death.

Methods:
We prospectively enrolled 120 patients with ischemic, 60 patients with dilated cardiomyopathy, and 30 patients with normal LVEF. Diastolic function was graded normal (N) or dysfunction grade I to III. Primary outcome parameter was arrhythmic death (AD) or resuscitated cardiac arrest (RCA).

Results:

Normal diastolic function was found in 23 (11%) patients, dysfunction grade I in 107 (51%), grade II in 31 (14.8%), and grade III in 49 (23.3%) patients, respectively. After an average follow-up of 7.0±2.6 years, AD or RCA was observed in 28 (13.3%) and 33 (15.7%) patients, respectively. Nonarrhythmic death was found in 41 (19.5%) patients. On Kaplan-Meier analysis, patients with dysfunction grade III had the highest risk for AD or RCA (
P
<0.001). This finding was independent from the degree of LVEF dysfunction and was observed in patients with LVEF≤35% (
P
=0.001) and with LVEF>35% (
P
=0.014). Nonarrhythmic mortality was the highest in patients with dysfunction grade III. This was true for patients with LVEF≤35% (
P
=0.009) or >35% (
P
<0.001). In an adjusted model for relevant confounding factors, grade III dysfunction was associated with a 3.5-fold increased risk for AD or RCA in the overall study population (hazard ratio=3.52;
P
<0.001).

Conclusions:
Diastolic dysfunction is associated with a high risk for AD or RCA regardless if LVEF is ≤35% or >35%. Diastolic function grading might improve risk stratification for AD.
Microtubules Increase Diastolic Stiffness in Failing Human Cardiomyocytes and Myocardium
Authors: Caporizzo Matthew A. , Chen Christina Yingxian , Bedi Ken , Margulies Kenneth B. , Prosser Benjamin L. 
Published: January 2020

Background:
Diastolic dysfunction is a prevalent and therapeutically intractable feature of heart failure (HF). Increasing ventricular compliance can improve diastolic performance, but the viscoelastic forces that resist diastolic filling and become elevated in human HF are poorly defined. Having recently identified posttranslationally detyrosinated microtubules as a source of viscoelasticity in cardiomyocytes, we sought to test whether microtubules contribute meaningful viscoelastic resistance to diastolic stretch in human myocardium.

Methods:
Experiments were conducted in isolated human cardiomyocytes and trabeculae. First, slow and rapid (diastolic) stretch was applied to intact cardiomyocytes from nonfailing and HF hearts and viscoelasticity was characterized after interventions targeting microtubules. Next, intact left ventricular trabeculae from HF patient hearts were incubated with colchicine or vehicle and subject to pre- and posttreatment mechanical testing, which consisted of a staircase protocol and rapid stretches from slack length to increasing strains.

Results:
Viscoelasticity was increased during diastolic stretch of HF cardiomyocytes compared with nonfailing counterparts. Reducing either microtubule density or detyrosination reduced myocyte stiffness, particularly at diastolic strain rates, indicating reduced viscous forces. In myocardial tissue, we found microtubule depolymerization reduced myocardial viscoelasticity, with an effect that decreased with increasing strain. Colchicine reduced viscoelasticity at strains below, but not above, 15%, with a 2-fold reduction in energy dissipation upon microtubule depolymerization. Post hoc subgroup analysis revealed that myocardium from patients with HF with reduced ejection fraction were more fibrotic and elastic than myocardium from patients with HF with preserved ejection fraction, which were relatively more viscous. Colchicine reduced viscoelasticity in both HF with preserved ejection fraction and HF with reduced ejection fraction myocardium.

Conclusions:
Failing cardiomyocytes exhibit elevated viscosity and reducing microtubule density or detyrosination lowers viscoelastic resistance to diastolic stretch in human myocytes and myocardium. In failing myocardium, microtubules elevate stiffness over the typical working range of strains and strain rates, but exhibited diminishing effects with increasing length, consistent with an increasing contribution of the extracellular matrix or myofilament proteins at larger excursions. These studies indicate that a stabilized microtubule network provides a viscous impediment to diastolic stretch, particularly in HF.