It is well known that branched-chain amino acids (BCAAs) promote protein synthesis in skeletal muscle and can cause muscle hypertrophy. However, it has also been reported that they may inhibit muscle ...atrophy induced by load-bearing and age-related changes. In this study, we investigated the effects of BCAA intake during joint fixation on the levels of protein kinase B (Akt), mammalian target of rapamycin (mTOR), and nebulin in a rat model of joint fixation. Akt and mTOR are signal factors of protein synthesis, whereas nebulin is a structural protein in the muscle. The effects of BCAAs on muscle atrophy were also investigated. The phosphorylation rate of mTOR was higher than that of Akt and increased with BCAA intake in the rat hind limb muscles (soleus) when the ankle joint was fixed. The relative level of nebulin and the phosphorylation rate of Neural Wiskott-Aldrich syndrome protein (N-WASP) also increased as a result of BCAA intake during fixation. This is important because nebulin and N-WASP are involved in the formation of the structure of sarcomere thin filaments. Furthermore, when the cross-sectional areas (CSAs) of different types of muscle fibers were measured during histological evaluation of muscle atrophy, it was found that the inhibitory effect of BCAA on muscle atrophy was higher in Type 1 fibers. Additionally, a positive correlation was found between nebulin level and the CSAs of the muscle fibers. It was found that there is a close relationship between the content of structural proteins and muscle atrophy.
Regulatory T cells (Tregs) expressing CC chemokine receptor 4 (CCR4) can suppress antitumor immune responses and are associated with poor prognoses in several cancers. We assessed the safety and ...efficacy of combined mogamulizumab (anti-CCR4 antibody) and nivolumab anti-programmed death-1 (PD-1) antibody in immunotherapy-naïve patients with advanced/metastatic solid tumors.
This study (NCT02476123) comprised dose-escalation (3+3 design) and expansion parts. Patients received nivolumab (3.0 mg/kg) every 2 weeks, with mogamulizumab (0.3 or 1.0 mg/kg in dose escalation, 1.0 mg/kg in expansion) once weekly for 4 weeks, then every 2 weeks, until progression or unacceptable toxicity. Primary objective was safety; secondary objectives were antitumor effects, pharmacokinetics, and immunogenicity. Exploratory biomarker analyses were conducted.
Ninety-six patients were enrolled (July 2015-November 2016): six patients in the dose-escalation part and 90 in the expansion part. No dose-limiting toxicities were observed in the dose-escalation part. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 29% of patients in the expansion part (no grade 5 TRAEs). The most frequent TRAEs were rash (39%), rash maculopapular (20%), diarrhea (13%), stomatitis (12%), and pruritus (11%). There were four (27%) confirmed tumor responses among 15 patients with hepatocellular carcinoma, and one confirmed and two unconfirmed responses among 15 patients with pancreatic adenocarcinoma. During treatment, populations of effector Tregs (CD4
CD45RA
FoxP3
) decreased and CD8
T cells in tumor-infiltrating lymphocytes increased.
Combining an anti-PD-1 antibody, nivolumab, with a Treg-depleting anti-CCR4 antibody, mogamulizumab, provides an acceptable safety profile, antitumor activity, and a potentially effective option in cancer immunotherapy.
α-catenin is a key mechanosensor that forms force-dependent interactions with F-actin, thereby coupling the cadherin-catenin complex to the actin cytoskeleton at adherens junctions (AJs). However, ...the molecular mechanisms by which α-catenin engages F-actin under tension remained elusive. Here we show that the α1-helix of the α-catenin actin-binding domain (αcat-ABD) is a mechanosensing motif that regulates tension-dependent F-actin binding and bundling. αcat-ABD containing an α1-helix-unfolding mutation (H1) shows enhanced binding to F-actin in vitro. Although full-length α-catenin-H1 can generate epithelial monolayers that resist mechanical disruption, it fails to support normal AJ regulation in vivo. Structural and simulation analyses suggest that α1-helix allosterically controls the actin-binding residue V796 dynamics. Crystal structures of αcat-ABD-H1 homodimer suggest that α-catenin can facilitate actin bundling while it remains bound to E-cadherin. We propose that force-dependent allosteric regulation of αcat-ABD promotes dynamic interactions with F-actin involved in actin bundling, cadherin clustering, and AJ remodeling during tissue morphogenesis.
Abstract
As massive rotator cuff tears progress, various radiographic changes occur; however, the factors associated with radiographic changes remain largely unknown. This study aimed to determine ...the factors that affect radiographic severity in massive rotator cuff tears using multivariate analyses. We retrospectively reviewed 210 shoulders with chronic massive rotator cuff tears. The dependent variables were superior migration of the humeral head (Hamada grades 2–3), narrowing of the glenohumeral joint (grade 4), and humeral head collapse (grade 5). Baseline variables that were significant in univariate analyses were included in multivariate models. There were 91, 59, 43, and 17 shoulders classified as Hamada grades 1, 2–3, 4, and 5, respectively. Multivariate analysis showed that infraspinatus tear (
P
= 0.015) and long head of biceps (LHB) tendon rupture (
P
= 0.007) were associated with superior migration of humeral head. Superior subscapularis tear (
P
= 0.003) and LHB tendon rupture (
P
< 0.001) were associated with narrowing of glenohumeral joint. Female sex (
P
= 0.006) and superior subscapularis tear (
P
= 0.006) were associated with humeral head collapse. This study identified the rupture of infraspinatus and LHB as risk factors of superior migration of humeral head, and the rupture of subscapularis and LHB and female sex as risk factors of cuff tear arthropathy.
Lung cancers developed in two boys who had been delivered by mothers with cervical cancer. The cancers in the sons resembled the cancers in the mothers histologically and shared oncogenic driver ...mutations and other unique maternal genes not inherited in their germline, but they did not carry a Y chromosome.
Aims/Introduction
Overproduction of reactive oxygen species (ROS) in endothelial cells (ECs) plays a pivotal role in endothelial dysfunction. Mitochondrial ROS (mtROS) is one of the key players in ...the pathogenesis of diabetic vascular complications. Hypoglycemia is linked to increased ROS production and vascular events; however, the underlying mechanisms remain unclear. In the present study, we aimed to determine whether and how low glucose (LG) mediates mtROS generation in ECs, and to examine the impact of LG‐induced mtROS on endothelial dysfunction.
Materials and Methods
Metabolomic profiling, cellular oxygen consumption rate, mtROS, endothelial nitric oxide synthase phosphorylation, and the expression of vascular cell adhesion molecule‐1 or intercellular adhesion molecule‐1 were evaluated in bovine aortic ECs.
Results
We found that LG increased mtROS generation in ECs; which was suppressed by overexpression of manganese superoxide dismutase. Comprehensive metabolic analysis using capillary electrophoresis‐mass spectrometry and oxygen consumption rate assessment showed that the pathway from fatty acid to acetyl‐CoA through fatty acid oxidation was upregulated in ECs under LG conditions. In addition, etomoxir, a specific inhibitor of the free fatty acid transporter, decreased LG‐induced mtROS production. These results suggested that LG increased mtROS generation through activation of fatty acid oxidation. We further revealed that LG inhibited endothelial nitric oxide synthase phosphorylation, and increased the expression of vascular cell adhesion molecule‐1 and intercellular adhesion molecule‐1. These effects were suppressed either by overexpression of manganese superoxide dismutase or by treatment with etomoxir.
Conclusions
The activation of fatty acid oxidation followed by mtROS production could be one of the causes for endothelial dysfunction during hypoglycemia.
Low glucose (LG) conditions increase mitochondrial reactive oxygen species (ROS) generation through enhanced fatty acid oxidation in endothelial cells. LG conditions decrease the phosphorylation of eNOS and increase the expression of VCAM‐1 and ICAM‐1, which wewe suppressed by either overexpression of MnSOD or etomoxir, a CPT1 inhibitor.
Members of the Foxo family, Foxo1 ( Fkhr ), Foxo3 ( Fkhrl1 ), and Foxo4 (Afx), are mammalian homologs of daf-16 , which influences life span and energy metabolism in Caenorhabditis elegans . ...Mammalian FOXO proteins also play important roles in cell cycle arrest, apoptosis, stress resistance, and energy metabolism.
In this study, we generated Foxo1 -deficient mice to investigate the physiological role of FOXO1. The Foxo1 -deficient mice died around embryonic day 11 because of defects in the branchial arches and remarkably impaired vascular development
of embryos and yolk sacs. In vitro differentiation of embryonic stem cells demonstrated that endothelial cells derived from wild-type and Foxo1 -deficient embryonic stem cells were able to produce comparable numbers of colonies supported by a layer of OP9 stromal cells.
Although the morphology of the endothelial cell colonies was identical in both genotypes in the absence of exogenous vascular
endothelial growth factor (VEGF), Foxo1 -deficient endothelial cells showed a markedly different morphological response compared with wild-type endothelial cells
in the presence of exogenous VEGF. These results suggest that Foxo1 is essential to the ability of endothelial cells to respond properly to a high dose of VEGF, thereby playing a critical role
in normal vascular development.
Bacillus Calmette-Guérin (BCG)–associated osteomyelitis is a rare adverse event following BCG vaccination, and there have been no previous reports of BCG-associated cervical spondylitis. Here, we ...describe the case of a 3-year-old immunocompetent girl who developed BCG-associated cervical spondylitis and was successfully treated by prompt surgical drainage of the abscess and administration of isoniazid and rifampicin for 9 months without sequelae.
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