Resistance Training Modulates Reticulum Endoplasmic Stress, Independent of Oxidative and Inflammatory Responses, in Elderly People.

Aging is related to changes in the redox status, low-grade inflammation, and decreased endoplasmic reticulum unfolded protein response (UPR). Exercise has been shown to regulate the inflammatory response, balance redox homeostasis, and ameliorate the UPR. This work aimed to investigate the effects of resistance training on changes in the UPR, oxidative status, and inflammatory responses in peripheral blood mononuclear cells of elderly subjects. Thirty elderly subjects volunteered to participate in an 8-week resistance training program, and 11 youth subjects were included for basal assessments. Klotho, heat shock protein 60 (HSP60), oxidative marker expression (catalase, glutathione, lipid peroxidation, nuclear factor erythroid 2-related factor 2, protein carbonyls, reactive oxygen species, and superoxide dismutase 1 and 2), the IRE1 arm of UPR, and TLR4/TRAF6/pIRAK1 pathway activation were evaluated before and following training. No changes in the HSP60 and Klotho protein content, oxidative status markers, and TLR4/TRAF6/pIRAK1 pathway activation were found with exercise. However, an attenuation of the reduced pIRE1/IRE1 ratio was observed following training. Systems biology analysis showed that a low number of proteins (RPS27A, SYVN1, HSPA5, and XBP1) are associated with IRE1, where XBP1 and RPS27A are essential nodes according to the centrality analysis. Additionally, a gene ontology analysis confirms that endoplasmic reticulum stress is a key mechanism modulated by IRE1. These findings might partially support the modulatory effect of resistance training on the endoplasmic reticulum in the elderly.

Evaluation of the Genotoxicity of Tobacco and Alcohol in Oral Mucosa Cells: A Pilot Study.

AIM AND OBJECTIVE: To define the genotoxic potential of tobacco and alcohol in the oral mucosa through a micronuclei (MN) test. MATERIALS AND METHODS: Samples of exfoliative cells from oral mucosa were collected using superficial scraping of the right- and left-cheek mucosa of 83 patients divided into four groups, namely: (G1) 24 individuals abstaining from tobacco and alcoholic beverages; (G2) 23 individuals who smoke and abstain from alcoholic beverages; (G3) 24 smokers and alcoholics; and (G4) 12 individuals who consume alcohol and abstain from tobacco. The samples were stained with Giemsa-Wright, and the frequencies of MN, binucleated cells, and metanuclear changes were recorded in the samples of each group (1,000 cells per patient). RESULTS: Analysis of variance (ANOVA) showed a difference between groups for changes concerning karyorrhexis (p = 0), pycnosis (p = 0.002), karyolysis (p = 0.003), and binucleated cells (p = 0.046). As for the total number of changes, G3, G2, and G4, respectively, were significantly higher than G1. CONCLUSION: It is suggested that the influence of smoking and drinking on exfoliating cells of oral mucosa may cause metanuclear changes due to genetic changes that these products cause, and the MN test is effective in detecting and monitoring such changes. CLINICAL SIGNIFICANCE: MN test may work for constantly monitoring the oral mucosa of smokers and/or alcoholic patients, so that early cell changes may be diagnosed, preventing the genesis of oral cancer.

A Subject-Specific Kinematic Model to Predict Human Motion in Exoskeleton-Assisted Gait.

The relative motion between human and exoskeleton is a crucial factor that has remarkable consequences on the efficiency, reliability and safety of human-robot interaction. Unfortunately, its quantitative assessment has been largely overlooked in the literature. Here, we present a methodology that allows predicting the motion of the human joints from the knowledge of the angular motion of the exoskeleton frame. Our method combines a subject-specific skeletal model with a kinematic model of a lower limb exoskeleton (H2, Technaid), imposing specific kinematic constraints between them. To calibrate the model and validate its ability to predict the relative motion in a subject-specific way, we performed experiments on seven healthy subjects during treadmill walking tasks. We demonstrate a prediction accuracy lower than 3.5° globally, and around 1.5° at the hip level, which represent an improvement up to 66% compared to the traditional approach assuming no relative motion between the user and the exoskeleton.

APOE and MS4A6A interact with GnRH signaling in Alzheimer's disease: Enrichment of epistatic effects.

INTRODUCTION: It is unknown if risk loci, identified by genome-wide association studies of late-onset Alzheimer's disease (LOAD), are linked to common molecular mechanisms through epistatic effects. METHODS: We performed genome-wide interaction studies of five risk variants for LOAD followed by enrichment analyses to find if there are pathways that simultaneously interact with more than one variant. This novel approach was applied to four independent cohorts (5393 cases and 3746 controls). RESULTS: We found enrichment of epistasis in gonadotropin-releasing hormone signaling with risk single-nucleotide polymorphisms in APOE and MS4A6A (P value = 3.7 × 10-5, P value = 5.6 × 10-6); vascular smooth muscle contraction pathway was also enriched in epistasis with these loci (P value = 9.6 × 10-5, P value = 2.4 × 10-7). MS4A6A risk variant also interacted with dilated cardiomyopathy pathway (P value = 3.1 × 10-7). DISCUSSION: In addition to APOE, MS4A6A polymorphisms should be considered in hormone trials targeting gonadotropins. Interactions of risk variants with neurovascular pathways may also be important in LOAD pathology.

Near-field photocurrent nanoscopy on bare and encapsulated graphene.

Optoelectronic devices utilizing graphene have demonstrated unique capabilities and performances beyond state-of-the-art technologies. However, requirements in terms of device quality and uniformity are demanding. A major roadblock towards high-performance devices are nanoscale variations of the graphene device properties, impacting their macroscopic behaviour. Here we present and apply non-invasive optoelectronic nanoscopy to measure the optical and electronic properties of graphene devices locally. This is achieved by combining scanning near-field infrared nanoscopy with electrical read-out, allowing infrared photocurrent mapping at length scales of tens of nanometres. Using this technique, we study the impact of edges and grain boundaries on the spatial carrier density profiles and local thermoelectric properties. Moreover, we show that the technique can readily be applied to encapsulated graphene devices. We observe charge build-up near the edges and demonstrate a solution to this issue.

Inhibition of HDAC increases the senescence induced by natural polyphenols in glioma cells.

Cellular senescence is an irreversible block of cellular division, and induction of senescence is being considered for treatment of many cancer types, mainly those resistant to classical pro-apoptotic therapies. Resveratrol (Rsv) and quercetin (Quer), two natural polyphenols, are able to induce senescence in different cancer models, including gliomas, the most common and aggressive primary brain tumor. These polyphenols modulate the activity of several proteins involved in cell growth and death in cancer cells, including histone deacetylases (HDAC), but the role of HDAC in senescence induced by Rsv and Quer is unclear. The HDAC inhibitor sodium butyrate (NaB) potentiated the pro-senescent effect of Rsv and Quer in human and rat glioma cell lines but not in normal rat astrocytes. Furthermore, the increment of Quer-induced senescence by NaB was accompanied by an increase of reactive oxygen species levels and an increment of the number of cells with nuclear abnormalities. Altogether, these data support a positive role of HDAC inhibition on the senescence induced by these polyphenols, and therefore co-treatment of HDAC inhibitors and polyphenols emerges as a potential alternative for gliomas.

Chemoradiation with raltitrexed and oxaliplatin in preoperative treatment of stage II-III resectable rectal cancer: Phase I and II studies.

PURPOSE: Two separate studies were conducted, the first to evaluate the maximal tolerated dose and the second the efficacy of raltitrexed plus oxaliplatin in conjunction with preoperative chemoradiation in patients with resectable T3 rectal carcinoma. METHODS AND MATERIALS: A total of 48 patients received radiotherapy (50 Gy) administered to the posterior pelvis 5 d/wk for 5 weeks. Combination raltitrexed (3 mg/m(2)) and oxaliplatin (60 to 130 mg/m(2)) was administered on Days 1, 19, and 38. RESULTS: The recommended dose of oxaliplatin is 130 mg/m(2) (maximal tolerated dose not reached). No patients developed Grade 4 acute toxicity. Grade 3 acute toxicity occurred in 9 patients (18.7%). It was hematologic in 1 patient and GI in 1 patient; 7 patients had an asymptomatic increase of transaminase. Surgery was performed in 47 (98%) of 48 patients. Of the 47 patients, 42 underwent sphincter-saving surgery; in 19, the tumor at diagnosis was located <30 mm from the anorectal ring. Chemoradiation in combination with raltitrexed and oxaliplatin produced high rates of tumor response. The overall tumor downstaging rate was 73% for T and N stages. A complete pathologic tumor response (pT0) or microscopic tumor foci (pTmic) was observed in 28 patients. The tumor regression grade (TRG), using the Mandard scoring system, was TRG1 in 16 patients (43.2%), TRG2 in 12 (32.4%), TRG3 in 12 (32.4%), TRG4 in 6 (16.2%), and TRG5 in 1 patient (2.7%). CONCLUSION: Raltitrexed plus oxaliplatin combined with pelvic radiotherapy was effective and well tolerated in patients with resectable T3 rectal carcinoma.