Relationship between “a body shape index (ABSI)” and body composition in obese patients with type 2 diabetes

Background: Obesity is known to be related to the development of type 2 diabetes mellitus (T2D). The most commonly used anthropometric indicator (body mass index [BMI]) presents several limitations such as the lack of possibility to distinguish adipose tissue distribution. Thus, this study examines the suitability of a body shape index (ABSI) for prediction of body composition and sarcopenic obesity in obese or overweight T2D subjects. Methods: Cross-sectional study in 199 overweight/obese T2D adults. Anthropometric (BMI, ABSI) and body composition (fat mass [FM], fat-free mass [FFM], fat mass index [FMI] and fat-free mass index, and the ratio FM/FFM as an index of sarcopenic obesity) data was collected, as well as metabolic parameters (glycated haemoglobin [ HbA1c], mean blood glucose, fasting plasma glucose [FPG], high-density-lipoprotein cholesterol [HDL], low-density-lipoprotein cholesterol, total cholesterol, and triglycerides [TG] levels; the ratio TG/HDL was also calculated as a surrogate marker for insulin resistance). Results: ABSI was significantly associated with age and waist circumference. It showed a statistically significant correlation with BMI exclusively in women. Regarding body composition, in men, ABSI was associated with FM (%), while in women it was associated with both FM and FFM. Both males and females groups with high ABSI scores were significantly older (men: 59.3 ± 10.8 vs 54.6 ± 10.1, p ≤ 0.05; women: 65.1 ± 9.8 vs 58.1 ± 13.3, p ≤ 0.005) and showed lower FFM values (men: 62.3 ± 9.0 vs 66.2 ± 9.3, p ≤ 0.05; women: 48.7 ± 5.6 vs 54.5 ± 8.9, p ≤ 0.001) compared with low-ABSI groups. Multiple linear regression revealed that ABSI independently predict FMI and the FM/FFM ratio in women. Sarcopenic obesity was identified in 70 (36.5%) individuals according to the FM/FFM ratio. The AUROC of ABSI was 63.1% (95% CI 54.6–71.6%; p = 0.003) and an ABSI value of 0.083 m11/6 kg−2/3 was the optimal threshold in discriminating patients with sarcopenic obesity (sensitivity: 48%, specificity: 73%). Moreover, a significant association between ABSI and FPG was found in men. Conclusions: ABSI could be useful to identify visceral and sarcopenic obesity in overweight/obese adults with T2D, adding some relevant clinical information to traditional anthropometric measures

Increased levels of RNA oxidation enhance the reversion frequency in aging pro-apoptotic yeast mutants

Despite recent advances in understanding the complexity of RNA processes, regulation of the metabolism of oxidized cellular RNAs and the mechanisms through which oxidized ribonucleotides affect mRNA translation, and consequently cell viability, are not well characterized. We show here that the level of oxidized RNAs is markedly increased in a yeast decapping Kllsm4Δ1 mutant, which accumulates mRNAs, ages much faster that the wild type strain and undergoes regulated-cell-death. We also found that in Kllsm4Δ1 cells the mutation rate increases during chronological life span indicating that the capacity to han- dle oxidized RNAs in yeast declines with aging. Lowering intracellular ROS levels by antioxidants recovers the wild- type phenotype of mutant cells, including reduced amount of oxidized RNAs and lower mutation rate. Since mRNA oxidation was reported to occur in different neurodegen- erative diseases, decapping-deficient cells may represent a useful tool for deciphering molecular mechanisms of cell response to such conditions, providing new insights into RNA modification-based pathogenesis

Transfer of extracellular vesicle-microRNA controls germinal center reaction and antibody production

Intercellular communication orchestrates effective immune responses against disease-causing agents. Extracellular vesicles (EVs) are potent mediators of cell-cell communication. EVs carry bioactive molecules, including microRNAs, which modulate gene expression and function in the recipient cell. Here, we show that formation of cognate primary T-B lymphocyte immune contacts promotes transfer of a very restricted set of T-cell EV-microRNAs (mmu-miR20-a-5p, mmu-miR-25-3p, and mmu-miR-155-3p) to the B cell. Transferred EV-microRNAs target key genes that control B-cell function, including pro-apoptotic BIM and the cell cycle regulator PTEN. EV-microRNAs transferred during T-B cognate interactions also promote survival, proliferation, and antibody class switching. Using mouse chimeras with Rab27KO EV-deficient T cells, we demonstrate that the transfer of small EVs is required for germinal center reaction and antibody production in vivo, revealing a mechanism that controls B-cell responses via the transfer of EV-microRNAs of T-cell origin. These findings also provide mechanistic insight into the Griscelli syndrome, associated with a mutation in the Rab27a gene, and might explain antibody defects observed in this pathogenesis and other immune-related and inflammatory disorders.This manuscript was funded by grants SAF2017-82886-R (FS-M) from the Spanish Ministry of Economy and Competitiveness; CAM (S2017/BMD-3671-INFLAMUNE-CM) from the Comunidad de Madrid (FS-M); CIBERCV (CB16/11/00272), BIOIMID PIE13/041 from the Instituto de Salud Carlos III and from the Fundación La MaratóTV3(grant122/C/2015). The current research has received funding from “la Caixa” Foundation under the project code HR17-00016. VGY is supported by the AECC foundation. A.R.R. is supported by CNIC funding. This project was funded by the Spanish Ministerio de Ciencia, Innovacion y Universidades SAF2016-75511-R, and La Caixa Health Research Program HR17-00247 grant to A.R.R. Grants from Ramón Areces Foundation “Ciencias de la Vida y de la Salud” (XIX Concurso-2018) and from Ayuda Fundación BBVA y Equipo de Investigación Científica (BIOMEDICINA-2018) (to FSM). The CNIC is supported by the Ministerio de Ciencia, Innovacion y Universidades and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505).S

A novel mutation in BRCA1 linked to breast and ovarian cancer and a genotype-phenotype correlation

We report a novel BRCA1 germline 4156delAA mutation detected in a 41-year-old woman with breast and ovarian cancer. Genomic DNA was obtained from peripheral blood. Standard polymerase chain reactions and direct sequencing were performed. This mutation originates a premature stop at codon 1354 of BRCA1 protein and has not been documented in any published report to the best of our knowledge. The mutation was not observed in any other family studied. Since this novel mutation was associated with both breast and ovarian cancer, the genotype-phenotype correlation was investigated in a patient base of 30 families

KRAS mutational status analysis of peripheral blood isolated circulating tumor cells in metastatic colorectal patients

The present study describes an optimized method for isolating peripheral blood circulating tumor cells (CTCs) and performing KRAS mutation analysis. The approach combines isolation of peripheral blood mononuclear cells and immunomagnetic labeling with CD45 and CD326 human microbeads with KRAS analysis performed with a Therascreen KRAS kit by quantitative PCR. KRAS mutations were detected in the CTCs of patients with metastatic colorectal cancer (mCRC). CTCs may represent an alternative to invasive procedures and their analysis may be representative of the current disease status of the patient. This proposed analysis may be performed in a daily clinical practice

Essential role of protein tyrosine phosphatase 1B in obesity-induced inflammation and peripheral insulin resistance during aging

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin signaling and a therapeutic target for type 2 diabetes (T2DM). In this study, we have evaluated the role of PTP1B in the development of aging-associated obesity, inflammation, and peripheral insulin resistance by assessing metabolic parameters at 3 and 16 months in PTP1B) ⁄ ) mice maintained on mixed genetic background (C57Bl ⁄ 6J · 129Sv ⁄ J). Whereas fat mass and adipocyte size were increased in wild-type control mice at 16 months, these parameters did not change with aging in PTP1B) ⁄ ) mice. Increased levels of pro-inflammatory cytokines, crown-like structures, and hypoxia-inducible factor (HIF)-1a wereobserved only in adipose tissue from 16-month-old wild-type mice. Similarly, islet hyperplasia and hyperinsulinemia were observed in wild-type mice with agingassociated obesity, but not in PTP1B) ⁄ ) animals. Leanness in 16- month-old PTP1B) ⁄ ) mice was associated with increased energy expenditure. Whole-body insulin sensitivity decreased in 16- month-old control mice; however, studies with the hyperinsulinemic– euglycemic clamp revealed that PTP1B deficiency prevented this obesity-related decreased peripheral insulin sensitivity. At a molecular level, PTP1B expression and enzymatic activity were upregulated in liver and muscle of 16-month-old wild-type mice as were the activation of stress kinases and the expression of p53. Conversely, insulin receptor-mediated Akt ⁄ Foxo1 signaling was attenuated in these aged control mice. Collectively, these data implicate PTP1B in the development of inflammation and insulin resistance associated with obesity during aging and suggest that inhibition of this phosphatase by therapeutic strategies might protect against age-dependentT2DMThis work was supported by grants from Ministerio de Ciencia e Innovación (Spain) SAF2009-08114 and (to A.M.V.), BFU2008- 04901-C03-02 and 03 (to M.R and J.M.C., respectively), BFU2008-01283 (to M.V), Comunidad de Madrid S2010/BMD- 2423 and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) (Instituto Salud Carlos III). CBMSO is recipient of institutional aid from Ramón Areces Foundation. We also acknowledge grants NIH-R01 DK080756, ADA 7-07-RA-80, and NIH U24-DK093000 (to J.K.K.) and UMass Mouse Phenotyping Center supported by UMass Diabetes and Endocrinology Research Center Grant (DK32520) and EFSD/Amylin Programme 2011 grant (to A.M.V.)

A novel BRCA1 mutation in a patient with breast and ovarian cancer: A case report

Germline mutations in the human breast cancer genes BRCA1 and BRCA2 account for a substantial proportion of familial, early-onset breast and ovarian cancers. The present study reports a novel disease-causing BRCA1 mutation, nucleotide 3020insCT/c.2901insCT, in a 55-year-old Spanish female with breast and ovarian cancer. This frameshift mutation creates a premature stop codon at amino acid 1000, leading to a truncated BRCA1 protein. To the best of our knowledge, this mutation has not been previously described in the Breast Cancer Information Core (BIC) database or the published literatur

Differential engagement of Tim-1 during activation can positively or negatively costimulate T cell expansion and effector function

It has been suggested that T cell immunoglobulin mucin (Tim)-1 expressed on T cells serves to positively costimulate T cell responses. However, crosslinking of Tim-1 by its ligand Tim-4 resulted in either activation or inhibition of T cell responses, thus raising the issue of whether Tim-1 can have a dual function as a costimulator. To resolve this issue, we tested a series of monoclonal antibodies specific for Tim-1 and identified two antibodies that showed opposite functional effects. One anti–Tim-1 antibody increased the frequency of antigen-specific T cells, the production of the proinflammatory cytokines IFN-γ and IL-17, and the severity of experimental autoimmune encephalomyelitis. In contrast, another anti–Tim-1 antibody inhibited the generation of antigen-specific T cells, production of IFN-γ and IL-17, and development of autoimmunity, and it caused a strong Th2 response. Both antibodies bound to closely related epitopes in the IgV domain of the Tim-1 molecule, but the activating antibody had an avidity for Tim-1 that was 17 times higher than the inhibitory antibody. Although both anti–Tim-1 antibodies induced CD3 capping, only the activating antibody caused strong cytoskeletal reorganization and motility. These data indicate that Tim-1 regulates T cell responses and that Tim-1 engagement can alter T cell function depending on the affinity/avidity with which it is engaged

Improving coeliac disease risk prediction by testing non-HLA variants additional to HLA variants

Background: The majority of coeliac disease (CD) patients are not being properly diagnosed and therefore remain untreated, leading to a greater risk of developing CD-associated complications. The major genetic risk heterodimer, HLA-DQ2 and DQ8, is already used clinically to help exclude disease. However, approximately 40% of the population carry these alleles and the majority never develop CD. Objective: We explored whether CD risk prediction can be improved by adding non-HLA-susceptible variants to common HLA testing. Design: We developed an average weighted genetic risk score with 10, 26 and 57 single nucleotide polymorphisms (SNP) in 2675 cases and 2815 controls and assessed the improvement in risk prediction provided by the non-HLA SNP. Moreover, we assessed the transferability of the genetic risk model with 26 non-HLA variants to a nested case–control population (n=1709) and a prospective cohort (n=1245) and then tested how well this model predicted CD outcome for 985 independent individuals. Results: Adding 57 non-HLA variants to HLA testing showed a statistically significant improvement compared to scores from models based on HLA only, HLA plus 10 SNP and HLA plus 26 SNP. With 57 non-HLA variants, the area under the receiver operator characteristic curve reached 0.854 compared to 0.823 for HLA only, and 11.1% of individuals were reclassified to a more accurate risk group. We show that the risk model with HLA plus 26 SNP is useful in independent populations. Conclusions: Predicting risk with 57 additional non-HLA variants improved the identification of potential CD patients. This demonstrates a possible role for combined HLA and non-HLA genetic testing in diagnostic work for CD