Pancreas-enriched miRNAs are altered in the circulation of subjects with diabetes: a pilot cross-sectional study

The clinical presentation of diabetes sometimes overlaps, contributing to ambiguity in the diagnosis. Thus, circulating pancreatic islet-enriched microRNAs (miRNAs) might be useful biomarkers of β-cell injury/dysfunction that would allow more accurate subtyping of diabetes. We measured plasma levels of selected miRNAs in subjects with prediabetes (n = 12), type 2 diabetes (T2D, n = 31), latent autoimmune diabetes of adults (LADA, n = 6) and type 1 diabetes (T1D, n = 16) and compared them to levels in healthy control subjects (n = 27). The study was conducted at the Translational Research Institute for Metabolism and Diabetes (TRI-MD), Florida Hospital. MiRNAs including miR-375 (linked to β-cell injury), miR-21 (associated with islet inflammation), miR-24.1, miR-30d, miR-34a, miR-126, miR-146, and miR-148a were significantly elevated in subjects with various forms of diabetes compared to healthy controls. Levels of several miRNAs were significantly correlated with glucose responses during oral glucose tolerance testing, HbA[subscript 1c], β-cell function, and insulin resistance in healthy controls, prediabetes, and T2D. These data suggest that miRNAs linked to β-cell injury and islet inflammation might be useful biomarkers to distinguish between subtypes of diabetes. This information could be used to predict progression of the disease, guide selection of optimal therapy and monitor responses to interventions, thus improving outcomes in patients with diabetes.Translational Research Institute for Metabolism and Diabetes (TRI

Study of the lineshape of the chi(c1) (3872) state

A study of the lineshape of the chi(c1) (3872) state is made using a data sample corresponding to an integrated luminosity of 3 fb(-1) collected in pp collisions at center-of-mass energies of 7 and 8 TeV with the LHCb detector. Candidate chi(c1)(3872) and psi(2S) mesons from b-hadron decays are selected in the J/psi pi(+)pi(-) decay mode. Describing the lineshape with a Breit-Wigner function, the mass splitting between the chi(c1 )(3872) and psi(2S) states, Delta m, and the width of the chi(c1 )(3872) state, Gamma(Bw), are determined to be (Delta m=185.598 +/- 0.067 +/- 0.068 Mev,)(Gamma BW=1.39 +/- 0.24 +/- 0.10 Mev,) where the first uncertainty is statistical and the second systematic. Using a Flatte-inspired model, the mode and full width at half maximum of the lineshape are determined to be (mode=3871.69+0.00+0.05 MeV.)(FWHM=0.22-0.04+0.13+0.07+0.11-0.06-0.13 MeV, ) An investigation of the analytic structure of the Flatte amplitude reveals a pole structure, which is compatible with a quasibound D-0(D) over bar*(0) state but a quasivirtual state is still allowed at the level of 2 standard deviations

Micrornas And The Metabolic Hallmarks Of Aging

Aging, the natural process of growing older, is characterized by a progressive deterioration of physiological homeostasis at the cellular, tissue, and organismal level. Metabolically, the aging process is characterized by extensive changes in body composition, multi-tissue/multi-organ insulin resistance, and physiological declines in multiple signaling pathways including growth hormone, insulin/insulin-like growth factor 1, and sex steroids regulation. With this review, we intend to consolidate published information about microRNAs that regulate critical metabolic processes relevant to aging. In certain occasions we uncover relationships likely relevant to aging, which has not been directly described before, such as the miR-451/AMPK axis. We have also included a provocative section highlighting the potential role in aging of a new designation of miRNAs, namely fecal miRNAs, recently discovered to regulate intestinal microbiota in mammals

Elevated and Correlated Expressions of miR-24, miR-30d, miR-146a, and SFRP-4 in Human Abdominal Adipose Tissue Play a Role in Adiposity and Insulin Resistance

Objective. We explored the relationships among microRNAs (miRNAs) and SFRP4, as they relate to adipose tissue functions including lipolysis, glucose and glycerol turnover, and insulin sensitivity. Methods. Abdominal adipose tissue (AbdAT) levels of thirteen microRNAs (miRNAs), SFRP4, and VEGF in lean nondiabetic subjects (n = 7), subjects with obesity (n = 5), and subjects with obesity and type 2 diabetes (T2DM) (n = 5) were measured by qPCR. Insulin sensitivity was measured by the euglycemic-hyperinsulinemic clamp. Osmium fixation and Coulter counting were used for adipocyte sizing. Data were analyzed using generalized linear models that adjusted for age, gender, and ethnicity. Results. AbdAT miR-24, miR-30d, and miR-146a were elevated in subjects with obesity (P < 0.05) and T2DM (P < 0.1) and positively correlated with measures of percent body fat by DXA (r[subscript miR.24] = 0.894, r[subscript miR.146a] = 0.883, P < 0.05), and AbdAT SFRP4 (r[subscript miR.30] = 0.93,r[subscript miR.146a]=0.88, P < 0.05). These three miRNAs additionally correlated among themselves (r[subscript miR.24 ~ miR.146a] = 0.90, r[subscript miR.30 ~ miR.146a] = 0.85, P = 0.05). Conclusions. This study suggests a novel association between the elevated levels of miRNAs miR-24, miR-30d, and miR-146a (apparently coregulated) and the level of SFRP4 transcript in AbdAT of subjects with obesity and T2DM. These molecules might be part of a regulatory loop involved in AbdAT remodeling/adiposity and systemic insulin resistance. This trial is registered with NCT00704197

Circulating Microrna Signature Of Genotype-By-Age Interactions In The Long-Lived Ames Dwarf Mouse

Recent evidence demonstrates that serum levels of specific miRNAs significantly change with age. The ability of circulating sncRNAs to act as signaling molecules and regulate a broad spectrum of cellular functions implicates them as key players in the aging process. To discover circulating sncRNAs that impact aging in the long-lived Ames dwarf mice, we conducted deep sequencing of small RNAs extracted from serum of young and old mice. Our analysis showed genotype-specific changes in the circulating levels of 21 miRNAs during aging [genotype-by-age interaction (GbA)]. Genotype-by-age miRNAs showed four distinct expression patterns and significant overtargeting of transcripts involved in age-related processes. Functional enrichment analysis of putative and validated miRNA targets highlighted cellular processes such as tumor suppression, anti-inflammatory response, and modulation of Wnt, insulin, mTOR, and MAPK signaling pathways, among others. The comparative analysis of circulating GbA miRNAs in Ames mice with circulating miRNAs modulated by calorie restriction (CR) in another long-lived mouse suggests CR-like and CR-independent mechanisms contributing to longevity in the Ames mouse. In conclusion, we showed for the first time a signature of circulating miRNAs modulated by age in the long-lived Ames mouse

Characteristic miRNA expression signature and random forest survival analysis identify potential cancer-driving miRNAs in a broad range of head and neck squamous cell carcinoma subtypes

AimTo characterize the miRNA expression profile in head and neck squamous cell carcinoma (HNSSC) accounting for a broad range of cancer subtypes and consequently identify an optimal miRNA signature with prognostic value.BackgroundHNSCC is consistently among the most common cancers worldwide. Its mortality rate is about 50% because of the characteristic aggressive behavior of these cancers and the prevalent late diagnosis. The heterogeneity of the disease has hampered the development of robust prognostic tools with broad clinical utility.Materials and methodsThe Cancer Genome Atlas HNSC dataset was used to analyze level 3 miRNA-Seq data from 497 HNSCC patients. Differential expression (DE) analysis was implemented using the limma package and multivariate linear model that adjusted for the confounding effects of age at diagnosis, gender, race, alcohol history, anatomic neoplasm subdivision, pathologic stage, T and N stages, and vital status. Random forest (RF) for survival analysis was implemented using the randomForestSRC package.ResultsA characteristic DE miRNA signature of HNSCC, comprised of 11 upregulated (i.e., miR-196b-5p, miR-1269a, miR-196a-5p, miR-4652-3p, miR-210-3p, miR-1293, miR-615-3p, miR-503-5p, miR-455-3p, miR-205-5p, and miR-21-5p) and 9 downregulated (miR-376c-3p, miR-378c, miR-29c-3p, miR-101-3p, miR-195-5p, miR-299-5p, miR-139-5p, miR-6510-3p, miR-375) miRNAs was identified. An optimal RF survival model was built from seven variables including age at diagnosis, miR-378c, miR-6510-3p, stage N, pathologic stage, gender, and race (listed in order of variable importance).ConclusionsThe joint differential miRNA expression and survival analysis controlling for multiple confounding covariates implemented in this study allowed for the identification of a previously undetected prognostic miRNA signature characteristic of a broad range of HNSCC

Pancreas-Enriched Mirnas Are Altered In The Circulation Of Subjects With Diabetes: A Pilot Cross-Sectional Study

The clinical presentation of diabetes sometimes overlaps, contributing to ambiguity in the diagnosis. Thus, circulating pancreatic islet-enriched microRNAs (miRNAs) might be useful biomarkers of β-cell injury/dysfunction that would allow more accurate subtyping of diabetes. We measured plasma levels of selected miRNAs in subjects with prediabetes (n = 12), type 2 diabetes (T2D, n = 31), latent autoimmune diabetes of adults (LADA, n = 6) and type 1 diabetes (T1D, n = 16) and compared them to levels in healthy control subjects (n = 27). The study was conducted at the Translational Research Institute for Metabolism and Diabetes (TRI-MD), Florida Hospital. MiRNAs including miR-375 (linked to β-cell injury), miR-21 (associated with islet inflammation), miR-24.1, miR-30d, miR-34a, miR-126, miR-146, and miR-148a were significantly elevated in subjects with various forms of diabetes compared to healthy controls. Levels of several miRNAs were significantly correlated with glucose responses during oral glucose tolerance testing, HbA 1c, β-cell function, and insulin resistance in healthy controls, prediabetes, and T2D. These data suggest that miRNAs linked to β-cell injury and islet inflammation might be useful biomarkers to distinguish between subtypes of diabetes. This information could be used to predict progression of the disease, guide selection of optimal therapy and monitor responses to interventions, thus improving outcomes in patients with diabetes

Characteristic Mirna Expression Signature And Random Forest Survival Analysis Identify Potential Cancer-Driving Mirnas In A Broad Range Of Head And Neck Squamous Cell Carcinoma Subtypes

Aim To characterize the miRNA expression profile in head and neck squamous cell carcinoma (HNSSC) accounting for a broad range of cancer subtypes and consequently identify an optimal miRNA signature with prognostic value. Background HNSCC is consistently among the most common cancers worldwide. Its mortality rate is about 50% because of the characteristic aggressive behavior of these cancers and the prevalent late diagnosis. The heterogeneity of the disease has hampered the development of robust prognostic tools with broad clinical utility. Materials and methods The Cancer Genome Atlas HNSC dataset was used to analyze level 3 miRNA-Seq data from 497 HNSCC patients. Differential expression (DE) analysis was implemented using the limma package and multivariate linear model that adjusted for the confounding effects of age at diagnosis, gender, race, alcohol history, anatomic neoplasm subdivision, pathologic stage, T and N stages, and vital status. Random forest (RF) for survival analysis was implemented using the randomForestSRC package. Results A characteristic DE miRNA signature of HNSCC, comprised of 11 upregulated (i.e., miR-196b-5p, miR-1269a, miR-196a-5p, miR-4652-3p, miR-210-3p, miR-1293, miR-615-3p, miR-503-5p, miR-455-3p, miR-205-5p, and miR-21-5p) and 9 downregulated (miR-376c-3p, miR-378c, miR-29c-3p, miR-101-3p, miR-195-5p, miR-299-5p, miR-139-5p, miR-6510-3p, miR-375) miRNAs was identified. An optimal RF survival model was built from seven variables including age at diagnosis, miR-378c, miR-6510-3p, stage N, pathologic stage, gender, and race (listed in order of variable importance). Conclusions The joint differential miRNA expression and survival analysis controlling for multiple confounding covariates implemented in this study allowed for the identification of a previously undetected prognostic miRNA signature characteristic of a broad range of HNSCC

Predicting and understanding the response to short-term intensive insulin therapy in people with early type 2 diabetes

Objective: Short-term intensive insulin therapy (IIT) early in the course of type 2 diabetes acutely improves beta-cell function with long-lasting effects on glycemic control. However, conventional measures cannot determine which patients are better suited for IIT, and little is known about the molecular mechanisms determining response. Therefore, this study aimed to develop a model that could accurately predict the response to IIT and provide insight into molecular mechanisms driving such response in humans. Methods: Twenty-four patients with early type 2 diabetes were assessed at baseline and four weeks after IIT, consisting of basal detemir and premeal insulin aspart. Twelve individuals had a beneficial beta-cell response to IIT (responders) and 12 did not (nonresponders). Beta-cell function was assessed by multiple methods, including Insulin Secretion-Sensitivity Index-2. MicroRNAs (miRNAs) were profiled in plasma samples before and after IIT. The response to IIT was modeled using a machine learning algorithm and potential miRNA-mediated regulatory mechanisms assessed by differential expression, correlation, and functional network analyses (FNA). Results: Baseline levels of circulating miR-145-5p, miR-29c-3p, and HbA1c accurately (91.7%) predicted the response to IIT (OR = 121 [95% CI: 6.7, 2188.3]). Mechanistically, a previously described regulatory loop between miR-145-5p and miR-483-3p/5p, which controls TP53-mediated apoptosis, appears to also occur in our study population of humans with early type 2 diabetes. In addition, significant (fold change > 2, P  0.4, P < 0.05) with the changes in measures of beta-cell function and insulin sensitivity. FNA identified a network of coordinately/cooperatively regulated miRNA-targeted genes that potentially drives the IIT response through negative regulation of apoptotic processes that underlie beta cell dysfunction and concomitant positive regulation of proliferation. Conclusions: Responses to IIT in people with early type 2 diabetes are associated with characteristic miRNA signatures. This study represents a first step to identify potential responders to IIT (a current limitation in the field) and provides important insight into the pathophysiologic determinants of the reversibility of beta-cell dysfunction.ClinicalTrial.gov identifier: NCT01270789. Keywords: Short-term intensive insulin therapy, Beta-cell dysfunction, Type 2 diabetes, MicroRNA, Response prediction, Cooperative overtargetin

Circulating Small Non Coding Rna Signature In Head And Neck Squamous Cell Carcinoma

The Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common human cancer, causing 350,000 individuals die worldwide each year. The overall prognosis in HNSCC patients has not significantly changed for the last decade. Complete understanding of the molecular mechanisms in HNSCC carcinogenesis could allow an earlier diagnosis and the use of more specific and effective therapies. In the present study we used deep sequencing to characterize small non-coding RNAs (sncRNAs) in serum from HNSCC patients and healthy donors. We identified, for the first time, a multi-marker signature of 3 major classes of circulating sncRNAs in HNSCC, revealing the presence of circulating novel and known miRNAs, and tRNA- and YRNA-derived small RNAs that were significantly deregulated in the sera of HNSCC patients compared to healthy controls. By implementing a triple-filtering approach we identified a subset of highly biologically relevant miRNA-mRNA interactions and we demonstrated that the same genes/pathways affected by somatic mutations in cancer are affected by changes in the abundance of miRNAs. Therefore, one important conclusion from our work is that during cancer development, there seems to be a convergence of oncogenic processes driven by somatic mutations and/or miRNA regulation affecting key cellular pathways