Visceral adiposity index among young girls with PCOS and its association with phenotypes and metabolic risk

Background: Polycystic Ovarian Syndrome (PCOS) is a growing endocrine-metabolic disease in India. Visceral Adiposity Index (VAI) is a surrogate marker of visceral adipose dysfunction and can be used as a useful predictor of unhealthy PCOS phenotypes in low resource settings. No cut-off has been assessed among Indian population.Methods: Secondary data from 106 diagnosed girls with PCOS and 121 controls was analysed to estimate (i) VAI and BMI among different phenotypes (ii) risk of metabolic disorders using VAI among different phenotypes of PCOS and (iii) compare the overall diagnostic performance (for metabolic syndrome) of VAI, BMI and waist circumference.Results: Majority of the girls in the sample considered for analysis were lean PCOS (61%). Mean VAI among PCOS (3.02) was significantly higher than normal controls (2.81). Classic and Mild Phenotypes had high VAI. A unit increase in VAI score was found associated with 5.23 times higher risk of metabolic syndrome (AOR: 5.23, 95% CI: 2.261-12.086). A higher VAI with cut off value of 2.73 could predict risk of metabolic syndrome among PCOS cases, unlike the cutoff among Caucassian population of 1.67. The cut-off for the non- obese group was even higher i.e. 2.81.Conclusions: Given that Indians are genetically more prone to have excess visceral fat the cut-offs for measuring adiposity also needs to be re-defined. The findings of this small sample throws light on the prevalence of visceral adiposity among lean girls with PCOS emphasizing the need to also screen them for metabolic syndrome, educate them about these complications and motivate them to practice healthy lifestyles

Modulation of digestibility of canine food using enzyme supplement: an in vitro simulated semi-dynamic digestion study

Digestibility and nutrient availability are important parameters when estimating the nutritional quality of pet food. We have developed a simulated semi-dynamic in vitro canine digestion model to evaluate the digestibility of dry extruded canine food. Canine food was assessed for digestible energy, dry matter digestibility, protein digestibility, non-fibrous carbohydrate (NFC) digestibility, and total antioxidant capacity (TAC) in the absence and presence of an enzyme blend (DigeSEB Super Pet). Enzyme blend supplementation in canine food was found to increase the dry matter digestibility (18.7%, p < 0.05), digestible energy (18.1%, p < 0.05), and protein digestibility (11%, p < 0.1) and reducing sugar release (106.3%, p < 0.005). The release of low molecular weight peptides (48.7%) and essential amino acids (15.6%) increased within 0.5 h of gastrointestinal digestion due to enzyme blend supplementation. Furthermore, the TAC of the digesta was also increased (8.1%, p < 0.005) in the canine food supplemented with enzyme blend. Overall, supplementation of enzyme blend in canine food is an effective strategy to enhance the food digestibility and nutrient availability for absorption

Parallel evolution of tumor subclones mimics diversity between tumors

Intratumour heterogeneity (ITH) may foster tumour adaptation and compromise the efficacy of personalized medicine approaches. The scale of heterogeneity within a tumour (intratumour heterogeneity) relative to genetic differences between tumours (intertumour heterogeneity) is unknown. To address this, we obtained 48 biopsies from eight stage III and IV clear cell renal cell carcinomas (ccRCCs) and used DNA copy-number analyses to compare biopsies from the same tumour with 440 single tumour biopsies from the Cancer Genome Atlas (TCGA). Unsupervised hierarchical clustering of TCGA and multi-region ccRCC samples revealed segregation of samples from the same tumour into unrelated clusters; 25% of multi-region samples appeared more similar to unrelated samples than to any other sample originating from the same tumour. We found that the majority of recurrent DNA copy number driver aberrations in single biopsies were not present ubiquitously in late-stage ccRCCs and were likely to represent subclonal events acquired during tumour progression. Such heterogeneous subclonal genetic alterations within individual tumours may impair the identification of robust ccRCC molecular subtypes classified by distinct copy number alterations and clinical outcomes. The co-existence of distinct subclonal copy number events in different regions of individual tumours reflects the diversification of individual ccRCCs through multiple evolutionary routes and may contribute to tumour sampling bias and impact upon tumour progression and clinical outcome. Copyright (c) 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd

Vancomycin gene selection in the microbiome of urban <i>Rattus norvegicus</i> from hospital environment

Background and objectives: Widespread use of antibiotics has resulted in selection pressure on genes that make bacteria non-responsive to antibiotics. These antibiotic-resistant bacteria are currently a major threat to global health. There are various possibilities for the transfer of antibiotic resistance genes. It has been argued that animal vectors such as Rattus norvegicus (R. norvegicus) living in hospital sewage systems are ideal for carrying pathogens responsible for fatal diseases in humans. Methodology: Using a metagenomic sequencing approach, we investigated faecal samples of R. norvegicus from three major cities for the presence of antibiotic resistance genes. Results: We show that despite the shared resistome within samples from the same geographic locations, samples from hospital area carry significantly abundant vancomycin resistance genes. Conclusions and implications: The observed pattern is consistent with a selection for vancomycin genes in the R. norvegicus microbiome, potentially driven by the outflow of antibiotics and antibiotic-resistant bacteria into the wastewater systems. Carriage of vancomycin resistance may suggest that R. norvegicus is acting as a reservoir for possible transmission to the human population

Integrative analysis of miRNA and gene expression reveals regulatory networks in tamoxifen-resistant breast cancer

Tamoxifen is an effective anti-estrogen treatment for patients with estrogen receptor-positive (ER+) breast cancer, however, tamoxifen resistance is frequently observed. To elucidate the underlying molecular mechanisms of tamoxifen resistance, we performed a systematic analysis of miRNA-mediated gene regulation in three clinically-relevant tamoxifen-resistant breast cancer cell lines (TamRs) compared to their parental tamoxifen-sensitive cell line. Alterations in the expression of 131 miRNAs in tamoxifen-resistant vs. parental cell lines were identified, 22 of which were common to all TamRs using both sequencing and LNA-based quantitative PCR technologies. Although the target genes affected by the altered miRNA in the three TamRs differed, good agreement in terms of affected molecular pathways was observed. Moreover, we found evidence of miRNA-mediated regulation of ESR1, PGR1, FOXM1 and 14-3-3 family genes. Integrating the inferred miRNA-target relationships, we investigated the functional importance of 2 central genes, SNAI2 and FYN, which showed increased expression in TamR cells, while their corresponding regulatory miRNA were downregulated. Using specific chemical inhibitors and siRNA-mediated gene knockdown, we showed that both SNAI2 and FYN significantly affect the growth of TamR cell lines. Finally, we show that a combination of 2 miRNAs (miR-190b and miR-516a-5p) exhibiting altered expression in TamR cell lines were predictive of treatment outcome in a cohort of ER+ breast cancer patients receiving adjuvant tamoxifen mono-therapy. Our results provide new insight into the molecular mechanisms of tamoxifen resistance and may form the basis for future medical intervention for the large number of women with tamoxifen-resistant ER+ breast cancer

MicroRNA Profiling in Ocular Adnexal Lymphoma: A Role for MYC and NFKB1 Mediated Dysregulation of MicroRNA Expression in Aggressive Disease

Citation: Hother C, Rasmussen PK, Joshi T, et al. MicroRNA profiling in ocular adnexal lymphoma: a role for MYC and NFKB1 mediated dysregulation of microRNA expression in aggressive disease. Invest Ophthalmol Vis Sci. 2013;54:5169-5174. DOI: 10.1167/iovs.13-12272 PURPOSE. Ocular adnexal lymphoma (i.e., lymphoma with involvement of the orbit, eyelids, conjunctiva, lacrimal gland, and lacrimal sac), although rare, is common among malignant tumors involving the ocular adnexal region. The main subtypes are low-grade extranodal marginal zone lymphoma (EMZL) and aggressive diffuse large B-cell lymphoma (DLBCL). In rare cases, low-grade EMZL are reported to transform to DLBCL. It is unclear, however, which genetic events distinguish low-grade disease from aggressive, potentially fatal disease. METHODS. Using LNA-based arrays from Exiqon, we performed global microRNA (miRNA) expression profiling of 18 EMZLs and 25 DLBCLs involving ocular adnexal sites to investigate changes in the miRNA expression in low-versus high-grade disease. Findings were confirmed by real-time quantitative PCR (RTq-PCR). RESULTS. Our analysis revealed 43 miRNAs with altered expression profiles in DLBCL compared to EMZL. Seven of the miRNAs down-regulated in DLBCL relative to EMZL showed enrichment for a direct transcriptional repression by the oncoprotein MYC. We also report a possible loss-of-regulation of NFKB1 and its downstream miRNAs. In addition, our analysis identified a group of DLBCLs whose expression profiles resembled that of EMZL. Although transformation of EMZL to DLBCL in the ocular adnexal region is rare, we hypothesize that the intermediate group potentially may derive from transformation of EMZL that was not recognized by histology. CONCLUSIONS. We conclude that fundamental differences in miRNA expression exist between ocular adnexal EMZL and DLBCL, mainly due to differences in MYC and NF-+B regulatory pathways

Pan-cancer analysis of genomic scar signatures associated with homologous recombination deficiency suggests novel indications for existing cancer drugs

Background: Ovarian and triple-negative breast cancers with BRCA1 or BRCA2 loss are highly sensitive to treatment with PARP inhibitors and platinum-based cytotoxic agents and show an accumulation of genomic scars in the form of gross DNA copy number aberrations. Cancers without BRCA1 or BRCA2 loss but with accumulation of similar genomic scars also show increased sensitivity to platinum-based chemotherapy. Therefore, reliable biomarkers to identify DNA repair-deficient cancers prior to treatment may be useful for directing patients to platinum chemotherapy and possibly PARP inhibitors. Recently, three SNP array-based signatures of chromosomal instability were published that each quantitate a distinct type of genomic scar considered likely to be caused by improper DNA repair. They measure telomeric allelic imbalance (named NtAI), large scale transition (named LST), and loss of heterozygosity (named HRD-LOH), and it is suggested that these signatures may act as biomarkers for the state of DNA repair deficiency in a given cancer. Results: We explored the pan-cancer distribution of scores of the three signatures utilizing a panel of 5371 tumors representing 15 cancer types from The Cancer Genome Atlas, and found a good correlation between scores of the three signatures (Spearman’s ρ 0.73–0.87). In addition we found that cancer types ordinarily receiving platinum as standard of care have higher median scores of all three signatures. Interestingly, we also found that smaller subpopulations of high-scoring tumors exist in most cancer types, including those for which platinum chemotherapy is not standard therapy. Conclusions: Within several cancer types that are not ordinarily treated with platinum chemotherapy, we identified tumors with high levels of the three genomic biomarkers. These tumors represent identifiable subtypes of patients which may be strong candidates for clinical trials with PARP inhibitors or platinum-based chemotherapeutic regimens. Electronic supplementary material The online version of this article (doi:10.1186/s40364-015-0033-4) contains supplementary material, which is available to authorized users