Airborne and belowground phytotoxicity of invasive Ageratina adenophora on native species in Nepal

Plant Ecology - Volatile compounds from leaf litter of invasive alien Ageratina adenophora are known to inhibit growth of native species in sub-tropical Asia, but there is not...     

XomAnnotate: Analysis of Heterogeneous and Complex Exome- A Step towards Translational Medicine

In translational cancer medicine, implicated pathways and the relevant master genes are of focus. Exome''s specificity, processing-time, and cost advantage makes it a compelling tool for this purpose. However, analysis of exome lacks reliable combinatory analysis tools and techniques. In this paper we present XomAnnotate – a meta- and functional-analysis software for exome. We compared UnifiedGenotyper, Freebayes, Delly, and Lumpy algorithms that were designed for whole-genome and combined their strengths in XomAnnotate for exome data through meta-analysis to identify comprehensive mutation profile (SNPs/SNVs, short inserts/deletes, and SVs) of patients. The mutation profile is annotated followed by functional analysis through pathway enrichment and network analysis to identify most critical genes and pathways implicated in the disease genesis. The efficacy of the software is verified through MDS and clustering and tested with available 11 familial non-BRCA1/BRCA2 breast cancer exome data. The results showed that the most significantly affected pathways across all samples are cell communication and antigen processing and presentation. ESCO1, HYAL1, RAF1 and PRKCA emerged as the key genes. Network analysis further showed the purine and propanotate metabolism pathways along with RAF1 and PRKCA genes to be master regulators in these patients. Therefore, XomAnnotate is able to use exome data to identify entire mutation landscape, pathways, and the master genes accurately with wide concordance from earlier microarray and whole-genome studies -- making it a suitable biomedical software for using exome in next-generation translational medicine.

Availability

http://www.iomics.in/research/XomAnnotate     

Identification of proteins secreted by head and neck cancer cell lines using LC-MS/MS: Strategy for discovery of candidate serological biomarkers

In search of blood-based biomarkers that would enhance the ability to diagnose head and neck/oral squamous cell carcinoma (HNOSCC) in early stages or predict its prognosis, we analyzed the HNOSCC secretome (ensemble of proteins secreted and/or shed from the tumor cells) for potential biomarkers using proteomic technologies. LC-MS/MS was used to identify proteins in the conditioned media of four HNOSCC cell lines (SCC4, HSC2, SCC38, and AMOSIII); 140 unique proteins were identified on the basis of 5% global false discovery rate, 122 of which were secretory proteins, with 29 being previously reported to be overexpressed in HNOSCC in comparison to normal head and neck tissues. Of these, five proteins including α-enolase, peptidyl prolyl isomerase A/cyclophilin A, 14-3-3 ζ, heterogeneous ribonucleoprotein K, and 14-3-3 σ were detected in the sera of HNOSCC patients by Western blot analysis. Our study provides the evidence that analysis of head and neck cancer cells' secretome is a viable strategy for identifying candidate serological biomarkers for HNOSCC. In future, these biomarkers may be useful in predicting the likelihood of transformation of oral pre-malignant lesions, prognosis of HNOSCC patients and evaluate response to therapy using minimally invasive tests.     

The Khatri Sikh Diabetes Study (SDS): study design, methodology, sample collection, and initial results

Non-insulin-dependent diabetes mellitus, or type 2 diabetes (T2DM), has become a major public health problem in India. The high prevalence, relatively young age of onset, and strong familial aggregation of T2DM in some Indian communities remains to be explained. Many of the traditional risk factors established for European populations do not appear to be present in Asian Indians. Phase I of the Sikh Diabetes Study (SDS) was launched to build the population resources required to initiate a large-scale genetic epidemiological study of diabetes in an Asian Indian population. The SDS is focused on the Khatri Sikh population of North India. In all, 1,892 subjects were enrolled to participate in the family-based study; 1,623 of these subjects belong to 324 families, each of which has at least 2 siblings affected with T2DM. The sample included 1,288 individuals affected with T2DM (siblings, parents, or relatives) and 335 unaffected siblings, parents, or relatives. The remaining 269 subjects were unrelated nondiabetic control subjects, including unaffected spouses of probands or siblings. This primarily nonvegetarian, nonsmoking endogamous caste group has presented an unusual clinical picture of uneven distribution of adiposity and a high rate of T2DM with secondary complications. Such well-characterized population isolates may offer unique advantages in mapping genes for common complex diseases.     

Prognostic significance of head-and-neck cancer biomarkers previously discovered and identified using iTRAQ-labeling and multidimensional liquid chromatography-tandem mass spectrometry

Diagnostic oncoproteomics is an emerging field; at present, studies on evaluation of prognostic utility of potential biomarkers identified using proteomic techniques are limited. Analysis with isobaric mass tags (iTRAQ) by multidimensional liquid chromatography-mass spectrometry (LC-MS/MS) to identify proteins that are differentially expressed in human head-and-neck/oral squamous cell carcinomas (HNOSCCs) versus noncancerous head-and-neck tissues has led to the discovery, identification, and verification of consistently increased expression of a panel of proteins, including stratifin (14-3-3sigma) and YWHAZ (14-3-3zeta), that may serve as potential cancer biomarkers. Herein, we describe the prognostic utility of these two candidate biomarkers for head-and-neck/oral squamous cell carcinoma (HNOSCC). To determine the clinical significance of stratifin and YWHAZ in head-and-neck tumorigenesis, the expressions of these two proteins were analyzed in HNOSCCs (51 cases) and nonmalignant tissues (39 cases) using immunohistochemistry. Significant increase in stratifin expression was observed in the HNOSCCs as compared to the nonmalignant mucosa [p=0.003, Odd's Ratio (OR)=3.8, 95% CI=1.6-9.2]. Kaplan-Meier survival analysis reveals correlation of stratifin overexpression with reduced disease-free survival of HNOSCC patients (p=0.06). The most intriguing finding is the significant decrease in median disease-free survival (13 months) in HNOSCC patients showing overexpression of both stratifin and YWHAZ proteins, as compared to patients that did not show overexpression of these proteins (median disease-free survival=38 months, p=0.019), underscoring their utility as adverse prognosticators for HNOSCCs. Co-immunoprecipitation assays show the formation of stratifin-YWHAZ heterodimers in HNOSCC cells and tissue samples, and interactions with NFkappaB, beta-catenin, and Bcl-2 proteins. These results suggest the involvement of these proteins in the development of head-and-neck cancer and their association with adverse disease outcome.     

Potent growth suppressive activity of curcumin in human breast cancer cells: Modulation of Wnt/β-catenin signaling

Abnormal activation of the Wnt/β-catenin signaling pathway and subsequent upregulation of β-catenin driven downstream targets—c-Myc and cyclin D1 is associated with development of breast cancer. The objective of our study was to determine if curcumin could modulate the key elements of Wnt pathway in breast cancer cells; an effect that might underscore its usefulness for chemoprevention/treatment of this malignancy. Curcumin showed a cytotoxic effect on MCF-7 cells with 50% inhibitory concentration (IC₅₀) of 35 μM; while IC₅₀ for MDA-MB-231 cells was 30 μM. Treatment with low cytostatic dose of 20 μM curcumin showed G₂/M arrest in both breast cancer cells. The effect of curcumin (20 μM) treatment on expression of Wnt/β-catenin pathway components in breast cancer cells (MCF-7 and MDA-MB-231) was analyzed by immunofluorescence and Western blotting. Curcumin was found to effectively inhibit the expression of several Wnt/β-catenin pathway components—disheveled, β-catenin, cyclin D1 and slug in both MCF-7 and MDA-MB-231. Immunofluorescence analysis showed that curcumin markedly reduced the nuclear expression of disheveled and β-catenin proteins. Further, the protein levels of the positively regulated β-catenin targets—cyclin D1 and slug, were downregulated by curcumin treatment. The expression levels of two integral proteins of Wnt signaling, GSK3β and E-cadherin were also altered by curcumin treatment. In conclusion, our data demonstrated that the efficacy of curcumin in inhibition of cell proliferation and induction of apoptosis might occur through modulation of β-catenin pathway in human breast cancer cells.     

Nuclear S100A7 Is Associated with Poor Prognosis in Head and Neck Cancer

Background

Tissue proteomic analysis of head and neck squamous cell carcinoma (HNSCC) and normal oral mucosa using iTRAQ (isobaric tag for relative and absolute quantitation) labeling and liquid chromatography-mass spectrometry, led to the identification of a panel of biomarkers including S100A7. In the multi-step process of head and neck tumorigenesis, the presence of dysplastic areas in the epithelium is proposed to be associated with a likely progression to cancer; however there are no established biomarkers to predict their potential of malignant transformation. This study aimed to determine the clinical significance of S100A7 overexpression in HNSCC.

Methodology

Immunohistochemical analysis of S100A7 expression in HNSCC (100 cases), oral lesions (166 cases) and 100 histologically normal tissues was carried out and correlated with clinicopathological parameters and disease prognosis over 7 years for HNSCC patients. Overexpression of S100A7 protein was significant in oral lesions (squamous cell hyperplasia/dysplasia) and sustained in HNSCC in comparison with oral normal mucosa (p_trend<0.001). Significant increase in nuclear S100A7 was observed in HNSCC as compared to dysplastic lesions (p = 0.005) and associated with well differentiated squamous cell carcinoma (p = 0.031). Notably, nuclear accumulation of S100A7 also emerged as an independent predictor of reduced disease free survival (p = 0.006, Hazard ratio (HR = 7.6), 95% CI = 1.3−5.1) in multivariate analysis underscoring its relevance as a poor prognosticator of HNSCC patients.

Conclusions

Our study demonstrated nuclear accumulation of S100A7 may serve as predictor of poor prognosis in HNSCC patients. Further, increased nuclear accumulation of S100A7 in HNSCC as compared to dysplastic lesions warrants a large-scale longitudinal study of patients with dysplasia to evaluate its potential as a determinant of increased risk of transformation of oral premalignant lesions.     

Replication of Association Between a Common Variant Near Melanocortin‐4 Receptor Gene and Obesity‐related Traits in Asian Sikhs

Recent genome‐wide association studies (GWAS) in Asian Indians reported strong associations of variants near melanocortin‐4 receptor (MC4R) and MLX interacting protein‐like (MLXIPL) genes with insulin resistance and several obesity‐related quantitative traits (QTs). Here, we evaluated the association of two variants (rs12970134 and rs4450508) near MC4R and a nonsynonymous (Gln241His) variant (rs3812316) in MLXIPL gene with type 2 diabetes (T2D) and obesity‐related QTs in our case–control cohort (n = 1,528; 745 T2D cases and 783 controls) from a Sikh population from North India. We have successfully replicated the association of MC4R (rs12970134) with BMI (P = 0.0005), total weight (WT) (P = 0.001), and waist circumference (WC) (P = 0.001). These associations remained significant after controlling for multiple testing by applying Bonferroni's correction. However, our data did not confirm the association of rs3812316 in the MLXIPL gene with triglyceride (TG) levels. These observations demonstrate that the genetic variation in MC4R locus can have a moderate contribution in the regional fat deposition and development of central obesity in Asian Indians.