Background: Autophagy is essential for ␤-cell function and survival. Results: Autophagic turnover is impaired in ␤-cells when treated with metabolic stressors. Conclusion: Diminished autophagy leads to apoptotic ␤-cell death. Significance: Therapeutic interventions using pharmacological agents, which can improve ER folding capacity, as well as target the autophagy machinery, could provide promising strategies for treating human diseases such as T2D.

Background: Arachidonic acid and its metabolites regulate pancreatic glucose-stimulated insulin secretion (GSIS) through multiple mechanisms. Results: Group X secretory phospholipase A 2 (GX sPLA 2 ) suppresses GSIS; suppression was abolished when COX-2 activity or PGE2-EP3 receptor signaling were inhibited. Conclusion: GX sPLA 2 inhibits GSIS by augmenting PGE2 production. Significance: GX sPLA 2 may be targeted for ameliorating beta cell dysfunction in type 2 diabetes.

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Kangri cancer is a unique thermally-induced squamous cell carcinoma (SCC) of skin that develops due to persistent use of Kangri (a brazier), used by Kashmiri people, to combat the chilling cold during winter months. We designed a large scale case-control study to characterize the frequency of two polymorphisms within the MHC class III-linked HSP70genes, Hsp70-2 and Hsp70-hom, in order to find any association of these genotypic variants for predisposition to and clinical outcome of Kangri cancer patients from Kashmir valley in North India. Polymerase Chain Reaction and restriction enzymes were utilized to characterize the frequency of two polymorphisms with in Hsp70-2 and Hsp70-hom genes in 118 Kangri carcinoma cases and 95 healthy controls from the same population of Kashmir. Association of high frequency allelic variants of Hsp70genes with various clinicopathological features of prognostic significance was assessed by Chi-square test using SPSS software. In this study, allelic frequency of Hsp70-2 A/G heterozygote (0.87) (P = 0.012) was found to be significantly high in Kangri cancer cases compared to control (0.736) with a Relative Risk of 2.45 fold. Conversely, the allelic frequency of Hsp70-2 A/A allele in homozygous condition was significantly low in Kangri cancer cases and worked out to be 0.084 (Vs 0.252 in control) with P is equal to 0.001, implicating it as a protective allele against Kangri cancer in subjects with this genotype. Similarly, significantly high frequency of 0.50 (Vs 0.29 in control) of Hsp70-homC/C allele was found in homozygous condition in Kangri cancer cases suggestive of a positive relative risk associated with this genotype (RR is equal to 2.47) (P is equal to 0.002). The overall allele frequency data analysis of Hsp70-2 and Hsp70-hom genes was significant (χ2 is equal to 12.38, P is equal to 0.002; and χ2 is equal to 12.21, P is equal to 0.002). The study also reveals considerable association of high frequency alleles of HSP70 genes, especially of Hsp70-2 A/G or G/G in Kangri tumors with clinico-pathological features of poor prognosis. These results indicate that the relative risk of Kangri cancer associated with Hsp70-2 and Hsp70- hom gene polymorphisms is confined to Hsp70-2 A/G or G/G and Hsp70homC/C haplotype in our population. The study, therefore, suggests Hsp70-2 A/G or G/G and Hsp70homC/C genotypes as potential susceptibility markers and independent prognostic indicators in Kangri carcinoma patients in Kashmiri population.

Background:Colorectal cancer (CRC) is one of the leading causes of mortality and morbidity. The Kashmir valley, in Northern India, has been described as a high-risk area for colorectal cancer.Aim:The aim was to make a preliminary attempt to study mutations in exons 5–8 (the DNA binding domain) of the tumour suppressor gene TP53 in 42 CRC patients from Kashmir.Materials and methods:The study population consisted of 42 patients diagnosed with colorectal cancer. Mutations in exons 5–8 of the TP53 gene were detected by means of single-strand conformation polymorphism (SSCP). All samples that showed different band migration patterns in the SSCP were confirmed by sequencing.Results:The 28 mutations were found in the TP53 gene in 19 patients, comprised 23 substitutions (17 transitions + six transversions), and five insertions. The 23 substitutions represent 18 missense mutations, leading to amino acid substitutions, two nonsense mutations, leading to stop codons, while the remaining three were silent mutations. The five insertions represented frameshifts. Two of 28 mutations (7.14%) have not been previously reported in colon cancer samples and were identified as novel TP53 mutations. Comparison of the mutation profile with other ethnic populations and regions reflected both differences and similarities indicating co-exposure to a unique set of risk factors.Conclusions:Mutation of the TP53 gene is one of the commonest genetic changes in the development of human colorectal cancer. The high frequency of TP53 gene mutations implicates TP53 as a predominant factor for colorectal cancer in the high-risk ethnic Kashmir population.