A novel G26A variation in 5' half of TGIF1 gene associates with high myopia in ethnic Kashmiri population from India.

This study aims to look at novel variations in TGIF1 gene and explores their potential association with high myopia in an ethnic population from Kashmir (India). Genomic DNA was genotyped for polymorphic variations, and allele frequencies were tested for the Hardy-Weinberg disequilibrium in 240 ethnic Kashmiri cases with high myopia with a spherical equivalent of >-6 diopters (D) and compared with emmetropic controls with spherical equivalent within -0.5D in one or both eyes represented by a sample size of 228. In this study, we found a novel sequence variation G26A (GAT to AAT) in 5' half of TGIF1 gene (p. aspartic acid >asparagine) at a frequency of 62% (148/240, P ≤ 0.0001). Variation appears to associate with high myopia significantly (P ≤ 0.001) as it happens to be present only in high myopia affected individuals. Further, it shows statistical significance for its association with gender and the degree of myopia (P ≤ 0.05). In addition, in silico predictions show that variation likely has an impact on the structure and functional properties of the protein. The assessment of the I-TASSER protein structure showed higher energy for a wild-type protein (-5820.186 kJ/mol) as compared to mutant protein (-6595.593 kJ/mol).

CSE-1034 versus Ceftriaxone: Efficacy and Safety Analysis from a Randomized, Open-labeled Phase III Study in Complicated Urinary Tract Infections.

OBJECTIVE: The aim of this study was to determine the clinical outcome, microbiological outcome and safety profile of CSE-1034, a novel combination of Ceftriaxone, Sulbactam and EDTA in patients with complicated urinary tract infections (cUTI). MATERIALS AND METHODS: This was a randomized, controlled, open-labeled Phase-3 trial with the primary objective of assessing the efficacy and safety of CSE-1034 versus Ceftriaxone for the empirical treatment of cUTI. Adult cUTI patients were randomized to receive either intravenous dose of CSE-1034 or Ceftriaxone. The primary end point was composite cure rate (clinical response and bacterial eradication) in mMITT population at test of cure (TOC) visit. Secondary measures included verification of primary endpoint across other visits in different population sets, safety of patients and treatment duration. RESULTS: Overall, 204 patients were enrolled in the study and received one of the two treatments. At primary endpoint (TOC visit), the composite cure rate was much higher in CSE-1034 treatment arm compared to Ceftriaxone arm i.e. 97% (68/70) vs 83% (58/71) (treatment difference 12.6%; 95% CI: 5.9% to 26.4%). The adverse events (AEs) rates reported in two treatment arms were 21% in CSE-1034 and 36% in Ceftriaxone groups. Additionally, the treatment duration in CSE-1034 arm was significantly less (P < 0.05). CONCLUSIONS: CSE-1034 3 g every 24 h showed a high favorable clinical and bacteriological response, and 95% CI around the treatment difference prove the superiority of CSE-1034 vs. Ceftriaxone for the treatment of cUTI. Therefore, CSE-1034 provides an effective alternative in the treatment of patients with cUTI.

Safety and efficacy of a novel drug elores (ceftriaxone + sulbactam + disodium edetate) in the management of multi-drug resistant bacterial infections in tertiary care centers: a post-marketing surveillance study

Abstract Objective: In India, Elores (CSE-1034: ceftriaxone + sulbactam + disodium edetate) was approved as a broad spectrum antibiotic in year 2011 and is used for management of Extended Spectrum Beta Lactamases/Metallo Beta lactamases infections in tertiary care centers. The objective of this study was to investigate the efficacy of this drug in patients with Extended Spectrum Beta Lactamases/Metallo Beta lactamases infections and identify the incidence of adverse events in real clinical settings. Methods: This Post Marketing Surveillance study was conducted at 17 centers across India and included 2500 patients of all age groups suffering from various bacterial infections and treated with Elores (CSE1034). Information regarding demographic, clinical and microbiological parameters, dosage and treatment duration, efficacy and adverse events (AEs) associated with the treatment were recorded. Results: A total of 2500 patients were included in the study and efficacy was evaluated in 2487 patients. In total, 409 AEs were reported in 211 (8.4%) patients. The major AEs reported were vomiting (3.0%), pain at injection site (2.5%), nausea (2.3%), redness at site (1.96%), thrombophlebitis (1.4%). Of total reported AEs, 40 (5.3%) AEs were reported in pediatric, 310 (20.6%) in adult, and 59 (23.6%) in geriatric group. No AE belonging to grade IV or V was reported in any patient. In terms of efficacy, 1977 (79.4%) patients were cured, 501 (20.1%) patients showed clinical improvement and 5 (0.2%) patients were complete failure. The treatment duration varied from 5 to 7 days in different patients depending on the infection type. Conclusion: In this post-marketing surveillance study, CSE-1034 was found to be an effective and safe option against Pip tazo and meropenem in management of patients with multi-drug resistant (MDR) bacterial infections under routine ward settings.

An androgen-regulated miR-2909 modulates TGFß signalling through AR/miR-2909 axis in prostate cancer.

In recent years, microRNAs (miRNAs) have emerged as promising biomarkers for PCa diagnosis and prognosis. miR-2909 is a novel miRNA that can regulate immunogenomics and oncogenomics. The present study investigated the role of miR-2909 in the pathogenesis of PCa and the potential signalling pathways through which it operates. We have identified miR-2909 as a novel mediator of androgen/androgen receptor (AR) signalling that enhances the proliferation potential of PCa cells and assists in cancer survival under reduced androgen levels. Our results revealed that miR-2909 down regulates TGFBR2 by targeting its 3'-UTR sequence. We also observed that miR-2909 over-expression attenuated TGFß-mediated SMAD3 activation, cell growth inhibition and apoptosis. Moreover, miR-2909 modulated the expression of p21CIP, c-MYC and CCND1 through TGFß signalling. Importantly, we also demonstrated that miR-2909 and AR regulates each other's expression resulting in a positive feedback loop. In conclusion, our study suggests that miR-2909 is an androgen-inducible miRNA that exerts its oncogenic effects by attenuating the tumor-suppressive effects of TGFß signalling.

miR-2909 regulates ISGylation system via STAT1 signalling through negative regulation of SOCS3 in prostate cancer.

One of the well-document strategies adopted by tumour cells for progression is to evade immune surveillance mechanisms. An understanding of the tight interaction between immunity and progression of cancer can provide novel treatment options for different malignancies including prostate cancer (PCa). Here, we have shown that AATF genome encoded miR-2909, known to play role both in immunity and cancer upregulates various interferon stimulating genes (ISGs) including ISGylation system through STAT1. Our results revealed that miR-2909 up-regulates STAT1 through negative regulation of SOCS3 and not through up-regulation of Type 1 interferon (IFN) production. It was observed that inhibition of ISGylation reduced the proliferation potential of PCa cells. Furthermore, androgens were found to negatively regulate ISGylation in LNCaP cells through androgen receptor signalling independently of miR-2909. TGF-ß mediated SMAD3 signalling was also seen to be suppressed by miR-2909 through induction of SMAD7 via enhanced STAT1 expression. Collectively, these studies suggest that miR-2909 could play a vital role in prostate carcinogenesis through modulation of ISGylation system and TGFß signalling via STAT1.

Safety and efficacy of a novel drug elores (ceftriaxone+sulbactam+disodium edetate) in the management of multi-drug resistant bacterial infections in tertiary care centers: a post-marketing surveillance study.

OBJECTIVE: In India, Elores (CSE-1034: ceftriaxone+sulbactam+disodium edetate) was approved as a broad spectrum antibiotic in year 2011 and is used for management of Extended Spectrum Beta Lactamases/Metallo Beta lactamases infections in tertiary care centers. The objective of this study was to investigate the efficacy of this drug in patients with Extended Spectrum Beta Lactamases/Metallo Beta lactamases infections and identify the incidence of adverse events in real clinical settings. METHODS: This Post Marketing Surveillance study was conducted at 17 centers across India and included 2500 patients of all age groups suffering from various bacterial infections and treated with Elores (CSE1034). Information regarding demographic, clinical and microbiological parameters, dosage and treatment duration, efficacy and adverse events (AEs) associated with the treatment were recorded. RESULTS: A total of 2500 patients were included in the study and efficacy was evaluated in 2487 patients. In total, 409 AEs were reported in 211 (8.4%) patients. The major AEs reported were vomiting (3.0%), pain at injection site (2.5%), nausea (2.3%), redness at site (1.96%), thrombophlebitis (1.4%). Of total reported AEs, 40 (5.3%) AEs were reported in pediatric, 310 (20.6%) in adult, and 59 (23.6%) in geriatric group. No AE belonging to grade IV or V was reported in any patient. In terms of efficacy, 1977 (79.4%) patients were cured, 501 (20.1%) patients showed clinical improvement and 5 (0.2%) patients were complete failure. The treatment duration varied from 5 to 7 days in different patients depending on the infection type. CONCLUSION: In this post-marketing surveillance study, CSE-1034 was found to be an effective and safe option against Pip tazo and meropenem in management of patients with multi-drug resistant (MDR) bacterial infections under routine ward settings.

Microdissecting the role of microRNAs in the pathogenesis of prostate cancer.

MicroRNAs (miRNAs) are naturally occurring, small, non-coding RNA molecules that post-transcriptionally regulate the expression of a large number of genes involved in various biological processes, either through mRNA degradation or through translation inhibition. Since the discovery of miRNAs, a vast amount of research has implicated the deregulated expression of miRNAs in different malignancies, including prostate cancer (PCa). Different miRNA expression profiles are reportedly associated with the development, progression, and emergence of castration-resistant PCa (CRPC), suggesting their use in the diagnosis, prognosis, and development of anti-cancer treatment models directed against this disease. However, before their exploitation in terms of therapeutics, a thorough understanding and in-depth mechanistic studies of these miRNAs and the gene networks they orchestrate are necessary for ascertaining their definitive role in the development and progression of PCa. This review attempts to extensively summarize the current knowledge of aberrantly expressed miRNAs and their mode of action in PCa, while highlighting the existing discrepancies and future research warranted.

Mutational analysis of the BRCA2 gene in breast carcinoma patients of Kashmiri descent.

Breast cancer demonstrates geographical and ethnic variation in its incidence reflecting the effect of local environmental conditions and lifestyle. The genesis of the disease has further been complexed by the involvement of a number of genes with small effects and above all by population heterogeneity. Accordingly, variations in genes, including breast cancer 1, early onset (BRCA1)/breast cancer 2, early onset (BRCA2), that have been markedly associated with the breast cancer phenotype exhibit a scattered mutational pattern in different populations. The present study was aimed to analyze the sequence variations in BRCA2 gene in a case control manner in ethnically pure Kashmiri population using PCR. Sequencing of BRCA2 exons revealed the presence of five sequence variations, four of which present in exon 11 alone were somatic and one was germline located in the U-terminal region (UTR) of exon 2. Out of these, the two somatic mutations comprised of substitutions, one representing a missense mutation leading to an amino-acid substitution at codon 991 and the other was a silent mutation at codon 1131, whereas the other two mutations located in exon 11 represented a loss of polymorphism. Codons for amino acid position 846 and 868 were demonstrated to be heterozygous polymorphic variants in 66% of the normal breast tissue samples, whereas the heterozygous polymorphic variant codons at the two loci were replaced by a homozygous genotype in associated tumor tissue in 88% of cases. These two mutations were always linked. Germline variation observed in exon 2 was located in the UTR region at contig position 13870572 (rs1799943). Other screened exons of BRCA2 did not demonstrate any sequence variation. These variations may contribute to breast cancer susceptibility along with variations in other low penetrating genes in sporadic types of breast cancer in this cohort of the population.

Epidemiological distribution and incidence of different cancers in Kashmir valley--2002-2006.

There are no population-based data available on cancer pattern in Kashmir and our study is the first kind which represents the trend in cancer pattern in the valley. The source of our data were cancer patients registered in the Department of Radiation Oncology, Sheri-Kashmir Institute of Medical Sciences, Srinagar, and Department of Radiation Oncology, SMHS, Srinagar during the period Jan 2002 to Dec 2006. These are leading medical centres in the valley and draw most all of cancer patients from all over Kashmir for treatment. During the period a total of 6,943 cases were registered of which 4,345 were males and 2,598 were females. The age standardized incidence rates were 34.9 per 100,000 for males and 24.8 per 100,000 for females. Oesophagus was the leading site of cancer in both sexes (male ASR 11.2; female ASR 8.3) followed by lung (ASR 6.5), brain (ASR 2.2) and head and neck (ASR 2.2) in males and breast (ASR 5.2), skin (ASR 1.6) and rectum (ASR 0.95) in females. The incidence of cervical cancer in females and prostate cancer in males was lower in Kashmir as compared to other Indian registries. Overall cancer incidence was significantly lower and cancer patterns were markedly different in Kashmir. The observed cancer pattern indicates that awareness campaigns, life style and dietary habit changes, tobacco-control measures and early detection of breast cancer are very important for cancer control in this population.