Role of miR-2909 in Prostate Carcinogenesis

The biggest challenge in prostate cancer treatment is to understand the signaling mechanisms controlling disease progression. In this context, microRNAs assume huge importance and have recently become an attractive area of research. MicroRNAs are naturally occurring, single-stranded, small non-coding RNAs of 19–25 nucleotides that regulate gene expression. MicroRNAs function as oncogenes or tumor-suppressor genes, and their deregulation is a common feature of human cancers including prostate cancer. Among deregulated microRNAs in prostate cancer, some microRNAs are directly under androgen receptor signaling control and function as the effectors of androgen signaling. Recent findings have shown that apoptosis antagonizing transcription factor (AATF) gene encodes a microRNA designated as miR-2909 that plays an important role in prostate cancer progression. miR-2909 is identified as an androgen-regulated microRNA acting as a novel effector of androgen/androgen receptor signaling. It enhances the proliferation potential of prostate cancer cells and assists in prostate cancer survival under reduced androgen levels by maintaining a positive feedback loop with AR. miR-2909 exerts its oncogenic effects via multiple mechanisms including attenuation of tumor-suppressive effects of TGFβ signaling by directly targeting TGFBR2 and via STAT1 pathway and upregulation of ISGylation pathway through SOCS3/STAT1 pathway

Advancing in the Direction of Right Solutions: Treating Multidrug-Resistant Pneumonia

Worldwide, antibiotic resistance is a major contemporary public health threat due to rapid emergence of resistant bacteria and endangering the efficacy of antibiotics. There are significant number of reports on clinical failure of β-lactam and β-lactamase inhibitor combination and even carbapenems due to various carbapenem resistance mechanisms. The increasing rate of the antibiotic resistance and its impact on treatment failure encouraged us to study newly reported concept of antibiotic adjuvant entities (AAEs) by which the increasing failure rate of antibiotics can be controlled. These AAEs have been developed for both Gram-positive and Gram-negative multidrug-resistant (MDR) infections. Elores (ceftriaxone + sulbactam with adjuvant ethylenediaminetetraacetic acid (EDTA)) and Potentox (cefepime + amikacin with adjuvant potassium chloride) are the AAEs for Gram-negative MDR pathogens each catering to a different type of resistance and Vancoplus (ceftriaxone + vancomycin with adjuvant L-arginine), another AAE, can help us to last longer in the war against antibiotic-resistant Gram-positive bugs particularly which cause complicated lower respiratory tract infection (LRTI) leading to pneumonia. These new antibiotic additions (Elores, Potentox, and Vancoplus) to the current armamentarium to treat MDR infections, including pneumonia, can help us combat against antimicrobial resistance more efficiently

Relative Incidence and Molecular Analysis of Breast Cancer in Kashmiri population

Breast cancer is the third most common tumor in the world and represents 9% of global cancer burden. In India, breast cancer is the second common cancer in women after cervical cancer and has of late replaced cervical cancer as the leading site of cancer among women in Indian cities. Preliminary indications point towards an increasing trend in the occurrence of breast cancer amongst Kashmiri population. However, authentic data with regard to prevalence is almost non-existent in the state of Jammu and Kashmir. To our knowledge, this is the first attempt to examine the epidemiological distribution of different cancer typ es with particular emphasis on breast cancer in the wh ole valley. The source of our data include cancer registry in the Department of Radiation Oncology, Sheri -Kashmir Institute of Medical Sciences, Srinagar, and Department of Radiation Oncology, SMHS, Srina gar during Jan 2002 to Dec 2006 . A total of 6943 cas es registered between 1st January 2002 to 31st December 2006 comprised of 4345 males and 2598 females. The age standardized incidence rates were 34.9 per 100,000 for males an d 24.8 per 100,000 for females. Oesophagus was the leading site of cancer in both the sexes (male ASR 11.2; female ASR 8.3) followed by lung (ASR 6.5), brain (ASR 2.2), 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 turned out to be surprisingly lo w in Kashmir i women as compared to other Indian Registries quite contrary to the pattern in rest of the country. Our studies imply that 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 cohort of population. Abstract 2 Section II Abstract Environmental and genetic factors are attributed to explain the spectrum of geographical and ethnic variations in the development and pathogenesis of disease. The genesis of disease has been further complexed by involvement of number of genes with small effe cts and above all by population heterogeneity. Accordingly variations in genes like Brca1/Brca2 that have been strongly associated with breast cancer phenotype present a scattered mutational pattern in different populations. This study attempts to analyze the frequently mutated exons of BRCA2 for sequence variations in surgically resected breast cancer tissue samples, from a high risk ethnic Kashmiri population. PCR followed b y direct sequencing revealed presence of five variations, with four somatic mutat ions located on exon 11 and one germline variation located in UTR region of exon 2 at contig position 13870572 (rs1799943). All the four somatic mutations comprised of substitutions; two representing missense mutations leading to amino -acid substitution at codon positions 868 (novel) and 991 whereas other two were silent mutations at codon positions 846 and 1131. Codons for amino-acid positions 846 (TCC/TCA) and 868 (CCT/ACT) were seen to be present in heterozygous state in normal breast tissue samples and the heterozygous nature of both the codons was seen to be lost i n associated tumor samples in 44 out of 50 patients. Incidentally these two mutations were always found to be linked.No sequence variations were observed in exons 9, 18, 20 and 25. Gap -junction gene C onnexin 43, which codes fo r a 43 -kd gap -junction protein is a predominantly expressed gap junction protein in normal breast tissue and plays an important role in normal mammogenesis, lactogenesis and involution. Studies have shown down- re gulation of connexin 43 gap -junction protein is involved in primary tumor formation as well as metastasis in breast cancer patients and restoration of gap-junction intercellular communication by up-regulation of Abstract 3 connexins has been shown to restore normal phenotypes in vitro and reduce tumor growth in vivo . However the molecular mechanisms behind these processes remain elusive and a better understanding of the key events is necessary to gain information relevant to the designing of anti -cancer treatment models against breast cancer. In this study, coding sequence of C onnexin 43 was analyzed for polymorphic changes to establish its role (if any) in breast cancer in this cohort of population. After sequence analysis, none of the screened samples reveal ed any kind of variations in early or advanced stage of the disease. The findings from this study add to the body of knowledge about mutation prevalence and nature of different breast cancer pre -disposing genes in ethnic Kashmiri population, and may inform strategies for genetic cancer risk assessment. Our studies also imply that mutational deactivation does not play any role in the down regulation of Connexin 43 expression in Kashmiri breast cancer patients. Instead, some other regulatory mechanism like hypermethylation or mutati on of the promoter region of thegene may be involved. Additionally increased understanding of breast carcinoma pathways may enhance our ability to device targeted approaches to the preve ntion of diseas

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. Keywords: Multi-drug resistance, Bacterial infections, IPD, CSE-103

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