Despite advances in biology and therapeutic modalities, existence of highly tumorigenic glioma stem-like cells (GSCs) makes glioblastomas (GBMs) invincible. N6-methyl adenosine (mA), one of the abundant mRNA modifications catalyzed by methyltransferase-like 3 and 14 (METTL3/14), influences various events in RNA metabolism. Here, we report the crucial role of METTL3-mediated mA modification in GSC (neurosphere) maintenance and dedifferentiation of glioma cells. METTL3 expression is elevated in GSC and attenuated during differentiation. RNA immunoprecipitation studies identified SOX2 as a bonafide mA target of METTL3 and the mA modification of SOX2 mRNA by METTL3 enhanced its stability. The exogenous overexpression of 3'UTR-less SOX2 significantly alleviated the inhibition of neurosphere formation observed in METTL3 silenced GSCs. METTL3 binding and mA modification in vivo required intact three METTL3/mA sites present in the SOX2-3'UTR. Further, we found that the recruitment of Human antigen R (HuR) to mA-modified RNA is essential for SOX2 mRNA stabilization by METTL3. In addition, we found a preferential binding by HuR to the m6A-modified transcripts globally. METTL3 silenced GSCs showed enhanced sensitivity to γ-irradiation and reduced DNA repair as evidenced from the accumulation of γ-H2AX. Exogenous overexpression of 3'UTR-less SOX2 in METTL3 silenced GSCs showed efficient DNA repair and also resulted in the significant rescue of neurosphere formation from METTL3 silencing induced radiosensitivity. Silencing METTL3 inhibited RasV12 mediated transformation of mouse immortalized astrocytes. GBM tumors have elevated levels of METTL3 transcripts and silencing METTL3 in U87/TIC inhibited tumor growth in an intracranial orthotopic mouse model with prolonged mice survival. METTL3 transcript levels predicted poor survival in GBMs which are enriched for GSC-specific signature. Thus our study reports the importance of mA modification in GSCs and uncovers METTL3 as a potential molecular target in GBM therapy.

An experimental study investigating the aerodynamic characteristics of generic delta wing-body combinations up to high angles of attack was carried out at a subsonic Mach number. Three delta wings having sharp leading edges and sweep angles of 50°, 60° and 70° were tested with two forebody configurations providing a variation of the nose fineness ratio. Measurements made included six-component forces and moments, limited static pressures on the wing lee-side and surface flow visualisation studies. The results showed symmetric flow features up to an incidence of about 25°, beyond which significant asymmetry was evident due to wing vortex breakdown, forebody vortex asymmetry or both. At higher incidence, varying degrees of forebody-wing vortex interaction effects were seen in the mean loads, which depended on the wing sweep and the nose fineness ratio. The vortex breakdown on these wings was found to be a gradual process, as implied by the wing pressures and the mean aerodynamic loads. Effects of forebody vortex asymmetry on the wing-body aerodynamics have also been assessed. Comparison of Datcom estimates with experimental data of longitudinal aerodynamic characteristics on all three wing-body combinations indicated good agreement in the symmetric flow regime.

Background: It is unclear whether Serum Uric Acid (SUA) promotes or protects against the cerebrovascular disease. Present study was done to estimate uric acid levels in patients of acute ischemic stroke.

Proton pump inhibitors (PPIs) have been associated with Clostridium difficile infection (CDI) in several recent studies. The exact mechanism through which PPIs may cause Clostridium difficile infection is not well understood. One potential mechanism to explain this association may be that elevated gastric pH levels facilitate the growth of potentially pathogenic upper and lower gastrointestinal tract flora. Although Clostridium difficile spores are acid resistant, vegetative forms are susceptible to acidity. Higher gastric PH therefore increases vegetative bacteria counts in the small and large intestine. Other potential mechanisms include impairment of leukocytes and other immune responses and antimicrobial properties of PPIs. In recent years, much research has been contributed to prove the relationship between PPIs and CDI as causal. Most studies however, fail to prove causality due to the use of antibiotics and other medications during time of initial diagnosis of CDI. PPIs continue to also be one of the most heavily prescribed drugs in our country. As primary and recurrent infection caused by Clostridium difficile continues to rise, more data must be collected to determine better treatment, overall management, and the role that PPIs may play in its propagation.

Introduction: The reported cancer detection rate of TransRectal Ultrasonography (TRUS) biopsies (TRUS biopsy yield) has been around 30 percent in western countries. However it is much lower in Asian countries, including India. Hence a larger proportion of patients in India undergo unnecessary biopsies. Aims:To find out the cancer detection rate of TRUS biopsy (TRUS biopsy yield) in contemporary Indian population. Also, to study the positive predictive values at different serum ProstateSpecific Antigen (PSA)/PSA Density (PSAD) cut off levels and suspicious Digital Rectal Examination (DRE) findings. Materials and Methods:This retrospective study was carried out in a tertiary care institute. All symptomatic patients who underwent TRUS guided biopsy for indication of raised serum PSA level (>4 ng/ml) or suspicious DRE findings (nodule, irregularity, hard consistency, immobile rectal mucosa) from January 2012 to December 2014 were included. For serum PSA range (4-10) ng/ml, TRUS guided biopsy was done in patients with percent free/total PSA < 25. Statistical analysis used were Chi-square test, Mann-Whitney U-test, Spearman's rank correlation analysis and Receiver-Operating Characteristic (ROC) curve.results: Out of the 235 patients included, 60 patients had malignancy (overall cancer detection rate= 25.53%). The cancer detection rate for PSA ranges of (4-10) and (10-20) ng/ ml was as low as 5.95% and 13.16% respectively. Patients with malignant disease had significantly smaller prostate gland size than patients with benign disease (53.89 vs 63.06; p-value <0.05). On the other hand, cancer detection rate was 100% for PSA greater than 50ng/ml. The cancer detection rates were only upto 10% for PSA density ranges upto 0.25 ng/ml/cm 3 . The Area Under the Curve (AUC) for PSA and PSAD was 0.876 and 0.884 respectively. Only one patient (0.43%) had post-biopsy complication (acute bacterial prostatitis) requiring hospital admission. conclusion:The current serum PSA and PSAD cut offs of 4 ng/ ml and 0.15 ng/ml/cm 3 need to be raised for Indian population to increase its positive predictive value. Prospective study validation of this finding is lacking. Sunil Raghunath Patil et al., TRUS Biopsy Study www.jcdr.net