Manipal University

About: Manipal University is a education organization based out in Manipal, Karnataka, India. It is known for research contribution in the topics: Population & Health care. The organization has 9525 authors who have published 11207 publications receiving 110687 citations.

Mcl-1 is an important therapeutic target for oral squamous cell carcinomas

Abstract: Oral and oropharyngeal cancers are the sixth most common cancers worldwide. Despite intensive investigation, oral squamous cell carcinomas (OSCC) represent a clinical challenge resulting in significant morbidity and mortality. Resistance to cell death is common in OSCC and is often mediated by the Bcl-2 family proteins. Among all anti-apoptotic Bcl-2 family members, Mcl-1 functions as a major survival factor, particularly in solid cancers. Despite the confirmed importance of Mcl-1 in several neoplasms, the role of Mcl-1 in OSCC survival has yet to be explored. In this study, we found that knocking down Mcl-1 sensitized OSCC cells to ABT-737, which binds to Bcl-2/Bcl-xL but not Mcl-1. We report for the first time that a BH3 mimetic, Sabutoclax, which functions as an inhibitor of all anti-apoptotic Bcl-2 proteins, induced cancer-specific cell death in an Mcl-1-dependent manner through both apoptosis and toxic mitophagy. In vivo studies demonstrated that Sabutoclax alone decreased tumor growth in a carcinogen-induced tongue OSCC mouse model. In a combination regimen, Sabutoclax and COX-2 inhibitor, Celecoxib, synergistically inhibited the growth of OSCC in vitro and also significantly reduced OSCC tumor growth in vivo. Overall, these results identify Mcl-1 as a therapeutic prospective target in OSCC.

Comprehensive network map of interferon gamma signaling.

Abstract: Interferon gamma (IFN-γ), is a cytokine, which is an important regulator of host defense system by mediating both innate and adaptive immune responses IFN-γ signaling is primarily associated with inflammation and cell-mediated immune responses IFN-γ is also represented as antitumor cytokine which facilitates immunosurveillance in tumor cells In addition, IFN-γ mediated signaling also elicits pro-tumorigenic transformations and promotes tumor progression Impact of IFN-γ signaling in mammalian cells has been widely studied which indicate that IFN-γ orchestrates distinct cellular functions including immunomodulation, leukocyte trafficking, apoptosis, anti-microbial, and both anti- and pro-tumorigenic role However, a detailed network of IFN-γ signaling pathway is currently lacking Therefore, we systematically curated the literature information pertaining to IFN-γ signaling and develop a comprehensive signaling network to facilitate better understanding of IFN-γ mediated signaling A total of 124 proteins were catalogued that were experimentally proven to be involved in IFN-γ signaling cascade These 124 proteins were found to participate in 81 protein-protein interactions, 94 post-translational modifications, 20 translocation events, 54 activation/inhibiton reactions Further, 236 differential expressed genes were also documented in IFN-γ mediated signaling IFN-γ signaling pathway is made freely available to scientific audience through NetPath at ( http://wwwnetpathorg/pathways?path_id=NetPath_32 ) We believe that documentation of reactions pertaining to IFN-γ signaling and development of pathway map will facilitate further research in IFN-γ associated human diseases including cancer

Impacts of the COVID-19 Pandemic on Cardiac Rehabilitation Delivery around the World

Abstract: Background To investigate impacts of COVID-19 on CR delivery around the globe, including effects on providers and patients. Methods In this cross-sectional study, a piloted survey was administered to CR programs globally via REDCap from April-June/2020. The 50 members of the ICCPR and personal contacts facilitated program identification. Results Overall, 1062(18.3% program response rate) responses were received from 70/111(63.1% country response rate) countries in the world with existent CR programs. Of these, 367(49.1%) programs reported they had stopped CR delivery, and 203(27.1%) stopped temporarily (mean=8.3±2.8weeks). Alternative models were delivered in 322(39.7%) programs, primarily through low-tech modes (n=226,19.3%). 353(30.2%) respondents were re-deployed, and 276 (37.3%) felt the need to work due to fear of losing their job, despite the perceived risk of contracting COVID-19 (mean=30.0%±27.4/100). 266(22.5%) reported anxiety, 241(20.4%) were concerned about exposing their family, 113(9.7%) reported increased workload to transition to remote delivery, and 105(9.0%) were juggling caregiving responsibilities during business hours. Patients were often contacting staff regarding grocery shopping for heart-healthy foods (n=333,28.4%), how to use technology to interact with the program (n=329,27.9%), having to stop their exercise because they have no place to exercise (n=303,25.7%), and their risk of death from COVID-19 due to pre-existing cardiovascular disease (n=249,21.2%). Respondents perceived staff (n=488,41.3%) and patient (n=453,38.6%) personal protective equipment, as well as COVID-19 screening (n=414,35.2%) and testing (n=411,35.0%) as paramount to in-person service resumption. Conclusion Approximately 4400 programs ceased service delivery. Those that remain open are implementing new technologies to ensure their patients receive CR safely, despite the challenges. Highlights -COVID-19 has impacted cardiac rehabilitation (CR) delivery around the globe. -In this cross-sectional study, a survey was completed by 1062 (18.3%) CR programs from 70 (63.1%) countries. -The pandemic has resulted in cessation of ∼75% of CR programs, with others ceasing initiation of new patients, reducing components delivered, and/or changing of mode delivery with little opportunity for planning and training. -There is also significant psychosocial and economic impact on CR providers. -Alternative CR model (e.g. home-based, virtual) reimbursement advocacy is needed, to ensure safe, accessible secondary prevention delivery.

Dexamethasone 12 mg versus 6 mg for patients with COVID-19 and severe hypoxaemia: a pre-planned, secondary Bayesian analysis of the COVID STEROID 2 trial.

Abstract: We compared dexamethasone 12 versus 6 mg daily for up to 10 days in patients with coronavirus disease 2019 (COVID-19) and severe hypoxaemia in the international, randomised, blinded COVID STEROID 2 trial. In the primary, conventional analyses, the predefined statistical significance thresholds were not reached. We conducted a pre-planned Bayesian analysis to facilitate probabilistic interpretation. We analysed outcome data within 90 days in the intention-to-treat population (data available in 967 to 982 patients) using Bayesian models with various sensitivity analyses. Results are presented as median posterior probabilities with 95% credible intervals (CrIs) and probabilities of different effect sizes with 12 mg dexamethasone. The adjusted mean difference on days alive without life support at day 28 (primary outcome) was 1.3 days (95% CrI −0.3 to 2.9; 94.2% probability of benefit). Adjusted relative risks and probabilities of benefit on serious adverse reactions was 0.85 (0.63 to 1.16; 84.1%) and on mortality 0.87 (0.73 to 1.03; 94.8%) at day 28 and 0.88 (0.75 to 1.02; 95.1%) at day 90. Probabilities of benefit on days alive without life support and days alive out of hospital at day 90 were 85 and 95.7%, respectively. Results were largely consistent across sensitivity analyses, with relatively low probabilities of clinically important harm with 12 mg on all outcomes in all analyses. We found high probabilities of benefit and low probabilities of clinically important harm with dexamethasone 12 mg versus 6 mg daily in patients with COVID-19 and severe hypoxaemia on all outcomes up to 90 days.