From bench to bedside : elucidating vestibular schwannoma pathobiology to devise effective pharmacotherapies

Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2014.Cataloged from PDF version of thesis.Includes bibliographical references (pages 158-169).Vestibular schwannomas (VSs), the most common tumors of the cerebellopontine angle, arise from Schwann cells of the vestibular nerve. VSs can lead to sensorineural hearing loss (SNHL), disequilibrium, facial nerve paralysis, and brainstem compression. Treatment options available today are associated with significant morbidity, leading to an unmet need for well-tolerated pharmacotherapies to curb VS growth and associated SNHL. To identify pharmacologic targets, this thesis investigated inflammatory pathways in VS. Proinflammatory transcription factor nuclear factor kappa B (NF-KB) and enzyme cyclooxygenase 2 (COX- 2) were aberrantly active in VS. NF-KB inhibition, achieved through siRNA, an experimental agent BAYl 1-7082 or a clinically relevant drug curcumin, was cytotoxic against primary VS cells and HEI-193 VS cell line. COX-2 inhibition, achieved through salicylates, was cytostatic against primary VS cells. Our in vitro findings are in line with our retrospective findings that VS patients taking aspirin demonstrate halted tumor growth. Anti-inflammatory drugs such as aspirin could be efficacious against VS. Additionally, as the etiology of SNHL due to VS is unknown, this thesis explored the potential of VS secreted factors to modulate SNHL. Applying human VS secretions to organotypic cochlear explant cultures, we demonstrate that VS secreted factors can lead to hair cell and neurite degeneration. Exogenous application of tumor necrosis factor alpha (TNF[alpha]), an ototoxic cytokine whose VS secreted levels correlate with degree of SNHL, led to neurite loss in cochlear explants and TNF[alpha] neutralization in VS secretions partially rescued cochlear degeneration due to VS secretions. Interestingly, otoprotective fibroblast growth factor 2 (FGF2) levels in VS secretions inversely correlate with degree of SNHL, suggesting that different ototoxic and otoprotective VS-secreted molecules modulate VS's effect on hearing. TNF[alpha] and FGF2 could serve as biomarkers or pharmacologic targets against VS associated SNHL. Exploring angiogenic pathways, cross-talk between vascular endothelial growth factor (VEGF-A) and hepatocyte growth factor (HGF) was found in Schwann cells, VS cells and in cochlear cells. VEGF-A neutralization in VS secretions could not rescue cochlear degeneration but VEGF-A or HGF receptor knockdown was cytostatic in VS cells. Overall, several pathobiological pathways were investigated to provide promising therapeutic targets against neoplastic VS growth and associated SNHL.by Sonam Dilwali.Ph. D

Imperatives of the Basic Structure Doctrine: A Semi-centennial Concept

The Basic Structure doctrine is the most relevant mechanism in the hands of the Indian Judiciary to strike a balance of powers and maintain checks and balances among the organs of the State, which is imperative for the smooth functioning of any democracy. The doctrine was a milestone in the development of constitutional law in India. This paper aims to trace its origins, efforts to preserve and promote the concept at its nascent stages and highlight its ever-evolving dynamism. The text also tries to outline the continuous war between the Parliament and the Judiciary, resulting in various Constitutional Amendments and their subsequent review before the Courts of law. The aim of this paper is to highlight the importance of the basic structure and its relevance in the recent times. Additionally, the authors delve into the struggle of supremacy between the powers and functions of the Parliament and the Supreme Court and the role of the system of checks and balances.Arvind P. Bhanu, Ambika Dilwali, Adityaraj Patodi

Use of Hepatitis C Viremic Donors to Expand the Pediatric Donor Pool

The use of hepatitis C virus (HCV)-positive donors in organ transplantation has become increasingly viable due to advancements in direct-acting antiviral (DAA) therapies, which offer high cure rates. This review aims to evaluate the current practices, benefits, and challenges of utilizing HCV-positive donors for organ transplantation. The recent data show that transplant centers are progressively accepting HCV-positive donors for various organs, including kidneys, livers, and hearts, given the efficacy of post-transplant antiviral treatment. Using these donors has helped mitigate the organ shortage crisis, increasing the donor pool and reducing waitlist times. Despite these advantages, the approach raises concerns about viral transmission, long-term outcomes, and the cost-effectiveness of post-transplant DAA therapy. Furthermore, this review highlights the ethical implications of informed consent and the monitoring of HCV-negative recipients following transplantation. The outcomes from recent studies suggest that with proper management, transplantations from HCV-positive donors to HCV-negative recipients can be safe and effective, leading to excellent graft function and patient survival. This review synthesizes existing research and offers insights into optimizing protocols for future transplants involving HCV-positive donors