Molecular Mechanism of Rapamycin Resistance in Cancer Cells

The mammalian target of rapamycin (mTOR) acts as the central regulator of multiple cellular processes including cell growth, proliferation, and survival by integrating signals via nutrients, growth factors, hormones, and energy sensing. In cancer cells, the mTOR pathway is highly dysregulated providing survival signals to the cells for their uncontrolled growth. Hence, mTOR has evolved to be a potential therapeutic target for cancer treatment for the past two decades. Application of micro-molar doses of Rapamycin in vitro has been found to successfully inhibit mTOR complex 1 (mTORC1) by blocking the phosphorylation of its downstream substrates- a) ribosomal protein p70 S6 kinase (S6K) and b) eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1). Previous studies have shown that Rapamycin acts as a cytostatic drug and causes G1 cell cycle arrest in the presence of transforming growth factor- β (TGF-β). However, in the absence of TGF-β signal, the drug induces cell-death. The rationale behind the cytotoxic effect of Rapamycin in the absence of TGF-β is that without TGF-β, the cells do not arrest in G1 and progress into S phase where they lack further survival signals from mTORC1 which has been inhibited by Rapamycin – therefore, the cells undergo apoptosis. Of significance, we have found that cancer cells with mutated RB and CDKN2A are not susceptible to cell-death upon Rapamycin treatment in the absence of TGF-β. The gene products of RB and CDKN2A (pRb and p14ARF respectively) suppress E2F family transcription factors that promote cell cycle progression from G1 into S. Restoration of wild type RB or inhibition of E2F activity in cancer cells led to Rapamycin sensitivity. These data provide evidence that the combination of mutant RB and mutant CDKN2A in cancer cells leads to Rapamycin resistance, which has implications for precision medicine approaches to anti-cancer therapies

Collaural Fistula: A Case Report

Introduction Collaural fistula or cervico-aural fistula is rare and accounts for less than 8% of branchial cleft anomalies. Their rarity and diverse presentations have frequently led to misdiagnosis and inappropriate treatment. Case Report We report one such case of a 7 year old girl who presented to us with two discharging cutaneous openings on the left side; one in the floor of the left external auditory canal and another in the upper neck and lower face (infra-auricular region). Discussion Surgical exploration and excision is the definitive treatment of a collaural fistula. A sinus/ fistula opening into the external auditory canal, should be removed with skin and cartilage. If more than 30% of the circumference of the external auditory canal is denuded, split thickness skin grafting and stenting are recommended. The potential post-operative complications are facial nerve paralysis and recurrence of the lesion. Fistulogram is a useful diagnostic tool

Interstitial Voids and Resultant Density of Liquid Water: A First-Principles Molecular Dynamics Study

Many anomalous properties of water can be explained on the basis of the coexistence of more than one density states: high-density water (HDW) and low-density water (LDW). We investigated these two phases of water molecules through first-principles molecular dynamics simulations using density functional theory (DFT) in conjunction with various van der Waals-corrected exchange and correlation functionals. Different density regions were found to exist due to the difference in short-range and long-range forces present in DFT potentials. These density regions were identified and analyzed on the basis of the distribution of molecules and voids present. We defined a local structure index to distinguish and find the probability of occurrence of these different states. HDW and LDW arise due to the presence of “interstitial water” molecules in between the first and second coordination shells. The population of interstitial water molecules is found to affect the overall dynamics of the system as they change the hydrogen bond pattern

Rare Cases in ENT

In our day to day ENT practice we commonly come across diseases involving the larynx, the oral cavity and the paranasal sinuses. These range from inflammatory disorders to benign and malignant neoplasms. Carcinomas involving the head and neck region are most commonly squamous cell carcinoma. However, a small proportion of cases present with other variants of carcinoma or infective pathology uncommon for the site. In this study we present three rare cases encountered in the out-patient department, namely, Primary Malignant Melanoma of the larynx, Neuroendocrine Tumor of the nose and paranasal sinuses and Rhinosporidiosis of cheek

Effectiveness of calcium channel blockade for organophosphorus and carbamate pesticide poisoning – study protocol for an open label, pragmatic, 3-arm RCT repurposing two widely available medicines

AbstractPesticide self-poisoning is one of the three most important global means of suicide, killing an estimated 110–168,000 people each year, mostly in poor rural Asian communities. Organophosphorus (OP) and carbamate anticholinesterase insecticides are responsible for about two-thirds of these deaths. Calcium channel blocking medicines (CCB) may reduce the effect of pesticides and prevent deaths. Two preclinical rodents’ studies and eight clinical studies utilising nimodipine and magnesium sulphate (MgSO4), respectively, showed mixed results. We have established a multi-centre randomised controlled trial (RCT) of patients with OP or carbamate self-poisoning admitted to at least six major hospitals in Bangladesh. The study aims to recruit maximum 3,243 patients over four years. One-third of the patients selected at random will receive standard treatment, while one-third will be treated with additional nimodipine and one-third with additional MgSO4. The additional treatments will be given for 48 h. We will check mortality (currently an estimated 11% die with standard treatment) and need for intensive care for mechanical ventilation across the three groups. This could lead to development of the first novel treatment for anticholinesterase poisoning in 50 years and its introduction into routine hospital practice worldwide

Global, regional, and national burden of stroke and its risk factors, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background Up-to-date estimates of stroke burden and attributable risks and their trends at global, regional, and national levels are essential for evidence-based health care, prevention, and resource allocation planning. We aimed to provide such estimates for the period 1990–2021. Methods We estimated incidence, prevalence, death, and disability-adjusted life-year (DALY) counts and age-standardised rates per 100 000 people per year for overall stroke, ischaemic stroke, intracerebral haemorrhage, and subarachnoid haemorrhage, for 204 countries and territories from 1990 to 2021. We also calculated burden of stroke attributable to 23 risk factors and six risk clusters (air pollution, tobacco smoking, behavioural, dietary, environmental, and metabolic risks) at the global and regional levels (21 GBD regions and Socio-demographic Index [SDI] quintiles), using the standard GBD methodology. 95% uncertainty intervals (UIs) for each individual future estimate were derived from the 2·5th and 97·5th percentiles of distributions generated from propagating 500 draws through the multistage computational pipeline. Findings In 2021, stroke was the third most common GBD level 3 cause of death (7·3 million [95% UI 6·6–7·8] deaths; 10·7% [9·8–11·3] of all deaths) after ischaemic heart disease and COVID-19, and the fourth most common cause of DALYs (160·5 million [147·8–171·6] DALYs; 5·6% [5·0–6·1] of all DALYs). In 2021, there were 93·8 million (89·0–99·3) prevalent and 11·9 million (10·7–13·2) incident strokes. We found disparities in stroke burden and risk factors by GBD region, country or territory, and SDI, as well as a stagnation in the reduction of incidence from 2015 onwards, and even some increases in the stroke incidence, death, prevalence, and DALY rates in southeast Asia, east Asia, and Oceania, countries with lower SDI, and people younger than 70 years. Globally, ischaemic stroke constituted 65·3% (62·4–67·7), intracerebral haemorrhage constituted 28·8% (28·3–28·8), and subarachnoid haemorrhage constituted 5·8% (5·7–6·0) of incident strokes. There were substantial increases in DALYs attributable to high BMI (88·2% [53·4–117·7]), high ambient temperature (72·4% [51·1 to 179·5]), high fasting plasma glucose (32·1% [26·7–38·1]), diet high in sugar-sweetened beverages (23·4% [12·7–35·7]), low physical activity (11·3% [1·8–34·9]), high systolic blood pressure (6·7% [2·5–11·6]), lead exposure (6·5% [4·5–11·2]), and diet low in omega-6 polyunsaturated fatty acids (5·3% [0·5–10·5]). Interpretation Stroke burden has increased from 1990 to 2021, and the contribution of several risk factors has also increased. Effective, accessible, and affordable measures to improve stroke surveillance, prevention (with the emphasis on blood pressure, lifestyle, and environmental factors), acute care, and rehabilitation need to be urgently implemented across all countries to reduce stroke burden. Funding Bill & Melinda Gates Foundation