8 research outputs found
Benzothiophenone Derivatives Targeting Mutant Forms of Estrogen Receptor-Ī± in Hormone-Resistant Breast Cancers
Estrogen receptor-Ī± positive (ERĪ±+) breast cancers represent 75% of all invasive breast cancer cases, while de novo or acquired resistance to ER-directed therapy is also on the rise. Numerous factors contribute to this phenomenon including the recently-reported ESR1 gene mutations such as Y537S, which amplifies co-activator interactions with ERĪ± and promotes constitutive activation of ERĪ± function. Herein, we propose that direct targeting of the activation function-2 (AF2) site on ERĪ± represents a promising alternative therapeutic strategy to overcome mutation-driven resistance in breast cancer. A systematic computer-guided drug discovery approach was employed to develop a potent ERĪ± inhibitor that was extensively evaluated by a series of experiments to confirm its AF2-specific activity. We demonstrate that the developed small-molecule inhibitor effectively prevents ERĪ±-coactivator interactions and exhibits a strong anti-proliferative effect against tamoxifen-resistant cells, as well as downregulates ERĪ±-dependent genes and effectively diminishes the receptor binding to chromatin. Notably, the identified lead compound successfully inhibits known constitutively-active, resistance-associated mutant forms of ERĪ± observed in clinical settings. Overall, this study reports the development of a novel class of ERĪ± AF2 inhibitors, which have the potential to effectively inhibit ERĪ± activity by a unique mechanism and to circumvent the issue of mutation-driven resistance in breast cancer.Other UBCReviewedFacult
Selectively targeting the DNA-binding domain of the androgen receptor as a prospective therapy for prostate cancer.
Selectively targeting the DNA-binding domain of the androgen receptor as a prospective therapy for prostate cancer.
ANN Based Alarming of Multi Model Urban Emergency Events In Crowdsourcing to Social Media
Effect of Organically Amended Growing Substrates on the Growth and Physiological Attributes of Citrus Plants
Factors associated with unexplained sudden deaths among adults aged 18-45 years in India ā A multicentric matched caseācontrol study
Background & objectives: In view of anecdotal reports of sudden unexplained deaths in India's apparently healthy young adults, linking to coronavirus disease 2019 (COVID-19) infection or vaccination, we determined the factors associated with such deaths in individuals aged 18-45 years through a multicentric matched caseācontrol study.
Methods: This study was conducted through participation of 47 tertiary care hospitals across India. Cases were apparently healthy individuals aged 18-45 years without any known co-morbidity, who suddenly (<24 h of hospitalization or seen apparently healthy 24 h before death) died of unexplained causes during 1st October 2021-31st March 2023. Four controls were included per case matched for age, gender and neighborhood. We interviewed/perused records to collect data on COVID-19 vaccination/infection and post-COVID-19 conditions, family history of sudden death, smoking, recreational drug use, alcohol frequency and binge drinking and vigorous-intensity physical activity two days before death/interviews. We developed regression models considering COVID-19 vaccination ā¤42 days before outcome, any vaccine received anytime and vaccine doses to compute an adjusted matched odds ratio (aOR) with 95 per cent confidence interval (CI).
Results: Seven hundred twenty nine cases and 2916 controls were included in the analysis. Receipt of at least one dose of COVID-19 vaccine lowered the odds [aOR (95% CI)] for unexplained sudden death [0.58 (0.37, 0.92)], whereas past COVID-19 hospitalization [3.8 (1.36, 10.61)], family history of sudden death [2.53 (1.52, 4.21)], binge drinking 48 h before death/interview [5.29 (2.57, 10.89)], use of recreational drug/substance [2.92 (1.1, 7.71)] and performing vigorous-intensity physical activity 48 h before death/interview [3.7 (1.36, 10.05)] were positively associated. Two doses lowered the odds of unexplained sudden death [0.51 (0.28, 0.91)], whereas single dose did not.
Interpretation & conclusions: COVID-19 vaccination did not increase the risk of unexplained sudden death among young adults in India. Past COVID-19 hospitalization, family history of sudden death and certain lifestyle behaviors increased the likelihood of unexplained sudden death