Treating ARID1A mutated cancers by harnessing synthetic lethality and DNA damage response.

Chromatin remodeling is an essential cellular process for organizing chromatin structure into either open or close configuration at specific chromatin locations by orchestrating and modifying histone complexes. This task is responsible for fundamental cell physiology including transcription, DNA replication, methylation, and damage repair. Aberrations in this activity have emerged as epigenomic mechanisms in cancer development that increase tumor clonal fitness and adaptability amidst various selection pressures. Inactivating mutations in AT-rich interaction domain 1A (ARID1A), a gene encoding a large nuclear protein member belonging to the SWI/SNF chromatin remodeling complex, result in its loss of expression. ARID1A is the most commonly mutated chromatin remodeler gene, exhibiting the highest mutation frequency in endometrium-related uterine and ovarian carcinomas. As a tumor suppressor gene, ARID1A is essential for regulating cell cycle, facilitating DNA damage repair, and controlling expression of genes that are essential for maintaining cellular differentiation and homeostasis in non-transformed cells. Thus, ARID1A deficiency due to somatic mutations propels tumor progression and dissemination. The recent success of PARP inhibitors in treating homologous recombination DNA repair-deficient tumors has engendered keen interest in developing synthetic lethality-based therapeutic strategies for ARID1A-mutated neoplasms. In this review, we summarize recent advances in understanding the biology of ARID1A in cancer development, with special emphasis on its roles in DNA damage repair. We also discuss strategies to harness synthetic lethal mechanisms for future therapeutics against ARID1A-mutated cancers.

Awareness of Adverse Drug Reactions and its Reporting among Third-year Undergraduate Medical Students.

BACKGROUND: Drug is a double-edged sword. Though important, Adverse Drug Reactions under-reporting is real and is mainly due to lack of awareness. No published research has ever evaluated the perspective of third year medical students towards Adverse Drug Reactions reporting. The objective of the study was to evaluate awareness of Adverse Drug Reactions and its reporting among Third-year Medical Students of BP Koirala Institute of Health Science. METHODS: It was a descriptive cross-sectional questionnaire-based survey using google form conducted between 09/01/2020 to 09/28/2020. Any consenting third-year medical student of BP Koirala Institute of Health Science was eligible. Descriptive analysis of the data was performed using Microsoft Excel. Ethical clearance was obtained from Departmental-Research-Unit which is under IRC. RESULTS: Out of 80 eligible students, 79(98.75%) participated in the survey. 31.6(25%) had reported Adverse Drug Reactions. 36.7(29%) were aware of National Adverse Drug Reactions monitoring service. 12.7(10%) were aware of BPKIHS ADR monitoring. Again, 35(49.30%) were familiar with Adverse Drug Reactions to a particular drug whereas 29(40.85%) and 28(39.44%) were even familiar with Adverse Drug Reactions to a new product and Adverse Drug Reactions of serious (life or organ threatening) nature respectively. Regarding barriers to Adverse Drug Reactions reporting, 64(83.12%) were uncertain how to report; 39(50.65%) were unaware of existing National ADR system and 33(42.86) could not decide if it was an Adverse Drug Reactions. Regarding recommendations to improve Adverse Drug Reactions reporting, 73(94.81%) recommended education and training, 57(74.03%) stressed on collaboration among health professionals; 52(67.53%) said Adverse Drug Reactions reporting should be professional obligation whereas 51(66.23%) highlighted feedback from Monitoring Centers. CONCLUSIONS: We evaluated the awareness of Adverse Drug Reactions and its reporting among third-year medical Students of the institute which was relatively poor compared to other study population like doctors and pharmacists.