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Rafiq, R.

Publications and source records attributed to Rafiq, R..

2 recordsLinked to original sources

Strenuous occupational physical activity - potential association with esophageal squamous cell carcinoma risk

The impact of leisure time or recreational physical activity (RPA) on cancer risk has been extensively studied. However, the association of the occupational physical activity (OPA), which differs in dose and intensity from RPA, with different cancers including esophageal squamous cell carcinoma (ESCC), has received less attention. Here, we present data from a case-control study which was conducted for assessing the risk factors for ESCC. Histopathologically confirmed 703 ESCC cases and 1664 controls, individually matched to the respective cases for age, sex and district of residence were recruited. Information on type, duration and intensity of physical activity was obtained in face-to-face interviews with participants using a structured questionnaire. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). A high level of occupational physical activity was associated with increased ESCC risk (OR = 2.17, 95% CI; 1.41 - 3.32), compared to subjects with moderate occupational physical activity. The association with ESCC risk was stronger in strenuous workers (OR = 3.64, 95% CI; 2.13 - 6.20). The association of strenuous OPA with ESCC risk persisted only in subjects that were involved in strenuous activities for equal to or greater than 5days/week. Our study suggests a possible association of strenuous occupational physical activity with ESCC risk. Although, our results were adjusted for multiple factors including indicators of socioeconomic status, more replicative occupational epidemiological studies are needed to rule out any residual confounding.

epidemiology↗

Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance

PARP inhibitors (PARPi) target homologous recombination defective tumour cells via synthetic lethality. Genome-wide and high-density CRISPR-Cas9 \"tag, mutate and enrich\" mutagenesis screens identified single amino acid mutations in PARP1 that cause profound PARPi-resistance. These included PARP1 mutations outside of the DNA interacting regions of the protein, such as mutations in solvent exposed regions of the catalytic domain and clusters of mutations around points of contact between ZnF, WGR and HD domains. These mutations altered PARP1 trapping, as did a mutation found in a clinical case of PARPi resistance. These genetic studies reinforce the importance of trapped PARP1 as a key cytotoxic DNA lesion and suggest that interactions between non-DNA binding domains of PARP1 influence cytotoxicity. Finally, different mechanisms of PARPi resistance (BRCA1 reversion, PARP1, 53BP1, REV7 mutation) had differing effects on chemotherapy sensitivity, suggesting that the underlying mechanism of PARPi resistance likely influences the success of subsequent therapies.

cancer biology↗