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BACKGROUND: In addition to cardiotoxicity, ocular toxicity induced by chemotherapeutic agents is not uncommon. OBJECTIVE: This study aimed to explore the association between ocular adverse events and major adverse cardiovascular events (composite endpoint) caused by chemotherapy, and whether specific ocular events could be potential predictors of some specific components of the composite endpoint. METHODS: A total of 5378 newly diagnosed patients (age > 18 y/o) with any malignancy or metastatic solid tumors who received chemotherapy from January 1997 to December 2010 were enrolled from the Taiwan National Health Insurance Research Database. Patients who developed new incident ocular diseases were classified as the study group, and those who did not develop incident ocular diseases as the control group. RESULTS: After propensity score matching, there was a significant increase in the incidence of stroke in the ocular diseases group compared to the no ocular diseases group (13.4% vs. 4.5%, p < 0.0001). Tear film insufficiency, keratopathy, glaucoma, and lens disorders were associated with a significantly higher risk of stroke. A longer duration of methotrexate and a longer duration with higher total amount of tamoxifen were associated with both incident ocular diseases and incident stroke. Cox proportional hazards regression showed that the only independent risk factor for stroke was incident ocular diseases [Adjusted relative risk (95% confidence interval): 2.96 (1.66-5.26), p = 0.0002]. In addition, incident ocular disease was the most significant risk factor compared with other traditional cardiovascular risk factors. CONCLUSIONS: Incident ocular diseases related to chemotherapy were associated with a significantly higher risk of stroke.

The Austronesians who returned from Taiwan introduced genes and language to the Kra-Dai people, spreading to southern China, and then to Laos, Thailand, and Vietnam or nearby regions at different times and places of dispersion, thereby enhancing the Kra-Dai–Austronesian relations through demic diffusion. Therefore, the ancestral Kra-Dai and Austronesian groups intermixed on the mainland at least twice.

Betel quid and areca nut are complex mixture carcinogens, but little is known about whether their derived single-agent arecoline or arecoline N-oxide (ANO) is carcinogenic, and the underlying mechanisms remain unclear. In this systematic review, we analyzed recent studies on the roles of arecoline and ANO in cancer and strategies to block carcinogenesis. In the oral cavity, flavin-containing monooxygenase 3 oxidizes arecoline to ANO, and both alkaloids conjugate with N-acetylcysteine to form mercapturic acid compounds, which are excreted in urine, reducing arecoline and ANO toxicity. However, detoxification may not be complete. Arecoline and ANO upregulated protein expression in oral cancer tissue from areca nut users compared to expression levels in adjacent normal tissue, suggesting a causal relationship between these compounds and oral cancer. Sublingual fibrosis, hyperplasia, and oral leukoplakia were diagnosed in mice subjected to oral mucosal smearing of ANO. ANO is more cytotoxic and genotoxic than arecoline. During carcinogenesis and metastasis, these compounds increase the expression of epithelial–mesenchymal transition (EMT) inducers such as reactive oxygen species, transforming growth factor-β1, Notch receptor-1, and inflammatory cytokines, and they activate EMT-related proteins. Arecoline-induced epigenetic markers such as sirtuin-1 hypermethylation, low protein expression of miR-22, and miR-886-3-p accelerate oral cancer progression. Antioxidants and targeted inhibitors of the EMT inducers used reduce the risk of oral cancer development and progression. Our review findings substantiate the association of arecoline and ANO with oral cancer. Both of these single compounds are likely carcinogenic to humans, and their mechanisms and pathways of carcinogenesis are useful indicators for cancer therapy and prognosis.