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Cyclin-dependent kinase 2 (CDK2) has been garnering considerable interest as a target to develop new cancer treatments and to ameliorate resistance to CDK4/6 inhibitors. However, a selective CDK2 inhibitor has yet to be clinically approved. With the desire to discover novel, potent, and selective CDK2 inhibitors, the phenylsulfonamide moiety of our previous lead compound 1 was bioisosterically replaced with pyrazole derivatives, affording a novel series of N,4-di(1H-pyrazol-4-yl)pyrimidin-2-amines that exhibited potent CDK2 inhibitory activity. Among them, 15 was the most potent CDK2 inhibitor (Ki = 0.005 µM) with a degree of selectivity over other CDKs tested. Meanwhile, this compound displayed sub-micromolar antiproliferative activity against a panel of 13 cancer cell lines (GI50 = 0.127–0.560 μM). Mechanistic studies in ovarian cancer cells revealed that 15 reduced the phosphorylation of retinoblastoma at Thr821, arrested cells at the S and G2/M phases, and induced apoptosis. These results accentuate the potential of the N,4-di(1H-pyrazol-4-yl)pyrimidin-2-amine scaffold to be developed into potent and selective CDK2 inhibitors for the treatment of cancer.

Understanding the relative contribution of modifiable risk factors to cancer morbidity and mortality is crucial for designing effective cancer prevention and control strategies. Our study estimated cancer-related deaths and disability-adjusted life years (DALYs) lost attributable to potentially modifiable risk factors in Australia using data from the Global Burden of Diseases 2021 study. In 2021, an estimated 20,409 cancer deaths (37.5%) and 431,575 cancer DALYs lost (37.9%) in Australia were attributable to potentially modifiable risk factors. Males had higher modifiable risk attributed to cancer death and DALY rates than females. Behavioral risks accounted for 25.0% of cancer deaths and 26.5% of DALYs. Metabolic risks and environmental/occupational risks accounted for 9.4% and 9.3% of deaths, respectively. Smoking remained the leading attributable risk factor, accounting for 12.2% cancer deaths and 13.1% DALYs lost. Dietary risks accounted for 40.0% of colorectal cancer deaths and DALYs lost. Cervical, larynx, liver, lung, and colorectal cancers had a high proportion of deaths and DALYs lost attributed to modifiable risks. Liver and nasopharyngeal cancers had the highest burden attributed to alcohol use (39.1% and 39.0%, respectively), while 21.3% liver cancer deaths were attributed to drug use. Strengthening public health interventions, such as multi-disciplinary approaches to promote a healthy lifestyle, is required.

Background. In Ethiopia, up to 80% of the population use traditional medicine for primary health care. Studies on the current knowledge and practices of communities in the era of modern health care expansion are lacking. Therefore, this study is aimed at assessing the knowledge, attitude, and practice of traditional medicine among communities in Merawi town. Methods. A descriptive cross-sectional study was carried out among 403 residents of Merawi town. A systematic random sampling was used to select households. Data was collected through house to house interview. Results. 392 out of 403 questionnaires were analysed. Among the participants, 220 (56.1%) were female. The mean (±s.d.) age of the participants was 32.5 (±12.4) years. Nearly two-thirds, 241 (61.5%), of study participants have good knowledge about traditional medicines. Three-quarters of participants prefer modern medicine to traditional drugs. 70.9% of participants had the experience of personal use of traditional therapies. Conclusions. The population in Merawi has good knowledge with high acceptability and use of traditional medicine. The main reasons for high acceptability and practice were cultural acceptability, lesser cost, and good outcome of traditional medicine.

Cyclin-dependent kinase 2 (CDK2) has been garnering considerable interest as a target to develop new cancer treatments and to ameliorate resistance to CDK4/6 inhibitors. However, a selective CDK2 inhibitor has yet to be clinically approved. With the desire to discover novel, potent, and selective CDK2 inhibitors, the phenylsulfonamide moiety of our previous lead compound 1 was bioisosterically replaced with pyrazole derivatives, affording a novel series of N,4-di(1H-pyrazol-4-yl)pyrimidin-2-amines that exhibited potent CDK2 inhibitory activity. Among them, 15 was the most potent CDK2 inhibitor (K[sub.i] = 0.005 µM) with a degree of selectivity over other CDKs tested. Meanwhile, this compound displayed sub-micromolar antiproliferative activity against a panel of 13 cancer cell lines (GI[sub.50] = 0.127–0.560 μM). Mechanistic studies in ovarian cancer cells revealed that 15 reduced the phosphorylation of retinoblastoma at Thr821, arrested cells at the S and G2/M phases, and induced apoptosis. These results accentuate the potential of the N,4-di(1H-pyrazol-4-yl)pyrimidin-2-amine scaffold to be developed into potent and selective CDK2 inhibitors for the treatment of cancer.