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Interleukin-1 receptor-associated kinase 4 (IRAK4) is a pivotal enzyme in the Toll-like receptor (TLR)/MYD88 dependent signaling pathway, which is highly activated in rheumatoid arthritis tissues and activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL). Inflammatory responses followed by IRAK4 activation promote B-cell proliferation and aggressiveness of lymphoma. Moreover, proviral integration site for Moloney murine leukemia virus 1 (PIM1) functions as an anti-apoptotic kinase in propagation of ABC-DLBCL with ibrutinib resistance. We developed a dual IRAK4/PIM1 inhibitor KIC-0101 that potently suppresses the NF- κ B pathway and proinflammatory cytokine induction in vitro and in vivo . In rheumatoid arthritis mouse models, treatment with KIC-0101 significantly ameliorated cartilage damage and inflammation. KIC-0101 inhibited the nuclear translocation of NF- κ B and activation of JAK/STAT pathway in ABC-DLBCLs. In addition, KIC-0101 exhibited an anti-tumor effect on ibrutinib-resistant cells by synergistic dual suppression of TLR/MYD88-mediated NF- κ B pathway and PIM1 kinase. Our results suggest that KIC-0101 is a promising drug candidate for autoimmune diseases and ibrutinib-resistant B-cell lymphomas., Competing Interests: The authors declare no conflicts of interest., (© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Two series of 2-substituted benzimidazole conjugated 1,3,4-oxadiazole derivatives were designed, synthesized and evaluated for their cytotoxic activities against the three human cancer cell lines (cervical cancer (HeLa), breast cancer (MCF-7) and lung cancer (A549)). As the results 14 compounds demonstrated consistent to stronger cytotoxicities compared to the control 5-fluorouracil (5-FU) towards the tested cell lines including 4c (HeLa); 4b, 4e, 4h, 7i-j, 7m-n, 7s (MCF-7); 7b (MCF-7, A549); 7h (HeLa, MCF-7); and 4d, 4i, 7c (HeLa, MCF-7, A549), with the IC 50 ranging from 2.7 to 38 µM. Notably, compound 4b illustrated almost 5-fold activity against the MCF-7 while 4d, 4i were 9- and 8-fold (HeLa), 4.5- and 13-fold (MCF-7), 4.7- and 4-fold (A549) increase in activity compared to 5-FU, respectively, and were found as lead compounds. These findings suggest that compounds 4b, 4d and 4i merit further characterization and can serve as promising scaffolds in the discovery of new potent anticancer agents.

Objective: To evaluate the association between suicidal behaviors and binge drinking among Brazilian adolescents., Methods: A cross-sectional study was conducted with 2,476 students 14 to 19 years of age from 26 public high schools in the city of Olinda, Brazil. Data collection occurred between March and June 2018 through the self-administered Youth Risk Behavior Survey. Descriptive analysis and Poisson regression (p < 0.05, 95%CI) were performed., Results: The prevalence of suicidal ideation, planning and attempt in the previous 12 months was 23.7%, 17.4% and 13.5%, respectively. Suicidal ideation was associated with binge drinking one to two days (PR:1.053, 95%CI:1.011-1.096) and ≥ three days in the previous 30 days (PR:1.069, 95%CI:1.016-1.125), sadness/hopelessness in the previous 12 months (PR:1.313, 95%CI:1.267-1.360), a report of family physical aggression in the previous 12 months (PR:1.111, 95%CI:1.068-1.155), the female sex (PR:1.082, 95%CI:1.049-1.115) and a non-nuclear family (PR:1.037, 95%CI:1.004-1.071). Suicidal planning was associated with sadness/hopelessness in the previous 12 months (PR:1.257, 95%CI:1.214-1.302), report of family physical aggression in the previous 12 months (PR:1.110, 95%CI:1.065-1.156) and the female sex (PR:1.072, 95%CI:1.041-1.104). Suicide attempt was associated with binge drinking ≥ three days in the previous 30 days (PR:1.062, 95%CI:1.008-1.119), sadness/hopelessness in the previous 12 months (PR:1.202, 95%CI:1.161-1.244), report of family physical aggression in the previous 12 months (PR:1.105, 95%CI:1.060-1.153) and the female sex (PR:1.064, 95%CI:1.034-1.095). The Catholic (PR:0.938, 95%CI:0.899-0.979; PR:0.925, 95%CI:0.888-0.9865; PR:0.937, 95%CI:0.899-0.977) and Evangelical (PR:0.956, 95%CI:0.922-0.992; PR:0.954, 95%CI:0.919-0.991) religions acted as a possible protective factor against suicidal behaviors., Conclusions: Suicidal ideation and attempt were associated with binge drinking.