MCL1 (Myeloid cell leukemia 1)

We identified circulating ERP29, MCL1, TNXB, DAGLB, FES, TRPM4, MAPK3, and TNF as promising, genetically supported druggable targets for CAD treatment. Notably, MAPK3 and TNF demonstrated strong protein-level interactions and close associations with cardiometabolic disorders.

We further propose a translational framework that emphasizes convergent resistance nodes, druggable pathways, and biomarker-driven patient stratification, outlining a roadmap from preclinical validation and CMC development to adaptive clinical trial design and companion diagnostic co-development. By uniting mechanistic insight with translational strategies, lncRNA-targeted interventions hold promise to overcome DOX resistance and advance precision oncology.

In addition to these mechanisms, Notch2 acts as a transcription factor that directly controls the expression of key targets, such as CD23 and Hes1, that are fundamental for B cell proliferation, differentiation, and survival in CLL. All of these circuits represent important therapeutic targets and help explain the cells' dependence on their niche, the formation of proliferation centers, and resistance to modern targeted agents.

Moreover, a decline in reactive oxygen species generation by pretreatment of Wwox+/+ MEFs with an antioxidant N-acetyl-L-cysteine leads to decreased WWOX induction upon serum starvation. Taken together, our results suggest that stress stimuli trigger WWOX induction by elevating the production of reactive oxygen species in cells, which promotes the degradation of Bcl-XL and Mcl-1 proteins via a lysosome-mediated pathway, thereby further aggravating oxidative stress and cell death.

Compound 4e emerged as the lead candidate, demonstrating exceptional cytotoxicity against HCC cells (HepG2: IC50 = 1.8 μg mL-1; Huh7: IC50 = 6.7 μg mL-1, and Hep3B: IC50 = 7.1 μg mL-1) with 23-fold greater potency than TFA and 2-fold superiority to doxorubicin while maintaining minimal toxicity in WI-38 fibroblasts...The compound also exhibited good inhibitory activity against VEGFR-2, with its binding interaction further supported by molecular docking studies. These findings suggest that compound 4e is a promising anticancer candidate worthy of further therapeutic development research.

Main Findings: BCL2 inhibitors like venetoclax have achieved high response rates (ORR >70%) in CLL and AML but face resistance via MCL1/BCL-XL upregulation. Next-generation agents (e.g., sonrotoclax) and combinations address this...These strategies represent a paradigm shift toward precision medicine, but challenges like toxicity and biomarker-driven resistance persist. Future directions include AI-guided predictions and novel degraders like proteolysis-targeting chimeras (PROTACs).

Risk modeling further predicted higher PM2.5-attributed lung cancer mortality in UR populations. Collectively, these findings indicated that elevated PM2.5 exposure was associated with early genotoxic and JAK2/STAT3-associated pro-carcinogenic alterations in airway cells and leukocytes of asymptomatic individuals, reflecting heightened biological sensitivity in urban populations.

This study identifies the NLRI pathway as a crucial vulnerability in venetoclax resistance and unveils CHRNB4 as a promising predictive biomarker for treatment response. These results suggest that targeting the NLRI pathway represents a novel strategy for developing next-generation therapies to improve the poor outcomes of current combination treatments.

This case highlights the role of TPR::NTRK1 fusion in driving abnormal melanocyte proliferation and the potential contribution of MCL1 amplification to tumor progression. These findings provide insights into the genetic underpinnings of APN in CMN and suggest potential therapeutic targets for high-risk lesions.

Compounds 12, 17, 27, 43, 45, and 49 demonstrated strong binding affinities and superior pharmacokinetic profiles compared to Gefitinib and Erlotinib. Overall, benzothiazole derivatives represent a promising scaffold for the design of EGFR inhibitors, potentially contributing to targeted anticancer therapy.

These findings establish XZ739 as a promising therapeutic candidate for BCL-XL-dependent CCA, highlighting its translational potential for rational combination with chemotherapy to overcome resistance while mitigating hematologic toxicity.

On the other hand, the expression of BCL-XL and MCL1 in leukemia cells could be easily semi-quantified by immunostaining, with these results correlating with those obtained by qPCR. These results indicate that immunostaining for BCL-XL and MCL1 upon bone marrow examination at diagnosis not only can predict susceptibility to VEN + AZA therapy, but may also be useful for patient stratification for VEN + AZA treatment in the future.