Novel markers of MCL1 inhibitor sensitivity in triple negative breast cancer cells.

Triple negative breast cancer (TNBC) is an aggressive breast cancer sub-type with limited treatment options and poor prognosis. Currently, standard treatments for TNBC includes surgery, chemotherapy, and anti-PDL1 therapy. These therapies have limited efficacy in advanced stages. Myeloid-cell leukemia 1 (MCL1) is an anti-apoptotic BCL2 family protein. High expression of MCL1 contributes to chemotherapy resistance and is associated with worse prognosis in TNBC. MCL1 inhibitors are in clinical trials for TNBC, but response rates to these inhibitors can vary and predictive markers are lacking. Currently we identified a 4-member (AXL, ETS1, IL6, EFEMP1) gene signature (GS) that predicts MCL1 inhibitor sensitivity in TNBC cells. Factors encoded by these genes regulate signaling pathways to promote MCL1 inhibitor resistance. Small molecule inhibitors of the GS factors can overcome resistance and sensitize otherwise resistant TNBC cells to MCL1 inhibitor treatment. These findings offer insights into potential therapeutic strategies and tumor stratification for MCL1 inhibitor use in TNBC.

CSE1L is a negative regulator of the RB-DREAM pathway in p53 wild-type NSCLC and can be targeted using an HDAC1/2 inhibitor.

P53 represses transcription by activating p21 expression and promoting formation of RB1-E2F1 and RBL1/RBL2-DREAM transcription repressor complexes. The DREAM complex is composed of DP1, RB-family proteins RBL1 or RBL2 (p107/p130), E2F4/5, and MuvB. We recently reported RBL2-DREAM contributes to improved therapy responses in p53 wild-type NSCLC cells and improved outcomes in NSCLC patients whose tumors express wild-type p53. In the current study we identified CSE1L as a novel inhibitor of the RBL2-DREAM pathway and target to activate RBL2-DREAM in NSCLC cells. CSE1L is an oncoprotein that maintains repression of genes that can be reactivated by HDAC inhibitors. Mocetinostat is a HDAC inhibitor in clinical trials with selectivity against HDACs 1 and 2. Knockdown of CSE1L in NSCLC cells or treatment with mocetinostat increased p21, activated RB1 and RBL2, repressed DREAM target genes, and induced toxicity in a manner that required wild-type p53. Lastly, we found high levels of CSE1L and specific DREAM-target genes are candidate markers to identify p53 wild-type NSCLCs most responsive to mocetinostat. Thus, we identified CSE1L as a critical negative regulator of the RB-DREAM pathway in p53 wild-type NSCLC that can be indirectly targeted with HDAC1/2 inhibitors (mocetinostat) in current clinical trials. High expression of CSE1L and DREAM target genes could serve as a biomarker to identify p53 wild-type NSCLCs most responsive to this HDAC1/2 inhibitor.

Trichomonas vaginalis infection and risk of cervical neoplasia: A systematic review and meta-analysis.

OBJECTIVES: The evidence in the literature regarding the relationship between Trichomonas vaginalis (TV) infection and cervical neoplasia is conflicting. The main aim of this study was to evaluate the magnitude of the risk of cervical neoplasia associated with TV infection. METHODS: A meta-analysis of observational studies, which provided raw data on the association of TV infection with cervical neoplasia, was performed. For this aim, we searched scientific databases (PubMed/Medline, Scopus, the Web of Sciences, and Embase) from inception to March 15, 2023. A random-effects model was applied by Stata 17.0 to calculate the pooled and adjusted odds ratios (ORs) with 95% confidence intervals (CI), including subgroup, sensitivity, and cumulative analyses to explore sources of heterogeneity. RESULTS: Of the 2584 records initially identified, 35 eligible studies contributed data for 67,856 women with cervical neoplasia, and 933,697 healthy controls from 14 countries were included. The pooled (2.15; 1.61-2.87; I2 = 87.7%) and adjusted (2.17; 1.82-2.60; I2 = 31.27%) ORs indicated a significant positive association between TV infection and the development of cervical neoplasia. There was no significant change in pooled and adjusted ORs by applying sensitivity and cumulative analyses, indicating the robustness of our findings. The pooled OR was significant in most sub-group analyses. There was no publication bias in the included studies. CONCLUSION: Our findings indicated that women with a TV infection are at significantly greater risk of cervical neoplasia. Future research, particularly longitudinal and experimental studies, should be done to better understand the various aspects of this association.