CBX2 shapes chromatin accessibility promoting AML via p38 MAPK signaling pathway

Abstract Background: The dynamic epigenome and proteins specialized in the interpretation of epigenetic marks critically contribute to leukemic pathogenesis but also offer alternative therapeutic avenues. Targeting newly discovered chromatin readers involved in leukemogenesis may thus provide new anticancer strategies. Accumulating evidence suggests that the PRC1 complex member CBX2 is overexpressed in solid tumors and promotes cancer cell survival. However, its role in leukemia is still unclear. Methods: We exploited reverse genetic approaches to investigate the role of CBX2 in human leukemic cell lines and ex vivo samples. We also analyzed phenotypic effects following CBX2 silencing using cellular and molecular assays and related functional mechanisms by ATAC-seq and RNA-seq. We then performed bioinformatic analysis of ChIPseq data to explore the influence of histone modifications in CBX2-mediated open chromatin sites. Lastly, we used molecular assays to determine the contribution of CBX2-regulated pathways to leukemic phenotype. Results: We found CBX2 overexpressed in leukemia both in vitro and ex vivo samples compared to CD34+ cells. Decreased CBX2 RNA levels prompted a robust reduction in cell proliferation and induction of apoptosis. Similarly, sensitivity to CBX2 silencing was observed in primary acute myeloid leukemia samples. CBX2 suppression increased genome-wide chromatin accessibility followed by alteration of leukemic cell transcriptional programs, resulting in enrichment of cell death pathways and downregulation of survival genes. Intriguingly, CBX2 silencing induced epigenetic reprogramming at p38 MAPK-associated regulatory sites with consequent deregulation of gene expression. Conclusions: Our results identify CBX2 as a crucial player in leukemia progression and highlight a potential druggable CBX2-p38 MAPK network in AML

Predictive clinico-pathological factors to identify BCG, unresponsive patients, after re-resection for T1 high grade non-muscle invasive bladder cancer

Introduction: Seventy-five percent of bladder cancers are non-muscle invasive. The treatment strategy includes the transurethral resection of bladder tumor (TURB) followed by intravesical immunotherapy with the bacillus of Calmette-Guerin (BCG) or chemotherapy, depending on the grade of bladder tumor. Despite a proper BCG intravesical instillations schedule, up to 40% of patients present a failure within 2 years. The aim of this retrospective study was to investigate the predictive factors in the response to BCG in patients with a high-grade non-muscle invasive bladder cancer diagnosis. Materials and methods: Patients with non-muscle invasive bladder cancer from 13 hospitals and academic institutions were identified and treated, from January 1, 2002, until December 31, 2012, with TURB and a subsequent re-TURB for restaging before receiving BCG. Follow-up was performed with urine cytology and cystoscopy every 3 months for 1 year and, successively every 6 months. Univariate and multivariate Cox regression models addressed the response to BCG therapy. Kaplan-Meier overall survival (OS) and cancer-specific survival (CSS) estimates were determined for BCG responsive vs. BCG unresponsive patients. Results: A total of 1,228 patients with non-muscle invasive bladder cancer were enrolled. Of 257 (20.9%) patients were BCG unresponsive. Independent predictive factors for response to BCG were: multifocality (HR: 1.4; 95% CI 1.05-1.86; P = 0.019), lymphovascular invasion (HR: 1.75; 95% CI 1.22-2.49; P = 0.002) and high-grade on re-TURB (HR: 1.39; 95% CI 1.02-1.91; P = 0.037). Overall survival was significantly reduced in BCG-unresponsive patients compared to BCG-responsive patients at 5 years (82.9% vs. 92.4%, P < 0.0001) and at 10 years (44.2% vs. 74.4%, P < 0.0001). Similarly, cancer-specific survival was reduced in BCG-unresponsive patients at 5 years (90.6% vs. 97.3%, P < 0.0001) and at 10 years (72.3% vs. 87.2%, P < 0.0001). Conclusion: Multifocality, lymphovascular invasion, and high-grade on re-TURB were independent predictors for response to BCG treatment. BCG-unresponsive patients reported worse oncological outcomes

Modified Glasgow Prognostic Score as a Predictor of Recurrence in Patients with High Grade Non-Muscle Invasive Bladder Cancer Undergoing Intravesical Bacillus Calmette–Guerin Immunotherapy

Background: A systemic inflammatory marker, the modified Glasgow prognostic score (mGPS), could predict outcomes in non-muscle-invasive bladder cancer (NIMBC). We aimed to investigate the predictive power of mGPS in oncological outcomes in HG/G3 T1 NMIBC patients undergoing Bacillus Calmette–Guérin (BCG) therapy. Methods: We retrospectively reviewed patient’s medical data from multicenter institutions. A total of 1382 patients with HG/G3 T1 NMIBC have been administered adjuvant intravesical BCG therapy, every week for 3 weeks given at 3, 6, 12, 18, 24, 30 and 36 months. The analysis of mGPS for recurrence and progression was performed using multivariable and univariable Cox regression models. Results: During follow-up, 659 patients (47.68%) suffered recurrence, 441 (31.91%) suffered progression, 156 (11.28%) died of all causes, and 67 (4.84%) died of bladder cancer. At multivariable analysis, neutrophil to lymphocyte ratio [hazard ratio (HR): 7.471; p = 0.0001] and erythrocyte sedimentation rate (ESR) (HR: 0.706; p = 0.006 were significantly associated with recurrence. mGPS has no statistical significance for progression (p = 0.076). Kaplan–Meier survival analysis showed a significant difference in survival among patients from different mGPS subgroups. Five-year OS was 93% (CI 95% 92–94), in patients with mGPS 0, 82.2% (CI 95% 78.9–85.5) in patients with mGPS 1 and 78.1% (CI 95% 60.4–70) in mGPS 2 patients. Five-year CSS was 98% (CI 95% 97–99) in patients with mGPS 0, 90% (CI 95% 87–94) in patients with mGPS 1, and 100% in mGPS 2 patients. Limitations are applicable to a retrospective study. Conclusions: mGPS may have the potential to predict recurrence in HG/G3 T1 NMIBC patients, but more prospective, with large cohorts, studies are needed to study the influence of systemic inflammatory markers in prediction of outcomes in NMIBC for a definitive conclusion

Diagnosis of prostate cancer with magnetic resonance imaging in men treated with 5-alpha-reductase inhibitors

Purpose The primary aim of this study was to evaluate if exposure to 5-alpha-reductase inhibitors (5-ARIs) modifies the effect of MRI for the diagnosis of clinically significant Prostate Cancer (csPCa) (ISUP Gleason grade >= 2).Methods This study is a multicenter cohort study including patients undergoing prostate biopsy and MRI at 24 institutions between 2013 and 2022. Multivariable analysis predicting csPCa with an interaction term between 5-ARIs and PIRADS score was performed. Sensitivity, specificity, and negative (NPV) and positive (PPV) predictive values of MRI were compared in treated and untreated patients.Results 705 patients (9%) were treated with 5-ARIs [median age 69 years, Interquartile range (IQR): 65, 73; median PSA 6.3 ng/ml, IQR 4.0, 9.0; median prostate volume 53 ml, IQR 40, 72] and 6913 were 5-ARIs naive (age 66 years, IQR 60, 71; PSA 6.5 ng/ml, IQR 4.8, 9.0; prostate volume 50 ml, IQR 37, 65). MRI showed PIRADS 1-2, 3, 4, and 5 lesions in 141 (20%), 158 (22%), 258 (37%), and 148 (21%) patients treated with 5-ARIs, and 878 (13%), 1764 (25%), 2948 (43%), and 1323 (19%) of untreated patients (p < 0.0001). No difference was found in csPCa detection rates, but diagnosis of high-grade PCa (ISUP GG >= 3) was higher in treated patients (23% vs 19%, p = 0.013). We did not find any evidence of interaction between PIRADS score and 5-ARIs exposure in predicting csPCa. Sensitivity, specificity, PPV, and NPV of PIRADS >= 3 were 94%, 29%, 46%, and 88% in treated patients and 96%, 18%, 43%, and 88% in untreated patients, respectively.Conclusions Exposure to 5-ARIs does not affect the association of PIRADS score with csPCa. Higher rates of high-grade PCa were detected in treated patients, but most were clearly visible on MRI as PIRADS 4 and 5 lesions.Trial registration The present study was registered at ClinicalTrials.gov number: NCT05078359

Is HCV elimination among persons living with HIV feasible? Data from the NoCo study in the setting of the ICONA cohort

Background and aims: Whether the HCV test-and-treat strategy impacted on the rate of new HCV infections among PLWH in Italy is unknown. Methods: Prospective study of PLWH in the ICONA network. At baseline, PLWH were tested for HCV-Ab; HCV-RNA (if HCV-Ab positive) and, if positive, treated with DAA. SVR12 indicated eradication. Seroconversions and re-infections were evaluated yearly in HCV-Ab neg and HCV-RNA neg at first screening. We estimated the following: HCV seroconversions, incidence of HCV reinfections, and access to DAA and SVR12 rates tighter with factors associated with each outcome. Data were analysed by Cox regression, Poisson regression and logistic regression models. Results: Sixteen thousand seven hundred and forty-three PLWH were included; 27.3% HCV-Ab positive; of these, 39.3% HCV-RNA positive. HCV seroconversion incidence: .48/100 PYFU (95% CI: .36-.65); re-infections incidence: 1.40/100 PYFU (95% CI: .91-2.04). The risk factor for HCV re-infection was young age: aIRR 1.85, 95% CI: 1.17-2.95) per 10 years younger. 86.4% of HCV viremic in follow-up started DAA. PWID vs. heterosexuals (aHR .75, 95% CI .62-.90), HIV-RNA >50 copies/mL (aHR .70, 95% CI .56-.87), HCV genotype other than G1, G2, G3, G4 or with multiple/missing HCV genotype and post-COVID-19 calendar periods were associated with lower DAA access. 922/965 (95.5%) PLWH achieved SVR12. We estimated 72% reduction of chance to achieve SVR12 in PLWH with a CD4 count <200/mm3 (vs. CD4 ≥200/mm3 aOR .18, 95% CI: .07-.46). 95.5% of DAA-treated individuals eradicated HCV, but they represent only 53.2% of HCV viremic PLWH and 66.4% of those in follow-up. HCV-RNA positivity by year decreased from 41.7% in 2017 to 11.7% in 2022. Conclusions: The screening-and-treat campaign implemented in Italy, even if only partially effective, resulted in a dramatic drop in HCV circulation in our cohort

Parkinson’s disease mouse models in translational research

Animal models with high predictive power are a prerequisite for translational research. The closer the similarity of a model to Parkinson’s disease (PD), the higher is the predictive value for clinical trials. An ideal PD model should present behavioral signs and pathology that resemble the human disease. The increasing understanding of PD stratification and etiology, however, complicates the choice of adequate animal models for preclinical studies. An ultimate mouse model, relevant to address all PD-related questions, is yet to be developed. However, many of the existing models are useful in answering specific questions. An appropriate model should be chosen after considering both the context of the research and the model properties. This review addresses the validity, strengths, and limitations of current PD mouse models for translational research