Inhibition of bromodomain and extra-terminal proteins increases sensitivity to venetoclax in chronic lymphocytic leukaemia.

The development of drugs able to target BTK, PI3k-delta and BCL2 has dramatically improved chronic lymphocytic leukaemia (CLL) therapies. However, drug resistance to these therapies has already been reported due to non-recurrent changes in oncogenic pathways and genes expression signatures. In this study, we investigated the cooperative role of the BCL2 inhibitor venetoclax and the BRD4 inhibitor JQ1. In particular, we found that JQ1 shows additional activity with venetoclax, in CLL cell lines and in ex vivo isolated primary CD19+ lymphocytes, arguing in favour of combination strategies. Lastly, JQ1 is also effective in venetoclax-resistant CLL cell lines. Together, our findings indicated that the BET inhibitor JQ1 could be a promising therapy in CLL, both as first-line therapy in combination with venetoclax and as second-line therapy, after the emergence of venetoclax-resistant clones.

Curcumin induces apoptosis in JAK2-mutated cells by the inhibition of JAK2/STAT and mTORC1 pathways.

Myeloproliferative neoplasms are chronic myeloid cancers divided in Philadelphia positive and negative. The JAK2 V617F is the most common mutation in Philadelphia negative patients and results in a constitutive activation of the JAK/STAT pathway, conferring a proliferative advantage and apoptosis inhibition. Recent studies identified a functional crosstalk between the JAK/STAT and mTOR pathways. The identification of an effective therapy is often difficult, so the availability of new therapeutic approaches might be attractive. Previous studies showed that curcumin, the active principle of the Curcuma longa, can suppress JAK2/STAT pathways in different type of cancer and injuries. In this study, we investigated the anti-proliferative and pro-apoptotic effects of curcumin in JAK2 V617F-mutated cells. HEL cell line and cells from patients JAK2 V617F mutated have been incubated with increasing concentrations of curcumin for different time. Apoptosis and proliferation were evaluated. Subsequently, JAK2/STAT and AKT/mTOR pathways were investigated at both RNA and protein levels. We found that curcumin induces apoptosis and inhibition of proliferation in HEL cells. Furthermore, we showed that curcumin inhibits JAK2/STAT and mTORC1 pathways in JAK2 V617F-mutated cells. This inhibition suggests that curcumin could represent an alternative strategy to be explored for the treatment of patients with myeloproliferative neoplasms.

Obstructive sleep apnea in the hemodialysis population: are clinicians putting existing scientific evidence into practice?

Introduction: Hemodialysis (HD) populations have a high prevalence of Obstructive Sleep Apnea (OSA), which was specifically linked with fluid overload. HD fluid management targeting a low dry weight was shown to reduce OSA severity, opening to novel therapeutic options. We assessed nephrologists' awareness of OSA diagnosis in HD patients and whether they integrate the current knowledge into their fluid management strategy. Material and methods: We performed a multicenter, cross-sectional study between July 2022 and July 2023, screening all HD patients of four HD units, and included those with confirmed OSA. We collected anthropometric parameters and fluid status from electronic dossiers. Predialysis fluid overload was measured by multifrequency bioelectrical impedance (BCM®). Nephrologists were asked to identify patients with known OSA, without consulting medical dossiers. The fluid management of patients identified as "OSA positive" was compared to that of patients misclassified as "OSA negative". Results: Among 193 HD patients, 23.0% (n=45) had confirmed OSA. The mean age was 76.0 ± 7.5 years, 82.2% were men. Only 60% were correctly identified as "OSA positive" by nephrologists; 14.7% of patients on CPAP were identified. BMI was the only factor associated with correct OSA identification. The predialysis fluid overload tended to be greater in "OSA positive" patients than in the "OSA negative" patients (2.2 ± 1.4 kg vs 1.5 ± 1.3 kg; p=0.08), but there was no difference in postdialysis achievement of dry weight between the groups (residual overweight 0.2 ± 1.0 kg and 0.1 ± 0.7 kg; p= 0.672). Conclusions: Our study suggests that the application of scientific evidence to the management of OSA in dialysis patients is not systematic. However, nephrologists have attempted to strictly achieve dry weight in all patients, regardless of OSA status. Sensibilization of nephrologists on the clinical and diagnostic peculiarities of OSA in HD patients may improve OSA diagnosis and therapeutic care.

Strategies For Targeting Chronic Myeloid Leukaemia Stem Cells.

Chronic Myeloid Leukaemia is a myeloproliferative disorder driven by the t(9;22) chromosomal translocation coding for the chimeric protein BCR-ABL. CML treatment represents the paradigm of molecular therapy of cancer. Since the development of the tyrosine kinase inhibitor of the BCR-ABL kinase, the clinical approach to CML has dramatically changed, with a stunning improvement in the quality of life and response rates of patients. However, it remains clear that tyrosine kinase inhibitors (TKIs) are unable to target the most immature cellular component of CML, the CML stem cell. This review summarizes new insights into the mechanisms of resistance to TKIs.