Overcoming the therapeutic limitations of EZH2 inhibitors in Burkitt’s lymphoma: a comprehensive study on the combined effects of MS1943 and Ibrutinib

Enhancer of zeste homolog 2 (EZH2) and Bruton’s tyrosine kinase (BTK) are both key factors involved in the development and progression of hematological malignancies. Clinical studies have demonstrated the potential of various EZH2 inhibitors, which target the methyltransferase activity of EZH2, for the treatment of lymphomas. However, despite their ability to effectively reduce the H3K27me3 levels, these inhibitors have shown limited efficacy in blocking the proliferation of lymphoma cells. To overcome this challenge, we employed a hydrophobic tagging approach utilizing MS1943, a selective EZH2 degrader. In this study, we investigated the inhibitory effects of two drugs, the FDA-approved EZH2 inhibitor Tazemetostat, currently undergoing clinical trials, and the novel drug MS1943, on Burkitt’s lymphoma. Furthermore, we assessed the potential synergistic effect of combining these drugs with the BTK inhibitor Ibrutinib. In this study, we evaluated the effects of combination therapy with MS1943 and Ibrutinib on the proliferation of three Burkitt’s lymphoma cell lines, namely RPMI1788, Ramos, and Daudi cells. Our results demonstrated that the combination of MS1943 and Ibrutinib significantly suppressed cell proliferation to a greater extent compared to the combination of Tazemetostat and Ibrutinib. Additionally, we investigated the underlying mechanisms of action and found that the combination therapy of MS1943 and Ibrutinib led to the upregulation of miR29B-mediated p53-upregulated modulator of apoptosis PUMA, BAX, cleaved PARP, and cleaved caspase-3 in Burkitt’s lymphoma cells. These findings highlight the potential of this innovative therapeutic strategy as an alternative to traditional EZH2 inhibitors, offering promising prospects for improving treatment outcomes in Burkitt’s lymphoma

Synergistic Inhibition of Burkitt’s Lymphoma with Combined Ibrutinib and Lapatinib Treatment

Burkitt’s lymphoma is a distinct subtype of non-Hodgkin’s lymphoma originating from B-cells that is notorious for its aggressive growth and association with immune system impairments, potentially resulting in rapid and fatal outcomes if not addressed promptly. Optimizing the use of Food and Drug Administration-approved medications, such as combining known safe drugs, can lead to time and cost savings. This method holds promise in accelerating the progress of novel treatments, ultimately facilitating swifter access for patients. This study explores the potential of a dual-targeted therapeutic strategy, combining the bruton tyrosine kinase-targeting drug Ibrutinib and the epidermal growth factor receptor/human epidermal growth factor receptor-2-targeting drug Lapatinib. Ramos and Daudi cell lines, well-established models of Burkitt’s lymphoma, were used to examine the impact of this combination therapy. The combination of Ibrutinib and Lapatinib inhibited cell proliferation more than using each drug individually. A combination treatment induced apoptosis and caused cell cycle arrest at the S and G2/M phases. This approach is multifaceted in its benefits. It enhances the efficiency of the drug development timeline and maximizes the utility of currently available resources, ensuring a more streamlined and resource-effective research process

Does whey protein supplementation during resistance exercise have additional benefits for decreasing hepatic fat content?

Background Exercise and diet have positive effects on hepatic fat reduction, and protein supplementation is known to lower hepatic fat accumulation. However, the effect of a combination of exercise and whey protein supplementation (WPS) on hepatic fat content (HFC) is unknown. Methods We investigated the effect of WPS on HFC during resistance exercise and diet control intervention for four weeks. A total of 34 sedentary males participated and were randomly assigned to two groups: a protein supplement group (PSG, n = 18) and a control group (CG, n = 16). The PSG took 60 g of WPS per day, and the CG took 60 g of an isocaloric placebo per day. All participants were fed a calorie-controlled diet throughout the study period, with their daily caloric intake determined by their resting metabolic rate and physical activity level. Both groups performed resistance exercises supervised by experts at 60–70% of their maximum efforts for 60 min/day, 6 days/week for 4 weeks. HFC was assessed using the controlled attenuation parameter (CAP) after an 8 h fast, at pre-, mid-, and post-intervention. Liver enzymes and lipid profile were also analyzed after an 8 h fast and pre- and post-intervention. Results The CAP was significantly reduced after 4 weeks of intervention in both groups (PSG, p < .001; CG, p = .002). However, there was no significant interaction between the group and changes in CAP. Interestingly, when comparing the pre- and mid-tests, both groups also had significantly reduced CAP (PSG, p = .027; CG, p = .028), but there was a significant difference in the amount of change in CAP between the two groups (PSG, -47.2 ± 25.4 dB/m; CG, -19.5 ± 15.1 dB/m; p = .042). For liver enzymes, there was a significant interaction between the two groups and a change in aspartate transaminase (AST) (p = .038). However, alanine aminotransferase (ALT) levels were significantly decreased only in the PSG group (p = .002). In lipids, both groups showed significantly decreased total cholesterol (p < .001) and low-density lipoprotein cholesterol (p < .001) after the intervention. Conclusion Our data showed that WPS may not enhance the overall effects of resistance exercise on HFC and lipid profiles. However, in part, WPS may have a beneficial effect on liver enzymatic changes and rapid response to resistance exercise-induced HFC reduction

An Artificial Intelligence Exercise Coaching Mobile App: Development and Randomized Controlled Trial to Verify Its Effectiveness in Posture Correction

BackgroundInsufficient physical activity due to social distancing and suppressed outdoor activities increases vulnerability to diseases like cardiovascular diseases, sarcopenia, and severe COVID-19. While bodyweight exercises, such as squats, effectively boost physical activity, incorrect postures risk abnormal muscle activation joint strain, leading to ineffective sessions or even injuries. Avoiding incorrect postures is challenging for novices without expert guidance. Existing solutions for remote coaching and computer-assisted posture correction often prove costly or inefficient. ObjectiveThis study aimed to use deep neural networks to develop a personal workout assistant that offers feedback on squat postures using only mobile devices—smartphones and tablets. Deep learning mimicked experts’ visual assessments of proper exercise postures. The effectiveness of the mobile app was evaluated by comparing it with exercise videos, a popular at-home workout choice. MethodsTwenty participants were recruited without squat exercise experience and divided into an experimental group (EXP) with 10 individuals aged 21.90 (SD 2.18) years and a mean BMI of 20.75 (SD 2.11) and a control group (CTL) with 10 individuals aged 22.60 (SD 1.95) years and a mean BMI of 18.72 (SD 1.23) using randomized controlled trials. A data set with over 20,000 squat videos annotated by experts was created and a deep learning model was trained using pose estimation and video classification to analyze the workout postures. Subsequently, a mobile workout assistant app, Home Alone Exercise, was developed, and a 2-week interventional study, in which the EXP used the app while the CTL only followed workout videos, showed how the app helps people improve squat exercise. ResultsThe EXP significantly improved their squat postures evaluated by the app after 2 weeks (Pre: 0.20 vs Mid: 4.20 vs Post: 8.00, P=.001), whereas the CTL (without the app) showed no significant change in squat posture (Pre: 0.70 vs Mid: 1.30 vs Post: 3.80, P=.13). Significant differences were observed in the left (Pre: 75.06 vs Mid: 76.24 vs Post: 63.13, P=.02) and right (Pre: 71.99 vs Mid: 76.68 vs Post: 62.82, P=.03) knee joint angles in the EXP before and after exercise, with no significant effect found for the CTL in the left (Pre: 73.27 vs Mid: 74.05 vs Post: 70.70, P=.68) and right (Pre: 70.82 vs Mid: 74.02 vs Post: 70.23, P=.61) knee joint angles. ConclusionsEXP participants trained with the app experienced faster improvement and learned more nuanced details of the squat exercise. The proposed mobile app, offering cost-effective self-discovery feedback, effectively taught users about squat exercises without expensive in-person trainer sessions. Trial RegistrationClinical Research Information Service KCT0008178 (retrospectively registered); https://cris.nih.go.kr/cris/search/detailSearch.do/2400

Dual Targeting of EZH2 Degradation and EGFR/HER2 Inhibition for Enhanced Efficacy against Burkitt’s Lymphoma

EZH2, a histone methyltransferase, contributes significantly to cancer cell survival and proliferation. Although various EZH2 inhibitors have demonstrated promise in treating lymphoma, they have not fully managed to curb lymphoma cell proliferation despite effective reduction of the H3K27me3 mark. We used MS1943, an EZH2 selective degrader, which successfully diminishes EZH2 levels in lymphoma cells. Additionally, lapatinib, a dual inhibitor of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) tyrosine kinases, targets a receptor protein that regulates cell growth and division. The overexpression of this protein is often observed in lymphoma cells. Our study aims to combine these two therapeutic targets to stimulate apoptosis pathways and potentially suppress Burkitt’s lymphoma cell survival and proliferation in a complementary and synergistic manner. We observed that a combination of MS1943 and lapatinib induced apoptosis in Daudi cells and caused cell cycle arrest at the S and G2/M phases in both Ramos and Daudi cells. This strategy, using a combination of MS1943 and lapatinib, presents a promising therapeutic approach for treating lymphoma and potentially Burkitt’s lymphoma

Image_2_Overcoming the therapeutic limitations of EZH2 inhibitors in Burkitt’s lymphoma: a comprehensive study on the combined effects of MS1943 and Ibrutinib.jpeg

Enhancer of zeste homolog 2 (EZH2) and Bruton’s tyrosine kinase (BTK) are both key factors involved in the development and progression of hematological malignancies. Clinical studies have demonstrated the potential of various EZH2 inhibitors, which target the methyltransferase activity of EZH2, for the treatment of lymphomas. However, despite their ability to effectively reduce the H3K27me3 levels, these inhibitors have shown limited efficacy in blocking the proliferation of lymphoma cells. To overcome this challenge, we employed a hydrophobic tagging approach utilizing MS1943, a selective EZH2 degrader. In this study, we investigated the inhibitory effects of two drugs, the FDA-approved EZH2 inhibitor Tazemetostat, currently undergoing clinical trials, and the novel drug MS1943, on Burkitt’s lymphoma. Furthermore, we assessed the potential synergistic effect of combining these drugs with the BTK inhibitor Ibrutinib. In this study, we evaluated the effects of combination therapy with MS1943 and Ibrutinib on the proliferation of three Burkitt’s lymphoma cell lines, namely RPMI1788, Ramos, and Daudi cells. Our results demonstrated that the combination of MS1943 and Ibrutinib significantly suppressed cell proliferation to a greater extent compared to the combination of Tazemetostat and Ibrutinib. Additionally, we investigated the underlying mechanisms of action and found that the combination therapy of MS1943 and Ibrutinib led to the upregulation of miR29B-mediated p53-upregulated modulator of apoptosis PUMA, BAX, cleaved PARP, and cleaved caspase-3 in Burkitt’s lymphoma cells. These findings highlight the potential of this innovative therapeutic strategy as an alternative to traditional EZH2 inhibitors, offering promising prospects for improving treatment outcomes in Burkitt’s lymphoma.</p

Image_1_Overcoming the therapeutic limitations of EZH2 inhibitors in Burkitt’s lymphoma: a comprehensive study on the combined effects of MS1943 and Ibrutinib.jpeg

Enhancer of zeste homolog 2 (EZH2) and Bruton’s tyrosine kinase (BTK) are both key factors involved in the development and progression of hematological malignancies. Clinical studies have demonstrated the potential of various EZH2 inhibitors, which target the methyltransferase activity of EZH2, for the treatment of lymphomas. However, despite their ability to effectively reduce the H3K27me3 levels, these inhibitors have shown limited efficacy in blocking the proliferation of lymphoma cells. To overcome this challenge, we employed a hydrophobic tagging approach utilizing MS1943, a selective EZH2 degrader. In this study, we investigated the inhibitory effects of two drugs, the FDA-approved EZH2 inhibitor Tazemetostat, currently undergoing clinical trials, and the novel drug MS1943, on Burkitt’s lymphoma. Furthermore, we assessed the potential synergistic effect of combining these drugs with the BTK inhibitor Ibrutinib. In this study, we evaluated the effects of combination therapy with MS1943 and Ibrutinib on the proliferation of three Burkitt’s lymphoma cell lines, namely RPMI1788, Ramos, and Daudi cells. Our results demonstrated that the combination of MS1943 and Ibrutinib significantly suppressed cell proliferation to a greater extent compared to the combination of Tazemetostat and Ibrutinib. Additionally, we investigated the underlying mechanisms of action and found that the combination therapy of MS1943 and Ibrutinib led to the upregulation of miR29B-mediated p53-upregulated modulator of apoptosis PUMA, BAX, cleaved PARP, and cleaved caspase-3 in Burkitt’s lymphoma cells. These findings highlight the potential of this innovative therapeutic strategy as an alternative to traditional EZH2 inhibitors, offering promising prospects for improving treatment outcomes in Burkitt’s lymphoma.</p

Ezetimibe added to statin therapy after acute coronary syndromes

BACKGROUND: Statin therapy reduces low-density lipoprotein (LDL) cholesterol levels and the risk of cardiovascular events, but whether the addition of ezetimibe, a nonstatin drug that reduces intestinal cholesterol absorption, can reduce the rate of cardiovascular events further is not known. METHODS: We conducted a double-blind, randomized trial involving 18,144 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and had LDL cholesterol levels of 50 to 100 mg per deciliter (1.3 to 2.6 mmol per liter) if they were receiving lipid-lowering therapy or 50 to 125 mg per deciliter (1.3 to 3.2 mmol per liter) if they were not receiving lipid-lowering therapy. The combination of simvastatin (40 mg) and ezetimibe (10 mg) (simvastatin-ezetimibe) was compared with simvastatin (40 mg) and placebo (simvastatin monotherapy). The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization ( 6530 days after randomization), or nonfatal stroke. The median follow-up was 6 years. RESULTS: The median time-weighted average LDL cholesterol level during the study was 53.7 mg per deciliter (1.4 mmol per liter) in the simvastatin-ezetimibe group, as compared with 69.5 mg per deciliter (1.8 mmol per liter) in the simvastatin-monotherapy group (P<0.001). The Kaplan-Meier event rate for the primary end point at 7 years was 32.7% in the simvastatin-ezetimibe group, as compared with 34.7% in the simvastatin-monotherapy group (absolute risk difference, 2.0 percentage points; hazard ratio, 0.936; 95% confidence interval, 0.89 to 0.99; P = 0.016). Rates of pre-specified muscle, gallbladder, and hepatic adverse effects and cancer were similar in the two groups. CONCLUSIONS: When added to statin therapy, ezetimibe resulted in incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes. Moreover, lowering LDL cholesterol to levels below previous targets provided additional benefit