The association between protease inhibitors and anal cancer outcomes in veterans living with HIV treated with definitive chemoradiation: a retrospective study

Background: The incidence of anal squamous cell carcinoma has been increasing, particularly in people living with HIV (PLWH). There is concern that radiosensitizing drugs, such as protease inhibitors, commonly used in the management of HIV, may increase toxicities in patients undergoing chemoradiation. This study examines treatment outcomes and toxicities in PLWH managed with and without protease inhibitors who are receiving chemoradiation for anal cancer. Methods: Patient demographic, HIV management, and cancer treatment information were extracted from multiple Veterans Affairs databases. Patients were also manually chart reviewed. Among PLWH undergoing chemoradiation for anal carcinoma, therapy outcomes and toxicities were compared between those treated with and without protease inhibitors at time of cancer treatment. Statistical analysis was performed using chi-square, Cox regression analysis, and logistic regression. Results: A total of 219 PLWH taking anti-retroviral therapy undergoing chemoradiation for anal cancer were identified and included in the final analysis. The use of protease inhibitors was not associated with any survival outcome including colostomy-free survival, progression-free survival, or overall survival (all adjusted hazard ratio p-values\u3e 0.05). Regarding toxicity, protease inhibitor use was not associated with an increased odds of hospitalizations or non-hematologic toxicities; however, protease inhibitor use was associated with increased hospitalizations for hematologic toxicities, including febrile neutropenia (p \u3c 0.01). Conclusion: The use of protease inhibitors during chemoradiation for anal carcinoma was not associated with any clinical outcome or increase in non-hematologic toxicity. Their use was associated with increased hospitalizations for hematologic toxicities. Further prospective research is needed to evaluate the safety and efficacy of protease inhibitors for patients undergoing chemoradiation

SIK2 inhibition enhances PARP inhibitor activity synergistically in ovarian and triple-negative breast cancers

Poly(ADP-ribose) polymerase inhibitors (PARP inhibitors) have had an increasing role in the treatment of ovarian and breast cancers. PARP inhibitors are selectively active in cells with homologous recombination DNA repair deficiency caused by mutations in BRCA1/2 and other DNA repair pathway genes. Cancers with homologous recombination DNA repair proficiency respond poorly to PARP inhibitors. Cancers that initially respond to PARP inhibitors eventually develop drug resistance. We have identified salt-inducible kinase 2 (SIK2) inhibitors, ARN3236 and ARN3261, which decreased DNA double-strand break (DSB) repair functions and produced synthetic lethality with multiple PARP inhibitors in both homologous recombination DNA repair deficiency and proficiency cancer cells. SIK2 is required for centrosome splitting and PI3K activation and regulates cancer cell proliferation, metastasis, and sensitivity to chemotherapy. Here, we showed that SIK2 inhibitors sensitized ovarian and triple-negative breast cancer (TNBC) cells and xenografts to PARP inhibitors. SIK2 inhibitors decreased PARP enzyme activity and phosphorylation of class-IIa histone deacetylases (HDAC4/5/7). Furthermore, SIK2 inhibitors abolished class-IIa HDAC4/5/7–associated transcriptional activity of myocyte enhancer factor-2D (MEF2D), decreasing MEF2D binding to regulatory regions with high chromatin accessibility in FANCD2, EXO1, and XRCC4 genes, resulting in repression of their functions in the DNA DSB repair pathway. The combination of PARP inhibitors and SIK2 inhibitors provides a therapeutic strategy to enhance PARP inhibitor sensitivity for ovarian cancer and TNBC

Effects of Oral Creatine Supplementation on Power Output during Repeated Treadmill Sprinting

The aim of the present study was to examine the effects of creatine (Cr) supplementation on power output during repeated sprints on a non-motorized treadmill. Sixteen recreationally active males volunteered for this study (age 25.5 ± 4.8 y, height 179 ± 5 cm, body mass 74.8 ± 6.8 kg). All participants received placebo supplementation (75 mg of glucose·kg−1·day−1) for 5 days and then performed a baseline repeated sprints test (6 × 10 s sprints on a non-motorised treadmill). Thereafter, they were randomly assigned into a Cr (75 mg of Cr monohydrate·kg−1·day−1) or placebo supplementation, as above, and the repeated sprints test was repeated. After Cr supplementation, body mass was increased by 0.99 ± 0.83 kg (p = 0.007), peak power output and peak running speed remained unchanged throughout the test in both groups, while the mean power output and mean running speed during the last 5 s of the sprints increased by 4.5% (p = 0.005) and 4.2% to 7.0%, respectively, during the last three sprints (p = 0.005 to 0.001). The reduction in speed within each sprint was also blunted by 16.2% (p = 0.003) following Cr supplementation. Plasma ammonia decreased by 20.1% (p = 0.037) after Cr supplementation, despite the increase in performance. VO2 and blood lactate during the repeated sprints test remained unchanged after supplementation, suggesting no alteration of aerobic or glycolytic contribution to adenosine triphosphate production. In conclusion, Cr supplementation improved the mean power and speed in the second half of a repeated sprint running protocol, despite the increased body mass. This improvement was due to the higher power output and running speed in the last 5 s of each 10 s sprint