Feasibility of Aerobic Exercise Training to Mitigate Cardiotoxicity of Breast Cancer Therapy: A Systematic Review and Meta-Analysis.

BACKGROUND: Current anticancer treatments for breast cancer (BC) may cause cardiotoxicity. This study aimed to investigate the effectiveness of aerobic exercise in mitigating cardiotoxicity caused by BC therapy. MATERIALS AND METHODS: PubMed, Embase, Cochrane Library, Web of Science, and the Physiotherapy Evidence Database were searched until February 7, 2023. Clinical trials investigating the effectiveness of exercise training, including aerobic exercise, in BC patients receiving treatments that could cause cardiotoxicity were eligible. Outcome measures included cardiorespiratory fitness (CRF) (peak oxygen consumption, VO2peak), left ventricular ejection fraction, and peak oxygen pulse. Intergroup differences were determined by standard mean differences (SMD) and 95% confidence intervals (CIs). Trial sequential analysis (TSA) was utilized to ensure whether the current evidence was conclusive. RESULTS: Sixteen trials involving 876 participants were included. Aerobic exercise significantly improved CRF measured by VO2peak in mL/kg/min (SMD 1.79, 95% CI 0.99-2.59) when compared to usual care. This result was confirmed through TSA. Subgroup analyses revealed that aerobic exercise given during BC therapy significantly improved VO2peak (SMD 1.84, 95% CI 0.74-2.94). Exercise prescriptions at a frequency of up to 3 times per week, an intensity of moderate to vigorous, and a >30-minute session length also improved VO2peak. CONCLUSION: Aerobic exercise is effective in improving CRF when compared to usual care. Exercise performed up to 3 times per week, at a moderate-to-vigorous intensity, and having a session length >30 minutes is considered effective. Future high-quality research is needed to determine the effectiveness of exercise intervention in preventing cardiotoxicity caused by BC therapy.

Extracorporeal Shock Wave Therapy Combined with Complex Decongestive Therapy in Patients with Breast Cancer-Related Lymphedema: A Systemic Review and Meta-Analysis.

Breast cancer-related lymphedema (BCRL) is one of the most significant complications seen after surgery. Several studies demonstrated that extracorporeal shock wave therapy (ESWT), in addition to conventional complex decongestive therapy (CDT), had a positive effect on BCRL in various aspects. The systematic review and meta-analysis aim to explore the effectiveness of ESWT with or without CDT on BRCL patients. We searched PubMed, Embase, PEDro, Cochrane Library Databases, and Google Scholar for eligible articles and used PRISMA2020 for paper selection. Included studies were assessed by the PEDro score, Modified Jadad scale, STROBE assessment, and GRADE framework for the risk of bias evaluation. The primary outcomes were the volume of lymphedema and arm circumference. Secondary outcome measures were skin thickness, shoulder joint range of motion (ROM), and an impact on quality-of-life questionnaire. Studies were meta-analyzed with the mean difference (MD). Eight studies were included in the systemic review and four in the meta-analysis. In summary, we found that adjunctive ESWT may significantly improve the volume of lymphedema (MD = -76.44; 95% CI: -93.21, -59.68; p < 0.00001), skin thickness (MD = -1.65; 95% CI: -3.27, -0.02; p = 0.05), and shoulder ROM (MD = 7.03; 95% CI: 4.42, 9.64; p < 0.00001). The evidence level was very low upon GRADE appraisal. ESWT combined with CDT could significantly improve the volume of lymphedema, skin thickness, and shoulder ROM in patients with BCRL. There is not enough evidence to support the use of ESWT as a replacement for CDT. This study was registered with PROSPERO: CRD42021277110.

Tumor cycling hypoxia induces chemoresistance in glioblastoma multiforme by upregulating the expression and function of ABCB1.

Tumor cycling hypoxia is now a well-recognized phenomenon in animal and human solid tumors. However, how tumor cycling hypoxia impacts chemotherapy is unclear. In the present study, we explored the impact and the mechanism of cycling hypoxia on tumor microenvironment-mediated chemoresistance. Hoechst 33342 staining and hypoxia-inducible factor-1 (HIF-1) activation labeling together with immunofluorescence imaging and fluorescence-activated cell sorting were used to isolate hypoxic tumor subpopulations from human glioblastoma xenografts. ABCB1 expression, P-glycoprotein function, and chemosensitivity in tumor cells derived from human glioblastoma xenografts or in vitro cycling hypoxic stress-treated glioblastoma cells were determined using Western blot analysis, drug accumulation and efflux assays, and MTT assay, respectively. ABCB1 expression and P-glycoprotein function were upregulated under cycling hypoxia in glioblastoma cells concomitant with decreased responses to doxorubicin and BCNU. However, ABCB1 knockdown inhibited these effects. Moreover, immunofluorescence imaging and flow cytometric analysis for ABCB1, HIF-1 activation, and Hoechst 3342 in glioblastoma revealed highly localized ABCB1 expression predominantly in potentially cycling hypoxic areas with HIF-1 activation and blood perfusion in the solid tumor microenvironment. The cycling hypoxic tumor cells derived from glioblastoma xenografts exhibited higher ABCB1 expression, P-glycoprotein function, and chemoresistance, compared with chronic hypoxic and normoxic cells. Tumor-bearing mice that received YC-1, an HIF-1α inhibitor, exhibited suppressed tumor microenvironment-induced ABCB1 induction and enhanced survival rate in BCNU chemotherapy. Cycling hypoxia plays a vital role in tumor microenvironment-mediated chemoresistance through the HIF-1-dependent induction of ABCB1. HIF-1 blockade before and concurrent with chemotherapy could suppress cycling hypoxia-induced chemoresistance.

Synthesis and antiplatelet activity of ethyl 4-(1-benzyl-1H-indazol-3-yl)benzoate (YD-3) derivatives.

Previously, ethyl 4-(1-benzyl-1H-indazol-3-yl)benzoate (YD-3) was identified by us as the first non-peptide protease-activated receptor 4 (PAR4) antagonist. To continue on our development of novel anti-PAR4 agents, YD-3 was used as a lead compound and a series of its derivatives were synthesized and evaluated for their selective anti-PAR4 activity. Through structure-activity relationship (SAR) study, we identified the important functional groups contributing to anti-PAR4 activity, and these functional groups were kept intact during subsequent structural modification. Several new compounds with anti-PAR4 activity comparable to YD-3 were identified. Among them, ethyl 4-[1-(3-chlorobenzyl)-1H-indazol-3-yl]benzoate (33) showed the most potent inhibitory effect on PAR4-mediated platelet aggregation, ATP release, and P-selectin expression. On the other hand, ethyl 4-(1-phenyl-1H-indazol-3-yl)benzoate (83) exhibited dual inhibitory effects on PAR4 and thromboxane formation from arachidonic acid. The above findings can be used as guidelines for development of novel antiplatelet drug candidates.

Predicting factors associated with costs of diabetic patients in Taiwan.

This study examined healthcare costs for medication-using diabetic patients in Taiwan and predicted which factors were associated with costs. We analyzed claims data from the National Health Insurance (NHI) program in Taiwan from 1998 to 1999. The approach included estimates of costs attributable to diabetes, diabetes-related complications, comorbidity incurred by diabetic patients. A multiple regression model was used to assess the contribution of patients' characteristics in 1998 on outpatient, inpatient, and total costs in 1998 and 1999. The prevalence of medication-using patients with diabetes was 2.6% in 1998 and 2.8% in 1999. Costs of healthcare were 13.3% of total costs of NHI in 1998 versus 13.0% in 1999. Health services delivered near the end of life consumed large portions of medical dollars. The three most prevalent clinical associations of diabetes were congestive heart failure, neuropathy, and ischemic heart disease. Adjusted for demographic and clinical characteristics in 1998, this model could explain 8.0, 9.3, and 12.5%, respectively, of the cost variation in outpatient, inpatient, and total costs in 1999.