Introduction: Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype associated with an increased risk of recurrence and cancer-related death. Unlike hormone receptor-positive or HER2-positive breast cancers, there are limited targeted therapies available to treat TNBC and cytotoxic chemotherapy remains the mainstay of treatment. Sacituzumab govitecan (IMMU-132) is an antibody-drug conjugate targeting Trop-2 expressing cells and selectively delivering SN-38, an active metabolite of irinotecan.
Areas covered: This review covers the mechanism of action, safety and efficacy of sacituzumab govitecan in patients with previously treated, metastatic TNBC. Additionally, efficacy data in other epithelial malignancies is included based on a PubMed search for ‘sacituzumab govitecan’ and ‘clinical trial’.
Expert opinion: Sacituzumab govitecan has promising anti-cancer activity in patients with metastatic TNBC previously treated with at least two prior lines of systemic therapy based on a single arm Phase I/II clinical trial. A confirmatory Phase III randomized clinical trial is ongoing. Sacituzumab govitecan has a manageable side effect profile, with the most common adverse events being nausea, neutropenia, and diarrhea. The activity of sacituzumab govitecan likely extends beyond TNBC with promising early efficacy data in many other epithelial cancers, including hormone receptor-positive breast cancer. 相似文献
Moderate weight loss improves numerous risk factors for cardiometabolic disease; however, long-term weight loss maintenance (WLM) is often thwarted by metabolic adaptations that suppress energy expenditure and facilitate weight regain. Skeletal muscle has a prominent role in energy homeostasis; therefore, we investigated the effect of WLM and weight regain on skeletal muscle in rodents. In skeletal muscle of obesity-prone rats, WLM reduced fat oxidative capacity and downregulated genes involved in fat metabolism. Interestingly, even after weight was regained, genes involved in fat metabolism were also reduced. We then subjected mice with skeletal muscle lipoprotein lipase overexpression (mCK-hLPL), which augments fat metabolism, to WLM and weight regain and found that mCK-hLPL attenuates weight regain by potentiating energy expenditure. Irrespective of genotype, weight regain suppressed dietary fat oxidation and downregulated genes involved in fat metabolism in skeletal muscle. However, mCK-hLPL mice oxidized more fat throughout weight regain and had greater expression of genes involved in fat metabolism and lower expression of genes involved in carbohydrate metabolism during WLM and regain. In summary, these results suggest that skeletal muscle fat oxidation is reduced during WLM and regain, and therapies that improve skeletal muscle fat metabolism may attenuate rapid weight regain. 相似文献
The current study investigated the effects of two exercise interventions on cognitive function amongst breast cancer survivors.
Design
Pilot randomised-controlled trial.
Methods
Seventeen female cancer survivors (mean: 62.9 ± 7.8 years) were randomised into three groups: high-intensity interval training (HIIT, n = 6); moderate-intensity continuous training (MOD, n = 5); or wait-list control (CON, n = 6). The HIIT and MOD groups exercised on a cycle ergometer 3 days/week for 12-weeks. Primary outcomes were cognitive function assessments utilising CogState. Secondary outcomes were resting middle cerebral artery blood flow velocity, cerebrovascular reactivity and aerobic fitness (VO2peak). Data were analysed with General Linear Mixed Models and Cohen’s d effect sizes were calculated.
Results
All 17 participants who were randomised were available for follow-up analysis and adherence was similar for HIIT and MOD (78.7 ± 13.2% vs 79.4 ± 12.0%; p = 0.93). Although there were no significant differences in the cognitive and cerebrovascular outcomes, HIIT produced moderate to large positive effects in comparison to MOD and CON for outcomes including episodic memory, working memory, executive function, cerebral blood flow and cerebrovascular reactivity. HIIT significantly increased VO2peak by 19.3% (d = 1.28) and MOD had a non-significant 5.6% (d = 0.72) increase, compared to CON which had a 2.6% decrease.
Conclusions
This study provides preliminary evidence that HIIT may be an effective exercise intervention to improve cognitive performance, cerebrovascular function and aerobic fitness in breast cancer survivors. Considering the sample size is small, these results should be confirmed through larger clinical trials. 相似文献
Loss of function variants in NOTCH1 cause left ventricular outflow tract obstructive defects (LVOTO). However, the risk conferred by rare and noncoding variants in NOTCH1 for LVOTO remains largely uncharacterized. In a cohort of 49 families affected by hypoplastic left heart syndrome, a severe form of LVOTO, we discovered predicted loss of function NOTCH1 variants in 6% of individuals. Rare or low-frequency missense variants were found in 16% of families. To make a quantitative estimate of the genetic risk posed by variants in NOTCH1 for LVOTO, we studied associations of 400 coding and noncoding variants in NOTCH1 in 1,085 cases and 332,788 controls from the UK Biobank. Two rare intronic variants in strong linkage disequilibrium displayed significant association with risk for LVOTO amongst European-ancestry individuals. This result was replicated in an independent analysis of 210 cases and 68,762 controls of non-European and mixed ancestry. In conclusion, carrying rare predicted loss of function variants in NOTCH1 confer significant risk for LVOTO. In addition, the two intronic variants seem to be associated with an increased risk for these defects. Our approach demonstrates the utility of population-based data sets in quantifying the specific risk of individual variants for disease-related phenotypes. 相似文献