Intratumoral heterogeneity contributes to the chemotherapy prognosis of breast cancer.

Context: Previous studies have shown that intratumoral heterogeneity (ITH) is associated with poor clinical outcomes and is thought to be a mechanism of resistance to chemotherapy and radiotherapy. Aims: We aimed to determine how ITH affects the response to drug therapy in breast cancer (BC). Settings and Design: We assessed ITH using mutated allele tumor heterogeneity (MATH) data from BC patients in the TCGA database. Methods and Material: The study enrolled 515 patients with BC treated with chemotherapy from the TCGA database who had available data on survival, whole-exome sequencing, and genome-wide transcriptome sequencing. Additionally, 399 MSK-BRCA cohort patients were treated with chemotherapy. Statistical Analysis Used: All statistical analyses were conducted using R. All comparisons were made using the two-sided Mann-Whitney test, Pearson's Chi-squared test, and the Kruskal-Wallis test. Statistical significance was defined as P values less than 0.05 (*P < 0.05). The survival package in R was used to conduct the analysis. Results: Additional analysis was performed on 515 BC patients receiving adjuvant chemotherapy. MATH was associated with overall survival (OS) in multivariate analysis (hazard ratio (HR), 1.432; 95% confidence interval, 1.073-1.913; P = 0.015). Pathway enrichment and immune cell analysis revealed that the low MATH group had significantly higher infiltration of 24 different types of immune cells than the high MATH group. Conclusions: Individuals with low MATH scores had a longer OS than those with high MATH scores. Immune responses were significantly enhanced in breast cancer patients with low MATH scores.

TAT-Modified ω-Conotoxin MVIIA for Crossing the Blood-Brain Barrier.

As the first in a new class of non-opioid drugs, ω-Conotoxin MVIIA was approved for the management of severe chronic pains in patients who are unresponsive to opioid therapy. Unfortunately, clinical application of MVIIA is severely limited due to its poor ability to penetrate the blood-brain barrier (BBB), reaching the central nervous system (CNS). In the present study, we have attempted to increase MVIIA's ability to cross the BBB via a fusion protein strategy. Our results showed that when the TAT-transducing domain was fused to the MVIIA C-terminal with a linker of varied numbers of glycine, the MVIIA-TAT fusion peptide exhibited remarkable ability to cross the bio-membranes. Most importantly, both intravenous and intranasal administrations of MVIIA-TAT in vivo showed therapeutic efficacy of analgesia. Compared to the analgesic effects of intracerebral administration of the nascent MVIIA, these systemic administrations of MVIIA-TAT require higher doses, but have much prolonged effects. Taken together, our results showed that TAT conjugation of MVIIA not only enables its peripheral administration, but also maintains its analgesic efficiency with a prolonged effective time window. Intranasal administration also rendered the MVIIA-TAT advantages of easy applications with potentially reduced side effects. Our results may present an alternative strategy to improve the CNS accessibility for neural active peptides.