PARP Inhibitor for Neoadjuvant Therapy in HER2-Negative Breast Cancer: A Systematic Review and Meta-Analysis of Efficacy and Safety.

Poly-ADP ribose polymerase inhibitor (PARPi) is approved for HER2-negative advanced breast cancer with BRCA1/2 mutation. In recent years, many studies have explored the application of PARPi in neoadjuvant therapy, but failed to reach a unified conclusion. PubMed, Clinicaltrials.gov, Cochrane CENTRAL, Embase, and key oncological meetings for trials were searched for studies reporting neoadjuvant regimens with PARPi in HER2-negative breast cancer. Pathological complete response (pCR), residual cancer burden (RCB), breast-conservation surgery rate (BCSR), clinical response, and adverse events were extracted and pooled in a meta-analysis using the Mantel Haenszel random/fixed effects model. Subgroup analyses of pCR were conducted according to BRCA1/2 status, and hormone receptor (HR) status. Five studies (N = 1223) were included, the addition of PARPi to neoadjuvant regimens significantly increased pCR rates (HR 1.45, 95%CI 1.09-1.92, P = .01, I2 = 86%). In subgroup analysis, the addition of PARPi increased the pCR rate both in HR-positive (n = 383) and HR-negative (n = 431) subgroups, which showed a dominant effect of PARPi regardless of HR status (HR 2.07, 95%CI 1.33-3.23, P = .001, I2 = 0%; HR 1.85, 95%CI 1.39-2.26, P < .0001, I2 = 0%, respectively). However, when we performed a subgroup analysis based on the status of BRCA1/2, no further benefit for PARPi was found. Adverse reactions were generally tolerable. Other outcome indexes, including RCB, clinical response, BCSR, and PARPi did not show a clinical benefit. Regardless of BRCA1/2 status, PARPi in neoadjuvant therapy, can improve the pCR rate of HER2-negative breast cancer, especially in HR-positive patients. Thus, we should have performed larger randomized trials and provided a stronger evidence-based basis.

Mechanism interpretation of Guhan Yangshengjing for protection against Alzheimer's disease by network pharmacology and molecular docking.

ETHNOPHARMACOLOGICAL RELEVANCE: Guhan Yangshengjing (GHYSJ) is an effective prescription for delaying progression of Alzheimer's disease (AD) based on the ancient Chinese medical classics excavated from Mawangdui Han Tomb. Comprising a combination of eleven traditional Chinese herbs, the precise protective mechanism through which GHYSJ acts on AD progression remains unclear and has significant implications for the development of new drugs to treat AD. AIM OF THE STUDY: To investigate the mechanism of GHYSJ in the treatment of AD through network pharmacology and validate the results through in vitro experiments. MATERIALS AND METHODS: Chemical composition-target-pathway network and protein-protein interaction network were constructed by network pharmacology to predict the potential targets of GHYSJ for the treatment of AD. The interaction relationship between active ingredients and targets was verified by molecular docking and molecular force. Furthermore, the chemical constituents of GHYSJ were analyzed by LC-MS and HPLC, the effects of GHYSJ on animal tissues were analyzed by H&E staining. An Aß-induced SH-SY5Y cellular model was established to validate the core pathways and targets predicted by network pharmacology and molecular docking. RESULTS: The results of the network pharmacology analysis revealed a total of 155 bioactive compounds capable of crossing the blood-brain barrier and interacting with 677 targets, among which 293 targets specifically associated with AD, which mainly participated in and regulated the amyloid aggregation pathway and PI3K/Akt signaling pathway, thereby treating AD. In addition, molecular docking analysis revealed a robust binding affinity between the principal bioactive constituents of GHYSJ and crucial targets implicated in AD. Our findings were further substantiated by in vitro experiments, which demonstrated that Liquiritigenin and Ginsenosides Rh4, crucial constituents of GHYSJ, as well as GHYSJ pharmaceutic serum, exhibited a significant down-regulation of BACE1 expression in Aß-induced damaged SH-SY5Y cells. This study provides valuable data and theoretical underpinning for the potential therapeutic application of GHYSJ in the treatment of AD and secondary development of GHYSJ prescription. CONCLUSION: Through network pharmacology, molecular docking, LC-MS, and cellular experiments, GHYSJ was initially confirmed to delay the progression of AD by regulating the expression of BACE1 in Amyloid aggregation pathway. Our observations provided valuable data and theoretical underpinning for the potential therapeutic application of GHYSJ in the treatment of AD.

Isophorone-based crystallization-induced-emission sensors detect proteome aggregation in live cells and tissues with breast cancer.

BACKGROUND: Protein misfolding and aggregation can lead to various diseases. Recent studies have shed light on the aggregated protein in breast cancer pathology, which suggests that it is crucial to design chemical sensors that visualize protein aggregates in breast cancer, especially in clinical patient-derived samples. However, most reported sensors are constrained in cultured cell lines. RESULTS: In this work, we present the development of two isophorone-based crystallization-induced-emission fluorophores for detecting proteome aggregation in breast cancer cell line and tissues biopsied from diseased patients, designated as A1 and A2. These probes exhibited viscosity sensitivity and recovered their fluorescence strongly at crystalline state. Moreover, A1 and A2 exhibit selective binding capacity and strong fluorescence for various aggregated proteins. Utilizing these probes, we detect protein aggregation in stressed breast cancer cells, xenograft mouse model of human breast cancer and clinical patient-derived samples. Notably, the fluorescence intensity of both probes light up in tumor tissues. SIGNIFICANCE: The synthesized isophorone-based crystallization-induced-emission fluorophores, A1 and A2, enable sensitive detection of protein aggregation in breast cancer cells and tissues. In the future, aggregated proteins are expected to become indicators for early diagnosis and clinical disease monitoring of breast cancer.