Penehyclidine hydrochloride

Clonal hematopoiesis of indeterminate potential (CHIP) is frequent in patients with solid tumors. Prospective data about CHIP prevalence at breast cancer diagnosis and its dynamic evolution under treatment selective pressure are limited.

We performed targeted error-corrected sequencing on 614 samples from 380 patients with breast cancer. We investigated the dynamics of CHIP on prospectively collected paired samples from patients with early breast cancer (eBC) receiving chemotherapy (CT) or endocrine therapy (ET). We assessed the correlation of CHIP with survival in patients with metastatic triple-negative breast cancer (mTNBC). We estimated the risk of progression to treatment-related myeloid neoplasms (t-MN) according to the clonal hematopoiesis risk score (CHRS). In exploratory analyses, we considered clonal hematopoiesis (CH) with variant allele fraction (VAF) ≥0.005.

CHIP was identified in 15% of patients before treatment. Few CHIP emerged after treatment, and the risk of developing new mutations was similar for patients receiving CT versus ET (odds ratio [OR], 1.16; P = .820). However, CT increased the risk of developing new CH with VAF ≥0.005 (OR, 3.45; P = .002). Five TP53- mutant CH with VAF ≥0.005 emerged among patients receiving CT. Most patients had low risk of t-MN according to the CHRS score. CHIP did not correlate with survival in mTNBC.

CHIP is frequent in patients with breast cancer. In this study, CT did not lead to emergence of new CHIP, and most patients had low risk of developing t-MN. This finding is reassuring, given long life expectancy of patients with eBC and the association of CHIP with morbidity and mortality. However, TP53 -mutant CH with VAF ≥0.005 emerged with CT, which carries high risk of t-MN. Evolution of these small clones and their clinical significance warrant further investigation.

Although penehyclidine hydrochloride (PHC) has been identified to alleviate myocardial injury induced by ischemia/reperfusion (I/R), the regulatory molecules and related mechanisms are unknown. In this study, bioinformatics, molecular biology, and biochemistry methods were used to explore the molecular mechanisms and targets of PHC. In the myocardial ischemia-reperfusion injury (MIRI)-induced rat model, PHC pretreatment significantly improved cardiac function (p < 0.01). Multiple differentially expressed genes, including Z-DNA binding protein 1 (ZBP1), were identified through mRNA sequencing analysis of myocardial ischemic penumbra tissue in MIRI rats. The transduction of the ZBP1 adenovirus vector (Ad-Zbp1) in PHC-pretreated rats exhibited a reversible augmentation in myocardial infarct size (p < 0.01), pronounced pathological damage to the myocardial tissue, as well as a significant elevation of serum myocardial enzymes (p < 0.05). The interaction among ZBP1, fas-associating via death domain (FADD), and receptor-interacting serine/threonine-protein kinase 3 (RIPK3) leads to a remarkable up-regulation of cleaved-Caspase-1 (Cl-Casp-1), N-terminal gasdermin D (N-GSDMD), phospho-mixed lineage kinase domain-like Ser358 (p-MLKL^S358), and other regulatory proteins, thereby triggering pyroptosis, apoptosis, and necroptosis (PANoptosis) in cardiomyocytes of MIRI rats. Moreover, the transduction of Ad-Zbp1 in the oxygen-glucose deprivation/re-oxygenation (OGD/R)-induced H9c2 cell model also dramatically augmented the number of cell deaths. However, the intervention of PHC considerably enhanced cell viability (p < 0.01), effectively mitigated the release of myocardial enzymes (p < 0.05), and markedly attenuated the expression levels of PANoptosis regulatory proteins through restraint of ZBP1 expression. Therefore, the therapeutic efficacy of PHC in improving MIRI might be attributed to targeting ZBP1-mediated PANoptosis.