Efficacy and Safety of Anti-HER2 Targeted Therapy for Metastatic HR-Positive and HER2-Positive Breast Cancer: A Bayesian Network Meta-Analysis.

Despite the development of HER2-targeted drugs, achieving favorable outcomes for patients with HR+/HER2+MBC remains challenging. This study utilized Bayesian Network Meta-analysis to compare the efficacy and safety of anti-HER2 combination regimens. The primary analysis focused on progression-free survival (PFS), while secondary analyses included objective response rate, overall survival (OS) and the incidence rate of grade 3/4 adverse events (AEs). A comprehensive search across seven databases identified 25 randomized controlled trials for inclusion in this meta-analysis. For patients eligible for endocrinotherapy, our findings revealed that dual-target combined endocrine therapy, such as Her2-mAb+Her2-mAb+Endo (HR = 0.38; 95%CrI: 0.16-0.88) and Her2-mAb+Her2-tki+Endo (HR = 0.45; 95%CrI: 0.23-0.89), significantly improved PFS compared to endocrine therapy alone. According to the surface under the cumulative ranking curves (SUCRAs), Her2-mAb+Her2-mAb+Endo and Her2-mAb+Her2-tki+Endo ranked highest in terms of PFS and OS, respectively. For patients unsuitable for endocrine therapy, anti-HER2 dual-target combined chemotherapy, such as Her2-mAb+Her2-mAb+Chem (HR = 0.76; 95%CrI: 0.6-0.96) and Her2-mAb+Her2-tki+Chem (HR = 0.48; 95%CrI: 0.29-0.81), demonstrated significant improvements in PFS compared to Her2-mAb+Chem. The results were the same when compared with Her2-tki+Chem. According to the SUCRAs, Her2-mAb+Her2-tki+Chem and Her2-mAb+Her2-mAb+Chem ranked highest for PFS and OS, respectively. Subgroup analyses consistently supported these overall findings, indicating that dual-target therapy was the optimal approach irrespective of treatment line.

Integrated testis transcriptome and whole genome analysis of sexual maturity in Large White and Tongcheng pigs.

Testicular development and spermatogenesis play critical roles in male fertility and sexual maturation. To explore the genetic basis and key genes related to sexual maturity, we measured serum testosterone content and analysed testis tissue sections of Large White (LW) and Tongcheng (TC) boars at an immature age. We then screened differentially expressed genes (DEGs) in testis development in both breeds using RNA-seq. Finally, we analysed the selection signatures of both breeds to investigate which DEGs were subjected to positive selection. Our findings showed that serum testosterone contents in TC pigs (~4 ng/mL) were much higher than those in LW pigs (<0.95 ng/mL). Haematoxylin and eosin staining of testicular sections showed that the cross-sectional areas and perimeters of the seminiferous tubules in TC testes were larger and longer than those in LW pigs. A total of 5068 DEGs were selected by filtering criteria of q value <0.05 and |log2 (fold change)| ≥ 1. Gene Ontology analysis revealed that 250 genes were enriched in 11 biological process categories involved in sexual maturity. Most candidate genes, including TRIP13, NR6A1, STRA8, PCSK4, ACRBP, TSSK1B and TSSK6, were under positive selection. These results provide a better understanding of the genetic basis for testicular maturation and are useful for enhancing boar reproductive traits through molecular breeding.

Integrated time-series transcriptomic and metabolomic analyses reveal different inflammatory and adaptive immune responses contributing to host resistance to PRRSV.

Porcine reproductive and respiratory syndrome virus (PRRSV) is a highly contagious disease that affects the global pig industry. To understand mechanisms of susceptibility/resistance to PRRSV, this study profiled the time-serial white blood cells transcriptomic and serum metabolomic responses to PRRSV in piglets from a crossbred population of PRRSV-resistant Tongcheng pigs and PRRSV-susceptible Large White pigs. Gene set enrichment analysis (GSEA) illustrated that PRRSV infection up-regulated the expression levels of marker genes of dendritic cells, monocytes and neutrophils and inflammatory response, but down-regulated T cells, B cells and NK cells markers. CIBERSORT analysis confirmed the higher T cells proportion in resistant pigs during PRRSV infection. Resistant pigs showed a significantly higher level of T cell activation and lower expression levels of monocyte surface signatures post infection than susceptible pigs, corresponding to more severe suppression of T cell immunity and inflammatory response in susceptible pigs. Differentially expressed genes between resistant/susceptible pigs during the course of infection were significantly enriched in oxidative stress, innate immunity and humoral immunity, cell cycle, biotic stimulated cellular response, wounding response and behavior related pathways. Fourteen of these genes were distributed in 5 different QTL regions associated with PRRSV-related traits. Chemokine CXCL10 levels post PRRSV infection were differentially expressed between resistant pigs and susceptible pigs and can be a promising marker for susceptibility/resistance to PRRSV. Furthermore, the metabolomics dataset indicated differences in amino acid pathways and lipid metabolism between pre-infection/post-infection and resistant/susceptible pigs. The majority of metabolites levels were also down-regulated after PRRSV infection and were significantly positively correlated to the expression levels of marker genes in adaptive immune response. The integration of transcriptome and metabolome revealed concerted molecular events triggered by the infection, notably involving inflammatory response, adaptive immunity and G protein-coupled receptor downstream signaling. This study has increased our knowledge of the immune response differences induced by PRRSV infection and susceptibility differences at the transcriptomic and metabolomic levels, providing the basis for the PRRSV resistance mechanism and effective PRRS control.

The CCCH-type transcription factor BnZFP1 is a positive regulator to control oleic acid levels through the expression of diacylglycerol O-acyltransferase 1 gene in Brassica napus.

In China, the high-oleic acid rapeseed has an oil content of ∼42% and oleic acid (18:1) content of ∼80%. Compared to ordinary rapeseed, high-oleic acid rapeseed has higher levels of monounsaturated fatty acids and lower levels of saturated fatty acid and polyunsaturated fatty acids, and thus is of high nutritional and health value. In addition, high-oleic acid rapeseed oil imparts cardiovascular protective effects. Based on these properties, high-oleic acid oil crops have been extensively investigated and cultivated. We previously identified a CCCH-type transcription factor (BnZFP1, GenBank accession number XM_013796508) that is associated with high oleic acid traits from a Brassica napus subtractive hybridization library. In the present study, we overexpressed and silenced the BnZFP1 gene of B. napus. BnZFP1-overexpressing plants exhibited an 18.8% increase in oleic acid levels and a 3.8% increase in oil content. However, BNZFP1-silenced plants showed a 4.5% decrease in oleic acid levels, whereas no significant change in oil content was observed. Microarray and pull-down assays indicated that BnZFP1 has a total of thirty potential target genes. Further analysis and validation of one of the potential target genes, namely, diacylglycerol O-acyltransferases 1 (DGAT1) gene, indicated that it is positively regulated by BnZFP1. We also observed a correlation between elevated DGAT1 gene expression levels and higher oil content and oleic acid levels in rapeseed.