A Novel Prognostic Prediction Model Based on Pyroptosis-Related Clusters for Breast Cancer.

Breast cancer (BC) is the most common cancer affecting women and the leading cause of cancer-related deaths worldwide. Compelling evidence indicates that pyroptosis is inextricably involved in the development of cancer and may activate tumor-specific immunity and/or enhance the effectiveness of existing therapies. We constructed a novel prognostic prediction model for BC, based on pyroptosis-related clusters, according to RNA-seq and clinical data downloaded from TCGA. The proportions of tumor-infiltrating immune cells differed significantly in the two pyroptosis clusters, which were determined according to 38 pyroptosis-related genes, and the immune-related pathways were activated according to GO and KEGG enrichment analysis. A 56-gene signature, constructed using univariate and multivariate Cox regression, was significantly associated with progression-free interval (PFI), disease-specific survival (DSS), and overall survival (OS) of patients with BC. Cox analysis revealed that the signature was significantly associated with the PFI and DSS of patients with BC. The signature could efficiently distinguish high- and low-risk patients and exhibited high sensitivity and specificity when predicting the prognosis of patients using KM and ROC analysis. Combined with clinical risk, patients in both the gene and clinical low-risk subgroup who received adjuvant chemotherapy had a significantly lower incidence of the clinical event than those who did not. This study presents a novel 56-gene prognostic signature significantly associated with PFI, DSS, and OS in patients with BC, which, combined with the TNM stage, might be a potential therapeutic strategy for individualized clinical decision-making.

A Novel TCGA-Validated, MiRNA-Based Signature for Prediction of Breast Cancer Prognosis and Survival.

Breast cancer (BC) is the most common cancer affecting women and the leading cause of cancer-related deaths worldwide. Compelling evidence indicates that microRNAs (miRNAs) are inextricably involved in the development of cancer. Here, we constructed a novel model, based on miRNA-seq and clinical data downloaded from The Cancer Genome Atlas (TCGA). Data from a total of 962 patients were included in this study, and the relationships among their clinicopathological features, survival, and miRNA-seq expression levels were analyzed. Hsa-miR-186 and hsa-miR-361 were identified as internal reference miRNAs and used to normalize miRNA expression data. A five-miRNA signature, constructed using univariate and multivariate Cox regression, was significantly associated with disease-specific survival (DSS) of patients with BC. Kaplan-Meier (KM) and receiver operating characteristic (ROC) analyses were conducted to confirm the clinical significance of the five-miRNA signature. Finally, a nomogram was constructed based on the five-miRNA signature to evaluate its clinical value. Cox regression analysis revealed that a five-miRNA signature was significantly associated with DSS of patients with BC. KM analysis demonstrated that the signature could efficiently distinguish high- and low-risk patients. Moreover, ROC analysis showed that the five-miRNA signature exhibited high sensitivity and specificity in predicting the prognosis of patients with BC. Patients in the high-risk subgroup who received adjuvant chemotherapy had a significantly lower incidence of mortality than those who did not. A nomogram constructed based on the five-miRNA signature was effective in predicting 5-year DSS. This study presents a novel five-miRNA signature as a reliable prognostic tool to predict DSS and provide theoretical reference significance for individualized clinical decisions for patients with BC.

Screening of Prognosis-Related Genes in Primary Breast Carcinoma Using Genomic Expression Data.

This study aimed at exploring the genes that may be related to the prognosis of primary breast cancer (BC) patients. The gene expression microarray data, together with sample survival data were acquired from The Cancer Genome Atlas database. The top 20% genes according to expression value variance were subjected to hierarchical cluster analysis. Bootstrap methods were utilized to assess the stability of cluster. Cox regression was applied to screen genes related to the survival time of patients with BC, and the Beta-Uniform Mixture model was applied to adjust the significance of numerous tests. Further, ingenuity pathway analysis (IPA) was carried out to analyze the functions of the potential prognostic genes. Cluster analysis revealed that there were at least five stable BC subtypes, each with specific gene expression. Further, 42 survival time-associated genes were found (p-value = 0.0006, false discovery rate = 0.2) by Cox regression analysis. According to Gene Ontology (GO) functional annotation, genes in clusters A, B, C, D, and E separately were implicated in cell adhesion cooperation, cell stress response, cell cycle, the assembly of nucleosome and chromosome, and immune regulation. IPA results showed that prognosis-related genes mainly participated in the pathways of cell apoptosis, and cell communication and morphology. Genes such as JAK2, TBP, PTGES3, and RYBP may be promising prognostic biomarkers for BC patients.

Effect of Previous Abdominal Surgery on Laparoscopic Roux-en-Y Gastric Bypass Surgery.

BACKGROUND: Previous abdominal surgery (PAS) is a relative contraindication of laparoscopic surgery. In this study, we aimed to investigate the effect of PAS on the feasibility and safety of laparoscopic Roux-en-Y gastric bypass surgery (LRYGB) in patients with obesity and type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: A retrospective analysis was conducted for a total of 235 consecutive patients with obesity and T2DM from Shanghai Tongren Hospital from February 2011 to December 2015. The patients were classified into two groups: no previous abdominal surgery group (NPAS group, n = 179) and previous abdominal surgery group (PAS group, n = 56). The patients underwent LRYGB, and the data of basic information, presence of adhesions, adhesiolysis requirement, operative time, blood loss, hospital stay, and perioperative and postoperative complications were collected and compared between the groups. RESULTS: Adhesion was found in 14 patients in the NPAS group and in 43 patients in the PAS group, with adhesiolysis requirement in 4 (2.23%) and 37 (66.07%) patients, respectively (P < 0.05). There were no complications directly associated with adhesiolysis. No patients were converted to open surgery. There were no significant differences in gender (P = 0.30), T2DM duration (P = 0.58), body mass index (P = 0.06), blood loss (P = 0.36), or perioperative or postoperative complications (P = 0.41) between the groups. Significant differences were observed in the mean age, ASA score, operative time, and hospital stay between the groups (P < 0.001). CONCLUSIONS: PAS is relatively safe and feasible for LRYGB in Chinese patients with obesity and T2DM.

Bioinformatics Analysis of Stromal Molecular Signatures Associated with Breast and Prostate Cancer.

This study aimed to identify stromal molecular signatures associated with breast and prostate cancer. The microarray data GSE26910 was downloaded from Gene Expression Omnibus database, including six invasive breast tumor stroma, six matched normal controls, six invasive prostate tumor stroma, and six matched controls. The differentially expressed genes (DEGs) in invasive breast and prostate tumors stroma were, respectively, identified. Then common stromal genes (B_P.DEGs) were further screened. Protein-protein interaction (PPI) network was constructed and Gene Ontology analysis was performed. Besides, gene-chemical interactions were mapped in Comparative Toxicogenomics Database to screen the chemicals related to feature genes. The results showed that, in total, 16 B_P.DEGs were identified. Thereinto, only seven B_P.DEGs were mapped into PPI, and only four functional modules (adenylate cyclase activating polypeptide 1 (pituitary) receptor type I (ADCYAP1R1) module, aspartoacylase (ASPA) module, glutathione S-transferase mu 5 (GSTM5) module, and periplakin (PPL) module) were involved in important biological processes associated with cancer progression. In addition, the chemicals, such as dihydrotestosterone, apocarotenal, testosterone, and progesterone, were screened for the roles of feature genes in the progression of breast and prostate cancer. In conclusion, ADCYAP1R1, GSTM5, and PPL were stromal molecular signatures and might play a key role in the progression of breast and prostate cancer.

Mindin deficiency protects the liver against ischemia/reperfusion injury.

BACKGROUND & AIMS: Hepatic ischemia/reperfusion (I/R) injury often occurs during liver surgery and may cause liver failure. Our previous studies revealed that Mindin is involved in the pathogenesis of ischemic stroke. However, the function of Mindin in hepatic I/R injury remains unknown. METHODS: Partial hepatic warm ischemia was induced in parallel in global Mindin knockout mice (Mindin KO), hepatocyte-specific Mindin knockdown mice, hepatocyte-specific Mindin transgenic mice (Mindin TG), myeloid cell-specific Mindin TG mice (LysM-Mindin TG), and their corresponding controls, followed by reperfusion. Hepatic histology, serum aminotransferase, inflammatory cytokines, and hepatocyte apoptosis and proliferation were examined to assess liver injury. The molecular mechanisms of Mindin function were explored in vivo and in vitro. RESULTS: Mindin KO and hepatocyte-specific Mindin knockdown mice exhibited less liver damage than controls, with smaller necrotic areas and lower serum transaminase levels. Mindin deficiency significantly suppressed inflammatory cell infiltration, cytokine and chemokine production, and hepatocyte apoptosis, but increased hepatocyte proliferation following hepatic I/R injury. In contrast, the opposite pathological and biochemical changes were observed in hepatocyte-specific Mindin TG mice, whereas no significant changes in liver damage were found in LysM-Mindin TG mice compared to non-transgenic controls. Mechanistically, Akt signaling was activated in livers of Mindin KO mice but was suppressed in Mindin TG mice. Most importantly, Akt inhibitor treatment blocked the protective effect of Mindin deficiency on hepatic I/R injury. CONCLUSIONS: Mindin is a novel modulator of hepatic I/R injury through regulating inflammatory responses, as well as hepatocyte apoptosis and proliferation via inactivation of the Akt signaling pathway.

CXCL9 attenuated chemotherapy-induced intestinal mucositis by inhibiting proliferation and reducing apoptosis.

Mucositis arising from cancer chemotherapy is a common problem for which there is no definitive treatment. 5-fluorouracil (5-FU) is a common cytotoxic agent used to treat solid tumors. A global gene expression array was performed to identify genetic signals involved in the pathogenesis of mucositis. The chemokine (C-X-C motif) ligand 9 (CXCL9) was one of the candidates identified that presented a characteristic gene expression profile; its temporal expression pattern was correlated with the damage and regeneration phases of the small intestine upon 5-FU chemotherapy. We found that prophylactic CXCL9 administration was able to attenuate the severity of mucositis, weight loss and diarrhea caused by chemotherapy. CXCL9 also increased the tolerance of the mice to lethal-dose chemotherapy. Moreover, we demonstrated that CXCL9 was able to promote the proliferation and regeneration of intestinal cells by inhibiting the proliferation of normal intestinal mucosal cells prior to chemotherapy and by reducing the 5-FU-induced apoptosis in intestinal crypts. Thus, pretreatment with CXCL9 is a new and promising strategy for the alleviation of chemotherapy-induced intestinal mucositis in clinical settings.