CD44ICD promotes breast cancer stemness via PFKFB4-mediated glucose metabolism.

CD44 is a single-pass cell surface glycoprotein that is distinguished as the first molecule used to identify cancer stem cells in solid tumors based on its expression. In this regard, the CD44high cell population demonstrates not only the ability to regenerate a heterogeneous tumor, but also the ability to self-regenerate when transplanted into immune-deficient mice. However, the exact role of CD44 in cancer stem cells remains unclear in part because CD44 exists in various isoforms due to alternative splicing. Methods: Gain- and loss-of-function methods in different models were used to investigate the effects of CD44 on breast cancer stemness. Cancer stemness was analyzed by detecting SOX2, OCT4 and NANOG expression, ALDH activity, side population (SP) and sphere formation. Glucose consumption, lactate secretion and reactive oxygen species (ROS) levels were detected to assess glycolysis. Western blot, immunohistochemical staining, ELISA and TCGA dataset analysis were performed to determine the association of CD44ICD and PFKFB4 with clinical cases. A PFKFB4 inhibitor, 5MPN, was used in a xenograft model to inhibit breast cancer development. Results: In this report, we found that the shortest CD44 isoform (CD44s) inhibits breast cancer stemness, whereas the cleaved product of CD44 (CD44ICD) promotes breast cancer stemness. Furthermore, CD44ICD interacts with CREB and binds to the promoter region of PFKFB4, thereby regulating PFKFB4 transcription and expression. The resultant PFKFB4 expression facilitates the glycolysis pathway (vis-à-vis oxidative phosphorylation) and promotes stemness of breast cancer. In addition, we found that CD44ICD and PFKFB4 expressions are generally up-regulated in the tumor portion of breast cancer patient samples. Most importantly, we found that 5MPN (a selective inhibitor of PFKFB4) suppresses CD44ICD-induced tumor development. Conclusion: CD44ICD promotes breast cancer stemness via PFKFB4-mediated glycolysis, and therapies that target PFKFB4 (e.g., 5MPN therapy) may lead to improved outcomes for cancer patients

Intratumor microbiome derived glycolysis-lactate signatures depicts immune heterogeneity in lung adenocarcinoma by integration of microbiomic, transcriptomic, proteomic and single-cell data

IntroductionMicrobiome plays roles in lung adenocarcinoma (LUAD) development and anti-tumor treatment efficacy. Aberrant glycolysis in tumor might promote lactate production that alter tumor microenvironment, affecting microbiome, cancer cells and immune cells. We aimed to construct intratumor microbiome score to predict prognosis of LUAD patients and thoroughly investigate glycolysis and lactate signature’s association with LUAD immune cell infiltration.MethodsThe Cancer Genome Atlas-LUAD (TCGA-LUAD) microbiome data was downloaded from cBioPortal and analyzed to examine its association with overall survival to create a prognostic scoring model. Gene Set Enrichment Analysis (GSEA) was used to find each group’s major mechanisms involved. Our study then investigated the glycolysis and lactate pattern in LUAD patients based on 19 genes, which were correlated with the tumor microenvironment (TME) phenotypes and immunotherapy outcomes. We developed a glycolysis-lactate risk score and signature to accurately predict TME phenotypes, prognosis, and response to immunotherapy.ResultsUsing the univariate Cox regression analysis, the abundance of 38 genera were identified with prognostic values and a lung-resident microbial score (LMS) was then developed from the TCGA-LUAD-microbiome dataset. Glycolysis hallmark pathway was significantly enriched in high-LMS group and three distinct glycolysis-lactate patterns were generated. Patients in Cluster1 exhibited unfavorable outcomes and might be insensitive to immunotherapy. Glycolysis-lactate score was constructed for predicting prognosis with high accuracy and validated in external cohorts. Gene signature was developed and this signature was elevated in epithelial cells especially in tumor mass on single-cell level. Finally, we found that the glycolysis-lactate signature levels were consistent with the malignancy of histological subtypes.DiscussionOur study demonstrated that an 18-microbe prognostic score and a 19-gene glycolysis-lactate signature for predicting prognosis of LUAD patients. Our LMS, glycolysis-lactate score and glycolysis-lactate signature have potential roles in precision therapy of LUAD patients

Psychological symptoms in Chinese nurses may be associated with predisposition to chronic disease: A cross-sectional study of suboptimal health status

© 2020, The Author(s). Background: Suboptimal health status (SHS) is a reversible state between ideal health and illness and it can be effectively reversed by risk prediction, disease prevention, and personalized medicine under the global background of predictive, preventive, and personalized medicine (PPPM) concepts. More and more Chinese nurses have been troubled by psychological symptoms (PS). The correlation between PS and SHS is unclear in nurses. The purpose of current study is to investigate the prevalence of SHS and PS in Chinese nurses and the relationship between SHS and PS along with predisposing factors as well as to discuss the feasibility of improving health status and preventing diseases according to PPPM concepts in Chinese nurses. Methods: A cross-sectional study was conducted with the cluster sampling method among 9793 registered nurses in Foshan city, China. SHS was evaluated with the Suboptimal Health Status Questionnaire-25 (SHSQ-25). Meanwhile, the PS of depression and anxiety were evaluated with Self-Rating Depression Scale (SDS) and Self-Rating Anxiety Scale (SAS) self-assessment questionnaires. The relationship between PS and SHS in Chinese nurses was subsequently analyzed. Results: Among the 9793 participants, 6107 nurses were included in the final analysis. The prevalence of SHS in the participants was 74.21% (4532/6107) while the symptoms of depression and anxiety were 47.62% (2908/6107) and 24.59% (1502/6107) respectively. The prevalence of SHS in the participants with depression and anxiety was significantly higher than those without the symptoms of depression (83.3% vs 16.7%, P \u3c 0.001) and anxiety (94.2% vs 5.8%, P \u3c 0.0001). The ratio of exercise habit was significantly lower than that of non-exercise habit (68.8% vs 78.4%, P \u3c 0.001) in SHS group. Conclusions: There is a high prevalence of SHS and PS in Chinese nurses. PS in Chinese nurses are associated with SHS. Physical exercise is a protective factor for SHS and PS so that the exercise should be strongly recommended as a valuable preventive measure well in the agreement with PPPM philosophy. Along with SDS and SAS, SHSQ-25 should also be highly recommended and applied as a novel predictive/preventive tool for the health measures from the perspectives of PPPM in view of susceptible population and individual screening, the predisposition to chronic disease preventing, personalization of intervention, and the ideal health state restoring

PFKFB4 Promotes Breast Cancer Metastasis via Induction of Hyaluronan Production in a p38-Dependent Manner

Background/Aims: The bi-functional enzyme 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase-4 (PFKFB4) is highly expressed in many types of cancer and its requirement for tumor survival has been demonstrated in glioma, lung, and prostate cancers. However, whether PFKFB4 plays a role in the tumor metastasis remains uncertain. This study explores the role of PFKFB4 in tumor metastasis and its underlying mechanisms in breast cancer cells. Methods: The expression of PFKFB4 was first analyzed using the Cancer Genome Atlas (TCGA) dataset, and confirmed by immunohistochemical staining of tissue microarray and breast cancer tissues from patient samples. Gain- and loss-of- function approaches were used to investigate the effects of PFKFB4 on breast cancer cell migration in vitro. Orthotopic xenograft model and experimental metastasis model were used to assess the effects of PFKFB4 on breast cancer cell metastasis in vivo. ELISA and immunofluorescence staining were used to examine HA production. Quantitative RT-PCR and western blotting were used to explore the mRNA and protein levels of HAS2, respectively. Results: We found that PFKFB4 enhances the migration/invasiveness of breast cancer cells in vitro as well as in vivo. Notably, the effects of PFKFB4 on migration are mediated by induction of HAS2 expression and HA production. Moreover, PFKFB4-induced HAS2 up-regulation depends upon the activation of p38 signaling. Conclusion: PFKFB4 promotes the metastasis of breast cancer cells via induction of HAS2 expression and HA production in a p38-dependent manner. Therefore, the PFKFB4/p38/HAS2 signaling pathway may serve as a potential therapeutic target for metastatic breast cancer

Forecasting Cohesionless Soil Highway Slope Displacement Using Modular Neural Network

The highway slope failures are triggered by the rainfall, namely, to create the disaster. However, forecasting the failure of highway slop is difficult because of nonlinear time dependency and seasonal effects, which affect the slope displacements. Starting from the artificial neural networks (ANNs) since the mid-1990s, an effective means is suggested to judge the stability of slope by forecasting the slope displacement in the future based on the monitoring data. In order to solve the problem of forecasting the highway slope displacement, a displacement time series forecasting model of cohesionless soil highway slope is given firstly, and then modular neural network (MNN) is used to train it. With the randomness of rainfall information, the membership function based on distance measurement is constructed; after that, a fuzzy discrimination method to sample data is adopted to realize online subnets selection to improve the self-adapting ability of artificial neural networks (ANNs). The experiment on the sample data of Beijing city’s highway slope demonstrates that this model is superior to others in accuracy and adaptability

Identification of Hub Genes and Biological Mechanisms Associated with Non-Alcoholic Fatty Liver Disease and Triple-Negative Breast Cancer

The relationship between non-alcoholic fatty liver disease (NAFLD) and triple-negative breast cancer (TNBC) has been widely recognized, but the underlying mechanisms are still unknown. The objective of this study was to identify the hub genes associated with NAFLD and TNBC, and to explore the potential co-pathogenesis and prognostic linkage of these two diseases. We used GEO, TCGA, STRING, ssGSEA, and Rstudio to investigate the common differentially expressed genes (DEGs), conduct functional and signaling pathway enrichment analyses, and determine prognostic value between TNBC and NAFLD. GO and KEGG enrichment analyses of the common DEGs showed that they were enriched in leukocyte aggregation, migration and adhesion, apoptosis regulation, and the PPAR signaling pathway. Fourteen candidate hub genes most likely to mediate NAFLD and TNBC occurrence were identified and validation results in a new cohort showed that ITGB2, RAC2, ITGAM, and CYBA were upregulated in both diseases. A univariate Cox analysis suggested that high expression levels of ITGB2, RAC2, ITGAM, and CXCL10 were associated with a good prognosis in TNBC. Immune infiltration analysis of TNBC samples showed that NCF2, ICAM1, and CXCL10 were significantly associated with activated CD8 T cells and activated CD4 T cells. NCF2, CXCL10, and CYBB were correlated with regulatory T cells and myeloid-derived suppressor cells. This study demonstrated that the redox reactions regulated by the NADPH oxidase (NOX) subunit genes and the transport and activation of immune cells regulated by integrins may play a central role in the co-occurrence trend of NAFLD and TNBC. Additionally, ITGB2, RAC2, and ITGAM were upregulated in both diseases and were prognostic protective factors of TNBC; they may be potential therapeutic targets for treatment of TNBC patients with NAFLD, but further experimental studies are still needed