Breast cancer (BC) is now the most frequent and lethal cancer among women. Cuproptosis is a newly identified programmed cell death process that has been connected to tumor therapeutic sensitivity, patient outcomes, and the genesis of cancer. Cuproptosis-related genes (CRGs) are involved in breast cancer, although their roles and potential mechanisms are still unclear. First, we examined the effect of gene mutations and copy number changes on overall survival in 1168 breast cancer samples. Breast cancer patients were split into two molecular categories as determined by the variation in CRG based on clinicopathological traits, overall survival, and cell-infiltrating traits in tumor microenvironments. In addition, we created and validated a CRG score to calculate breast cancer patients' OS. Finally, we created a comprehensive nomogram for the clinical use of the CRG score. Patients whose CRG scores were low showed increased odds of developing OS, a larger mutation load, and immunological activation than those with high CRG scores. The CRG score, the cancer stem cell index, and the responsiveness to chemotherapy or targeted therapies were also shown to be statistically significantly correlated. Our thorough examination of CRGs in breast cancer patients demonstrated that they may be useful predictors of prognosis, clinical characteristics, and tumor microenvironment. These findings provide fresh insight into CRGs in breast cancer and might inspire brand-new approaches to both diagnosing and treating patients there.

We have examined the effect of exogenous linear chain high molecular weight hyaluronic acid (HMW HA) on endogenously synthesized hyaluronic acid (HA) and associated binding proteins in primary cultures of fibroblast-like stromal cells that were obtained by collagenase digestion of the murine peripatellar fat pad. The cultures were expanded in DMEM that was supplemented with fetal bovine serum and basic fibroblast growth factor (bFGF) then exposed to macrophage-colony-stimulating factor (MCSF) to induce macrophage properties, before activation of inflammatory pathways using E. coli lipopolysaccharide (LPS). Under all culture conditions, a significant amount of endogenously synthesized HA localized in LAMP1-positive lysosomal vesicles. However, this intracellular pool was depleted after the addition of exogenous HMW HA and was accompanied by enhanced proteolytic processing and secretion of de novo synthesized versican, much of which was associated with endosomal compartments. No changes were detected in synthesis, secretion, or proteolytic processing of aggrecan or lubricin (PRG4). The addition of HMW HA also modulated a range of LPS-affected genes in the TLR signaling and phagocytosis pathways, as well as endogenous HA metabolism genes, such as Has1, Hyal1, Hyal2, and Tmem2. However, there was no evidence for association of endogenous or exogenous HMW HA with cell surface CD44, TLR2 or TLR4 protein, suggesting that its physiochemical effects on pericelluar pH and/or ionic strength might be the primary modulators of signal transduction and vesicular trafficking by this cell type. We discuss the implications of these findings in terms of a potential in vivo effect of therapeutically applied HMW HA on the modification of osteoarthritis-related joint pathologies, such as pro-inflammatory and degradative responses of multipotent mesenchymal cells residing in the synovial membrane, the underlying adipose tissue, and the articular cartilage surface.

Background: Triple-negative breast cancer (TNBC) is the subtype of breast cancer with the worst prognosis, and traditional survival analysis methods are biased when predicting mortality. To predict the risk of death in patients with triple-negative breast cancer more precisely, a competing risk model was developed. Methods:The clinicopathological data of the TNBC patients from 2010 to 2015 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. The data were assigned into a training set and testing set at a ratio of 7:3 in a randomized pattern. Univariate and multivariate competing risk models were applied to find the independent prognostic factors. A prediction nomogram for cancer-specific mortality (CSM) risk was constructed. The accuracy and discrimination of the nomogram were assessed using receiver operating characteristic (ROC) area under the curve (AUC), concordance index (C-index), and a calibration curve using the training and testing sets, respectively.Results: A total of 28,430 TNBC patients were randomly grouped into the training set (n=19,900) and the testing set (n=8,530). The median time for follow-up was 59 [1-107] months. A total of 7,014 (24.67%) patients died, among whom 4,801 (68.45%) died from breast cancer and 2,213 (31.55%) due to non-breast cancer events. The independent risk factors were primary site of tumor, grade, tumor-node-metastasis (TNM) stage, T stage, approach of surgery, chemotherapy, axillary lymph node metastases, brain metastases, and liver metastases. The prediction nomogram was constructed by using the aforementioned variables. The 1-, 3-, and 5-year AUC of CSM were predicted to be 0.856, 0.81, and 0.782, respectively, in the training set, and 0.856, 0.81, and 0.782 in the testing set, respectively. The C-index of the nomogram was 0.801 and 0.799 in the training and testing sets, respectively. As confirmed by the validation and training calibration curves, the nomogram was consistent with the results. Conclusions:We used competing risk models to identify risk factors for CSM and constructed a CSM risk prediction nomogram for TNBC patients, that may be utilized to predict CSM risk in TNBC patients clinically and assist in the creation of individualised clinical treatment options.