Unraveling the causal links and novel molecular classification of Crohn's disease in breast Cancer: a two-sample mendelian randomization and transcriptome analysis with prognostic modeling.

BACKGROUND: Crohn's disease (CD), a prominent manifestation of chronic gastrointestinal inflammation, and breast cancer (BC), seemingly disparate in the medical domain, exhibit a shared characteristic. This convergence arises from their involvement in chronic inflammation and immune responses, an aspect that has progressively captivated the attention of investigators but remain controversial. METHODS: We used two-sample Mendelian Randomization (MR) and transcriptomics to explore the relationship between CD and BC. MR assessed causality of CD on different BC subtypes and reverse causality of BC on CD. We identified CD-related differentially expressed genes and their prognostic impact on BC, and developed a new molecular BC classification based on these key genes. RESULTS: MR revealed a causal link between CD and increased BC risk, especially in estrogen receptor-positive (ER+) patients, but not in ER-negative (ER-) cases. BC showed no causal effect on CD. Transcriptomics pinpointed genes like B4GALNT2 and FGF19 that affected BC prognosis in CD patients. A nomogram based on these genes predicted BC outcomes with high accuracy. Using these genes, a new molecular classification of BC patients was proposed. CONCLUSIONS: CD is a risk factor for ER + BC but not for ER- BC. BC does not causally affect CD. Our prognostic model and new BC molecular classifications offer insights for personalized treatment strategies.

The immune checkpoint TIGIT/CD155 promotes the exhaustion of CD8 + T cells in TNBC through glucose metabolic reprogramming mediated by PI3K/AKT/mTOR signaling.

OBJECTIVE: The CD155/TIGIT axis has attracted considerable interest as an emerging immune checkpoint with potential applications in cancer immunotherapy. Our research focused on investigating the role of CD155/TIGIT checkpoints in the progression of triple-negative breast cancer (TNBC). METHODS: We evaluated CD155 and TIGIT expression in TNBC tissues using both immunohistochemistry (IHC) and gene expression profiling. Our experiments, both in vivo and in vitro, provided evidence that inhibiting the CD155/TIGIT pathway reinstates the ability of CD8 + T cells to generate cytokines. To assess the impact of CD155/TIGIT signaling blockade, we utilized Glucose Assay Kits and Lactate Assay Kits to measure alterations in glucose and lactate levels within CD8 + T cells. We employed western blotting (WB) to investigate alterations in glycolytic-related proteins within the PI3K/AKT/mTOR pathways following the inhibition of CD155/TIGIT signaling. RESULTS: CD155 exhibits heightened expression within TNBC tissues and exhibits a negative correlation with the extent of infiltrating CD8 + T cells. Furthermore, patients with TNBC demonstrate elevated levels of TIGIT expression. Our findings indicate that the interaction between CD155 and TIGIT disrupts the glucose metabolism of CD8 + T cells by suppressing the activation of the PI3K/AKT/mTOR signaling pathway, ultimately leading to the reduced production of cytokines by CD8 + T cells. Both in vivo and in vitro experiments have conclusively demonstrated that the inhibition of CD155/TIGIT interaction reinstates the capacity of CD8 + T cells to generate cytokines. Moreover, in vivo administration of the blocking antibody against TIGIT not only inhibits tumor growth but also augments the functionality of CD8 + T lymphocytes. CONCLUSIONS: Our research findings strongly suggest that CD155/TIGIT represents a promising therapeutic target for treating TNBC.

Methylation modification of non-histone proteins in breast cancer: An emerging targeted therapeutic strategy.

Breast cancer is a major public health concern worldwide, being the most commonly diagnosed cancer among women and a leading cause of cancer-related deaths. Recent studies have highlighted the significance of non-histone methylation in breast cancer, which modulates the activity, interaction, localization, and stability of target proteins. This regulation affects critical processes such as oncogenesis, tumor growth, proliferation, invasion, migration, and immune responses. This review delves into the enzymes responsible for non-histone methylation, such as protein arginine methyltransferases (PRMTs), lysine methyltransferases (KMTs), and demethylases, and explores their roles in breast cancer. By elucidating the molecular mechanisms and functional consequences of non-histone methylation, this review aims to provide insights into novel therapeutic strategies targeting these pathways. The therapeutic potential of targeting non-histone methylation to overcome drug resistance and enhance treatment efficacy in breast cancer is also discussed, highlighting promising avenues for future research and clinical applications.

Evacuation assisted by endoscopy has better efficacy for supratentorial intracerebral hematoma than CT-guided minimally invasive aspiration: a retrospective observational cohort study.

Objective: This retrospective study aimed to compare the efficacy of evacuation assisted by endoscopy and CT-guided minimally invasive aspiration for supratentorial intracerebral hematoma (SICH). Methods: Total 81 patients were classified into two groups to receive evacuation assisted by endoscopy or CT-guided minimally invasive aspiration. The therapeutic outcomes were compared between two groups. Results: The evacuation rate was significantly higher while infection rate was significantly lower in endoscopy group than in minimally invasive aspiration group (p < .05). Mortality rate showed no significant difference between the two groups. The patients operated within six hours had better outcome than those operated between 6-24 h (p < .05). Conclusion: For the patients with SICH, evacuation assisted by endoscopy is recommended for significantly shorter hospital stay and lower cost compared with CT-guided minimally invasive aspiration.

Identification of novel cuproptosis-related lncRNA signatures to predict the prognosis and immune microenvironment of breast cancer patients.

Background: Cuproptosis is a new modality of cell death regulation that is currently considered as a new cancer treatment strategy. Nevertheless, the prognostic predictive value of cuproptosis-related lncRNAs in breast cancer (BC) remains unknown. Using cuproptosis-related lncRNAs, this study aims to predict the immune microenvironment and prognosis of BC patients. and develop new therapeutic strategies that target the disease. Methods: The Cancer Genome Atlas (TCGA) database provided the RNA-seq data along with the corresponding clinical and prognostic information. Univariate and multivariate Cox regression analyses were performed to acquire lncRNAs associated with cuproptosis to establish predictive features. The Kaplan-Meier method was used to calculate the overall survival rate (OS) in the high-risk and low-risk groups. High risk and low risk gene sets were enriched to explore functional discrepancies among risk teams. The mutation data were analyzed using the "MAFTools" r-package. The ties of predictive characteristics and immune status had been explored by single sample gene set enrichment analysis (ssGSEA). Last, the correlation between predictive features and treatment condition in patients with BC was analyzed. Based on prognostic risk models, we assessed associations between risk subgroups and immune scores and immune checkpoints. In addition, drug responses in at-risk populations were predicted. Results: We identified a set of 11 Cuproptosis-Related lncRNAs (GORAB-AS1, AC 079922.2, AL 589765.4, AC 005696.4, Cytor, ZNF 197-AS1, AC 002398.1, AL 451085.3, YTH DF 3-AS1, AC 008771.1, LINC 02446), based on which to construct the risk model. In comparison to the high-risk group, the low-risk patients lived longer (p < 0.001). Moreover, cuproptosis-related lncRNA profiles can independently predict prognosis in BC patients. The AUC values for receiver operating characteristics (ROC) of 1-, 3-, and 5-year risk were 0.849, 0.779, and 0.794, respectively. Patients in the high-risk group had lower OS than those in the low-risk group when they were divided into groups based on various clinicopathological variables. The tumor burden mutations (TMB) correlation analysis showed that high TMB had a worse prognosis than low-TMB, and gene mutations were found to be different in high and low TMB groups, such as PIK3CA (36% versus 32%), SYNE1 (4% versus 6%). Gene enrichment analysis indicated that the differential genes were significantly concentrated in immune-related pathways. The predictive traits were significantly correlated with the immune status of BC patients, according to ssGSEA results. Finally, high-risk patients showed high sensitivity in anti-CD276 immunotherapy and conventional chemotherapeutic drugs such as imatinib, lapatinib, and pazopanib. Conclusion: We successfully constructed of a cuproptosis-related lncRNA signature, which can independently predict the prognosis of BC patients and can be used to estimate OS and clinical treatment outcomes in BRCA patients. It will serve as a foundation for further research into the mechanism of cuproptosis-related lncRNAs in breast cancer, as well as for the development of new markers and therapeutic targets for the disease.

Expression of Krüppel-like factor 9 in breast cancer patients and its effect on prognosis.

Expression of Krüppel-like factor 9 (KLF9) in breast cancer tissue and its influence on prognosis was investigated. Sixty-eight patients with breast cancer admitted in Ningde Hospital Affiliated to Fujian Medical University from February 2014 to August 2015 were collected, and the expression level of KLF9 in cancerous tissue (n=68) and normal tissue (n=68) of the patients was measured by quantitative real-time PCR (RT-qPCR). The relationship between the expression and clinical pathological features and prognosis of patients was analyzed. The expression level of KLF9 in cancerous tissue was significantly lower than that in normal tissue (P<0.05). The expression in breast cancer tissue was not significantly correlated with age, height, menstrual status, lymph node metastasis or pathological differentiation (P>0.05), but was significantly correlated with tumor size and clinical stage (P<0.05). The 1-, 2-, and 3-year survival rates in the high expression group were significantly higher than those in the low expression group (P<0.001). Univariate Cox regression analysis was carried out according to the 3-year survival of the patients, and the results showed that tumor size (P=0.009), lymph node metastasis (P=0.002), pathological differentiation (P=0.015), clinical stage (P=0.013), and KLF9 (P=0.018) were factors affecting the survival of breast cancer patients. Subsequently, multivariate Cox regression analysis of the indicators with differences showed that those indicators were independent predictors of survival of breast cancer patients. In conclusion, KLF9 expression is low in breast cancer tissue, and its expression level is related to tumor size and clinical stage. Moreover, tumor size >5 cm, lymph node metastasis, low pathological differentiation, high clinical stage and low expression of KLF9 are all important factors that cause death of patients.

Transferrin-modified Doxorubicin-loaded biodegradable nanoparticles exhibit enhanced efficacy in treating brain glioma-bearing rats.

Doxorubicin (Dox) is widely used for the treatment of solid tumors but its clinical utility on glioma is limited. In this study, we developed a novel nano-scale drug delivery system employing biodegradable nanoparticle (NP) as carriers to load Dox. Transferrin (Tf) was conjugated to the surface of NP to specifically target the NP to glioma. Tf-NP-Dox was prepared via emulsification-solvent evaporation method, and characterized for the size, Drug loading capacity (DLC), entrapment efficiency, and Tf number on the surface. The antitumor efficiency in vitro was evaluated via CCK-8 assay. The transmembrane transportation was evaluated via HPLC assay. The antitumor efficiency in vivo was assessed in C6 glioma intracranial implant rat model. The average diameter of Tf-NP-Dox was 100 nm with ∼32 Tf molecules on the surface. DLC was 4.4%. CCK-8 assay demonstrated much stronger cytotoxicity of Tf-NP-Dox to C6 glioma cells compared to NP-Dox or Dox. HPLC assay showed that Tf-NP-Dox transported Dox into C6 cells with high efficiency. In vivo, Tf-NP-Dox could transport Dox into tumors compare to contralateral part, with tumor inhibitory ratio and survival higher than NP-Dox or Dox. Taken together, our results suggest that Tf-NP-Dox exhibits better therapeutic effects against glioma both in vitro and in vivo, and is a potential nano-scale drug delivery system for glioma chemotherapy.