A diagnostic model for Parkinson's disease based on circadian rhythm-related genes.

BACKGROUND: Circadian rhythm (CR) disturbance is intricately associated with Parkinson's disease (PD). However, the involvement of CR-related mechanisms in the pathogenesis and progression of PD remains elusive. METHODS: A total of 141 PD patients and 113 healthy participants completed CR-related clinical examinations in this study. To further investigate the CR-related mechanisms in PD, we obtained datasets (GSE7621, GSE20141, GSE20292) from the Gene Expression Omnibus database to identify differentially expressed genes between PD patients and healthy controls and further selected CR-related genes (CRRGs). Subsequently, the least absolute shrinkage and selection operator (LASSO) followed by logistic algorithms were employed to identify the hub genes and construct a diagnostic model. The predictive performance was evaluated by area under the curve (AUC), calibration curve, and decision curve analyses in the training set and external validation sets. Finally, RT‒qPCR and Western blotting were conducted to verify the expression of these hub genes in blood samples. In addition, Pearson correlation analysis was utilized to validate the association between expression of hub genes and circadian rhythm function. RESULTS: Our clinical observational study revealed that even early-stage PD patients exhibited a higher likelihood of experiencing sleep disturbances, nocturnal hypertension, reverse-dipper blood pressure, and reduced heart rate variability compared to healthy controls. Furthermore, 4 CR-related hub genes (AGTR1, CALR, BRM14, and XPA) were identified and subsequently incorporated as candidate biomarkers to construct a diagnostic model. The model showed satisfactory diagnostic performance in the training set (AUC = 0.941), an external validation set GSE20295 (AUC = 0.842), and our clinical centre set (AUC = 0.805). Additionally, the up-regulation of CALR, BRM14 and the down-regulation of AGTR1, XPA were associated with circadian rhythm disruption. CONCLUSION: CR disturbance seems to occur in the early stage of PD. The diagnostic model based on CR-related genes demonstrated robust diagnostic efficacy, offering novel insights for future clinical diagnosis of PD and providing a foundation for further exploration into the role of CR-related mechanisms in the progression of PD.

Special issue "The advance of solid tumor research in China": Discoidin domain receptor 2 promotes colorectal cancer metastasis by regulating epithelial mesenchymal transition via activating AKT signaling.

Tumor metastasis is one of the main reasons for the high mortality rate associated with colorectal cancer (CRC). However, its underlying mechanisms have not been fully understood. Here, we reported that the expression of discoidin domain receptor 2 (DDR2) was significantly upregulated in CRC tissues compared to that in normal adjacent tissues. The expression level of DDR2 was negatively associated with prognosis of CRC patients. Therefore, DDR2 may play an oncogenic role in CRC development. Furthermore, DDR2 induced epithelial mesenchymal transition in CRC cells and regulated their invasive and metastatic capacity in vitro and in vivo. Mechanistically, increased DDR2 expression level activated the AKT/GSK-3ß/Slug signaling pathway. In conclusion, these findings showed that DDR2 promoted CRC metastasis and DDR2 inhibition might represent an effective therapeutic strategy for local advanced and metastatic CRC treatment.

DDR1 functions as an immune negative factor in colorectal cancer by regulating tumor-infiltrating T cells through IL-18.

Immunotherapies represented by programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) immune checkpoint inhibitors have made great progress in the field of anticancer treatment, but most colorectal cancer patients do not benefit from immunotherapy. Discoidin domain receptor 1 (DDR1), a tyrosine kinase receptor, is activated by collagen binding and overexpressed in various malignancies. However, the role of DDR1 in colorectal cancer and immunoregulation remains unclear. In this study, we found DDR1 is highly expressed in colorectal cancer tissues and negatively associated with patient survival. We demonstrated that DDR1 promotes colorectal tumor growth only in vivo. Mechanistically, DDR1 is a negative immunomodulator in colorectal cancer and is involved in low infiltration of CD4+ and CD8+ T cells by inhibiting IL-18 synthesis. We also reported that DDR1 enhances the expression of PD-L1 through activating the c-Jun amino terminal kinase (JNK) signaling pathway. In conclusion, our findings elucidate the immunosuppressive role of DDR1 in colorectal cancer, which may represent a novel target to enhance the efficacy of immunotherapy in colorectal cancer.

mPEG-PDLLA Micelles Potentiate Docetaxel for Intraperitoneal Chemotherapy in Ovarian Cancer Peritoneal Metastasis.

Ovarian cancer is the second most common cause of gynecological cancer death in women. It is usually diagnosed late and accompanied by peritoneal metastasis. For ovarian cancer with peritoneal metastasis, intraperitoneal (IP) chemotherapy can maintain a high drug concentration in the abdominal cavity and reduce local and systemic toxicity. Recently, docetaxel (DTX) has shown broad-spectrum antitumor activity against various malignant tumors, including ovarian cancer with peritoneal metastasis. However, DTX has limited clinical applications due to its poor water solubility, predisposition to hypersensitivity, fluid retention, and varying degrees of neurotoxicity. In this study, we prepared methoxy-poly(ethylene glycol)-block-poly(D,L-lactide) (mPEG-PDLLA) micelles loaded with DTX and developed an alternative, less toxic, more effective DTX formulation, without Tween 80, and evaluated its pharmacokinetics in the abdominal cavity and its efficacy in ovarian cancer with peritoneal metastasis. The mean diameter of DTX-mPEG-PDLLA was about 25 nm, and the pharmacokinetics of BALB/c mice via IP showed that the plasma exposure of DTX-mPEG-PDLLA was about four times lower than that of DTX. Importantly, DTX-mPEG-PDLLA was significantly more effective than DTX and prolonged the survival period in a SKOV-3 ovarian cancer peritoneal metastasis model. Moreover, the apoptosis rate was significantly increased in vitro. Based on these findings, it is expected that DTX-mPEG-PDLLA can enhance efficacy against ovarian cancer peritoneal metastasis, while reducing toxic side effects, and has the potential to be used in the clinical treatment of peritoneal metastatic cancer.

RIPK1 contributes to cisplatin-induced apoptosis of esophageal squamous cell carcinoma cells via activation of JNK pathway.

AIMS: Previous studies have uncovered the function of receptor-interacting protein kinase 1 (RIPK1) to mediate both cell survival and death. Moreover, RIPK1 modulates apoptosis and necroptosis depending on its activity, phosphorylation or ubiquitylation status. Many studies have explained the role or mechanism of RIPK1 in necroptosis. However, the role of RIPK1 has not been elucidated fully in human esophageal squamous cell carcinoma (ESCC) cells. MATERIALS AND METHODS: The protein and mRNA expression levels of RIPK1 in a panel of ESCC cell lines by Western blot and real-time quantitative reverse transcription PCR (qRT-PCR) were analyzed. MTS assay was used to examine cellular proliferation, flow cytometric analysis to detect apoptosis, mitochondrial membrane potential and reactive oxygen species production. ESCC cells with either inhibitor or overexpressed RIPK1were analyzed to determine cell proliferation, colony formation and apoptosis. Flow cytometry and western blotting assays were used to explore the underlying mechanism. KEY FINDINGS: In our study, RIPK1 expression was found to contribute significantly to cisplatin-induced apoptosis in the human ESCC cells. The reduced RIPK1 expression promoted cells proliferation and overexpressed RIPK1 facilitated cell apoptosis. Mechanistic investigations have revealed that the inhibition of proliferation for RIPK1 in ESCC cells was regulated via activation of c-Jun NH2-terminal kinase signaling. Additionally, damages were observed in the mitochondrial membrane, depletion of ATP and increased generation in reactive oxygen species. SIGNIFICANCE: Our findings verified the evidence that RIPK1 can promote cell death in ESCC cells, with potential implications for activating c-Jun NH2-terminal kinase pathway as a novel approach to the disease.