Aidi injection,a traditional Chinese biomedical preparation for gynecologic tumors: a systematic review and PRISMA-compliant meta-analysis

Aidi injection (ADI), a traditional Chinese biomedical preparation, is a promising adjuvant therapy for gynecologic tumors (GTs), including cervical cancer (CC), endometrial cancer (EC), and ovarian cancer (OC). Although studies have reported positively on ADI therapy, its exact effects and safety in GT patients remain controversial. Therefore, a wide-ranging systematic search of electronic databases was performed for this meta-analysis. Data from 38 trials including 3309 GT patients were analyzed. The results indicated that the combination of conventional treatment and ADI markedly improved the patients’ overall response rate (P<0.00001), disease control rate (P<0.00001), and quality of life (P<0.05) compared with conventional treatment alone. Furthermore, patient immunity was enhanced with combined treatment, as indicated by significantly increased percentages of CD3⁺ (P=0.005) and CD4⁺ (P<0.00001) and increased CD4⁺/CD8⁺ ratio (P=0.001). Most of the adverse events caused by radiochemotherapy such as gastrointestinal issues, leukopenia, thrombocytopenia, and hepatotoxicity, (P<0.05 for all) were significantly alleviated when ADI was used in the GT patients. However, other adverse events such as nephrotoxicity, diarrhea, alopecia, and neurotoxicity did not significantly differ between the two groups. Overall, these results suggest that the combination of conventional and ADI treatment is more effective than conventional treatment alone.     

Efficacy of RyR2 inhibitor EL20 in induced pluripotent stem cell-derived cardiomyocytes from a patient with catecholaminergic polymorphic ventricular tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited cardiac arrhythmia syndrome that often leads to sudden cardiac death. The most common form of CPVT is caused by autosomal-dominant variants in the cardiac ryanodine receptor type-2 (RYR2) gene. Mutations in RYR2 promote calcium (Ca²⁺) leak from the sarcoplasmic reticulum (SR), triggering lethal arrhythmias. Recently, it was demonstrated that tetracaine derivative EL20 specifically inhibits mutant RyR2, normalizes Ca²⁺ handling and suppresses arrhythmias in a CPVT mouse model. The objective of this study was to determine whether EL20 normalizes SR Ca²⁺ handling and arrhythmic events in induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from a CPVT patient. Blood samples from a child carrying RyR2 variant RyR2 variant Arg-176-Glu (R176Q) and a mutation-negative relative were reprogrammed into iPSCs using a Sendai virus system. iPSC-CMs were derived using the Stemdiff^TM kit. Confocal Ca²⁺ imaging was used to quantify RyR2 activity in the absence and presence of EL20. iPSC-CMs harbouring the R176Q variant demonstrated spontaneous SR Ca²⁺ release events, whereas administration of EL20 diminished these abnormal events at low nanomolar concentrations (IC₅₀ = 82 nM). Importantly, treatment with EL20 did not have any adverse effects on systolic Ca²⁺ handling in control iPSC-CMs. Our results show for the first time that tetracaine derivative EL20 normalized SR Ca²⁺ handling and suppresses arrhythmogenic activity in iPSC-CMs derived from a CPVT patient. Hence, this study confirms that this RyR2-inhibitor represents a promising therapeutic candidate for treatment of CPVT.     

Prostaglandin E3 attenuates macrophage-associated inflammation and prostate tumour growth by modulating polarization

Alternative polarization of macrophages regulates multiple biological processes. While M1-polarized macrophages generally mediate rapid immune responses, M2-polarized macrophages induce chronic and mild immune responses. In either case, polyunsaturated fatty acid (PUFA)-derived lipid mediators act as both products and regulators of macrophages. Prostaglandin E₃ (PGE₃) is an eicosanoid derived from eicosapentaenoic acid, which is converted by cyclooxygenase, followed by prostaglandin E synthase successively. We found that PGE₃ played an anti-inflammatory role by inhibiting LPS and interferon-γ-induced M1 polarization and promoting interleukin-4-mediated M2 polarization (M2a). Further, we found that although PGE₃ had no direct effect on the growth of prostate cancer cells in vitro, PGE₃ could inhibit prostate cancer in vivo in a nude mouse model of neoplasia. Notably, we found that PGE₃ significantly inhibited prostate cancer cell growth in a cancer cell-macrophage co-culture system. Experimental results showed that PGE₃ inhibited the polarization of tumour-associated M2 macrophages (TAM), consequently producing indirect anti-tumour activity. Mechanistically, we identified that PGE₃ regulated the expression and activation of protein kinase A, which is critical for macrophage polarization. In summary, this study indicates that PGE₃ can selectively promote M2a polarization, while inhibiting M1 and TAM polarization, thus exerting an anti-inflammatory effect and anti-tumour effect in prostate cancer.     

Development and validation of glycolysis-related prognostic score for prediction of prognosis and chemosensitivity of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with aggressive biological behaviour. Its rapid proliferation and tumour growth require reprogramming of glucose metabolism or the Warburg effect. However, the association between glycolysis-related genes with clinical features and prognosis of PDAC is still unknown. Here, we used the meta-analysis to correlate the hazard ratios (HR) of 106 glycolysis genes from MSigDB by the cox proportional hazards regression analysis in 6 clinical data sets of PDAC patients to form a training cohort, and a single group of PDAC patients from the TCGA, ICGC, Arrayexpress and GEO databases to form the validation cohort. Then, a glycolysis-related prognosis (GRP) score based on 29 glycolysis prognostic genes was established in 757 PDAC patients from the training composite cohort and validated in 267 ICGC-CA validation cohort (all P < .05). In addition, including PADC, the prognostic value was also confirmed in other 7 out of 30 pan-cancer cohorts. The GRP score was significantly related to specific metabolism pathways, immune genes and immune cells in the patients with PADC (all P < .05). Finally, by combining with immune cells, the GRP score also well-predicted the chemosensitivity of patients with PADC in the TCGA cohort (AUC = 0.709). In conclusion, this study developed a GRP score for patients with PDAC in predicting prognosis and chemosensitivity for PDAC.