Yuantong Tian

Background and aim: Previous studies have demonstrated the efficacy and safety of combining Gemcitabine and Erlotinib (Gem-Erlo) for the treatment of pancreatic cancer (PaC). However, there is a limited number of clinical studies and multiple prospective randomized controlled clinical trials (RCTs) have yielded inconsistent conclusions. The question of whether Gem-Erlo has significant advantages over conventional chemotherapy in the treatment of PaC has been controversial. In order to provide valuable insights for PaC treatment, this study conducted a meta-analysis based on the current evidence from RCTs. Method: We searched several databases including PubMed/Medline, Web of Science, Cochrane Library, and Embase, as well as relevant conference abstracts from the beginning of their inception to July 2023. We used the patient/population, intervention, comparison, outcomes and study design (PICOS) principle to screen the literature. After title, abstract and full text filtering, we extract the data from each study to assess the risk of bias by examining the quality of the literature. We used a meta-analysis with random effects model to synthesize and summarize the results regarding objective response rate (ORR), disease control rate (DCR), median progression-free survival (median PFS), median overall survival (median OS) and one-year survival rate. Results: Seven RCTs were included, involving 2,152 PaC patients treated with either Gem-Erlo or Gemcitabine alone. The results showed that Gem-Erlosignificantly improved DCR (DCR = 1.74; 95% CI=[1.03, 2.92]; P = 0.04); but did not significantly improve median OS (SMD = −0.20; 95%CI=[−1.46, 1.06]; P = 0.75), median PFS (SMD = −0.97; 95%CI=[−4.01, 2.07]; P = 0.53), ORR (ORR = 1.29; 95%CI=[0.84, 1.97]), or one-year survival rate (ORR = 1.18; 95%CI=[0.88, 1.57]). The most common adverse events (AEs) were rash, diarrhea, fatigue, neutropenia and thrombocytopenia in both groups, but the Gem-Erlo group is more often than the Gemcitabine alone (ORR = 1.40, 95% CI= [1.19, 1.65]; P < 0.0001), and all AEs were within the acceptable range for patients. Conclusion: Gem-Erlo can improve DCR when compared to Gemcitabine. There was no statistically significant improvement in median PFS, median OS, ORR and one-year survival rate. However, sensitivity analysis showed a statistical difference in the median OS. Our study indicated that Gem-Erlo had better efficacy than Gemcitabine alone in PaC therapy. The occurrence of AEs is under the acceptable range for patients.

Objective: The widespread use of antibiotics has inevitably led to the emergence of multidrug-resistant bacterial strains, such as methicillin-resistant Staphylococcus aureus (MRSA), making treatment of this infection a serious challenge. This study aimed to explore new treatment strategies for MRSA infection.Methods: The structure of Fe₃O₄ NPs with limited antibacterial activity was optimized, and the Fe²⁺ ↔ Fe³⁺ electronic coupling was eliminated by replacing 1/2 Fe²⁺ with Cu²⁺. A new type of copper-containing ferrite nanoparticles (hereinafter referred to as Cu@Fe NPs) that fully retained oxidation–reduction activity was synthesized. First, the ultrastructure of Cu@Fe NPs was examined. Then, antibacterial activity was determined by testing the minimum inhibitory concentration (MIC) and safety for use as an antibiotic agent. Next, the mechanisms underlying the antibacterial effects of Cu@Fe NPs were investigated. Finally, mice models of systemic and localized MRSA infections was established for in vivo validation.Results: It was found that Cu@Fe NPs exhibited excellent antibacterial activity against MRSA with MIC of 1 μg/mL. It effectively inhibited the development of MRSA resistance and disrupted the bacterial biofilms. More importantly, the cell membranes of MRSA exposed to Cu@Fe NPs underwent significant rupture and leakage of the cell contents. Cu@Fe NPs also significantly reduced the iron ions required for bacterial growth and contributed to excessive intracellular accumulation of exogenous reactive oxygen species (ROS). Therefore, these findings may important for its antibacterial effect. Furthermore, Cu@Fe NPs treatment led to a significant reduction in colony forming units within intra-abdominal organs, such as the liver, spleen, kidney, and lung, in mice with systemic MRSA infection, but not for damaged skin in those with localized MRSA infection.Conclusion: The synthesized nanoparticles has an excellent drug safety profile, confers high resistant to MRSA, and can effectively inhibit the progression of drug resistance. It also has the potential to exert anti-MRSA infection effects systemically in vivo. In addition, our study revealed a unique multifaceted antibacterial mode of Cu@Fe NPs: (1) an increase in cell membrane permeability, (2) depletion of Fe ions in cells, (3) generation of ROS in cells. Overall, Cu@Fe NPs may be potential therapeutic agents for MRSA infections.

Introduction: AKR1C3, as a crucial androgenic enzyme, implicates the androgen biosynthesis and promoting prostate cancer cell growth in vitro. This study provides a new gene therapy strategy for targeting AKR1C3 to treat castration-resistant prostate cancer.Methods: siAKR1C3@PPA is assembled from PEG3500, PAMAM, Aptamer-PSMA, and siRNA for AKR1C3. We analyzed the relationship between AKR1C3 expression and the survival rate of prostate cancer patients based on the GEPIA online database to perform disease-free survival, and found that AKR1C3 may be an important factor leading to poor prognosis in prostate cancer. Considering AKR1C3 as a therapeutic target for castration-resistant prostate cancer, we constructed a complex nucleic acid nanoparticle, siAKR1C3@PPA to investigate the inhibitory effect on castration-resistant prostate cancer.Results: Aptamer-PSMA acts as a target to guide siAKR1C3@PPA into PSMA-positive prostate cancer cells and specifically down regulate AKR1C3. Cyclin D1 was decreased as a result of siAKR1C3@PPA treatment. Changes in Cyclin D1 were consistent with decreased expression of AKR1C3 in LNCaP-AKR1C3 cells and 22RV1 cells. Furthermore, in the LNCaP-AKR1C3 group, 1070 proteins were upregulated and 1015 proteins were downregulated compared to the LNCaP group according to quantitative 4D label-free proteomics. We found 42 proteins involved in cell cycle regulation. In a validated experiment, we demonstrated that PCNP and CINP were up-regulated, and TERF2 and TP53 were down-regulated by western blotting.Conclusion: We concluded that siAKR1C3@PPA may arrest the cell cycle and affect cell proliferation.

Original Article High expression of hypoxia-inducible factor 1-alpha predicts poor prognosis in pancreatic ductal adenocarcinoma: a meta-analysis and database validation protocol Alexis Zoa, Yingjie Yang, Wenjin Wang, Jing Yang, Jiangping Wang, Haibo Wang, Minghua Dong, Yuantong Tian

Aldo-keto reductase family 1 member C3 (AKR1C3) is a key steroidogenic enzyme that is overexpressed in prostate cancer (PCa) and is associated with the development of castration-resistant prostate cancer (CRPC). The aim of this study was to investigate the correlation between the expression level of AKR1C3 and the progression of PCa.