Hyperthermia enhances the efficacy of chemotherapeutic drugs in heat-sensitive cells through interfering with DNA damage repair.

Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) has been shown to be clinically effective, but the mechanisms by which hyperthermia enhances the sensitivity of cells to chemotherapeutic drugs has not yet been elucidated. Methods: To identify the key molecules involved in thermochemotherapy, this study used mass spectrometry (MS)-based quantitative proteomics technology to analyze the effects of thermochemotherapy on the heat-sensitive ovarian cancer cell line A2780. We divided the A2780 cell line into four groups, one group served as blank control, and the other three groups were stimulated by oxaliplatin, stimulated by hyperthermia at 42 ℃, and stimulated by hyperthermia combined with oxaliplatin. Samples were then collected for tandem mass tag (TMT) labeling, high-performance liquid chromatography fractionation, and MS-based quantitative proteomics for analysis The differentially expressed proteins were quantitatively compared and identified, and Gene Ontology (GO) assessment and cluster analyses were performed. Finally, the above MS results were verified again by Western blotting experiments. Results: A total of 349 differentially expressed proteins were identified between cells treated with chemotherapy alone (group B) and cells treated with a combination of chemotherapy and hyperthermia (group D). There were 145 upregulated proteins and 204 downregulated proteins. Among the top 20 proteins with significantly different expression levels, nearly two-thirds were involved in DNA damage repair. These proteins were subsequently verified by Western blot analysis. Indeed, consistent with MS data, the expression of the RBL1 protein was significantly upregulated in cells treated with thermochemotherapy (group D) compared to cells treated with chemotherapy alone (group B). Conclusions: In heat-sensitive ovarian cancer cells, the damage repair of tumor cell DNA is disturbed by hyperthermia, making it unable to fully repair when damaged by chemotherapeutic drugs. As a result, hyperthermia enhances the efficacy of chemotherapeutic drugs. RBL1, as a tumor suppressor gene, may be associated with the repair of DNA damage, and thus it may be a key target for hyperthermia to enhance the sensitivity of thermosensitive cells to chemotherapeutic drugs.

Human Umbilical Cord Mesenchymal Stem Cells to Treat Neuromyelitis Optica Spectrum Disorder (hUC-MSC-NMOSD): A Study Protocol for a Prospective, Multicenter, Randomized, Placebo-Controlled Clinical Trial.

Background: Neuromyelitis Optica spectrum disorder (NMOSD) is severe relapsing and disabling autoimmune disease of the central nervous system. Its optimal first-line treatment to reduce relapse rate and ameliorate neurological disability remains unclear. We will conduct a prospective, multicenter, randomized, placebo-controlled clinical trial to study the safety and effectiveness of human umbilical cord mesenchymal stem cells (hUC-MSCs) in treating NMOSD. Methods: The trial is planned to recruit 430 AQP4-IgG seropositive NMOSD patients. It consists of three consecutive stages. The first stage will be carried out in the leading center only and aims to evaluate the safety of hUC-MSCs. Patients will be treated with three different doses of hUC-MSCs: 1, 2, or 5 × 106 MSC/kg·weight for the low-, medium-, and high-dose group, respectively. The second and third stages will be carried out in six centers. The second stage aims to find the optimal dosage. Patients will be 1:1:1:1 randomized into the low-, medium-, high-dose group and the controlled group. The third stage aims to evaluate the effectiveness. Patients will be 1:1 randomized into the optimal dose and the controlled group. The primary endpoint is the first recurrent time and secondary endpoints are the recurrent times, EDSS scores, MRI lesion numbers, OSIS scores, Hauser walking index, and SF-36 scores. Endpoint events and side effects will be evaluated every 3 months for 2 years. Discussion: Although hUC-MSC has shown promising treatment effects of NMOSD in preclinical studies, there is still a lack of well-designed clinical trials to evaluate the safety and effectiveness of hUC-MSC among NMOSD patients. As far as we know, this trial will be the first one to systematically demonstrate the clinical safety and efficacy of hUC-MSC in treating NMOSD and might be able to determine the optimal dose of hUC-MSC for NMOSD patients. Trial registration: The study was registered with the Chinese Clinical Trial Registry (CHICTR.org.cn) on 2 March 2016 (registration No. ChiCTR-INR-16008037), and the revised trial protocol (Protocol version 1.2.1) was released on 16 March 2020.

Egg consumption and risk of type 2 diabetes mellitus in middle and elderly Chinese population: An observational study.

Data on the association between egg consumption and the risk of type 2 diabetes mellitus (T2DM) in the Chinese population are scarce. In the present study, we aimed to examine the association between egg consumption and the risk of T2DM in a middle and elderly Chinese population. A total of 3298 subjects (1645 men and 1653 women) from the Nutrition and Health Survey (2015-2017) in Hangzhou city were selected for the final analysis. Egg consumption was assessed using a validated food frequency questionnaire. All biochemical data and anthropometric measurements were collected following standardized procedures. Multivariable logistic regression analyses were used to assess the association between egg consumption and the risk of T2DM and the results were presented as odds ratios and 95% confidence interval (CI). Restricted cubic spline combined with logistic regression was used to explore the dose-response relationship between egg consumption and T2DM. Among 3298 subjects, 693 (21.0%) people had T2DM. Compared with participants who did not consume egg per week, the multivariable-adjusted odds ratios were 0.97 (95%CI : 0.78-1.21), 1.08 (95%CI : 0.91-1.06), 1.20 (95%CI : 0.94-1.55), 1.27 (95%CI : 0.99-1.68) in men (P > .05); 1.06 (95%CI : 0.81-1.37), 0.97 (95%CI : 0.78-1.21), 1.26 (95%CI : 0.99-1.59), 1.19 (0.92-1.54) in women (P > .05); 0.89 (95%CI : 0.79-1.04), 0.98 (95%CI : 0.91-1.06), 1.06 (95%CI : 0.87-1.30), 1.09 (95%CI : 0.88-1.34) in both men and women for egg consumption 0∼7, 7, 7∼14, and ≥14 eggs/week, respectively (P > .05). The dose-response curve showed that, with the increase of egg consumption, the risk of T2DM first increased and then decreased (P = .027).We found that the association between egg consumption and T2DM was nonlinear, and higher egg consumption was not associated with an elevated risk for T2DM in middle-aged and elderly Chinese. However, future prospective studies are needed to confirm these findings.