2020年 · 第100卷第32期

Colon cancer (CRC) is one of the common cancers, and metastasis is the leading cause of death. Recent studies have found that first-line chemotherapy drugs irinotecan or oxaliplatin combined with epidermal growth factor receptor (EGFR) -targeted drugs can improve the median overall survival of patients with metastatic colorectal cancer (mCRC) by more than 2 years. However, KRAS-mutated colon cancer patients (about 30% to 50%) show resistance to EGFR-targeted drugs. Therefore, EGFR-targeted drugs cannot be used to treat mCRC patients with KRAS mutations. Many previous studies have pointed out that metformin has anti-tumor effects, and taking metformin is closely related to a good prognosis of patients. However, many retrospective studies have found that metformin is not related to the prognosis of cancer patients, and there are still many questions and differences about the therapeutic effect and molecular mechanism of metformin on tumors.

To evaluate vitamin D supplementation₃Impact on mortality and tuberculosis incidence in HIV-infected individuals initiating antiretroviral therapy (ART) A vitamin D supplementation was administered to HIV-infected individuals with serum 25-hydroxyvitamin D concentrations below 30 ng/ml and initiating ART at four large HIV care and treatment centers in Dar es Salaam, Tanzania₃A randomized, double-blind, placebo-controlled trial of. Age of exclusion<18 years of age, pregnant, or participating in any other clinical trial. Subjects were randomly assigned in a 1:1 ratio to oral vitamin D during the first month of ART₃50 000 U/week, followed by vitamin D supplementation₃2 000 U/d, the control group was given placebo at the same time interval and frequency. The randomized control list was computer-generated by a non-statistical investigator with a sequence block of 10, ensuring complete assignment concealment, and subjects, field groups, and researchers were assigned in disguise. The trial was followed up for 1 year and the primary outcome measures were death and new tuberculosis in HIV-infected subjects. An intention-to-treat analysis of all-cause mortality was performed, and subjects diagnosed with tuberculosis at the time of randomization, who were receiving antituberculous therapy, or who were suspected of having tuberculosis and were later diagnosed were excluded from the study tuberculosis incidence analysis. Between 24 February 2014 and 24 February 2017, 6 250 ART-initiated adult subjects were screened for serum 25-hydroxyvitamin D, of which 4 000 subjects participated in the trial and were followed for 1 year (all subject follow-ups were completed on 7 March 2018). 2 001 subjects were randomized to vitamin D₃Group, 1 999 subjects were randomly assigned to placebo. A total of 415 subjects died, including vitamin D₃211 cases in the group and 204 cases in the placebo group were supplemented with vitamin D₃There was no statistically significant effect on the risk of death in HIV-infected persons (HR=1.04，95%CI：0.85~1.25）。 Vitamin D₃There was no statistically significant difference in the new prevalence of pulmonary tuberculosis between the group and the placebo group (HR=0.78，95%CI：0.54~1.13）。 Vitamin D₃There were 3 and 2 cases of hypercalcemia in the group and the placebo group, respectively, and vitamin D supplementation was found₃Does not increase the risk of hypercalcemia (RR=1.25，95%CI：0.43~3.66）。 For hospitalization rates, vitamin D₃There were 101 cases in the placebo group and 94 cases in the placebo group, and the difference was not statistically significant (IRR=1.06，95%CI：0.80~1.41）。

In order to understand the effects of vitamin A and D supplementation on symptom relief and sputum smear conversion time in pulmonary tuberculosis patients, a 2×2 factorial design randomized controlled trial was conducted in Qingdao, China. Symptom relief of tuberculosis patients was evaluated by TB-score including cough, expectoration, hemoptysis, dyspnea, chest pain, night hot flashes, night sweats, fatigue, anorexia, fever and body mass index. Between October 2012 and March 2015, a total of 800 patients with pulmonary tuberculosis who received standardized chemotherapy (isoniazid, rifampicin, ethambutol, pyrazinamide for February/isoniazid, rifampicin for April) were randomly assigned 1:1:1:1. 39 patients were withdrawn because they could not complete standard chemotherapy. Finally, 190 patients received standard pulmonary tuberculosis treatment only (control group), 187 patients received vitamin A supplementation (2 000 U/d), 199 patients received vitamin D supplementation (400 U/d), and 185 patients received both vitamin A (2 000 U/d) and vitamin D (400 U/d) combined supplementation were included in the symptom analysis. Finally, 761 patients were included in the tuberculosis symptom analysis. Of the 761 patients with pulmonary tuberculosis, 203 patients had negative sputum smear at baseline, 37 patients had no subsequent sputum smear results, and the remaining 521 patients were included in the sputum smear conversion analysis (128 patients in the vitamin A supplementation group, 145 patients in the vitamin D supplementation, 121 patients in the combined vitamin A and vitamin D supplementation, and 127 patients in the control groupHR=1.021，95%CI: 0.821 to 1.271), vitamin D (HR=0.949，95%CI: 0.760~1.185) had no significant effect on the negative conversion time of sputum smear, and there was no significant interaction between vitamin A and vitamin D supplementation. However, vitamin D supplementation significantly improved the symptoms of tuberculosis patients, and their TB-score decreased at 2 to 4 weeks (MD=-0.2，95%CI：-0.4~0）。

SARS-CoV-2 is a member of Beta-CoV lineage B and has 75% to 80% homology to the severe acute respiratory syndrome coronavirus (SARS-CoV) genome sequence. Vaccines are an effective measure to control ongoing COVID-19 and previous coronavirus infections such as MERS/SARS. Spike receptor binding domain (RBD) is an ideal target for coronavirus vaccines, but the limited immunogenicity of RBD limits vaccine development against this domain. This study found that a dimeric form of Middle East respiratory syndrome coronavirus (MERS-CoV) RBD can effectively improve RBD immunogenicity. RBD-dimer significantly increased the titer of neutralizing antibodies (NAb) and protected mice from MERS-CoV infection compared to conventional monomeric forms. Crystal structure studies revealed that the RBD-dimer completely exposed the dual receptor binding motif (the primary target of NAbs). Structure-guided design further yielded stable RBD-dimers, i.e. tandem repeating single chains (RBD-SC-dimers), preserving the efficacy of the vaccine. The researchers generalized the strategy to vaccine designs against COVID-19 and SARS, resulting in a 10-to 100-fold increase in NAb titers. The RBD-SC-dimer achieved higher yield in pilot production, which provided a theoretical basis for subsequent clinical development and application. This strategy can be generalized to design vaccines against multiple beta-CoVs, providing safeguards for controlling coronavirus infections such as SARS-CoV-2, MERS, and SARS-CoV.