Synthesis of Multisubstituted 1,2,3-Triazoles: Regioselective Formation and Reaction Mechanism.

A synthetically useful approach to functionalized triazoles is described via the reaction of ß-carbonyl phosphonates and azides. 1,4- and 1,5-disubstituted and 1,4,5-trisubstituted triazoles can be regio- and chemoselectively accessed under mild conditions in good to excellent yields (31 examples, up to 99%). A mechanism is proposed that rationalizes the avoidance of the 4-phosphonate byproducts, which is aligned with crystallographic and experimental evidence.

Long-term efficacy and predictors of pembrolizumab-based regimens in patients with advanced esophageal cancer in the real world.

BACKGROUND: Pembrolizumab combined with chemotherapy has been proven effective as first-line therapy in patients with advanced esophageal cancer. Few trials have assessed the safety and efficacy of this treatment in patients with locally advanced disease. AIM: To analyze long-term outcomes of pembrolizumab in locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) in the real world. METHODS: Patients with advanced ESCC admitted to our center from October 2019 to October 2021 were enrolled in this study. Clinical staging of the patients was based on the 8th edition of the American Joint Committee on Cancer TNM staging system. The patients received different treatments based on clinical stage. In brief, patients with locally advanced and resectable ESCC received neoadjuvant therapy combined with surgery. For those who were not candidates for resection, radical concurrent chemoradiotherapy plus pembrolizumab was more preferable. Patients with metastatic ESCC or who were unsuitable for radiotherapy underwent chemotherapy in combination with pembrolizumab. Long-term survival outcomes such as overall survival (OS), progression-free survival, disease-free survival, long-term adverse effects (AEs), immune maintenance therapy and predictors of immune checkpoint inhibitors (ICIs) efficacy were evaluated. RESULTS: A total of 55 patients with advanced ESCC were enrolled in this retrospective, observational study. The median age was 61 years (range 44-74), with 47.3% (26/55) of the patients in stage IV and 45.5% of the patients had the tumor (25/55) located in the middle third of the esophagus. The median OS in all patients was not reached. The 12-mo OS rate among all patients was 78.8% and the 18-mo OS rate was 72.7%. 9 patients died due to tumor progression and 7 patients died due to treatment-related complications. The therapeutic effect evaluated at the interim evaluation was significantly reflected in the long-term outcome. Patients with complete response or partial response in all patients (P = 0.005) and in the chemoradiotherapy plus pembrolizumab group (P = 0.007) obtained a better prognosis than non-responders. A total of 20 patients (20/55, 36%) received immune maintenance therapy. Baseline peripheral blood biomarkers of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and neutrophil-to-(leukocyte-neutrophil) ratio did not predict the efficacy of ICIs. CONCLUSION: Pembrolizumab combined with chemotherapy or radiotherapy resulted in favorable long-term survival in patients with locally advanced or metastatic ESCC, with safe and manageable long-term AEs.

Short-term and long-term effectiveness of acupuncture and Tuina on knee osteoarthritis: study protocol for a randomized controlled trial.

Background: The effectiveness of acupuncture and tuina in treating knee osteoarthritis (KOA) is still controversial, which limits their clinical application in practice. This study aims to evaluate the short-term and long-term effectiveness of acupuncture and tuina on KOA. Methods/design: This parallel-group, multicenter randomized clinical trial (RCT) will be conducted at the outpatient clinic of five traditional Chinese medicine hospitals in China. Three hundred and thirty participants with KOA will be randomly assigned to acupuncture, tuina, or home-based exercise group with a ratio of 1:1:1. The primary outcome is the proportion of participants achieving a minimal clinically important improvement defined as a ≥ 12% reduction on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain dimension on short term (week 8) and long term (week 26) compared with baseline. Secondary outcomes are knee joint conditions (pain, function, and stiffness), self-efficacy of arthritis, quality of life, and psychological conditions, which will be evaluated by the WOMAC score and the Patient Global Assessment (PGA), and in addition, the respondents index of OMERACT-OARSI, Short Form 12 Health Survey (SF-12), arthritis self-efficacy scale, and European five-dimensional health scale (EQ-5D). Adverse events will be collected by self-reported questionnaires predefined. Clinical trial registration: https://www.chictr.org.cn.

A dose-response meta-analysis reveals an association between vitamin B12 and colorectal cancer risk.

OBJECTIVE: The current meta-analysis evaluated the association between vitamin B12 intake and blood vitamin B12 level and colorectal cancer (CRC) risk. DESIGN: The PubMed and EMBASE databases were searched. A dose-response analysis was performed with generalized least squares regression, with the relative risk (RR) and 95 % CI as effect values. SETTING: The meta-analysis included seventeen studies. SUBJECTS: A total of 10 601 patients. RESULTS: The non-linear dose-response relationship between total vitamin B12 intake and CRC risk was insignificant (P=0·690), but the relationship between dietary vitamin B12 intake and CRC risk was significant (P<0·001). Every 4·5 µg/d increment in total and dietary vitamin B12 intake was inversely associated with CRC risk (total intake: RR=0·963; 95 % CI 0·928, 0·999; dietary intake: RR=0·914; 95 % CI 0·856, 0·977). The inverse association between vitamin B12 intake and CRC risk was also significant when vitamin B12 intake was over a dosage threshold, enhancing the non-linear relationship. The non-linear dose-response relationship between blood vitamin B12 level and CRC risk was insignificant (P=0·219). There was an insignificant association between every 150 pmol/l increment in blood vitamin B12 level and CRC risk (RR=1·023; 95 % CI 0·881, 1·187). CONCLUSIONS: Our meta-analysis indicates that evidence supports the use of vitamin B12 for cancer prevention, especially among populations with high-dose vitamin B12 intake, and that the association between CRC risk and total vitamin B12 intake is stronger than between CRC risk and dietary vitamin B12 intake only.

Clinicopathologic and Prognostic Value of Serum Carbohydrate Antigen 19-9 in Gastric Cancer: A Meta-Analysis.

BACKGROUND: The clinical value of carbohydrate antigen (CA) 19-9 in gastric cancer is controversial. We evaluated the clinicopathologic and prognostic value of CA 19-9 in gastric cancer. METHODS: A literature search was conducted in PubMed and Embase databases. Odds ratios (ORs), risk ratios (RR), hazard ratios (HRs), and 95% confidence intervals (CIs) were used as effect measures. RESULTS: Thirty-eight studies were included. Results showed that there were significant differences in the incidence of high CA 19-9 levels between stages III/IV and I/II groups (OR = 3.36; 95% CI = 2.34-4.84), the pT3/T4 and pT1/T2 groups (OR = 2.40; 95% CI = 1.60-3.59), the lymph node-positive and node-negative groups (OR = 2.91; 95% CI = 2.21-3.84), the metastasis-positive and metastasis-negative groups (OR = 2.76; 95% CI = 1.12-6.82), and vessel invasion-positive and invasion-negative groups (OR = 1.66; 95% CI = 1.11-2.48). Moreover, CA 19-9 was significantly associated with poor overall survival (HR = 1.83; 95% CI = 1.56-2.15), disease-free survival (HR = 1.85; 95% CI = 1.16-2.95), and disease-specific survival (HR = 1.33; 95% CI = 1.10-1.60) in gastric cancer. CONCLUSIONS: Our meta-analysis showed that CA 19-9 indicates clinicopathologic characteristics of gastric cancer and is associated with a poor prognosis.