METHODS: Chronic unpredictable mild stress- (CUMS-) induced rats were established for the depression animal model. There were a total of four rat groups, including the control group, the CUMS group, the CUMS+acupuncture group, and the CUMS+fluoxetine group. The acupuncture group and the fluoxetine group were given a 3-week treatment after the modeling intervention. The researcher performed the open-field, elevated plus maze, and sucrose preference tests to evaluate depressive behaviors. The number of nerve cells, dendrites' length, and the prefrontal cortex's spine density were detected using Golgi staining. The prefrontal cortex expression, such as BDNF, PSD95, SYN, and PKMZ protein, was detected using the western blot and RT-PCR.
RESULTS: Acupuncture could alleviate depressive-like behaviors and promote the recovery of the neural plasticity functions in the prefrontal cortex, showing the increasing cell numbers, prolonging the length of the dendrites, and enhancing the spine density. The neural plasticity-related proteins in the prefrontal cortex, including BDNF, PSD95, SYN, and PKMZ, were all downregulated in the CUMS-induced group; however, these effects could be partly reversed after being treated by acupuncture and fluoxetine (P < 0.05).
CONCLUSION: Acupuncture can ameliorate depressive-like behaviors by promoting the recovery of neural plasticity functions and neural plasticity-related protein upregulation in the prefrontal cortex of CUMS-induced depressed rats. Our study provides new insights into the antidepressant approach, and further studies are warranted to elucidate the mechanisms of acupuncture involved in depression treatment.
PATIENTS AND METHODS: Considering the limited placebo effect and significant clinical benefit of olaparib in previous trials, and the rapid approval of olaparib in China, this phase III study was designed as an open-label, single-arm trial. Patients with high-grade epithelial PSR ovarian cancer were enrolled from country-wide clinical centers across China and Malaysia. Patients received oral olaparib (300 mg) twice daily until disease progression or unacceptable toxicity. Primary endpoint was median PFS (mPFS). Primary analysis of PFS using the Kaplan-Meier method was performed when data reached 60% maturity (clinicaltrials.gov NCT03534453).
RESULTS: Between 2018 and 2020, 225 patients were enrolled, and 224 received olaparib; 35.7% had received ≥3 lines of chemotherapy, 35.3% had achieved complete response to their last line of platinum-based chemotherapy, and 41.1% had a platinum-free interval ≤12 months. At primary data cut-off (December 25, 2020), overall mPFS was 16.1 months; mPFS was 21.2 and 11.0 months in BRCA-mutated and wild-type BRCA subgroups, respectively. Adverse events (AE) occurred in 99.1% of patients (grade ≥3, 48.7%); 9.4% discontinued therapy due to treatment-related AEs.
CONCLUSIONS: Olaparib maintenance therapy was highly effective and well tolerated in Asian patients with PSR ovarian cancer, regardless of BRCA status. This study highlights the promising efficacy of olaparib in this Asian population. See related commentary by Nicum and Blagden, p. 2201.
METHODS: In this single-arm, open-label, phase 3 trial, we recruited patients from 38 sites across China, Thailand, Vietnam, Singapore, and Malaysia, who were chronically infected with HCV genotypes 1-6, and were HCV treatment-naive or treatment-experienced, either without cirrhosis or with compensated cirrhosis. Patients self-administered a combined sofosbuvir (400 mg) and velpatasvir (100 mg) tablet once daily for 12 weeks. The primary efficacy endpoint was sustained virological response, defined as HCV RNA less than 15 IU/mL at 12 weeks after completion of treatment (SVR12), assessed in all patients who received at least one dose of study drug. The primary safety endpoint was the proportion of adverse events leading to premature discontinuation of study drug. This trial is registered with ClinicalTrials.gov, number NCT02671500, and is completed.
FINDINGS: Between April 14, 2016, and June 30, 2017, 375 patients were enrolled in the study, of whom 374 completed the full treatment course and one discontinued treatment. Overall, 362 (97% [95% CI 94-98]) of 375 patients achieved SVR12. Among 42 patients with HCV genotype 3b, all of whom had baseline resistance-associated substitutions in NS5A, 25 (89% [95% CI 72-98]) of 28 patients without cirrhosis and seven (50% [23-77]) of 14 patients with cirrhosis achieved SVR12. The most common adverse events were upper respiratory tract infection (36 [10%] patients) and headache (18 [5%] patients). There were no discontinuations due to adverse events. Serious adverse events were reported in three (1%) patients, none of which was judged to be related to sofosbuvir-velpatasvir treatment.
INTERPRETATION: Consistent with data from other phase 3 studies, single-tablet sofosbuvir-velpatasvir for 12 weeks is an efficacious and safe treatment for Asian patients with chronic HCV infection, but might have lower efficacy in those infected with HCV genotype 3b and with cirrhosis.
FUNDING: Gilead Sciences.