Background: and Purpose Acute ischemic stroke (AIS) is a leading cause of disability worldwide. While intravenous thrombolysis is recommended within 4.5 hours of last known well (LKW) time, many patients present beyond this window. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) investigating tenecteplase (TNK) administration in AIS patients within 4.5 to 24 hours of LKW. The primary outcomes assessed functional independence and ordinal modified Rankin Scale (mRS) shift at 90 days. Safety outcomes included symptomatic intracranial hemorrhage (sICH) and mortality at 90 days. Results: Three RCTs were included, comprising 1,054 patients (532 TNK and 522 standard medical therapy) with a mean age of 69 years, 59% males, and median baseline National Institutes of Health Stroke Scale score of 10.5. TNK treatment was associated with mRS 0–2 at 90 days (odds ratio [OR]: 1.33, 95% confidence interval [CI]: 1.04–1.70, P=0.023), indicating a 33% higher likelihood of achieving functional independence. However, the ordinal mRS shift showed no significant difference (standardized mean difference: 0.01, 95% CI: -0.37–0.39, P=0.09). Safety outcomes indicated no difference in the rates of sICH (OR: 2.07, 95% CI: 0.86–5.00, P=0.1), and no difference in 90-day mortality (OR: 1.08, 95% CI: 0.76–1.53, P=0.67). Conclusion This meta-analysis suggests TNK might be safe and effective for selected AIS patients in the 4.5- to 24-hour time window, offering improved functional outcomes without a significant increase in hemorrhagic complications.

Background: and Purpose Acute ischemic stroke (AIS) is a leading cause of disability worldwide. While intravenous thrombolysis is recommended within 4.5 hours of last known well (LKW) time, many patients present beyond this window. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) investigating tenecteplase (TNK) administration in AIS patients within 4.5 to 24 hours of LKW. The primary outcomes assessed functional independence and ordinal modified Rankin Scale (mRS) shift at 90 days. Safety outcomes included symptomatic intracranial hemorrhage (sICH) and mortality at 90 days. Results: Three RCTs were included, comprising 1,054 patients (532 TNK and 522 standard medical therapy) with a mean age of 69 years, 59% males, and median baseline National Institutes of Health Stroke Scale score of 10.5. TNK treatment was associated with mRS 0–2 at 90 days (odds ratio [OR]: 1.33, 95% confidence interval [CI]: 1.04–1.70, P=0.023), indicating a 33% higher likelihood of achieving functional independence. However, the ordinal mRS shift showed no significant difference (standardized mean difference: 0.01, 95% CI: -0.37–0.39, P=0.09). Safety outcomes indicated no difference in the rates of sICH (OR: 2.07, 95% CI: 0.86–5.00, P=0.1), and no difference in 90-day mortality (OR: 1.08, 95% CI: 0.76–1.53, P=0.67). Conclusion This meta-analysis suggests TNK might be safe and effective for selected AIS patients in the 4.5- to 24-hour time window, offering improved functional outcomes without a significant increase in hemorrhagic complications.

Background: and Purpose Acute ischemic stroke (AIS) is a leading cause of disability worldwide. While intravenous thrombolysis is recommended within 4.5 hours of last known well (LKW) time, many patients present beyond this window. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) investigating tenecteplase (TNK) administration in AIS patients within 4.5 to 24 hours of LKW. The primary outcomes assessed functional independence and ordinal modified Rankin Scale (mRS) shift at 90 days. Safety outcomes included symptomatic intracranial hemorrhage (sICH) and mortality at 90 days. Results: Three RCTs were included, comprising 1,054 patients (532 TNK and 522 standard medical therapy) with a mean age of 69 years, 59% males, and median baseline National Institutes of Health Stroke Scale score of 10.5. TNK treatment was associated with mRS 0–2 at 90 days (odds ratio [OR]: 1.33, 95% confidence interval [CI]: 1.04–1.70, P=0.023), indicating a 33% higher likelihood of achieving functional independence. However, the ordinal mRS shift showed no significant difference (standardized mean difference: 0.01, 95% CI: -0.37–0.39, P=0.09). Safety outcomes indicated no difference in the rates of sICH (OR: 2.07, 95% CI: 0.86–5.00, P=0.1), and no difference in 90-day mortality (OR: 1.08, 95% CI: 0.76–1.53, P=0.67). Conclusion This meta-analysis suggests TNK might be safe and effective for selected AIS patients in the 4.5- to 24-hour time window, offering improved functional outcomes without a significant increase in hemorrhagic complications.

Objective: To investigate the knowledge of hepatitis C prevention and treatment and related factors among two groups of female sex workers (FSW) and men who have sex with men (MSM) in the Xizang Autonomous Region (Xizang) to provide a basis for the subsequent development of Hepatitis C publicity and education strategies. Methods: From August to September 2021, a special survey was conducted among 1 244 FSW and 234 MSM in 5 districts (counties) of 4 regions in Xizang. A one-on-one face-to-face questionnaire survey was adopted, and the χ² test and logistic regression were used to analyze the related factors of awareness of hepatitis C prevention and treatment among FSW and MSM. Results: The awareness rates of hepatitis C prevention and treatment knowledge among FSW and MSM were 35.0% (436/1 244) and 11.1% (26/234), respectively. Multivariate logistic regression analysis revealed that the positive related factors of FSW' awareness of hepatitis C prevention and treatment knowledge among those who had high school or technical secondary school education (aOR=4.72, 95%CI: 3.30-6.74) and college education or above (aOR=2.24, 95%CI: 1.58-3.18), those who experienced self-perceived risk of HCV infection (aOR=1.87, 95%CI: 1.43-2.45), negative related factors included married or cohabiting (aOR=0.58, 95%CI: 0.35-0.95), divorce or windowless (aOR=0.44, 95%CI: 0.27-0.72), no condom was used in the most recent commercial sexual activity (aOR=0.54, 95%CI: 0.43-0.69). The positive related factors of MSM's awareness of hepatitis C prevention and treatment knowledge were over 40 years old (aOR=8.65, 95%CI: 3.19-23.42) and having a self-perceived risk of HCV infection (aOR=6.25, 95%CI: 2.50-15.61). Conclusions: The awareness rate of hepatitis C prevention and treatment among FSW and MSM was relatively low in Xizang in 2021 and urgently needs to be improved. It is necessary to formulate targeted publicity strategies based on the characteristics of these two groups of people, increase publicity efforts, and expand the coverage of knowledge publicity to popularize key points about the clinical manifestations, treatment options, and transmission routes of hepatitis C, and carry out necessary warnings and education.
Humans ; Male ; Hepatitis C/therapy* ; Health Knowledge, Attitudes, Practice ; Surveys and Questionnaires ; Sex Workers/psychology* ; Homosexuality, Male ; Female ; Adult ; China ; Young Adult ; Middle Aged ; Logistic Models

OBJECTIVE: To investigate the effect of miR-483-5p on hepatocellular carcinoma (HCC) cells proliferation and stemness, as well as the attenuating effect of Pien Tze Huang (PZH). METHODS: Differentially expressed miRNA between HepG2 cells and hepatic cancer stem-like cells (HCSCs) were identified by a miRNA microarray assay. miR-483-5p mimics were transfected into HepG2 cells to explore the effects of miR-483-5p on cell proliferation and stemness. HepG2 cells and HCSCs were treated with PZH (0, 0.25, 0.50 and 0.75 mg/mL) to explore the effects of PZH on the proliferation and stemness, both in non-induced state and the state induced by miR-483-5p mimics. RESULTS: miR-483-5p was significantly up-regulated in HCSCs and its overexpression increased cell proliferation and stemness in HepG2 cells (P<0.05). PZH not only significantly inhibited proliferation in HepG2 cells, but also significantly suppressed the cell proliferation and self-renewal of HCSCs (P<0.05). The effects of miR-483-5p mimics on proliferation and stemness of HepG2 cells were partially abolished by PZH. CONCLUSIONS miR-483-5p promotes proliferation and enhances stemness of HepG2 cells, which were attenuated by PZH, demonstrating that miR-483-5p is a potential molecular target for the treatment of HCC and provide experimental evidence to support clinical use of PZH for patients with HCC.
Humans ; MicroRNAs/metabolism* ; Cell Proliferation/drug effects* ; Liver Neoplasms/drug therapy* ; Carcinoma, Hepatocellular/drug therapy* ; Hep G2 Cells ; Neoplastic Stem Cells/metabolism* ; Drugs, Chinese Herbal/therapeutic use* ; Gene Expression Regulation, Neoplastic/drug effects*

(+)-Borneol, the main component of "Natural Borneol" in the Chinese Pharmacopoeia, is a high-end spice and precious medicine. Plant extraction cannot meet the increasing demand for (+)-borneol, while microbial biosynthesis offers a sustainable supply route. However, its production was extremely low compared with other monoterpenes, even with extensively optimizing the mevalonate pathway. We found that the key challenge is the complex and unusual dephosphorylation reaction of bornyl diphosphate (BPP), which suffers the side-reaction and the competition from the cellular dephosphorylation process, especially lipid metabolism, thus limiting (+)-borneol synthesis. Here, we systematically optimized the dephosphorylation process by identifying, characterizing phosphatases, and balancing cellular dephosphorylation metabolism. For the first time, we identified two endogenous phosphatases and seven heterologous phosphatases, which significantly increased (+)-borneol production by up to 152%. By engineering BPP dephosphorylation and optimizing the MVA pathway, the production of (+)-borneol was increased by 33.8-fold, which enabled the production of 753 mg/L under fed-batch fermentation in shake flasks, so far the highest reported in the literature. This study showed that rewiring dephosphorylation metabolism was essential for high-level production of (+)-borneol in Saccharomyces cerevisiae, and balancing cellular dephosphorylation is also helpful for efficient biosynthesis of other terpenoids since all whose biosynthesis involves the dephosphorylation procedure.

Episodic memory, our ability to recall past experiences, is supported by structures in the medial temporal lobe (MTL) particularly the hippocampus, and its interactions with fronto-parietal brain regions. Understanding how these brain regions coordinate to encode, consolidate, and retrieve episodic memories remains a fundamental question in cognitive neuroscience. Non-invasive brain stimulation (NIBS) methods, especially transcranial magnetic stimulation (TMS), have advanced episodic memory research beyond traditional lesion studies and neuroimaging by enabling causal investigations through targeted magnetic stimulation to specific brain regions. This review begins by delineating the evolving understanding of episodic memory from both psychological and neurobiological perspectives and discusses the brain networks supporting episodic memory processes. Then, we review studies that employed TMS to modulate episodic memory, with the aim of identifying potential cortical regions that could be used as stimulation sites to modulate episodic memory networks. We conclude with the implications and prospects of using NIBS to understand episodic memory mechanisms.
Humans ; Memory, Episodic ; Transcranial Magnetic Stimulation/methods* ; Brain/physiology* ; Nerve Net/physiology* ; Mental Recall/physiology* ; Neural Pathways/physiology*

Objective: In the global phase 3 Study 309/KEYNOTE-775 (NCT03517449) at the first interim analysis, lenvatinib+pembrolizumab significantly improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) versus treatment of physician’s choice chemotherapy (TPC) in patients with previously treated advanced/recurrent endometrial cancer (EC). This exploratory analysis evaluated outcomes in patients enrolled in East Asia at the time of prespecified final analysis. Methods: Women ≥18 years with histologically confirmed advanced, recurrent, or metastatic EC with progressive disease after 1 platinum-based chemotherapy (2 if 1 given in neoadjuvant/ adjuvant setting) were enrolled. Patients were randomized 1:1 to lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg intravenously every 3 weeks (≤35 cycles) or TPC (doxorubicin or paclitaxel). Primary endpoints were PFS per RECIST v1.1 by blinded independent central review and OS. No alpha was assigned for this subgroup analysis. Results: Among 155 East Asian patients (lenvatinib+pembrolizumab, n=77; TPC, n=78), median follow-up time (data cutoff: March 1, 2022) was 34.3 (range, 25.1–43.0) months.Hazard ratios (HRs) with 95% confidence intervals (CIs) for PFS (lenvatinib+pembrolizumab vs. TPC) were 0.74 (0.49–1.10) and 0.64 (0.44–0.94) in the mismatch repair proficient (pMMR) and all-comer populations, respectively. HRs (95% CI) for OS were 0.68 (0.45–1.02) and 0.61 (0.41–0.90), respectively. ORRs were 36% with lenvatinib+pembrolizumab and 22% with TPC (pMMR) and 39% and 21%, respectively (all-comers). Treatment-related adverse events occurred in 97% and 96% (grade 3–5, 74% and 72%), respectively. Conclusion Lenvatinib+pembrolizumab provided clinically meaningful benefit with manageable safety compared with TPC, supporting its use in East Asian patients with previously treated advanced/recurrent EC.

Humans ; Female ; Receptors, Estrogen/metabolism* ; Breast Neoplasms/metabolism* ; Receptors, Progesterone/metabolism* ; Immunohistochemistry ; Estrogen Receptor alpha

Biliary fibrosis (BF) is the result of pathological repair of bile tract injury, characterized by thickening and sclerosis of the bile duct wall and progressive stricture of the lumen, which may ultimately lead to serious adverse outcomes such as biliary obstruction, biliary cirrhosis, liver failure, and hepatobiliary malignancies. Current research describes BF as a pathological feature of certain bile tract diseases, lacking a systematic summary of its etiology, pathophysiology, molecular mechanisms, and treatment. BF is a common but easily neglected disease state in biliary system, which may promote the development and progression of hepatobiliary diseases through abnormal repair mechanism after pathological biliary tract injury. Based on the latest research progress from both domestic and international perspectives, the authors review the concept, clinical manifestation, etiology, pathogenesis, and therapeutic strategies of BF to provide a reference for clinical physicians.