Background Recurrent hepatocellular carcinoma (RHCC) after curative resection is a major challenge for hepatic surgeons. A better understanding of the clonal origin of RHCC will help clinicians ...design personalized therapy and assess postoperative outcomes. The current study was performed to determine the clonal origin of RHCC and its clinical significance. Study Design Fifteen high-frequency of loss of heterozygosity of DNA microsatellites were determined on 100 tumor nodules in 60 matched pairs of RHCC from 40 patients who underwent liver re-resections. The relationships among the origin of clonal patterns of RHCC and the surgicopathologic features and clinical outcomes were analyzed. Results Of 60 pairs of RHCC, there were 2 clonal patterns with 6 subclonal types. Pattern I was multicentric occurrence (MO type) in 14 pairs (23.3%) and pattern II was intrahepatic metastasis (IM type) in 46 pairs (76.7%). The clinicopathologic features, including recurrence time, tumor size, vascular invasion, histological grading, and associated chronic liver diseases in patients with the MO type of RHCC were significantly different from those with the IM type of RHCC (p < 0.05 to 0.001). Compared with patients in the IM group, patients in the MO group had significantly better overall survival (130.8 ± 8.5 months vs 80.8 ± 8.5 months; p < 0.05) and recurrence-free survival (33.8 ± 4.5 months vs 14.2 ± 2.5 months; p < 0.001). Conclusions The MO-type RHCC was closely associated with better postoperative outcomes when compared with the IM-type RHCC. Generally, we recommend liver re-resection for MO-type RHCC, and interventional therapy for IM-type RHCC. Microdissection-based microsatellite loss of heterozygosity protocol has advantages in assessing the clonal origin, modes of personalized treatment, and clinical outcomes of RHCC.
Summary Background The current influenza pandemic calls for a safe and effective vaccine. We assessed the safety and immunogenicity of eight formulations of 2009 pandemic influenza A H1N1 vaccine ...produced by ten Chinese manufacturers. Methods In this multicentre, double-blind, randomised trial, 12 691 people aged 3 years or older were recruited in ten centres in China. In each centre, participants were stratified by age and randomly assigned by a random number table to receive one of several vaccine formulations or placebo. The study assessed eight formulations: split-virion formulation containing 7·5 μg, 15 μg, or 30 μg haemagglutinin per dose, with or without aluminium hydroxide adjuvant, and whole-virion formulation containing 5 μg or 10 μg haemagglutinin per dose, with adjuvant. All formulations were produced from the reassortant strain X-179A (A/California/07/2009-A/PR/8/34). We analysed the safety (adverse events), immunogenicity (geometric mean titre GMT of haemagglutination inhibition antibody), and seroprotection (GMT ≥1:40) of the formulations. Analysis was by per protocol. Two sites registered their trial with ClinicalTrials.gov , numbers NCT00956111 and NCT00975572 . The other eight studies were registered with the State Food and Drug Administration of China. Findings 12 691 participants received the first dose on day 0, and 12 348 participants received the second dose on day 21. The seroprotection rate 21 days after the first dose of vaccine ranged from 69·5% (95% CI 65·9–72·8) for the 7·5 μg adjuvant split-virion formulation to 92·8% (91·9–93·6) for the 30 μg non-adjuvant split-virion formulation. The seroprotection rate was 86·5% (796 of 920; 84·1–88·7) in recipients of one dose of the 7·5 μg non-adjuvant split-virion vaccine compared with 9·8% (140 of 1432; 8·3–11·4) in recipients of placebo (p<0·0001). One dose of the 7·5 μg non-adjuvant split-virion vaccine induced seroprotection in 178 of 232 children (aged 3 years to <12 years; 76·7%, 70·7–82·0), 211 of 218 adolescents (12 years to <18 years; 96·8%, 93·5–98·7), 289 of 323 adults (18–60 years; 89·5%, 85·6–92·6), and 118 of 147 adults older than 60 years (80·3%, 72·9–86·4), meeting the European Union's licensure criteria for seroprotection in all age-groups. In children, a second dose of the 7·5 μg formulation increased the seroprotection rate to 97·7% (215 of 220, 94·8–99·3). Adverse reactions were mostly mild or moderate, and self-limited. Severe adverse effects occurred in 69 (0·6%, 0·5–0·8) recipients of vaccine compared with one recipient (0·1%, 0–0·2) of placebo. The most common severe adverse reaction was fever, which occurred in 25 (0·22%; 0·14–0·33) recipients of vaccine after the first dose and four (0·04%; 0·01–0·09) recipients of vaccine after the second dose compared with no recipients of placebo after either dose. Interpretation One dose of non-adjuvant split-virion vaccine containing 7·5 μg haemagglutinin could be promoted as the formulation of choice against 2009 pandemic influenza A H1N1 for people aged 12 years or older. In children (aged <12 years), two 7·5 μg doses might be needed. Funding Sinovac Biotech, Hualan Biological Bacterin, China National Biotec Group, Beijing Tiantan Biological Products, Changchun Institute of Biological Products, Changchun Changsheng Life Sciences, Jiangsu Yanshen Biological Technology Stock, Zhejiang Tianyuan Bio-Pharmaceutical, Lanzhou Institute of Biological Products, Shanghai Institute of Biological Products, and Dalian Aleph Biomedical.
The composition of influenza vaccines is updated annually. To ensure vaccine safety, the coverage and adverse events following immunization (AEFI) of 6 manufacturers of trivalent inactivated ...influenza vaccine (TIV3) need to be evaluated. In January 2022, we analyzed data from more than 1.59 million children in the Childhood Vaccination Information Management System and the AEFI Surveillance Information Management System and evaluated influenza vaccines for children aged 6 to 35 months in Guangzhou from 2016/17 to 2019/20 Vaccination rates and AEFI reporting rates. From 2016/17 to 2019/20, the 1-dose influenza vaccination rate was 25.0% (range: 20.7%-30.2%), and the 2-dose (full course) influenza vaccination rate was 21.6% (range: 17.7%-26.4%). The full vaccination coverage rate has trended down since 2017/2018 (2017/18: 26.0%; 2018/19: 8.3; 2019/20: 17.7%). Fifty-two cases (13.1/100 000) and 24 cases (6.9/100 000) received AEFI reports for 1 dose and 2 doses, respectively, mainly due to fever ≥38.6°C (39 cases for 1 dose, 9.8/100 000; 15 cases for 2 dose, 4.3/100 000) and allergic rash (9 cases with 1 dose, 2.3/100 000; 5 cases with 2 doses, 1.4/100 000). Patients who received A and F manufacturers were more likely to report side effects. The safety of influenza vaccines from 6 manufacturers is good, and it is necessary to improve the recommended information on influenza vaccines to dispel people’s concerns and increase the vaccination rate.
Abstract Background Relapsed or refractory Hodgkin's lymphoma is a challenge for medical oncologists because of poor overall survival. We aimed to assess the feasibility, safety, and efficacy of ...CD30-targeting CAR T cells in patients with progressive relapsed or refractory Hodgkin's lymphoma, in which CD30 expression is mostly positive. Methods This open-label, phase 1 study took place at the Chinese PLA General Hospital. Eligible patients (aged 16–80 years) had relapsed or refractory Hodgkin's lymphoma. All patients received a conditioning chemotherapy regimen at the discretion of physician, followed by the infusion of CD30-directed CAR T cells. Using escalating doses to avoid severe toxicity associated with infusion, patients received a starting dose of 3·2 × 105 CAR T cells per kg and then infused by 5-fold increments continuously for 3–5 days. After the dose-escalation infusion, no patients experienced greater than grade 3 toxicity events. We periodically monitored the expression level of CAR transgenes in peripheral blood and biopsied tumour tissues according to assigned protocol by quantitative PCR. Two-way analysis of variance (ANOVA) was used to determine the significance of the differences between means in all experiments. This trial was approved by the Institutional Review Board at the Chinese PLA General Hospital and is registered with ClinicalTrials.gov , number NCT02259556 . All patients gave written informed consent before enrolment. Findings Between Dec 1, 2014, and Mar 1, 2015, 11 patients were enrolled. All of whom had a heavy pretreatment history (15 previous treatments, range 6–24) or multiple tumour lesions (3·3 lymph node regions involved, range 0-7; involvement of one or more extralymphatic organs), or both. The patients received a mean of 1·5×107 CAR-positive T cell per kg (SD 0·25, range 1·2–2·1) in total during infusion. Nine (82%) patients responded to the treatment: one (9%) patient maintained continuous complete remission, five (46%) patients achieved partial response, and three (27%) patients achieved stable disease. All patients experienced tolerable infusion-related febrile syndrome. One (9%) patient had 5 days of self-limiting arthralgia, myalgia, and dual knee swelling 2 weeks after cell infusion. The copy number of CAR transgene in peripheral blood peaked 3–17 days after infusion, which was accompanied by a two-times higher increase in the number of lymphocytes. Analysis of biopsied tissues revealed a highly efficient trafficking of CAR T cells into the targeted sites. Interpretation CD30-directed CAR T-cell therapy was safe, feasible, and efficient in patients with relapsed or refractory Hodgkin's lymphoma and guaranteed a large-scale patients recruitment. Funding Science and Technology Planning Project of Beijing City (No. Z151100003915076) and National Natural Science Foundation of China (Nos. 31270820, 81230061, 81121004, and 81402566).
Abstract Objective Recent studies have shown the existence of autophagy in cerebral ischemia; however, there has been no research on the role of autophagy in cerebral injury after cardiopulmonary ...resuscitation (CPR). This study was conducted to determine the role of autophagy in an animal model of ventricular fibrillation (VF)/CPR. Methods Experiment 1: A total of 48 adult Wistar rats were untreated for 7 minutes after induction of VF using an external transthoracic alternating current, and subsequent CPR was performed to observe the existence of autophagy after the return of spontaneous circulation (ROSC). Experiment 2: A total of 72 rats were pretreated with intracerebroventricular injection of physiologic saline (control group), the autophagy inducer (rapamycin group), or the autophagy inhibitor 3-methyladenine (3-methyladenine group) before ROSC to evaluate the contribution of autophagy to neuronal injury after ROSC. Results The activation of autophagy was attenuated 2 to 4 hours after ROSC, which was related to the activity decrease of 5′-adenosine monophosphate–activated protein kinase after ROSC. Rapamycin treatment significantly increased the expressions of LC3-II and Beclin-1 after ROSC, attenuated the activation of caspase-3, promoted neuronal survival and decreased neuronal apoptosis, and improved the neurologic deficit score after CPR. Conclusions The activation of autophagy after ROSC offered a remarkable tolerance to VF/CPR ischemic insult and improved the neurologic outcomes.
Objective The objective of the study was to investigate the expression and regulation of polycomb group (PcG) proteins in human neural tube defects (NTDs). Study Design PcG proteins in human NTD ...fetuses and age-matched controls were detected by Western blot. The relation between PcG proteins and microribonucleic acids was predicted and confirmed by the bioinformatics method, real-time polymerase chain reaction (PCR), dual-luciferase activity assay, and Western blot. The trimethyl condition of histone H3 Lys27 (H3K27) was detected by immunohistochemical and immunofluorescence. Results Embryonic ectoderm development protein (EED) was differentially detected in placenta, cerebral cortex, and spinal cord from NTDs and age-matched controls. MiR-30b can interact with 3'-untranslated region (UTR) of Eed and regulate endogenous EED expression in neural tissues. In addition, we found an inverse relationship between the miR-30b expression and the amount of trimethyl H3K27. Conclusion Differential expression of EED exists in the nerves system in human NTDs and that is regulated by miR-30b.
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