BackgroundCervical cancer is a major public health concern in China. We report the end‐of‐study results of a phase II/III trial to assess the efficacy, immunogenicity, and safety of the AS04‐human papillomavirus (HPV)‐16/18 vaccine in Chinese women aged 18‐25 years followed for up to 72 months after first vaccination. Results of approximately 57 months following first vaccination have been previously reported.MethodsHealthy 18‐25‐year‐old women (N = 6051) were randomized (1:1) to receive three doses of AS04‐HPV‐16/18 vaccine or Al(OH)3 (control) at Months 0‐1‐6. Vaccine efficacy against HPV‐16/18 infection and cervical intraepithelial neoplasia (CIN), cross‐protective vaccine efficacy against infections and lesions associated with nonvaccine oncogenic HPV types, immunogenicity, and safety were assessed. Efficacy was assessed in the according‐to‐protocol efficacy (ATP‐E) cohort (vaccine N = 2888; control N = 2892), total vaccinated cohort for efficacy (TVC‐E; vaccine N = 2987; control N = 2985) and TVC‐naïve (vaccine N = 1660; control N = 1587).ResultsIn initially HPV‐16/18 seronegative/DNA‐negative women, vaccine efficacy against HPV‐16/18‐associated CIN grade 2 or worse was 87.3% (95% CI: 5.5, 99.7) in the ATP‐E, 88.7% (95% CI: 18.5, 99.7) in the TVC‐E, and 100% (95% CI: 17.9, 100) in the TVC‐naïve. Cross‐protective efficacy against incident infection with HPV‐31, HPV‐33 and HPV‐45 was 59.6% (95% CI: 39.4, 73.5), 42.7% (95% CI: 15.6, 61.6), and 54.8% (95% CI: 19.3, 75.6), respectively (ATP‐E). At Month 72, >95% of initially seronegative women who received HPV vaccine in the ATP cohort for immunogenicity (N = 664) remained seropositive for anti‐HPV‐16/18 antibodies; anti‐HPV‐16 and anti‐HPV‐18 geometric mean titers were 678.1 EU/mL (95% CI: 552.9, 831.5) and 343.7 EU/mL (95% CI: 291.9, 404.8), respectively. Serious adverse events were infrequent (1.9% vaccine group [N = 3026]; 2.7% control group [N = 3025]). Three and zero women died in the control group and the vaccine group respectively. New onset autoimmune disease was reported in two women in the vaccine group and two in the control group.ConclusionsThis is the first large‐scale randomized clinical trial of HPV vaccination in China. High and sustained vaccine efficacy against HPV‐16/18‐associated infection and cervical lesions was demonstrated up to Month 72. The vaccine had an acceptable safety profile. Combined with screening, prophylactic HPV vaccination could potentially reduce the high burden of HPV infection and cervical cancer in China.Trial registrationNCT00779766.

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We previously reported the results of a phase II/III, double‐blind, randomized controlled study in Chinese women (NCT00779766) showing a 94.2% (95% confidence interval: 62.7–99.9) HPV‐16/18 AS04‐adjuvanted vaccine efficacy (VE) against cervical intraepithelial neoplasia grade 1 or higher (CIN1+) and/or 6‐month (M) persistent infection (PI) with a mean follow‐up of <2 years, and immunogenicity until 7 months post‐dose 1. Here, we report efficacy and safety results from an event‐triggered analysis with ~3 years longer follow‐up, and immunogenicity until M24. Healthy 18–25‐year‐old women (N = 6051) were randomized (1:1) to receive three doses of HPV‐16/18 vaccine or Al(OH)3 (control) at M0, 1, 6. VE against HPV‐16/18‐associated CIN2+, and cross‐protective VE against infections with nonvaccine oncogenic HPV types, immunogenicity, and safety were assessed. In the according‐to‐protocol efficacy cohort, in initially seronegative/DNA‐negative women (vaccine group: N = 2524; control group: N = 2535), VE against HPV‐16/18‐associated CIN2+ was 87.3% (5.3–99.7); VE against incident infection or against 6‐month persistent infection associated with HPV‐31/33/45 was 50.1% (34.3–62.3) or 52.6% (24.5–70.9), respectively. At least, 99.6% of HPV‐16/18‐vaccines remained seropositive for anti‐HPV‐16/18 antibodies; anti‐HPV‐16 and ‐18 geometric mean titers were 1271.1 EU/mL (1135.8–1422.6) and 710.0 EU/ml (628.6–801.9), respectively. Serious adverse events were infrequent (1.7% vaccine group [N = 3026]; 2.5% control group [N = 3026]). Of the 1595 reported pregnancies, nine had congenital anomalies (five live infants, three elective terminations, one stillbirth) that were unlikely vaccination‐related (blinded data). VE against HPV‐16/18‐associated CIN2+ was demonstrated and evidence of cross‐protective VE against oncogenic HPV types was shown. The vaccine was immunogenic and had an acceptable safety profile.

Lupus nephritis (LN) is a common and severe organ manifestation of systemic lupus erythematosus (SLE) and is a major cause of SLE related deaths. Early diagnosis is essential to improve the prognosis of patients with LN. To screen the potential biomarkers associated with LN, we downloaded the gene expression profile of GSE99967 from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was utilized to construct a gene co-expression network and identify gene modules associated with LN. Gene Ontology (GO) analysis was also applied to explore the biological function of genes and identify the key module. Differentially expressed genes (DEGs) were identified and Maximal Clique Centrality (MCC) values were calculated to screen hub genes. Furthermore, we selected promising biomarkers for real-time PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) validation in independent cohorts. Our results indicated that five hub genes, including IFI44, IFIT3, HERC5, RSAD2, and DDX60 play vital roles in the pathogenesis of LN. Importantly, IFI44 may considered as a key biomarker in LN for its diagnostic capabilities, which is also a promising therapeutic target in the future.

Ischemic stroke is usually followed by inflammatory responses mediated by microglia. However, the effect of statins on directly preventing posthypoxia microglia inflammatory factors to prevent injury to surrounding healthy neurons is unclear. Atorvastatin and rosuvastatin, which have different physical properties regarding their lipid and water solubility, are the most common HMG-CoA reductase inhibitors (statins) and might directly block posthypoxia microglia inflammatory factors to prevent injury to surrounding neurons. Neuronal damage and microglial activation of the peri-infarct areas were investigated by Western blotting and immunofluorescence after 24 hours in a middle cerebral artery occlusion (MCAO) rat model. The decrease in neurons was in accordance with the increase in microglia, which could be reversed by both atorvastatin and rosuvastatin. The effects of statins on blocking secretions from posthypoxia microglia and reducing the secondary damage to surrounding normal neurons were studied in a coculture system in vitro. BV2 microglia were cultured under oxygen glucose deprivation (OGD) for 3 hours and then cocultured following reperfusion for 24 hours in the upper wells of transwell plates with primary neurons being cultured in the bottom wells. Inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and cyclooxygenase-2 (COX2), which are activated by the nuclear factor-kappa B (NF-κB) signaling pathway in OGD-induced BV2 microglia, promoted decreased release of the anti-inflammatory cytokine IL-10 and apoptosis of neurons in the coculture systems according to ELISA and Western blotting. However, pretreatment with atorvastatin or rosuvastatin significantly reduced neuronal death, synaptic injury, and amyloid-beta (Aβ) accumulation, which might lead to increased low-density lipoprotein receptors (LDLRs) in BV2 microglia. We concluded that the proinflammatory mediators released from postischemia damage could cause damage to surrounding normal neurons, while HMG-CoA reductase inhibitors prevented neuronal apoptosis and synaptic injury by inactivating microglia through blocking the NF-κB signaling pathway.

Hemorrhagic transformation (HT) is a serious complication that stimulates inflammation during reperfusion therapy after acute ischemic stroke. Rosuvastatin, a 3-hydroxymethyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, might improve the outcome of HT by inhibiting neuroinflammation. This study aimed to explore the protective effects of rosuvastatin against HT after recombinant tissue plasminogen activator (rt-PA) treatment in mice with experimental stroke via the attenuation of inflammation. A total of one hundred sixty-nine male BALB/c mice were used in the experiment. HT was successfully established in 70 mice that were subjected to 3 h of middle cerebral artery occlusion (MCAO) followed by a 10 mg/kg rt-PA injection over 10 min and reperfusion for 24 h. The mice were then administered rosuvastatin (1 mg/kg, 5 mg/kg) or saline (vehicle). The brain water content and neurological deficits (wire hang and adhesive removal somatosensory tests) were assessed at 24 h after rt-PA reperfusion following MCAO surgery. The morphology, blood-brain barrier (BBB) permeability and number of astrocytes and microglia were assessed by immunohistochemistry, electron microscopy and western blotting at 24 h after rt-PA reperfusion following MCAO surgery. Rosuvastatin protected against impaired neurological function and reversed the BBB leakage observed in the HT group. The increased activation of astrocytes and microglia and secretion of inflammatory factors caused by HT damage were significantly attenuated by high-dose rosuvastatin treatment vs. normal-dose rosuvastatin treatment. Related inflammatory pathways, such as the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, were downregulated in the rosuvastatin-treated groups compared with the HT group. In conclusion, our results indicate that rosuvastatin is a promising therapeutic agent for HT after rt-PA reperfusion following MCAO surgery in mice, as it attenuates neuroinflammation. Additionally, high-dose rosuvastatin treatment could have a greater anti-inflammatory effect on HT than normal-dose rosuvastatin treatment.

Exploring and expanding the indications of common clinical drugs, such as statins, is important to improve the prognosis of patients with permanent cerebral infarction. It has been suggested that reversing the defects in cellular autophagy and ER stress with statin therapy may be a potential treatment option for reducing ischemic damage. Male Sprague-Dawley rats underwent permanent middle cerebral artery occlusion (PMCAO) by electrocoagulation surgery. Atorvastatin (ATV, 10 mg/kg/day) or vehicle was administered intraperitoneally. Rats were divided into the vehicle-treated (SHAM), ATV pretreatment for MCAO (AMCAO), and 3-methyladenine (3MA) combined with ATV pretreatment (3MAMCAO) groups. Magnetic resonance imaging, as well as immunohistochemical and Western blot assessments, were performed 24 h after MCAO. Each ATV-treated group demonstrated significant reductions in infarct volume compared with that in the vehicle-treated group at 24 h after MCAO, which was associated with autophagy reduction and ER stress attenuation in neurons and neovascularization. Next, Western blotting was used to detect the levels of the autophagy-related proteins LC3B and P62 and of ER stress pathway proteins. However, 3MA significantly partially inhibited the ER stress pathway via limiting the autophagic flux in the AMCAO group. In conclusion, our results imply that the neuroprotective function of ATV depends on autophagic activity to diminish ER stress-related cell apoptosis in rats with PMCAO and suggest that compounds that inhibit autophagic activity might reduce the neuroprotective effect of ATV after brain ischemia.

Sepsis is a heterogeneous syndrome induced by infection and results in high mortality. Even though more than 100 biomarkers for sepsis prognosis were evaluated, prediction of patient outcomes in sepsis continues to be driven by clinical signs because of unsatisfactory specificity and sensitivity of these biomarkers. This study aimed to elucidate the key candidate genes involved in sepsis response and explore their downstream effects based on weighted gene co-expression network analysis (WGCNA). The dataset GSE63042 with sepsis outcome information was obtained from the Gene Expression Omnibus (GEO) database and then consensus WGCNA was conducted. We identified the hub gene SDF4 (stromal cell derived factor 4) from the M6 module, which was significantly associated with mortality. Subsequently, two datasets (GSE54514 and E-MTAB-4421) and cohort validation (n=89) were performed. Logistic regression analysis was used to build a prediction model and the combined score resulting in a satisfactory prognosis value (area under the ROC curve=0.908). The model was subsequently tested by another sepsis cohort (n=70, ROC= 0.925). We next demonstrated that endoplasmic reticulum (ER) stress tended to be more severe in patients PBMCs with negative outcomes compared to those with positive outcomes and SDF4 was related to this phenomenon. In addition, our results indicated that adenovirus-mediated Sdf4 overexpression attenuated ER stress in cecal ligation and puncture (CLP) mice lung. In summary, our study indicates that incorporation of SDF4 can improve clinical parameters predictive value for the prognosis of sepsis, and decreased expression levels of SDF4 contributes to excessive ER stress, which is associated with worsened outcomes, whereas overexpression of SDF4 attenuated such activation.