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Ependymomas arise from ependymal cells lining the ventricles and central canal of the spinal cord and can occur throughout the whole neuraxis. The lesion rarely occurs in extracranial or extraspinal regions, particularly in the uterine broad ligament. Thus, for the pathogenesis of nonsacral extra-central nervous system (CNS) ependymomas remains elusive. Here, we describe a rare case of primary uterine broad ligament. ependymoma with cell-cycle-checkpoint kinase 2 (CHEK2) p.H371Y germline mutation. A 45-year-old woman presented with a uterine mass. The transvaginal sonographic examination confirmed a 4.4 cm × 3.7 cm, cystic and solid, mass located on the right side uterine wall near isthmus. First, laparoscopy with the neoplasm resection was carried out. Based on morphological and immunohistochemical characteristics of tumor cells that expressed glial fibrillary acidic protein (GFAP), S-100, and vimentin, the tumor was diagnosed as an ependymoma. After that, she underwent a laparotomic total hysterectomy, bilateral salpingo-oophorectomy, and lymphadenectomy. Furthermore, we performed next-generation sequencing (NGS) of the patient's resected tumor tissue and peripheral blood and identified a novel CHEK2 p.H371Y germline mutation. Following surgery, the patient received oral tamoxifen (10 mg 2/day) and followed by letrozole (2.5 mg/day) for 6 months. The patient remained disease-free after 4 years of follow-up. Conceivably, CHEK2 p.H371Y is a driving gene for the development of extra-CNS ependymoma.

Agomelatine was a novel and melatonergic antidepressant. The present study was conducted to find out whether age was an important factor for agomelatine in treating depressed type 2 diabetes mellitus (T2DM) patients. In total, 193 depressed T2DM patients were included. There were 84 patients ranged from 27 years old to 49 years old (age phase I) (n = 44 receiving agomelatine, n = 40 receiving paroxetine or fluoxetine), and 109 patients ranged from 50 years old to 70 years old (age phase II) (n = 56 receiving agomelatine, n = 53 receiving paroxetine or fluoxetine). The Hamilton Depression Rating Scale (HDRS) score, Hamilton Anxiety Rating Scale (HARS) score, fasting plasma glucose (FPG), hemoglobin A1c (HbA1c) level and body mass index (BMI) were assessed after 12 weeks treatment. After treatment, we found that among patients in age phase I, there were no significant differences in final average HDRS score, HARS score, FPG, HbA1c level, BMI, response rate and remission rate between the two groups. However, among patients in age phase II, compared to patients receiving paroxetine or fluoxetine, patients receiving agomelatine had the significantly lower average HDRS score, HARS score, HbA1c level and BMI, and significantly higher response rate and remission rate. The incidence of treatment-related adverse events was similar between the two groups in both age phases. These results suggested that age was an important factor for agomelatine in treating depressed T2DM patients. Compared to paroxetine/fluoxetine, agomelatine might be more appropriate for elderly depressed T2DM patients.

BackgroundMicroparticles (MPs) are extracellular vesicles that are associated with cancer development and progression. Advanced non-small cell lung cancer (NSCLC) still shows disease progression after multiple lines of treatment. Therefore, the objective of this study was to explore the correlation between circulating MPs and disease progression in advanced NSCLC, and to find a new method for concise and rapid determination of disease progression.MethodsPatients with advanced NSCLC admitted to hospital between October 2019 and October 2020 were included and divided into objective remission (OR) and progressive disease (PD) groups. The morphology of MPs was observed using transmission electron microscopy. The circulating total MPs, neutrophil MPs (NMPs), and platelet MPs (PMPs) before and after treatment were detected by flow cytometry, and a predictive model for disease progression in advanced NSCLC was developed.ResultsEighty-six patients were included; 60 in the OR group and 26 in the PD group. There was no significant difference in total MPs, NMPs, or PMPs at baseline between the two groups. After treatment, total MPs, NMPs, and PMPs were significantly higher in the PD than those in the OR group. Multivariate regression analysis showed that post-treatment NMPs≥160 events/μL(OR,3.748;95%CI,1.147–12.253,p = 0.029), PMPs≥80 events/μL(OR,10.968;95%CI,2.973–40.462,p< 0.0001) and neutrophil/lymphocyte ratio (NLR) ≥3.3 (OR,4.929;95%CI,1.483–16.375,p = 0.009) were independently associated with progression of advanced NSCLC. Post-treatment NMPs and PMPs combined with NLR were used to build a predictive model for progression of advanced NSCLC. The area under the curve was 0.825 (95%CI,0.715–0.934,p< 0.0001), optimal cut-off value was 16, sensitivity was 80.8%, and specificity was 88.3%.ConclusionNMPs and PMPs are associated with progression of advanced NSCLC. The predictive model for progression of advanced NSCLC, established combining NMPs, PMPs, and NLR, can screen out 80.8% of patients with PD. This is helpful for real-time accurate, concise and rapid assessment of disease progression and timely adjustment of drug therapy.Trial registrationChinese Clinical Trial Registry,ChiCTR1800020223. Registered 20 December 2018,http://www.chictr.org.cn/index.aspx.

H6 avian influenza virus (AIV) is one of the most prevalent AIV subtypes in the world. Our previous studies have demonstrated that H6 AIVs isolated from live poultry markets pose a potential threat to human health. In recent years, increasing number of H6 AIVs has been constantly isolated from poultry farms. In order to understand the biological characteristics of H6 AIVs in the context of farms, here, we analyzed the phylogenetic relationships, antigenicity, replication in mice and receptor binding properties of H6 AIVs isolated from farms in China between 2014 and 2018. Phylogenetic analysis showed that 19 different genotypes were formed among 20 representative H6 viruses. Notably, the internal genes of these H6 viruses exhibited complicated relationships with different subtypes of AIVs worldwide, indicating that these viruses are the products of complex and frequent reassortment events. Antigenic analysis revealed that 13 viruses tested were divided into 3 antigenic groups. 10 viruses examined could all replicate in the respiratory organs of infected mice without prior adaptation. Receptor binding analysis demonstrated that some of the H6 AIVs bound to both α-2, 3-linked glycans (avian-type receptor) and α-2, 6-linked glycans (human-type receptor), thereby posing potential threat to human health. Together, these findings revealed the prevalence, complicated genetic evolution, diverse antigenicity, and dual receptor binding specificity of H6 AIVs in the settings of poultry farms, which emphasize the importance to continuously monitor the evolution and biological properties of H6 AIVs in nature. This article is protected by copyright. All rights reserved.

Damage or injury to the skin creates wounds that are vulnerable to bacterial infection, which in turn retards the process of skin regeneration and wound healing. In patients with severe burns and those with chronic diseases, such as diabetes, skin infection by multidrug-resistant bacteria can be lethal. Therefore, a broad-spectrum therapy to effectively eradicate bacterial infection through a mechanism different from that of antibiotics is much sought after. We successfully synthesized antibacterial photodynamic gold nanoparticles (AP-AuNPs), which are self-assembled nanocomposites of an antibacterial photodynamic peptide and poly(ethylene glycol) (PEG)-stabilized AuNPs. The AP-AuNPs exhibited aqueous and light stability, a satisfactory generation of reactive oxygen species (ROS), and a remarkable antibacterial effect toward both Gram-positive

A novel peptide containing antimicrobial sequence and gelatinase cleavage sites was designed for Staphylococcus aureus detection. Since Staphylococcus aureus could secrete gelatinase, the fluorescein labeled peptide GKRWWKWWRRPLGVRGC could be recognized and cleaved. The obtained products were able to be analyzed by capillary electrophoresis with fluorescence detection. To explore the effect of Staphylococcus aureus concentration on enzyme digestion ability of peptide, Staphylococcus aureus with different concentrations were incubated with the peptide. Results indicated that capillary electrophoretic method was efficient for determining Staphylococcus aureus content. Compared with traditional approaches for Staphylococcus aureus detection, capillary electrophoresis possessed higher efficiency, enhanced sensitivity, and low sample consumption. Moreover, the proposed peptide also presented desirable antimicrobial activity. It suggested that the novel antimicrobial peptide used in this research opens a new path of detecting Staphylococcus aureus by capillary electrophoretic method.

Background Rationale exists for combining immune checkpoint inhibitors and PARP inhibitors (PARPi), and results of clinical trials in ovarian cancer are promising, but data in other cancers are limited. Method Efficacy and safety of PARPi/anti-PD-1 in advanced solid tumors were retrospectively analyzed. The efficacy measures included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Results This retrospective study included data from 40 patients. The ORR was 27.5% (95% CI, 13.0–42.0%), with a DCR of 85.0% (95% CI, 73.4–96.6%). Except four patients in first-line treatment (three with PR and one with SD), the ORR of ≥second-line treatment, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) was 22.2%, 23.1% and 28.6%, and the DCR was 83.3%, 84.6% and 71.4%, separately. The median PFS of all patients, ≥second-line treatment, NSCLC and SCLC was 4.6 m, 4.2 m, 4.5 m and 3.7 m. The median OS was 9.4 m, 11.4 m, 12.7 m and 5.4 m, respectively. Multivariable analysis revealed that BRCA1/2 mutation was positively correlated with ORR (P = 0.008), and LDH≥250U/L was negatively correlated with lowered DCR (P = 0.018), while lymphocyte number, ECOG and LDH significantly influenced both PFS and OS. We found that the possible resistant mechanisms were sarcomatous degeneration and secondary mutation, including BRCA2 truncation mutation, A2M, JAK1,T790M, KEAP1 and mTOR mutation. 37.5% patients had ≥grade 3 adverse events. Conclusion PARPi/anti-PD-1 is an effective and tolerable method for patients with advanced solid tumors, and BRCA1/2 is a potential biomarker.

BACKGROUND: Advanced non-small cell lung cancer (NSCLC) patients with poor performance status (PS) are likely to receive programmed cell death 1 (PD-1) inhibitors, despite limited evidence. The aim of the present study was to report the clinical outcomes and potential prognostic biomarkers in advanced NSCLC patients with poor PS receiving PD-1 inhibitors. METHODS: We conducted a retrospective study enrolling 101 advanced NSCLC patients from our hospital. Data of patients with poor PS 2–4 receiving PD-1 inhibitors were retrieved from medical records. Patients were stratified based on dichotomized baseline neutrophil-to-lymphocyte ratio (NLR), change in NLR (ΔNLR; 6 weeks post-treatment NLR minus baseline NLR), and their combination. The receiver-operating characteristic curve was used to assess the best cutoff for NLR. Multivariate Cox analysis was used to evaluate the prognostic value of NLR and ΔNLR for patients’ survival. RESULTS: The optimal cutoff for NLR was 4.5. The median follow-up was 25.7 months, baseline NLR ≥4.5, and ΔNLR ≥0, which were independently and significantly associated with shorter overall survival (both P=0.002) and progression-free survival (P=0.004 for NLR and P

Staphylococcus aureus (S. aureus) related staphylococcal infection is one of the most common types of hospital-acquired infections, which requires selective and effective treatment in clinical practice. Considering gelatinase as a characteristic feature of S. aureus, gelatinase-responsive release of the antibiotic reagent thereby can target the pathogenic S. aureus while sparing beneficial bacteria in the microflora. In this work, we design a hybrid antibacterial photodynamic peptide (APP, Ce6-GKRWWKWWRRPLGVRGC) based on the polycationic antimicrobial peptide GKRWWKWWRR by introducing a photosensitizer chlorin e6 (Ce6) at the N-terminus, a cysteine residue at the C-terminus, and a gelatinase cleavage site (PLGVRG) inserted between the C-terminal cysteine and the polycationic peptide. This multi-motif peptide assembles with gold nanoclusters (AuNc) via Au–thiol bonding and affords a gelatinase-responsive antibacterial photodynamic nanocomposite (GRAPN). In vitro results show that the gelatinase secreted by S. aureus can cleave and release APP from AuNc, thereby resulting in preferential killing of S. aureus over E. coli. In a mouse model of staphylococcal skin wound infection, by integrating gelatinase-responsive drug release and the synergistic effect of a photodynamic agent and APP, GRAPN exhibits a marked photodynamic antibacterial activity, effectively eradicates S. aureus infection, and promotes rapid healing of the infected wounds.

Continuous cuff-less blood pressure (BP) monitoring has become a research hotspot in recent years. Researches have studied the impact of pulse transit time (PTT) and ballistocardiogram (BCG) signals on BP. However, the accuracy of these methods are not high enough to put them into practice on a large scale. In this paper, we propose a new BP estimation model which combines features extracted from electrocardiogram (ECG), BCG and photoplethysmogram (PPG). We calculate several features containing amplitude, time and energy from these three signals and use stepwise regression to select key ones for this combination model. The combination model was examined in 20 young healthy subjects and it presents good results: a correlation coefficient (R) of 0.84 (systolic blood pressure, SBP) and 0.7 (diastolic blood pressure, DBP), a root-mean-squared error (RMSE) of 8.16 mmHg (SBP) and 6.63 mmHg (DBP), and a mean absolute error (MAE) of 6.84 mmHg (SBP) and 5.46 mmHg (SBP). Besides, The PTT-based BP estimation model and BCG-based estimation model are also established in this paper. The comparison of these three models shows that the PPG-ECG-BCG-based model has better performance.

H9N2 avian influenza viruses are widely prevalent in birds and pose an increasing threat to humans because of their enhanced virulence and transmissibility in mammals. Active surveillance on the prevalence and evolution of H9N2 viruses in different avian hosts will help develop eradication measures. We isolated 16 H9N2 viruses from chickens, green peafowls, and wild birds in eastern China from 2017 to 2019 and characterized their comparative genetic evolution, receptor-binding specificity, antigenic diversity, replication, and transmission in chickens and mice. The phylogenetic analysis indicated that the green peafowl viruses and swan reassortant shared the same ancestor with the poultry H9N2 viruses prevalent in eastern China, while the seven wild bird viruses belonged to wild bird lineage. The chicken, peafowl, and swan H9N2 viruses that belonged to the poultry lineage preferentially recognized α-2, 6-linked sialic acids (human-like receptor), but the wild bird lineage viruses can bind both α-2, 3 (avian-like receptor) and human-like receptor similarly. Interestingly, the H9N2 viruses of poultry lineage replicated well and transmitted efficiently, but the viruses of wild bird lineage replicated and transmitted with low efficiency. Importantly, the H9N2 viruses of poultry lineage replicated in higher titer in mammal cells and mice than the viruses of wild birds lineage. Altogether, our study indicates that co-circulation of the H9N2 viruses in poultry, wild birds, and ornamental birds increased their cross-transmission risk in different birds because of their widespread dissemination.

Background Immune checkpoint inhibitors (ICIs) represent a breakthrough in cancer treatment. However, they have rarely been used to treat biliary tract cancer (BTC). In the current study, we aimed to evaluate and compare the efficacy and safety of anti-programmed cell death-1 (PD-1) therapy used alone or in combination with chemotherapy or targeted therapy in the treatment of advanced BTC. Methods Patients with advanced BTC who were treated either with anti-PD-1 therapy alone or anti-PD-1 therapy plus chemotherapy or targeted therapy between December, 2015 and October, 2017 were retrospectively screened for eligibility. Patients who had previously received treatment with any agent targeting T-cell co-stimulation or immune checkpoints were excluded. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety were evaluated. Results A total of 37 patients were included in this study (15 cases in the monotherapy group and 22 cases in the combination group). Patients in the combination group had significantly longer OS [median, 8.2 vs. 3.6 months, HR 0.47 (0.20-1.10), P=0.011] and PFS (median, 3.9 vs. 2.0 months, HR 0.58 (0.28-1.19), P=0.034) than patients in the monotherapy group. The ORR was 18.2% (4/22) and 0% in the combination group and monotherapy group, respectively, and the difference was not significant (P=0.131). Furthermore, no significant difference was found between the two groups with respect to the incidence of grade 3-4 treatment-related adverse events (P=0.388). Conclusions Anti-PD-1 therapy plus chemotherapy or targeted therapy is an effective and tolerable treatment for patients with advanced BTC and is promising as a first-line treatment or beyond.

Soaring cases of coronavirus disease (COVID-19) are pummeling the global health system. Overwhelmed health facilities have endeavored to mitigate the pandemic, but mortality of COVID-19 continues to increase. Here, we present a mortality risk prediction model for COVID-19 (MRPMC) that uses patients’ clinical data on admission to stratify patients by mortality risk, which enables prediction of physiological deterioration and death up to 20 days in advance. This ensemble model is built using four machine learning methods including Logistic Regression, Support Vector Machine, Gradient Boosted Decision Tree, and Neural Network. We validate MRPMC in an internal validation cohort and two external validation cohorts, where it achieves an AUC of 0.9621 (95% CI: 0.9464–0.9778), 0.9760 (0.9613–0.9906), and 0.9246 (0.8763–0.9729), respectively. This model enables expeditious and accurate mortality risk stratification of patients with COVID-19, and potentially facilitates more responsive health systems that are conducive to high risk COVID-19 patients., Methods to stratify patients according to mortality risk are essential to allocate limited heath resources during the COVID-19 crisis. Here, using machine learning methods, the authors present a mortality risk prediction model for COVID-19 that uses patients’ clinical data on admission to stratify patients by mortality risk.

Anti-programmed cell death protein 1 or its ligand (anti-PD-1/L1) monotherapy has become the standard second-line treatment in advanced lung adenocarcinoma. However, the strategy treatment of anti-PD-1/L1 plus anti-angiogenesis therapy has not been evaluated. We conducted this retrospective study to assess the efficacy and safety of anti-PD-1/L1 plus anti-angiogenesis therapy in patients with advanced lung adenocarcinoma in the second-line or later setting. Patients with advanced lung adenocarcinoma who received anti-PD-1/L1 plus anti-angiogenesis therapy or anti-PD-1/L1 monotherapy in the second-line or later treatment from March 2015 to May 2019 in PLA General Hospital were retrospectively analyzed. The progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety were assessed. Multivariate analyses of PFS and OS were performed with Cox proportional hazard regression models. Seventy-four patients were included in our study. Twenty-five patients were treated with anti-PD-1/L1 plus anti-angiogenesis therapy, and forty-nine patients were treated with anti-PD-1/L1 monotherapy. The disease control rate (DCR) was higher in the anti-PD-1/L1 plus anti-angiogenesis group than in the anti-PD-1/L1 monotherapy group (92.0% vs. 46.9%, P = 0.0004). The median progression-free survival (PFS) was 5.1 months vs. 2.0 months (HR 0.551 [95% confidence interval 0.337–0.902], P = 0.002) and median overall survival (OS) was 14.3 months vs. 8.4 months (HR 0.549 [95% CI 0.305–0.990], P = 0.046), respectively. Multivariate Cox proportional hazard regression models showed that anti-PD-1/L1 plus anti-angiogenesis group had prolonged PFS (HR 0.541 [95% CI 0.298–0.981], P = 0.033). The incidences of grade 3/4 adverse events were 12% (3/25) in anti-PD-1/L1 plus anti-angiogenesis group and 6% (3/49) in anti-PD-1/L1 monotherapy group. Compared with anti-PD-1/L1 monotherapy, anti-PD-1/L1 plus anti-angiogenesis therapy could significantly improve the clinical response and bring longer PFS and OS in patients with advanced lung adenocarcinoma who had failed first-line or later treatment. Further prospective studies are needed to validate our findings.

The efficacies of pembrolizumab and nivolumab have never been directly compared in a real-world study. Therefore, we sought to retrospectively evaluate the objective response rate (ORR) and the progression-free survival (PFS) of patients with recurrent or advanced non-small cell lung cancer (NSCLC) in a real-world setting. This study included patients with recurrent or advanced NSCLC diagnosed between September 1, 2015 and August 31, 2019, who were treated with programmed cell death 1 (PD-1) inhibitors at the Cancer Center of the Chinese People’s Liberation Army. PFS was estimated for each treatment group using Kaplan–Meier curves and log-rank tests. The multivariate analysis of PFS was performed with Cox proportional hazards regression models. A total of 255 patients with advanced or recurrent NSCLC treated with PD-1 inhibitors were identified. The ORR was significantly higher in the pembrolizumab group than in the nivolumab group, while PFS was not significantly different between the two groups. Subgroup analysis showed that the ORR was significantly higher for pembrolizumab than for nivolumab in patients in the first-line therapy subgroup and in those in the combination therapy as first-line therapy subgroup. Survival analysis of patients receiving combination therapy as second- or further-line therapy showed that nivolumab had better efficacy than pembrolizumab. However, the multivariate analysis revealed no significant difference in PFS between patients treated with pembrolizumab and those treated with nivolumab regardless of the subgroup. In our study, no significant difference in PFS was noted between patients treated with pembrolizumab and those treated with nivolumab in various clinical settings. This supports the current practice of choosing either pembrolizumab or nivolumab based on patient preferences.

BACKGROUND: Distant metastasis, particularly visceral metastasis (VM), represents an important negative prognostic factor for prostate cancer (PCa) patients. However, due to the lower rate of occurrence of VM, studies on these patients are relatively rare. Consequently, studies focusing on prognostic factors associated with PCa patients with VM are highly desirable. AIM: To investigate the prognostic factors for overall survival (OS) in PCa patients with lung, brain, and liver metastases, respectively, and evaluate the impact of site-specific and number-specific VM on OS. METHODS: Data on PCa patients with VM were extracted from the Surveillance, Epidemiology, and End Results database between 2010 and 2015. Univariate and multivariate Cox regression analyses were used to analyze the association between clinicopathological characteristics and survival of patients with different site-specific VM. Kaplan-Meier analyses and Log-rank tests were performed to analyze the differences among the groups. RESULTS: A total of 1358 PCa patients with site-specific VM were identified from 2010 to 2015. Older age (> 70 years) (P < 0.001), higher stage (T3/T4) (P = 0.004), and higher Gleason score (> 8) (P < 0.001) were found to be significant independent prognostic factors associated with poor OS in PCa patients with lung metastases. Higher stage (T3/T4) (P = 0.047) was noted to be the only independent risk factor affecting OS in PCa patients with brain metastases. Older age (> 70 years) (P = 0.010) and higher Gleason score (> 8) (P = 0.001) were associated with shorter OS in PCa patients with liver metastases. PCa patients with isolated lung metastases exhibited significantly better survival outcomes compared with PCa patients with other single sites of VM (P < 0.001). PCa patients with a single site of VM exhibited a superior OS compared with PCa patients with multiple sites of VM (P < 0.001). CONCLUSION: This is the first Surveillance, Epidemiology, and End Results-based study to determine prognostic factors affecting OS in PCa patients with different site-specific VM. Clinical assessments of these crucial prognostic factors become necessary before establishing a treatment strategy for these patients with metastatic PCa.

Lethal infection of wild birds with different subtypes of H5 viruses continuously occur. To investigate the genetic evolution and pathogenicity of H5 viruses in wild birds, we performed a detailed genetic and biologic analysis of 27 viruses, including H5N1, H5N2, H5N6, and H5N8 subtypes, that were responsible for avian influenza outbreaks in wild birds in China over the past decade. We found that these 27 viruses, bearing different clades/subclades of HA, were complicated reassortants and formed 12 different genotypes. Ten of the viruses tested were highly pathogenic in chickens, but showed distinct pathotypes in ducks and mice. Five of these 10 viruses, which were all from clade2.3.4.4, could bind human-type receptors. Our findings reveal the diversity of the genetic and biologic properties of H5 viruses circulating in wild birds and highlight the need to carefully monitor and evaluate the risks these viruses pose to animal and public health.

Immune checkpoint inhibitor combination therapy exhibited outstanding efficacy in first line setting for advanced non-small cell lung cancer (aNSCLC) patients. However, whether PD-1 inhibitor combined treatment is effective in second line or later setting remains unknown. Therefore, we retrospectively evaluated the efficacy of combined therapy of PD-1 inhibitor with chemotherapy and/or bevacizumab compared to PD-1 inhibitor alone for aNSCLC patients in second line or later setting. Patients with aNSCLC who have received anti-PD-1 based therapy between 2015 and 2017 were screened, and 55 patients were ultimately included and divided into the monotherapy group (N=33) and the combination group (N=22). Patients treated with combination therapy exhibited superior PFS versus those treated with monotherapy (median PFS, 7.5 months vs 3.3 months; hazard ratio 0.28; 95% CI, 0.14-0.56; P

In order to avoid the discomfort of digesting milk protein and make full use of the gastrointestinal digestive function, a milk macromolecular peptide was prepared with ACE inhibitory activity after gastrointestinal digestion as the index. Then, the antihypertensive activity of the milk macromolecular peptide in rats was evaluated. The results showed that the ACE inhibitory activity of hydrolysate after simulated gastrointestinal digestion was the highest in which the degree of hydrolysis was 17% and the ACE inhibitory activity reached 78.48%. The optimum enzymatic parameters were obtained with the protein concentration of 3.4%, enzymatic temperature of 55 °C, pH value of 7.0, and 7% enzyme amount using neutral protease. Under these conditions, the ACE inhibitory activity of hydrolysate after simulated gastrointestinal digestion was as high as 89.49%. Compared to traditional peptides, the ACE inhibitory activity of the macromolecular peptide increased after simulated gastrointestinal digestion. After 4 weeks of gavage tests of the milk macromolecular peptide, the blood pressure of rats with spontaneous hypertension dropped to below 140 mmHg, with a decrease of 60 mmHg. The antihypertensive effect of the milk macromolecular peptide was similar to that of captopril. The milk macromolecular peptide decreased the blood pressure of spontaneously hypertensive rats by inhibiting the ACE activity of the lung, kidney and arteries, and regulating the content of the signal factors of endothelin, NO, angiotensin II and renin in serum indicators. These results indicated that the macromolecular ACE inhibitory peptide with an antihypertensive effect could be prepared by the enzymatic hydrolysis of milk protein to realize the full utilization of protein resources.

Background In 2017–2018, a new highly pathogenic H5N6 avian influenza virus (AIV) variant appeared in poultry and wild birds in Asian and European countries and caused multiple outbreaks. These variant strains are different from the H5N6 virus associated with human infection in previous years, and their genetic taxonomic status and antigenicity have changed. Therefore, revision of the primers and probes of fluorescent RT-PCR is important to detect the new H5N6 subtype AIV in poultry and reduce the risk of an epidemic in birds or humans. Methods In this study, the primers and probes including three groups of HA and four groups of NA for H5N6 influenza virus were evaluated. Then a set of ideal primer and probes were selected to further optimize the reaction system and established a method of double rRT-PCR assay. The specificity of this method was determined by using H1~H16 subtype AIV. Results The results showed that fluorescence signals were obtained for H5 virus in FAM channel and N6 virus in VIC channel, and no fluorescent signal was observed in other subtypes of avian influenza viruses. The detection limit of this assay was 69 copies for H5 and 83 copies for N6 gene. And, the variability tests of intra- and inter-assay showed excellent reproducibility. Moreover, this assay showed 100% agreement with virus isolation method in detecting samples from poultry. Conclusion The duplex rRT-PCR assay presented here has high specificity, sensitivity and reproducibility, and can be used for laboratory surveillance and rapid diagnosis of newly emerged H5N6 subtype avian influenza viruses.

The H5N8 avian influenza viruses have been widely circulating in wild birds and are responsible for the loss of over 33 million domestic poultry in Europe, Russia, Middle East, and Asia since January 2020. To monitor the invasion and spread of the H5N8 virus in China, we performed active surveillance by analyzing 317 wild bird samples and swab samples collected from 41,172 poultry all over the country. We isolated 22 H5N8 viruses from wild birds and 14 H5N8 viruses from waterfowls. Genetic analysis indicated that the 36 viruses formed two different genotypes: one genotype viruses were widely detected from different wild birds and domestic waterfowls; the other genotype was isolated from a whopper swan. We further revealed the origin and spatiotemporal spread of these two distinct H5N8 virus genotypes in 2020 and 2021. Animal studies indicated that the H5N8 isolates are highly pathogenic to chickens, mildly pathogenic in ducks, but have distinct pathotypes in mice. Moreover, we found that vaccinated poultry in China could be completely protected against H5N8 virus challenge. Given that the H5N8 viruses are likely to continue to spread in wild birds, vaccination of poultry is highly recommended in high-risk countries to prevent H5N8 avian influenza.

Plants are readily exposed to the antibiotics residues in reclaimed water indicating an urgent need to comprehensively analyze their ecotoxicological effects and fate of these emerging contaminants. Here, we unraveled the dissemination of enrofloxacin (ENR) in a pasture grass, Lolium perenne L., and identified multistage defense systems as its adaptation mechanism. Uptaken concentrations of ENR ranged from 1.28 to 246.60 µg g-1 with bioconcentration factors (BCF) upto 15.13, and translocation factors (TF) upto 0.332. The antioxidant enzymatic activities such as superoxide dismutase, peroxidase, and catalase were increased by upto 115%. Further transcriptomics demonstrated that differentially expressed genes (DEGs) involved in glycolysis, oxidative phosphorylation and glutathione metabolism were significantly up-regulated by 1.56-5.93 times, 3-7 times and 1.04-6.42 times, respectively, whilst, the DEGs in nitrogen and sulfur metabolism pathways were significantly up-regulated by 1.06-5.64 times and 2.64-3.54 times, respectively. These processes can supply energy, signaling molecules, and antioxidants for detoxification of ENR in ryegrass. Such results provide understanding into fasting grass adaptability to antibiotics by enhancing the key protective pathways under organic pollutant stresses in environments.

Background: It remains controversial whether postoperative adjuvant treatment is beneficial for the survival of patients after surgery for early-stage endometrial cancer. To evaluate whether postoperative adjuvant treatment is beneficial for the survival of patients after surgery for early-stage endometrial cancer. We analyzed the outcomes of patients treated with radiotherapy, chemotherapy, or progestagen combined with other adjuvant treatments. Methods: We retrospectively examined disease-free survival (DFS), overall survival (OS) and high risk factors that affected the survival status of all patients who received different postoperative adjuvant therapies. Results: The total relapse and mortality rates were 5.57% and 1.68%, respectively. During follow-up period, fourteen patients (7.29%) developed isolated local recurrence, and 2 patients died (1.04%) of recurrence. The 5-year DFS and OS rates in all patients were 95.83% and 93.75%, respectively. No significant differences were observed in the 5-year DFS, 5-year OS, OS, or DFS among the four groups of patients with FIGO stage I endometrial cancer. The differences in the log-rank test results of the estimates of the 5-year DFS, 5-year OS, DFS and OS of patients with different disease stages and different ages were all significant, but no differences were observed in these parameters between patients with varying degrees of differentiation. Histologic grade, CA125 level, ER and PR status and whether adjuvant therapies had no significant effect on the DFS and OS of all patients according to univariate and multivariate regression analyses, but age stratification did reveal significant differences in DFS and OS in the univariate and multivariate analyses. Conclusion: This retrospective study showed that adjuvant treatments after surgery were not significantly associated with improved DFS or OS in patients with early-stage endometrial cancer. However, FIGO stage and age affected the survival of patients with stage I endometrial cancer.

Chemotherapy-induced ovarian damage and fertility loss have negative impacts on the quality of life for female cancer patients worldwide. Thus, we aimed to explore the feasibility and safety of gene therapy for prevention of such damage. First, we validated doxorubicin-induced ovarian damage in human and mouse ovarian tissues and identified two key genes (Sirt1 and Tgfbr2). Next, we generated AdV-Sirt1 and AdV-Tgfbr2 after vectors screening (AdV,AAV and LV) for their ability to transduce mouse ovaries. Finally, we conducted in situ ovarian injection of AdV-Sirt1 and AdV-Tgfbr2 in doxorubicin-treated mice and assessed their ovarian functions and reserves. The interventions dramatically alleviated doxorubicin-induced ovarian damage without apparently influencing the health status of their offspring. Together, our results indicate that AdV-Sirt1 and AdV-Tgfbr2 can serve as effective and safe agents for reducing doxorubicin-induced ovarian damage and also suggest that they may be potentially applicable for post-chemotherapy protection in female cancer patients.

Background: Caesarean scar pregnancy (CSP) can have catastrophic consequences. A standardized diagnosis and treatment for CSP are still lacking. The currently available treatment methods are confusing, and at least 10 different treatment measures exist. The aim of this study was to compare the outcomes of with laparotomy or laparoscopy in the treatment of high-risk CSP. Methods: We reviewed 935 patients with CSP from 1 January 2013 and 31 December 2018. A total of 278 patients were included in the study, of whom 121 were treated with laparoscopy and 157 were treated with laparotomy.Results: We compared and analysed the characteristics of the laparoscopic and open surgeries in the treatment of high-risk CSP and the advantages and disadvantages of different methods of vascular pretreatment. Intraoperative bleeding, transfusion rate, total days of hospitalization and postoperative hospital stay were better in laparoscopy than in laparotomy (P < 0.05). There was no difference in the factors (β-HCG decrease, reoperation and tissue residues) closely related to the success of the surgery in the two groups. Furthermore, we pretreated blood vessels differently before the operation in some patients. Tissue residue, reoperation and intraoperative blood transfusion rates in patients with temporary vascular occlusion were better than in patients with permanent vascular occlusion. Conclusions: This study revealed that laparoscopic surgery is superior to laparotomic surgery in the treatment of high-risk CSP. Patients benefited from temporary arterial occlusion in both groups. Temporary arterial occlusion under laparoscopic surgery may be the best treatment for high-risk CSP.

Reactive oxygen species (ROS) are the weapons of neutrophiles against bacterial pathogens, and also the central effectors in reactive oxygen therapy for skin and soft tissue infection. Nanozymes that spontaneously generate ROS under physiological conditions are new antibacterials that hold promise towards multidrug resistant pathogens. The clinical use of the nanozymes is however limited by their low biocompatibility and toxicity in vivo. Here, we develop an oleic acid (OA) nanoemulsion template method for the one-pot synthesis of OA-manganese dioxide (MnO2) nanozyme. The OA-MnO2 nanozyme showed high stability and biocompatibility under physiological conditions with marked oxidase-like activity. The ROS generated by the OA-MnO2 nanozyme effectively kill the Gram-positive Staphylococcus aureus and the Gram-negative Escherichia coli strains. Moreover, the OA-MnO2 nanozyme shows promising abilities to prevent and destruct biofilm formation by Staphylococcus aureus, and result in superior in vivo antibacterial performance as compared to vancomycin. The reactive oxygen therapy based on OA-MnO2 nanozyme cures the infected skin and promotes wound healing in mice, manifesting its potential use in skin and soft tissue infection.

BackgroundDue to the rarity of adenosquamous carcinoma of the cervix (ASCC), studies on the incidence, prognostic factors, and treatment outcomes of ASCC remain scarce. Therefore, we performed a retrospective population-based study to systematically investigate the characteristics of ASCC patients.MethodsPatients with a histopathologically confirmed diagnosis of ASCC were enrolled from the Surveillance, Epidemiology, and End Results database between 1975 and 2016. Univariate and multivariate Cox regression analyses were performed to identify the potential predictors of cancer-specific survival (CSS) in patients with ASCC. Selected variables were integrated to establish a predictive nomogram and the predictive performance of the nomogram was estimated using Harrell’s concordance index (C-index), calibration curve, and decision curve analysis (DCA).ResultsA total of 1142 ASCC patients were identified and included in this study and were further randomized into the training and validation cohorts in a 7:3 ratio. The age-adjusted incidence of ASCC declined from 0.19 to 0.09 cases per 100,000 person-years between 2000 and 2017, with an annual percentage change of -4.05% (PConclusionsWe established and validated an accurate predictive nomogram for ASCC patients based on several clinical characteristics. This model might serve as a useful tool for clinicians to estimate the prognosis of ASCC patients.

The detection of protease activity in the body plays a significant role in the early diagnosis of diseases. However, enzymes inevitably come into contact with various complex biological fluids in the body during the flow, which greatly increases the detection difficulty. Therefore, protease detection in vivo has great challenges. Herein, we report a new assay for detecting protease using capillary electrophoresis inside a capillary with semicircular bends. We first designed a peptide substrate, and then the peptide was self-assembled with quantum dots to form a QDs-peptide substrate. The capillary was bent to semicircular-shaped turns and served as a micro-reactor to allow protease and substrate react in it. Due to the different electrophoretic velocity, the protease and the substrate were mixed inside the bent capillary with sequential injections and the cleavage of the substrate can be detected using capillary electrophoresis combined with Forster resonance energy transfer technology. This novel assay will greatly expand the detection of enzyme activity in vivo.

BackgroundImmune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have demonstrated promise in treating a variety of advanced cancers; however, little is known regarding their efficacy under various clinical situations, including different cancer types, treatment lines, drug combinations, and therapeutic regimens.MethodsPublished articles and conference abstracts (in English) in PubMed, Embase, the Cochrane Central Register, and Web of Science were searched up to February 10, 2020. The data were analyzed by the meta-analysis program in Stata.ResultsA total of 16,400 patients from 91 clinical trials were included in this meta-analysis. PD-1/PD-L1 inhibitors had a mean ORR of 19.56% (95% CI: 15.09–24.03), a median TTR of 2.05 months (m) (95%CI: 1.85–2.26), and a median DOR of 10.65 m (95%CI: 7.78–13.52). First-line treatment had a higher ORR (36.57% vs. 13.18%) but a shorter DOR (9.00 m vs. 13.42 m) compared to the second-line or subsequent treatment. Immunotherapy combined with chemotherapy (I+C) (46.81% [95%CI: 36.02–57.60]) had a statistically significant higher ORR compared to immunotherapy (I) (17.75% [95%CI: 14.47–21.03]) or immunotherapy combined with immunotherapy (I+O) (12.25% [95%CI: 1.56–22.94]), while I+C (8.09 m [95%CI: 6.86–9.32]) appeared to reduce the DOR compared to I (12.39 m [95%CI: 7.60–17.18]). PD-1 inhibitors were associated with better ORR (21.65% vs. 17.60%) and DOR (11.26 m vs. 10.03 m) compared to PD-L1 inhibitors. There were no significant differences in TTR under different situations.ConclusionsPD-1/PD-L1 inhibitors were promising immunotherapeutic agents to achieve satisfactory response efficacies with different cancer types, treatment lines, drug combinations, and therapeutic regimens. This comprehensive summary of the response efficacy of PD-1/PD-L1 inhibitors serves as a reference for clinicians to make evidence-based decisions.

Background Evidence for the efficacy of immunotherapy in biliary tract cancer (BTC) is limited and unsatisfactory. Methods Chinese BTC patients receiving a PD-1 inhibitor with chemotherapy, PD-1 inhibitor monotherapy or chemotherapy alone were retrospectively analyzed. The primary outcome was overall survival (OS). The key secondary outcomes were progression-free survival (PFS) and safety. Patients previously treated with any agent targeting T cell costimulation or immune checkpoints were excluded. Results The study included 77 patients (a PD-1 inhibitor plus chemotherapy, n = 38; PD-1 inhibitor monotherapy, n = 20; chemotherapy alone, n = 19). The median OS was 14.9 months with a PD-1 inhibitor plus chemotherapy, significantly longer than the 4.1 months with PD-1 inhibitor monotherapy (HR 0.37, 95% CI 0.17–0.80, P = 0.001) and the 6.0 months with chemotherapy alone (HR 0.63, 95% CI 0.42–0.94, P = 0.011). The median PFS was 5.1 months with a PD-1 inhibitor plus chemotherapy, significantly longer than the 2.2 months with PD-1 inhibitor monotherapy (HR 0.59, 95% CI 0.31–1.10, P = 0.014) and the 2.4 months with chemotherapy alone (HR 0.61, 95% CI 0.45–0.83, P = 0.003). Grade 3 or 4 treatment-related adverse events were similar between the anti-PD-1 combination group and the chemotherapy alone group (34.2% and 36.8%, respectively). Conclusions Anti-PD-1 therapy plus chemotherapy is an effective and tolerable approach for advanced BTC.

Wild and domestic aquatic birds are the natural reservoirs of avian influenza viruses (AIVs). All subtypes of AIVs, including 16 hemagglutinin (HA) and nine neuraminidase (NA), have been isolated from the waterfowls. The H5 viruses in wild birds display distinct biological differences from their highly pathogenic H5 counterparts. Here, we isolated seven H5N3 AIVs including three from wild birds and four from domestic ducks in China from 2015 to 2018. The isolation sites of all the seven viruses were located in the region of the East Asian-Australasian Migratory Flyway. Phylogenetic analysis indicated that the surface genes of these viruses originated from the wild bird H5 HA subtype and the N3 Eurasian lineage. The internal genes of the seven H5N3 isolates are derived from the five gene donors isolated from the wild birds or ducks in Eastern-Asia region. They were also divided into five genotypes according to their surface genes and internal gene combinations. Interestingly, two of the seven H5N3 viruses contributed their partial internal gene segments (PB1, M and NS) to the newly emerged H7N4 reassortants, which have caused first human H7N4 infection in China in 2018. Moreover, we found that the H5N3 virus used in this study react with the anti-serum of the H5 subtype vaccine isolate (Re-11 and Re-12) and reacted well with the Re-12 anti-serum. Our findings suggest that worldwide intensive surveillance and the H5 vaccination (Re-11 and Re-12) in domestic ducks are needed to monitor the emergence of novel H5N3 reassortants in wild birds and domestic ducks and to prevent H5N3 viruses transmission from the apparently healthy wild birds and domestic ducks to chickens.

Previous studies have shown that miRNAs involved in a number of biological processes, such as cell growth, development, differentiation, and apoptosis. The dysregulation of miRNA expression is associated with various diseases, including cervical cancer. However, the involvement of miR‐3647‐5p in the progression of tumors is unclear. In this study, we confirmed that miR‐3647‐5p was down‐regulated during cervical carcinogenesis and development, which was positively correlated with the prognosis of patients with cervical cancer. In addition, our study showed that miR‐3647‐5p can inhibit the proliferation of cervical cancer cells and promote apoptosis, suggesting that miR‐3647‐5p is involved in the development of cervical cancer as a tumor suppressor gene. Furthermore, we found that transcription factor TP53 could promote the expression of miR‐3647‐5p, suggesting that the dysfunction of miR‐3647‐5p in cervical cancer may be related to TP53. In addition, we also found that miR‐3647‐5p can inhibit the proliferation of cervical cancer cells and promote apoptosis by targeting AGR2. In summary, our research reveals that transcription factor TP53 promotes the expression of miR‐3647‐5p, while up‐regulated miR‐3647‐5p targets AGR2, inhibiting cervical cancer cell proliferation and promoting apoptosis. Our study reveals the mechanism of TP53/miR‐3647‐5p/AGR2 axis in cervical cancer, which may be useful for targeted therapy of cervical cancer., Our research reveals that TP53 acts as a transcription factor to promote the expression ofmiR‐3647‐5p, while up‐regulated miR‐3647‐5p targets AGR2, inhibiting cervical cancer cell proliferation and promoting apoptosis.

Poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated great promise for treating cancers with homologous recombination (HR) defects, such as germline BRCA1/2 mutation. Further studies suggest that PARP inhibitors (PARPi) can also exhibit efficacy in HR-competent cancers, by amplifying the DNA damage and inducing immunogenic cell death, and PARPi lead to increasing tumor neoantigen, upregulation of interferons and PD-L1, and modulation of the tumor microenvironment, which may facilitate a more profound antitumor immune response. Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 or CTLA-4 have achieved impressive success in the treatment of different malignancies. However, only a subset of populations derive clinical benefit, and the biomarkers and resistance mechanisms are not fully understood. Therefore, given that PARPi could potentiate the therapeutic effect of ICIs, PARPi combined with ICIs are becoming an alternative for patients who cannot benefit from ICI monotherapy. In this review, we focus on the mechanisms and immune role of PARPi and discuss the rationale and clinical studies of this combined regimen.

Background Avian infectious bronchitis virus (IBV) is a gamma coronavirus that severely affects the poultry industry worldwide. Long non-coding RNAs (lncRNAs), a subset of non-coding RNAs with a length of more than 200 nucleotides, have been recently recognized as pivotal factors in the pathogenesis of viral infections. However, little is known about the function of lncRNAs in host cultured cells in response to IBV infection. Results We used next-generation high throughput sequencing to reveal the expression profiles of mRNAs and lncRNAs in IBV-infected HD11 cells. Compared with the uninfected cells, we identified 153 differentially expressed (DE) mRNAs (106 up-regulated mRNAs, 47 down-regulated mRNAs) and 181 DE lncRNAs (59 up-regulated lncRNAs, 122 down-regulated lncRNAs) in IBV-infected HD11 cells. Moreover, gene ontology (GO) and pathway enrichment analyses indicated that DE mRNAs and lncRNAs were mainly involved in cellular innate immunity, amino acid metabolism, and nucleic acid metabolism. In addition, 2640 novel chicken lncRNAs were identified, and a competing endogenous RNA (ceRNAs) network centered on gga-miR-30d and miR-146a-5p was established. Conclusions We identified expression profiles of mRNAs and lncRNAs during IBV infection that provided new insights into the pathogenesis of IBV.

Objective: This study was intended to investigate the relationship between COVID-19 disease and ovarian function in reproductive-aged women.Methods: Female COVID-19 patients of reproductive age were recruited between January 28 and March 8, 2020 from Tongji Hospital in Wuhan. Their baseline and clinical characteristics, as well as menstrual conditions, were recorded. Differentials in ovarian reserve markers and sex hormones (including anti-Müllerian hormone [AMH], follicle-stimulating hormone [FSH], the ratio of FSH to luteinizing hormone [LH], estradiol [E2], progesterone [P], testosterone [T], and prolactin [PRL] were compared to those of healthy women who were randomly selected and individually matched for age, region, and menstrual status. Uni- and multi-variable hierarchical linear regression analyses were performed to identify risk factors associated with ovarian function in COVID-19 women.Results: Seventy eight patients agreed to be tested for serum hormone, of whom 17 (21.79%) were diagnosed as the severe group and 39 (50%) were in the basal level group. Menstrual status (P = 0.55), menstrual volumes (P = 0.066), phase of menstrual cycle (P = 0.58), and dysmenorrhea history (P = 0.12) were similar without significant differences between non-severe and severe COVID-19 women. Significant lower serum AMH level/proportion (0.19/0.28 vs. 1.12 ng/ml, P = 0.003/0.027; AMH ≤ 1.1 ng/ml: 75/70.4 vs. 49.7%, P = 0.009/0.004), higher serum T (0.38/0.39 vs. 0.22 ng/ml, P < 0.001/0.001) and PRL (25.43/24.10 vs. 12.12 ng/ml, P < 0.001/0.001) levels were observed in basal level and the all-COVID-19 group compared with healthy age-matched control. When adjusted for age, menstrual status and parity variations in multivariate hierarchical linear regression analysis, COVID-19 disease was significantly associated with serum AMH (β = −0.191; 95% CI: −1.177–0.327; P = 0.001), T (β = 0.411; 95% CI: 11.154–22.709; P < 0.001), and PRL (β = 0.497; 95% CI: 10.787–20.266; P < 0.001), suggesting an independent risk factor for ovarian function, which accounted for 3.2% of the decline in AMH, 14.3% of the increase in T, and 20.7% of the increase in PRL.Conclusion: Ovarian injury, including declined ovarian reserve and reproductive endocrine disorder, can be observed in women with COVID-19. More attention should be paid to their ovarian function under this pandemic, especially regarding reproductive-aged women.Clinical Trial Number: ChiCTR2000030015.

Posttranslational modifications, such as SUMOylation, play specific roles in the life cycle of invading pathogens. However, the effect of SUMOylation on the adaptation, pathogenesis, and transmission of influenza A virus (IAV) remains largely unknown. Here, we found that a conserved lysine residue at position 612 (K612) of the polymerase basic protein 1 (PB1) of IAV is a bona fide SUMOylation site. SUMOylation of PB1 at K612 had no effect on the stability or cellular localization of PB1, but was critical for viral ribonucleoprotein (vRNP) complex activity and virus replication in vitro. When tested in vivo, we found that the virulence of SUMOylation-defective PB1/K612R mutant IAVs was highly attenuated in mice. Moreover, the airborne transmission of a 2009 pandemic H1N1 PB1/K612R mutant virus was impaired in ferrets, resulting in reversion to wild-type PB1 K612. Mechanistically, SUMOylation at K612 was essential for PB1 to act as the enzymatic core of the viral polymerase by preserving its ability to bind viral RNA. Our study reveals an essential role for PB1 K612 SUMOylation in the pathogenesis and transmission of IAVs, which can be targeted for the design of anti-influenza therapies., Author summary IAV has evolved to exploit the host posttranslational modifications system for its own benefit. The transcription and replication of IAV genome occur in the nucleus of infected cells, which is catalyzed by the RNA-dependent RNA polymerase (RdRp). PB1 is the catalytic subunit and the assembly core of the RdRp. The ability to efficiently bind viral RNA by PB1 is a prerequisite for the RdRp to fulfil its function. In this study, we demonstrated that PB1 protein from different subtypes of IAV is a target of SUMOylation in both transfected and infected cells, and identified K612 of PB1 as the key SUMOylation site. The vRNP complex activity, replication in vitro, pathogenicity in mice and airborne transmission among ferrets were dramatically attenuated when the SUMOylation-defective PB1/K612R mutation was introduced. Notably, we found that SUMOylation at K612 is essential for PB1 to acquire the ability to efficiently bind viral RNA, thus allowing for the RdRp to transcribe and replicate the viral genome. Our findings therefore thoroughly explore the contribution of PB1 SUMOylation on influenza infection and establish SUMOylation site PB1 K612 as a potential target for anti-influenza drug development.

Pharmaceutical contaminants (PCs) have been recognized as emerging contaminants causing unexpected consequences to environment and humans. There is an urgent need for development of efficient technologies to treat these PCs from water. The current study has investigated the removal capacity of a green microalgal species, Scenedesmus obliquus, for doxylamine, chemical oxygen demand (COD), and nutrients from real wastewater. Results have indicated that S. obliquus can grow well in the doxylamine-polluted wastewater with the achievement of 56, 78.5, 100, and 89% removal of doxylamine, COD, total nitrogen (TN), and total phosphorus (TP). Addition of 2 g L−1 bicarbonate enhanced the removal of doxylamine up to 63% and slightly inhibited the removal of COD. Decreased carbohydrate (28–26%) and increased protein content (30–33%) of the harvested biomass have been observed after cultivation in the wastewater. The current study has shown the feasibility of using microalgae-based biotechnologies for PC-contaminated wastewater.

As the barrier between the human body and the outside world, the skin is vulnerable to pathogenic microorganisms, especially when suffering from skin injuries such as burns. Staphylococcus aureus remains the most common type of bacteria that infects humans, and the surging drug resistance poses a major threat to the treatment of these infections. Here we report the development of antibacterial photodynamic peptides (APPs) that are constructed based on the covalent conjugation of an antibacterial peptide and the photosensitizer chlorin e6 (Ce6). Peptide conjugation significantly increases the photo-stability of Ce6, while retaining its ROS generation capability under photo-irradiation. The APPs combine the antibacterial activity of the peptide and the photodynamic therapy of Ce6, and under the assistance of mild laser irradiation, can eradicate bacterial infection and inhibit the formation of bacterial biofilms ex vivo. One of the APPs, (GKRWWKWWRR)2KGGK(Ce6)G, AMP2-Ce6, with Ce6 conjugated with the dimeric peptide, showed exceptional antibacterial activity with an MIC90 value around 3.2 μM without photo-irradiation and

In this study, a total of 14 vaginal samples (GPV1‐14) from giant pandas were analyzed. These vaginal samples were divided into two groups as per the region and age of giant pandas. All the vaginal samples were analyzed using metagenomic sequencing. As per the outcomes of metagenomic analysis, Proteobacteria (39.04%), Firmicutes (5.27%), Actinobacteria (2.94%), and Basidiomycota (2.77%) were found to be the dominant phyla in the microbiome of the vaginal samples. At the genus level, Pseudomonas (21.90%) was found to be the most dominant genus, followed by Streptococcus (3.47%), Psychrobacter (1.89%), and Proteus (1.38%). Metastats analysis of the microbial species in the vaginal samples of giant pandas from Wolong Nature Reserve, Dujiangyan and Ningbo Youngor Zoo, and Ya'an Bifengxia Nature Reserve was found to be significantly different (p, In this study, metagenomic sequencing methods were used to analyze the vaginal microbial population structure and gene functional activity in giant pandas. Significant differences were found in the different components of the microbiota in the reproductive tract, and they may be related to the regional and age differences. The main microbial pathways and carbohydrate‐active enzymes also varied with giant pandas’ age and region.

Shixue Chen,1,2,* Ziwei Huang,2,3,* Wangping Jia,1,4,* Haitao Tao,2 Sujie Zhang,2 Junxun Ma,2 Zhefeng Liu,2 Jinliang Wang,2 Lijie Wang,2 Pengfei Cui,1,2 Zhibo Zhang,1,2 Di Huang,2,3 Zhaozhen Wu,2,3 Xuan Zheng,1,2 Yi Hu2 1Department of Graduate Administration, Chinese PLA General Hospital, Beijing, People’s Republic of China; 2Department of Medical Oncology, Chinese PLA General Hospital, Beijing, People’s Republic of China; 3School of Medicine, Nankai University, Tianjin, People’s Republic of China; 4Institute of Geriatrics, Beijing Key Laboratory of Aging and Geriatrics, National Clinical Research Center for Geriatrics Diseases, Second Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yi HuDepartment of Medical Oncology, Chinese PLA General Hospital, 28 Fuxing Road, Haidian, Beijing, People’s Republic of ChinaEmail huyi0401301@sina.comPurpose: At present, there are no validated biomarkers that can predict whether patients with advanced hepatocellular carcinoma (aHCC) are likely to benefit from anti-PD-1 therapy. We aimed to determine whether lung immune prognostic index (LIPI) is associated with outcomes in patients with aHCC treated with PD-1 inhibitors.Patients and Methods: Patients undergoing initial treatment with PD-1 inhibitors for aHCC at a single center from January 1, 2015 to August 31, 2019 were included. The patients were stratified according to pretreatment LIPI based on a derived neutrophils/(leukocytes minus neutrophils) ratio (dNLR) ≥ 3 and a lactate dehydrogenase (LDH) level ≥ the upper limit of normal (ULN). Kaplan–Meier analysis and the Log rank test were used to calculate and compare survival between good LIPI and intermediate/poor LIPI scores. The prognostic values of LIPI for survival and disease control rate were evaluated using Cox proportional hazard and logistic regression models, respectively.Results: Of the 108 study patients, 53 (49%) had a good LIPI (dNLR < 3 and LDH normal) and 55 (51%) had intermediate/poor LIPI (dNLR ≥ 3 or/and LDH ≥ ULN). With a median follow-up of 12.4 months, intermediate/poor LIPI was independently associated with shorter overall survival (OS) (hazard ratio [HR] 4.00; 95% CI, 2.00– 8.03) and progression-free survival (PFS) (HR 2.65; 95% CI, 1.61– 4.37). The median OS for good and intermediate/poor LIPI was not reached and was 13.7 (95% CI, 8.2– 19.1) months, respectively, and the median PFS was 10.9 (95% CI, 8.9– 12.9) and 4.0 (95% CI, 2.2– 5.8) months (both P < 0.001), respectively.Conclusion: Pretreatment LIPI combined with a dNLR ≥ 3 and/or LDH ≥ ULN is associated with poor outcomes in patients with aHCC treated with PD-1 inhibitors. Further validation in large, prospective studies are warranted.Keywords: PD-1 inhibitor, hepatocellular carcinoma, biomarker, LIPI, dNLR, LDH

Background Recent studies have indicated that females with coronavirus disease 2019 (COVID-19) have a lower morbidity, severe case rate, and mortality and better outcome than those of male individuals. However, the reasons remained to be addressed. Methods To find the factors that potentially protect females from COVID-19, we recruited all confirmed patients hospitalized at 3 branches of Tongji Hospital (N = 1902), and analyzed the correlation between menstrual status (n = 509, including 68 from Mobile Cabin Hospital), female hormones (n = 78), and cytokines related to immunity and inflammation (n = 263), and the severity/clinical outcomes in female patients, Nonmenopausal females with COVID-19 had milder severity, better outcome, and shorter hospital stays than menopausal patients. E2 might be a potential protective factor against COVID-19, partly through its regulation of cytokines, which significantly correlated with severity of infection.

Background The ferocious global assault of COVID-19 continues. Critically ill patients witnessed significantly higher mortality than severe and moderate ones. Herein, we aim to comprehensively delineate clinical features of COVID-19 and explore risk factors of developing critical disease. Methods This is a Mini-national multicenter, retrospective, cohort study involving 2,387 consecutive COVID-19 inpatients that underwent discharge or death between January 27 and March 21, 2020. After quality control, 2,044 COVID-19 inpatients were enrolled. Electronic medical records were collected to identify the risk factors of developing critical COVID-19. Findings The severity of COVID-19 climbed up straightly with age. Critical group was characterized by higher proportion of dyspnea, systemic organ damage, and long-lasting inflammatory storm. All-cause mortality of critical group was 85•45%, by contrast with 0•58% for severe group and 0•18% for moderate group. Logistic regression revealed that sex was an effect modifier for hypertension and coronary heart disease (CHD), where hypertension and CHD were risk factors solely in males. Multivariable regression showed increasing odds of critical illness associated with hypertension, CHD, tumor, and age ≥ 60 years for male, and chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), tumor, and age ≥ 60 years for female. Interpretation We provide comprehensive front-line information about different severity of COVID-19 and insights into different risk factors associated with critical COVID-19 between sexes. These results highlight the significance of dividing risk factors between sexes in clinical and epidemiologic works of COVID-19, and perhaps other coronavirus appearing in future. Funding National Science Foundation of China .

Yaks provide necessities such as meat and milk for Tibetans living at high altitudes on and around the Qinghai-Tibetan Plateau. Enterococci are ubiquitous members of the animal gut microbiota that can cause biofilm-associated opportunistic infections. Meanwhile, multidrug-resistant Enterococcus also poses a serious threat to public health. This study aims to characterize antibiotic resistance, virulence genes, and biofilm formation of enterococci from yaks. From April 2018 to July 2019, we collected 395 fecal samples of yaks in Aba Tibetan Autonomous Prefecture, China. Enterococci isolated from the samples were identified and classified according to the 16S rDNA sequence. The antibiotic resistance of each isolate was detected according to the Kirby-Bauer disk diffusion method, and antibiotic resistance genes were detected by polymerase chain reaction (PCR) and sequencing. Enterococcal biofilms were assessed using standard procedures. Different virulence genes were detected by PCR and sequencing. In total, 381 enterococci strains were recovered, with Enterococcus faecalis (41.99%) and Enterococcus faecium (37.80%) being the predominant species. Many isolates were multidrug- resistant (60.37%) and showed a high resistance rate to rifampicin (64.30%) and tetracycline (61.54%). We also detected various antimicrobial resistance (AMR) genes in the tested strains. The E. faecalis strains had higher frequency of biofilm formation and virulence genes than other enterococcal species. This is the first report that shows yaks are repositories for drug-resistant enterococci with virulent determinants and biofilms that may spread into humans and to environment. This study also provides useful data suggesting that enterococci may pose a potential health risk to yaks. Therefore, active surveillance of AMR and pathogenesis in enterococci from yaks is urgently warranted.