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Background We performed an integrative genomic and transcriptomic profiling to identify molecular subtypes and prognostic markers with special focus on immune-related pathways. Methods Totally, 50 Chinese patients were subjected to targeted next-generation sequencing and transcriptomic sequencing. Results Two distinct subgroups were identified as immune (22.0%) and non-immune (78.0%) based on the immune-pathway related hierarchical clustering. Surprisingly, patients with immune subtype had a significantly worse survival. The prognostic capacity was validated in external cohorts. The immune group had higher expression of genes involved in pro-inflammation and checkpoints. PD-1 signalling pathway was enriched in the immune subtype. Besides, the immune cluster presented enriched expression of genes involved in epithelial-mesenchymal transition, angiogenesis and PI3K-AKT-mTOR signalling, while the non-immune subtype had higher expression of metabolic pathways. The immune subtype had a higher mutation rate of PIK3CA though significance was not achieved. Lastly, we established a prognostic immune signature for overall survival. Interestingly, the immune signature could also be applied to renal clear cell carcinoma, but not to other histologic subtype of ovarian cancer. Conclusions An immune subtype of OCCC was identified with poor survival and enrichment of PD-1 and PI3K-AKT-mTOR signalling. We constructed and validated a robust prognostic immune signature of OCCC patients.

APP9mer prefers to embed in the pocket of SD1 in a parallel orientation and generate the most probable APPmer-SD1 stable complex.

Because of the relatively limited understanding of COVID-19 pathogenesis, immunological analysis for vaccine development is needed. Mice and macaques were immunized with an inactivated SARS-CoV-2 vaccine prepared by two inactivators. Various immunological indexes were tested, and viral challenges were performed on day 7 or 150 after booster immunization in monkeys. This inactivated SARS-CoV-2 vaccine was produced by sequential inactivation with formaldehyde followed by propiolactone. The various antibody responses and specific T cell responses to different viral antigens elicited in immunized animals were maintained for longer than 150 days. This comprehensive immune response could effectively protect vaccinated macaques by inhibiting viral replication in macaques and substantially alleviating immunopathological damage, and no clinical manifestation of immunopathogenicity was observed in immunized individuals during viral challenge. This candidate inactivated vaccine was identified as being effective against SARS-CoV-2 challenge in rhesus macaques., Graphical Abstract, This twice inactivated candidate SARS-CoV-2 vaccine was safe, effective in inducing immune responses and effective against SARS-CoV-2 challenge in rhesus macaques.

Background Mucosal melanoma is rare and has distinct clinical and genetic features. Even with advances in targeted and immune therapies, the survival of patients with advanced or recurrent mucosal melanomas remains poor. The standard treatment remains controversial and we conducted this real-world study aimed to explore continuous intravenous recombinant human endostatin (Rh-endostatin) infusion plus chemotherapy in this population in the first-line setting. Methods Overall, 43 patients with advanced or recurrent mucosal melanoma treated at Fudan University Shanghai Cancer Center between April 2017 and August 2020 were retrospectively included. Patients received dacarbazine plus cisplatin or temozolomide plus cisplatin per the investigators' preference. Rh-endostatin (105 mg/m2) was administered with continuous infusion for 168 h (Civ 168 h). Results Of the 43 patients, 72.1% had metastatic disease, and the most common primary site was the gastrointestinal tract (51.2%). The most commonly observed mutations were NRAS (23.1%), BRAF (7.7%) and CKIT mutations (5.1%). An objective response was observed in 12 (30.0%) of the 40 evaluable patients, and disease control was achieved in 31 (77.5%) patients. With a median follow-up of 17.6 months, the median progression-free survival (PFS) and overall survival (OS) were 4.9 and 15.3 months, respectively. Additionally, high lymphocyte-to-monocyte ratio (LMR) (p = 0.023, HR 0.29, 95% CI: 0.10-0.84) and BRAF/KIT/RAS mutation (p = 0.028, HR 0.24, 95% CI: 0.07-0.86) were independently correlated with prolonged OS. Toxicity was manageable overall. Conclusion Continuous Rh-endostatin infusion plus chemotherapy was effective and safe for the treatment of advanced or recurrent mucosal melanoma. High LMR was correlated with favorable PFS and OS in this patient population.

Neutralizing antibodies in volunteers who received two doses of an inactivated SARS-CoV-2 vaccine deceased over several months. A three-dose procedure study suggested that the boost conferred by a third dose rescued the waning of neutralizing antibodies after the two doses of the inactivated vaccine. Importantly, a booster dose can also elicit a more robust neutralizing antibody response than the two-dose procedure. This article is protected by copyright. All rights reserved.

Metal-N4 single-atom catalysts have emerged as the frontier of catalysis. However, the low metal loading and abundance of single atoms embedded in carbon skeleton hinder their practical application. Herein, we report an effective “trapping and exposing” strategy for constructing single-atom Fe–N4 catalysts with high density of single-atom active sites. The strategy involves the strong binding of metal ions to sucrose (trapping) to prevent the migration and agglomeration of Fe3+, followed by the introduction of a mesoporous structure using an SBA-15 template to achieve sufficient exposure of the Fe–N4 sites (exposing). The as-prepared catalyst comprises Fe–N4 moieties (10.8 wt%) with a hierarchical structure. Density functional theory calculations reveal that the chelating reaction between sucrose and Fe3+ ions has a low free energy, resulting in the formation of highly dispersed Fe–N4 single atoms. The single-atom catalyst displays a high peak power density of 0.784 W cm−2 in a H2–O2 proton exchange membrane fuel cell and achieves an impressive CO current density of 109 A g−1 at negligible overpotentials in a flow cell. This work provides an efficient strategy for designing high-performance single-atom catalysts for practical electrocatalysis applications.

Background Dietary bamboo leaf flavonoids (BLFs) are rarely used in poultry production, and it is unknown whether they influence meat texture profile, perceived color, or microstructure. Results A total of 720 one-day-old Arbor Acres broilers were supplemented with a basal diet with 20 mg bacitracin/kg, 50 mg BLFs/kg, or 250 mg BLFs/kg or without additions. Data showed that the dietary BLFs significantly (P P P Conclusions Dietary BLFs supplementation could play a beneficial role in improving meat quality and sensory color in the poultry industry by changing protein secondary structures and modulating metabolites.

Summary Background The benefits of secondary cytoreduction for platinum-sensitive relapsed ovarian cancer are still widely debated. We aimed to assess the efficacy of secondary cytoreduction plus chemotherapy versus chemotherapy alone in this patient population. Methods This multicentre, open-label, randomised, controlled, phase 3 trial (SOC-1), was done in four primarily academic centres in China (two in Shanghai, one in Hangzhou, and one in Guangzhou). Eligible patients were women aged 18 years and older with platinum-sensitive relapsed epithelial ovarian cancer with a platinum-free interval of at least 6 months after the end of first-line platinum-based chemotherapy and were predicted to have potentially resectable disease according to the international model (iMODEL) score and PET-CT imaging. iMODEL score was calculated using six variables: International Federation of Gynecology and Obstetrics stage, residual disease after primary surgery, platinum-free interval, Eastern Cooperative Oncology Group performance status, serum level of cancer antigen 125 at recurrence, and presence of ascites at recurrence. An iMODEL score of 4·7 or lower predicted a potentially complete resection. As per a protocol amendment, patients with an iMODEL score of more than 4·7 could only be included if the serum level of cancer antigen 125 was more than 105 U/mL, but the principal investigators assessed the disease to be resectable by PET-CT. Eligible participants were randomly assigned (1:1) via a permuted block design (block size of six) and stratified by study centre, iMODEL score, residual disease at primary surgery, and enrolment in the Shanghai Gynecologic Oncology Group SUNNY trial, to undergo secondary cytoreductive surgery followed by intravenous chemotherapy (six 3-weekly cycles of intravenous paclitaxel [175 mg/m2] or docetaxel [75 mg/m2] combined with intravenous carboplatin [area under the curve of 5 mg/mL per min]; surgery group) or intravenous chemotherapy alone (no surgery group). Primary endpoints were progression-free survival and overall survival, analysed in all participants randomly assigned to treatment, regardless of treatment received (intention-to-treat [ITT] population). Here, we report the final analysis of progression-free survival and the prespecified interim analysis of overall survival. Safety was assessed in all participants who received their assigned treatment and had available adverse event data. This study is registered with ClinicalTrials.gov, NCT01611766, and is ongoing but closed to accrual. Findings Between July 19, 2012, and June 3, 2019, 357 patients were recruited and randomly assigned to the surgery group (182) or the no surgery group (175; ITT population). Median follow-up was 36·0 months (IQR 18·1–58·3). In the no surgery group, 11 (6%) of 175 participants had secondary cytoreduction during second-line therapy while 48 (37%) of 130 participants who had disease progression crossed-over and had surgery at a subsequent recurrence. Median progression-free survival was 17·4 months (95% CI 15·0–19·8) in the surgery group and 11·9 months (10·0–13·8) in the no surgery group (hazard ratio [HR] 0·58; 95% CI 0·45–0·74; p Interpretation Secondary cytoreduction followed by chemotherapy was associated with significantly longer progression-free survival than was chemotherapy alone in patients with platinum-sensitive relapsed ovarian cancer, and patients should be counselled about the option of secondary cytoreduction in specialised centres. Long-term survival outcomes will be assessed using mature data on overall survival. Funding Zhongshan Development Program. Translation For the Chinese translation of the abstract see Supplementary Materials section.

Heavy evidence has confirmed that Aβ42 oligomers are the most neurotoxic aggregates and play a critical role in the occurrence and development of Alzheimer's disease by causing functional neuron death, cognitive damage, and dementia. Disordered Aβ42 oligomers are challenging therapeutic targets, and no drug is currently in clinical use that modifies the properties of their monomeric states. Here, a negatively charged molecule (ER), rather than the neutral TS1 one, is identified by a molecular dynamics simulation method to be more capable of binding and sequestering the intrinsically disordered amyloid-β peptide Aβ42 in its soluble pentameric state as well as its monomeric components. Results reveal that the ERs interact with Aβ and inhibit the primary nucleation pathways in its aggregation process in entropic expansion mechanism for both Aβ42 and Aβ40 oligomers but with opposite characteristics of hydrophobic surface area (HSA). The interaction between Aβ42 oligomer and either charged ER or neutral TS1/TS0 characterizes decreased HSA, and the decrease in ER-involved case is highly visible, consistent with the observations from in silico and in vitro studies. By contrast, the presence of these inhibitors causes the HSA of Aβ40 oligomer to change undetectably and there is even a bit of increase in the histidine isomerized Aβ40 oligomer. The HSA distinction between Aβ42 and Aβ40 oligomer is possibly derived from the different effects of M35-inhibitor interaction, which is analogous to the effect of M35 oxidation. In comparison with the neutral TS1/TS0 inhibitors, ER is more prone to bind the residues located in the central (β1) and C-terminal (β2) regions of Aβ42 peptide, two key nucleation regions for Aβ intramolecular folding, intermolecular aggregation, and assembly. Notably, ER can strongly bind the charged residues, such as K16, K28, D23, to greatly disturb the potential stabilizer (e.g., salt-bridge, etc.) in metastable Aβ42 oligomers and protofibrils. These results illustrate the strategy of overcoming Alzheimer's disease from inhibiting its early stage Aβ aggregation with two kinds of small molecules to alter their behavior for therapeutic purposes and strongly recommend paying more attention to the engineering and development of negatively charged inhibitors, the long-term underappreciated ones, targeting the early stage Aβ aggregates.

Recombinant proteins provide new means for disease treatment, while creating considerable economic benefits. Using commercial crops (mainly tobacco), cereal crops, legumes, and vegetable crops to produce recombinant proteins with medicinal value is a hot-spot for research in "molecular farming". Although many recombinant proteins have been expressed in plants, only a small number have been successfully put into use. To overcome the problems that greatly hamper the development of recombinant protein production in plants, researchers have improved expression systems to increase the yield of recombinant proteins. Starting from analyzing the problems of low yield and/or low biological activity of recombinant proteins produced by plants, the optimization strategies to solve these problems were reviewed, and future research directions for improving the yield of recombinant proteins produced by plants were proposed.

Diabetic kidney disease (DKD) is one of the severe microvascular complications of type 2 diabetes mellitus (T2DM), which eventually leads to irreversible renal damage and develops into end-stage renal disease (ESRD). Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a new class of antidiabetic drugs that act on the kidney to reduce glucose reabsorption. Increasing evidence confirms that dapagliflozin exerts a protective effect on DKD, but the mechanisms have not been reported. The aims of this study were to observe the therapeutic efficacy of dapagliflozin on DKD and investigate the possible immunological mechanism.T2DM was modeled by a high-sugar and high-fat diet combined with STZ. Then, rats were treated with 10 mg/kg dapagliflozin for 8 weeks. The protective efficacy of dapagliflozin was evaluated by observing body weight, blood glucose, blood serum creatinine, blood urea nitrogen, 24-h urine protein, renal histology and ultrastructure, and oxidative stress levels. The immunological mechanisms were monitored by measuring the levels of TLR2/Myd88/NF-κB by immunohistochemical staining, RT-qPCR and Western blotting.After treatment with dapagliflozin, renal damage was greatly improved. The levels of blood glucose, renal function and proteinuria were significantly decreased, and renal pathological and ultrastructural damage was obviously extenuated, possibly due to the reduction in inflammation and the levels of oxidative stress.Dapagliflozin has therapeutic potential for DKD. This effect was possibly mediated by inhibiting inflammation and oxidative stress levels.

Production of high-affinity and specific antibodies to small molecules with molecular weight (MW) lower than 200 Da is challenging. Here, we designed a novel hapten, named hapten H6, for the detection of 3-methyl-quinoxaline-2-carboxylic acid (MQCA, MW of 189 Da), a residual marker of olaquindox, one of important veterinary antibiotics. The hapten H6 maintained all structural features of MQCA, especially in mulliken atomic charge distribution. Then, a monoclonal antibody (mAb) named 8C9 was obtained with an IC

Tea plants can accumulate aluminum (Al) in their leaves to a greater extent than most other edible plants. Few studies, however, address the Al concentration in leaves at different positions, which is important information for tea quality control. Leaves from four different cultivars of