Design, synthesis and molecular modeling of novel D-ring substituted steroidal 4,5-dihydropyrazole thiazolinone derivatives as anti-inflammatory agents by inhibition of COX-2/iNOS production and down-regulation of NF-κB/MAPKs in LPS-induced RAW264.7 macrophage cells.

It has been reported that 4,5-dihydropyrazole and thiazole derivatives have many biological functions, especially in the aspect of anti-inflammation. According to the strategy of pharmacophore combination, we introduced thiazolinone and dihydropyrazole moiety into steroid skeleton to design and synthesize a novel series of D-ring substituted steroidal 4,5-dihydropyrazole thiazolinone derivatives, and assessed their in vitro anti-inflammatory profiles against Lipopolysaccharide (LPS)-induced inflammation in RAW 264.7 macrophage cells. The anti-inflammatory activities assay demonstrated that compound 12e was considered as the most effective anti-inflammatory drug, which suppressed the expression of pro-inflammatory mediators including nitric oxide (NO), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), it also dose-dependently inhibited the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in LPS-induced RAW 264.7 macrophage cells. Furthermore, the results of the Western blot analysis showed a correlation between the inhibition of the Nuclear factor-kappa B (NF-κB) and Mitogen-activated protein kinases (MAPKs) signaling pathways and the suppressive effects of compound 12e on pro-inflammatory cytokines. Molecular docking studies of compound 12e into the COX-2 protein receptor (PDB ID: 5IKQ) active site was performed to rationalize their COX-2 inhibitory potency. The results were found to be in line with the biological findings as they exerted more favorable interactions compared to that of dexamethasone (DXM), explaining their remarkable COX-2 inhibitory activity. The findings revealed that these candidates could be identified as potent anti-inflammatory agents, compound 12e could be a promising drug for the treatment of inflammatory diseases.

Generation and characterization of a nanobody against the avian influenza virus H7 subtype.

Avian influenza virus (AIV) H7N9 diseases have been recently reported, raising concerns about a potential pandemic. Thus, there is an urgent need for effective therapeutics for AIV H7N9 infections. Herein, camelid immunization and yeast two-hybrid techniques were used to identify potent neutralizing nanobodies (Nbs) targeting the H7 subtype hemagglutinin. First, we evaluated the binding specificity and hemagglutination inhibition activity of the screened Nbs against the H7 subtype hemagglutinin. Nb-Z77, with high hemagglutination inhibition activity was selected from the screened Nbs to optimize the yeast expression conditions and construct oligomeric forms of Nb-Z77 using various ligation methods. The oligomers Nb-Z77-DiGS, Nb-Z77-TriGS, Nb-Z77-Fc and Nb-Z77-Foldon were successfully constructed and expressed. Nb-Z77-DiGS and Nb-Z77-Foldon exhibited considerably greater activity than did Nb-Z77 against H7 subtype hemagglutinin, with median effective concentrations of 384.7 and 27.33 pM and binding affinity values of 213 and 5.21 pM, respectively. Nb-Z77-DiGS and Nb-Z77-Foldon completely inhibited the hemagglutination activity of the inactivated virus H7-Re1 at the lowest concentration of 0.938 µg/mL. This study screened a strain of Nb with high hemagglutination inhibition activity and enhanced its antiviral activity through oligomerization, which may have great potential for developing effective agents for the prevention, diagnosis, and treatment of AIV H7 subtype infection.

Harnessing tetrahedral framework nucleic acids for enhanced delivery of microRNA-149-3p: A new frontier in oral squamous cell carcinoma therapy.

Oral squamous cell carcinoma (OSCC), a type of malignant tumour that primarily occurs in the oral mucosa, has drawn considerable attention owing to its aggressive growth and potentially high metastatic rate. Surgical resection is the primary treatment method for OSCC and is typically combined with radiation therapy and chemotherapy. microRNA-149-3p (miR-149) is a negative regulator of the Pi3k/Akt pathway and can effectively inhibit the proliferation of tumour cells. However, the application of miR-149 is limited owing to its relatively low efficiency of cellular uptake and poor stability when used alone. To overcome these challenges, this study adopted a novel nucleic acid nanostructured material, tetrahedral framework nucleic acids (tFNAs). The use of tFNAs as carriers to assemble the T-miR-149 complex reduced the expression of Pi3k and Akt involved in tumorigenesis and alterations in proteins related to cell apoptosis. The results indicated that the bionic drug delivery system has an effective tumour suppressive effect on OSCC in mice, revealing its potential clinical value in the treatment of OSCC.

Comorbidity profiling identifies potential subtype of elderly patients with nasopharyngeal carcinoma.

BACKGROUND: Few studies have assessed the comprehensive associations among comorbid diseases in elderly patients with nasopharyngeal carcinoma (NPC). This study sought to identify potential comorbidity patterns and explore the relationship of comorbidity patterns with the mortality risk in elderly patients with NPC. METHODS: A total of 452 elderly patients with NPC were enrolled in the study. The network analysis and latent class analysis were applied to mine comorbidity patterns. Propensity score matching was used for adjusting confounders. A restricted cubic spline model was used to analyze the nonlinear association between age and the risk of all-cause mortality. RESULTS: We identified 2 comorbidity patterns, metabolic disease-related comorbidity (MDRC) and organ disease-related comorbidity (ODRC) in elderly patients with NPC. Patients in MDRC showed a significantly higher risk of all-cause mortality (71.41% vs 87.97%, HR 1.819 [95% CI, 1.106-2.994], P = .031) and locoregional relapse (68.73% vs 80.88%, HR 1.689 [95% CI, 1.055-2.704], P = .042). Moreover, in patients with MDRC pattern, we observed an intriguing inverted S-shaped relationship between age and all-cause mortality among patients aged 68 years and older. The risk of mortality up perpetually with age increasing in ODRC group, specifically within the age range of 68-77 years (HR 4.371, 1.958-9.757). CONCLUSION: Our study shed light on the potential comorbidity patterns in elderly patients with NPC, thereby providing valuable insights into the development of comprehensive health management strategies for this specific population.

Machine learning-based survival prediction nomogram for postoperative parotid mucoepidermoid carcinoma.

Parotid mucoepidermoid carcinoma (P-MEC) is a significant histopathological subtype of salivary gland cancer with inherent heterogeneity and complexity. Existing clinical models inadequately offer personalized treatment options for patients. In response, we assessed the efficacy of four machine learning algorithms vis-à-vis traditional analysis in forecasting the overall survival (OS) of P-MEC patients. Using the SEER database, we analyzed data from 882 postoperative P-MEC patients (stages I-IVA). Single-factor Cox regression and four machine learning techniques (random forest, LASSO, XGBoost, best subset regression) were employed for variable selection. The optimal model was derived via stepwise backward regression, Akaike Information Criterion (AIC), and Area Under the Curve (AUC). Bootstrap resampling facilitated internal validation, while prediction accuracy was gauged through C-index, time-dependent ROC curve, and calibration curve. The model's clinical relevance was ascertained using decision curve analysis (DCA). The study found 3-, 5-, and 10-year OS rates of 0.887, 0.841, and 0.753, respectively. XGBoost, BSR, and LASSO stood out in predictive efficacy, identifying seven key prognostic factors including age, pathological grade, T stage, N stage, radiation therapy, chemotherapy, and marital status. A subsequent nomogram revealed a C-index of 0.8499 (3-year), 0.8557 (5-year), and 0.8375 (10-year) and AUC values of 0.8670, 0.8879, and 0.8767, respectively. The model also highlighted the clinical significance of postoperative radiotherapy across varying risk levels. Our prognostic model, grounded in machine learning, surpasses traditional models in prediction and offer superior visualization of variable importance.

Frequency-encoded eye tracking smart contact lens for human-machine interaction.

Eye tracking techniques enable high-efficient, natural, and effortless human-machine interaction by detecting users' eye movements and decoding their attention and intentions. Here, a miniature, imperceptible, and biocompatible smart contact lens is proposed for in situ eye tracking and wireless eye-machine interaction. Employing the frequency encoding strategy, the chip-free and battery-free lens successes in detecting eye movement and closure. Using a time-sequential eye tracking algorithm, the lens has a great angular accuracy of <0.5°, which is even less than the vision range of central fovea. Multiple eye-machine interaction applications, such as eye-drawing, Gluttonous Snake game, web interaction, pan-tilt-zoom camera control, and robot vehicle control, are demonstrated on the eye movement model and in vivo rabbit. Furthermore, comprehensive biocompatibility tests are implemented, demonstrating low cytotoxicity and low eye irritation. Thus, the contact lens is expected to enrich approaches of eye tracking techniques and promote the development of human-machine interaction technology.

Gene-based association tests in family samples using GWAS summary statistics.

Genome-wide association studies (GWAS) have led to rapid growth in detecting genetic variants associated with various phenotypes. Owing to a great number of publicly accessible GWAS summary statistics, and the difficulty in obtaining individual-level genotype data, many existing gene-based association tests have been adapted to require only GWAS summary statistics rather than individual-level data. However, these association tests are restricted to unrelated individuals and thus do not apply to family samples directly. Moreover, due to its flexibility and effectiveness, the linear mixed model has been increasingly utilized in GWAS to handle correlated data, such as family samples. However, it remains unknown how to perform gene-based association tests in family samples using the GWAS summary statistics estimated from the linear mixed model. In this study, we show that, when family size is negligible compared to the total sample size, the diagonal block structure of the kinship matrix makes it possible to approximate the correlation matrix of marginal Z scores by linkage disequilibrium matrix. Based on this result, current methods utilizing summary statistics for unrelated individuals can be directly applied to family data without any modifications. Our simulation results demonstrate that this proposed strategy controls the type 1 error rate well in various situations. Finally, we exemplify the usefulness of the proposed approach with a dental caries GWAS data set.

Influence of chlorine on co-processing of hazardous wastes in brick kilns.

Brick kiln co-treatment is a novel industrial hazardous wastes (IHWs) utilization process. However, the effects of chlorine (Cl) in wastes on heavy metals (HMs) during this process are overlooked. This study investigated the stabilization/solidification (S/S) and volatilization, as well as long and short-term leaching, of HMs in Cl-containing bricks. The results indicated enhanced formations of stable mineral phases (NiFe2O4, Ni2SiO4, Cd3Al2Si3O12, CdSiO3, FeCr2O4, Cr2O3, CuFe2O4, and CuAl2O4) in bricks at a low sintering temperature (800 °C) due to the affinity between Cl and HMs. By comparing HM concentrations before and after sintering in bricks, the study observed that Cl's presence significantly elevated the volatilization rates for Cd and Cu by 30.8% and 14.2%, respectively. In contrast, the effect on volatilization for Ni and Cr was not significant. Additionally, utilizing the NEN 7375 method, the cumulative leaching rates of Ni, Cd, Cr, and Cu over a 64-day experiment under extremely acidic conditions were 0.22%, 7.18%, 0.01%, and 1.46%, respectively. Similarly, higher short-term leaching rates of Cd (4.03%) and Cu (5.73%) than those of Ni (0.94%) and Cr (0.08%) were observed. This finding might be attributed to the lower stability of the Cd and Cu solid phases under acidic environments compared to those of Ni and Cr. Surface wash-off, dissolution, and diffusion were the processes governing HM leaching from bricks. The 10-year projections revealed a minimal release of HMs during future extended leaching, implying the successful S/S of HMs. This study provides a reference for assessing the environmental impacts of brick kiln co-processing of Cl-containing IHWs.

ALKBH5-Mediated RNA m6 A Methylation Regulates the Migration, Invasion, and Proliferation of Rheumatoid Fibroblast-Like Synoviocytes.

OBJECTIVE: Fibroblast-like synoviocytes (FLSs) are critical for promoting joint damage in rheumatoid arthritis (RA). N6 -methyladenosine (m6 A) modification plays key roles in various diseases, but its role in the pathogenesis of RA is largely unknown. Here, we investigate increased demethylase ALKBH5 promotion of proliferation, migration, and invasion of RA FLSs via regulating JARID2 expression. METHODS: ALKBH5 expression in FLSs was evaluated using real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot. 5-ethynyl-2'-deoxyuridine, scratch wound healing, and transwell assays were implemented to determine the role of ALKBH5 on RA FLS proliferation, mobility, and migration. Then, m6 A sequencing combined with RNA sequencing was performed to identify the potential targets of ALKBH5. RNA immunoprecipitation and RNA pulldown were then used to validate the interaction between the protein and messenger RNA (mRNA). Collagen-induced arthritis (CIA) and delayed-type hypersensitivity arthritis (DTHA) models were further established to assess the therapeutic potency of ALKBH5 in vivo. RESULTS: We demonstrated that ALKBH5 expression was increased in FLSs and synovium from RA. Functionally, ALKBH5 knockdown inhibited the proliferation, migration, and invasion of RA FLSs, whereas overexpression of ALKBH5 displayed the opposite effect. Mechanistically, ALKBH5 mediated m6 A modification in the JARID2 mRNA and enhanced its mRNA stability in cooperation with IGF2BP3. Intriguingly, the severity of arthritis was attenuated in mice with DTHA and ALKBH5 knockout or rats with CIA and intra-articular injection of ALKBH5 short hairpin RNA. CONCLUSION: Our findings suggest that ALKBH5-mediated m6 A modification is crucial for synovial hyperplasia and invasion in RA. ALKBH5 might be a potential therapeutic target for RA and even for dysregulated fibroblasts in a wide range of diseases.

Trastuzumab deruxtecan versus chemotherapy treated in patients with HER2-positive metastatic breast cancer: a cost-effectiveness analysis based on the DESTINY-Breast02 trial.

OBJECTIVES: This study aims to conduct a cost-effectiveness analysis of trastuzumab deruxtecan versus chemotherapy for HER2-positive metastatic breast cancer from the perspective of the Chinese healthcare system. METHODS: A three-state partitioned survival model was constructed to simulate the treatment. The analysis yielded information on the costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). Sensitivity analyses have been carried out to scrutinize the model's uncertainties. RESULTS: The total cost for the trastuzumab deruxtecan group was found to be $228601.57, while the chemotherapy group incurred a total cost of $84901.38. It was found that the trastuzumab deruxtecan group exhibited an incremental gain of 2.95 QALYs in comparison to the chemotherapy group. However, this additional benefit came at an additional cost of $143700.19 for the trastuzumab deruxtecan treatment, calculated in the ICER at $48711.93/QALY, which surpasses the willingness-to-pay threshold of $37304.34/QALY in China. Sensitivity analyses indicated that the results were robust to variations in key parameters and assumptions. CONCLUSION: Trastuzumab deruxtecan was not a cost-effective treatment option for patients with HER2-positive metastatic breast cancer in China. However, the use of trastuzumab deruxtecan may offer a cost-effective treatment alternative provided that its price is diminished.

Virome in immunodeficiency: what we know currently.

ABSTRACT: Over the past few years, the human virome and its complex interactions with microbial communities and the immune system have gained recognition as a crucial factor in human health. Individuals with compromised immune function encounter distinctive challenges due to their heightened vulnerability to a diverse range of infectious diseases. This review aims to comprehensively explore and analyze the growing evidence regarding the role of the virome in immunocompromised disease status. By surveying the latest literature, we present a detailed overview of virome alterations observed in various immunodeficiency conditions. We then delve into the influence and mechanisms of these virome changes on the pathogenesis of specific diseases in immunocompromised individuals. Furthermore, this review explores the clinical relevance of virome studies in the context of immunodeficiency, highlighting the potential diagnostic and therapeutic gains from a better understanding of virome contributions to disease manifestations.

Effects of Ecological Restoration and Climate Change on Herbaceous and Arboreal Phenology.

With global climate change, changes in vegetation phenology have become increasingly evident. Horqin Sandy Land is located near the eastern part of the West Liaohe River. It is the largest sandy land in China and its ecological environment is fragile. Investigating the changes in vegetation phenology in these sandy areas and determining the relationship between vegetation phenology and meteorological factors are of great importance for predicting the impacts of future climate change and understanding the response mechanisms of ecosystems. In this study, we used the time series of the Normalized Difference Vegetation Index (NDVI) from 2000 to 2021 and extracted the vegetation phenology in the Horqin Sandy Land using high-order curve fitting methods, including the start date of the growing season (SOS), the end date of the growing season (EOS), and the length of the growing season (LOS). We analyzed their temporal variation and used partial correlation analysis to determine their relationship with meteorological factors (temperature and precipitation). In addition, we compared the phenology and microclimate of forest and grassland within the study area. In the Horqin Sandy Land, the vegetation SOS was concentrated between the 115th and 150th day, the EOS was concentrated between the 260th and 305th day, and the LOS ranged from 125 to 190 days. Over the past 22 years, the SOS, EOS, and LOS of vegetation in the Horqin Sandy Land showed trends of delay, shift, and extension, with rates of change of 0.82 d/10a, 5.82 d/10a, and 5.00 d/10a, respectively. The start date of the growing season in the Horqin Sandy Land was mainly influenced by precipitation in April of the current year, while the end date was mainly influenced by precipitation in August of the current year. Overall, the SOS in the forested areas of the Horqin Sandy Land was slightly later than in the grasslands, but the EOS in the forested areas was significantly later than in the grasslands, resulting in a longer LOS in the forests. In addition, annual precipitation and the rate of precipitation increase were higher in the forested areas than in the grasslands, but soil temperature was higher in the grasslands than in the forests. Vegetation phenology in the Horqin Sandy Land has undergone significant changes, mainly manifested in the delayed end date of the growing season, the extended length of the growing season, and the differences between forest and grassland. This indicates that climate change has indeed affected phenological changes and provides a theoretical basis for subsequent ecological restoration and desertification prevention efforts in the region.

MendelianRandomization v0.9.0: updates to an R package for performing Mendelian randomization analyses using summarized data.

The MendelianRandomization package is a software package written for the R software environment that implements methods for Mendelian randomization based on summarized data. In this manuscript, we describe functions that have been added or edited in the package since version 0.5.0, when we last described the package and its contents. The main additions to the package since that time are: 1) new robust methods for performing Mendelian randomization, particularly in the cases of bias from weak instruments and/or winner's curse, and pleiotropic variants, 2) methods for performing Mendelian randomization with correlated variants using dimension reduction to summarize large numbers of highly correlated variants into a limited set of principal components, 3) functions for calculating first-stage F statistics, representing instrument strength, in both univariable and multivariable contexts, and with uncorrelated and correlated genetic variants. We also discuss some pragmatic issues relating to the use of correlated variants in Mendelian randomization.

Effect of Dexmedetomidine and Two Different Doses of Esketamine Combined Infusion on the Quality of Recovery in Patients Undergoing Modified Radical Mastectomy for Breast Cancer - A Randomised Controlled Study.

Purpose: This study evaluated the effect of a combined infusion of dexmedetomidine and esketamine on the quality of recovery in patients undergoing modified radical mastectomy. Methods: A total of 135 patients were randomly divided into three groups: dexmedetomidine group (group D) received dexmedetomidine (0.5 µg/kg loading, 0.4 µg/kg/h infusion), dexmedetomidine plus low-dose esketamine group (group DE1) received dexmedetomidine (0.5 µg/kg loading, 0.4 µg/kg/h infusion) and esketamine (0.5 mg/kg loading, 2 µg/kg/min infusion), dexmedetomidine plus high-dose esketamine group (group DE2) received dexmedetomidine (0.5 µg/kg loading, 0.4 µg/kg/h infusion) and esketamine (0.5 mg/kg loading, 4 µg/kg/min infusion). The primary outcome was the overall quality of recovery-15 (QoR-15) scores at 1 day after surgery. The secondary endpoints were total QoR-15 scores at 3 days after surgery, propofol and remifentanil requirement, awaking and extubation time, postoperative visual analogue scale (VAS) pain scores, rescue analgesic, nausea and vomiting, bradycardia, excessive sedation, nightmares, and agitation. Results: The overall QoR-15 scores were much higher in groups DE1 and DE2 than in groups D 1 and D 3 days after surgery (P < 0.05). VAS pain scores at 6, 12, 24 h postoperatively, propofol and remifentanil requirements were significantly lower in groups DE1 and DE2 than in group D (P < 0.05). Compared with group D, awaking time, extubation time, and post-anesthesia care unit (PACU) stay were significantly prolonged in groups DE1 and DE2 (P < 0.05) and were much longer in group DE2 than in group DE1 (P < 0.05). The proportion of postoperative rescue analgesics and bradycardia was higher and the incidence of excessive sedation was lower in group D than in groups DE1 and DE2 (P < 0.05). Conclusion: Dexmedetomidine plus esketamine partly improved postoperative recovery quality and decreased the incidence of bradycardia but prolonged awaking time, extubation time, and PACU stay, especially dexmedetomidine plus 4 µg/kg/min esketamine.

Effects of Remimazolam and Propofol on Emergence Agitation in Elderly Patients Undergoing Hip Replacement: A Clinical, Randomized, Controlled Study.

Purpose: The aim of this study was to compare the effects of remimazolam and propofol on emergence agitation (EA) in elderly patients undergoing hip replacement. Methods: A total of 60 elderly patients undergoing hip replacement were recruited for this prospective, single-center, clinical, randomized, controlled study from February to April 2023. They were randomly assigned to two groups: the remimazolam group (group R) and the propofol group (group P). In group R, remimazolam was administered intravenously during the induction and maintenance of anesthesia, In group P, propofol was used during the induction and maintenance of anesthesia. The incidence of EA was recorded as the primary indicator. Secondary indicators included heart rate (HR) and mean arterial pressure (MAP) values at the following moments: 5 min prior to anesthetic induction (T0), 1 min following induction (T1), 5 min after the laryngeal mask was inserted (T2), the beginning of surgery (T3), the moment the laryngeal mask was removed (T4), and the overall incidence of postoperative adverse events (bleeding or splitting of the surgical incision, removal of the intravenous infusion needle, falling off the bed, hypoxemia, and hypertension). Results: The incidence of EA was significantly lower in group R than in group P (10% vs 33%, P < 0.05). At T1, T2, and T3, the HR and MAP values of group R were higher than those of group P (P < 0.05). The overall incidence of postoperative adverse events was significantly lower in group R than in group P (P < 0.05). Conclusion: Remimazolam further reduced the incidence of emergence agitation when compared to propofol during geriatric hip replacement. Moreover, it has a minor hemodynamic effect and lower the incidence of postoperative adverse events.

Maximizing Electrostatic Polarity of Non-Sacrificial Electrolyte Additives Enables Stable Zinc-Metal Anodes for Aqueous Batteries.

Although additives are widely used in aqueous electrolytes to inhibit the formation of dendrites and hydrogen evolution reactions on Zn anodes, there is a lack of rational design principles and systematic mechanistic studies on how to select a suitable additive to regulate reversible Zn plating/stripping chemistry. Here, using saccharides as the representatives, we reveal that the electrostatic polarity of non-sacrificial additives is a critical descriptor for their ability to stabilize Zn anodes. Non-sacrificial additives are found to continuously modulate the solvation structure of Zn ions and form a molecular adsorption layer (MAL) for uniform Zn deposition, avoiding the thick solid electrolyte interphase layer due to the decomposition of sacrificial additives. A high electrostatic polarity renders sucrose the best hydrated Zn2+ desolvation ability and facilitates the MAL formation, resulting in the best cycling stability with a long-term reversible plating/stripping cycle life of thousands of hours. This study provides theoretical guidance for the screening of optimal additives for high-performance ZIBs.

A/B-Site Management Strategy to Boost Electrocatalytic Overall Water Splitting on Perovskite Oxides in an Alkaline Medium.

In this paper, Pr0.7Sr0.3Co1-xRuxO3 perovskite oxides were synthesized by the sol-gel method as bifunctional catalysts for hydrogen evolution reaction (HER) and oxygen evolution reaction (OER). The overpotentials of PSCR0.05 against HER and OER at 10 mA cm-2 were 319 and 321 mV in alkaline medium, respectively. The Tafel slopes of HER and OER were 87.32 and 118.1 mV/dec, respectively. PSCR0.05 showed the largest electrochemical active area, the smallest charge transfer resistance, and excellent long-term durability. Meanwhile, the PSCR0.05 electrocatalyst was applied for overall water splitting and its cell voltage was maintained at 1.77 V at 10 mA cm-2. The super-exchange interaction between adjacent RuO6-CoO6 octahedra in perovskite made of PSCR0.05 contains sufficient active sites (such as Co2+/Co3+, Ru3+/Ru4+, and O22-/O-). The increase of surface oxygen vacancy and active site is the main reason for the improvement of difunctional catalyst performance. In this work, the electrocatalytic performance of perovskite-type oxides was further optimized by the method of A- and B-site cationic doping regulation, which provides a new idea for perovskite-type bifunctional electrocatalysts.

Preoperative Prognostic Nutritional Index Predict Survival in Patients with Resectable Adenocarcinoma of the Gastroesophageal Junction: A Retrospective Study Based on Propensity Score Matching Analyses.

Background: This study evaluated the value of PNI to predicting relapse-free survival (RFS) and overall survival (OS) in patients with resectable gastroesophageal junction adenocarcinoma (AGE). Methods: Between 2016 and 2020, there were 236 resectable AGE patients underwent a retrospective review via propensity score matched (PSM) analysis. The PNI values were computed for each patient prior to surgery [PNI= 10×albumin (gr/dL) + 0.005×total lymphocyte count (mm3)]. By using disease progression and mortality as the end points, a receiver operating characteristic(ROC) curve was plotted to identify the PNI cut-off value. Kaplan-Meier curves and Cox proportional hazard models were used for survival analysis. Results: The ROC curve indicated that the ideal cutoff value was 45.60. After propensity score matching, there were 143 patients in our retrospective study, which included 58 patients in the low-PNI group and 85 patients in the high-PNI group. When compared to the low PNI group, the high PNI group substantially increased RFS and OS (p<0.001, p=0.003, respectively) according to the Kaplan-Meier analysis and Log rank test. Advanced pathological N stage (p=0.011) and poor PNI (p=0.004) were also significant risk factors for a shorter OS, according to a univariate analysis. Multivariate analysis revealed that the N0 plus N1 group had an endpoint mortality risk that was 0.39 times lower than the N2 plus N3 group's (p=0.008). In comparison to the high PNI group, the hazard of endpoint mortality was 2.442 times greater in the low PNI group (p = 0.003). Conclusion: PNI is a simplistic and practical predictive predictor of the RFS and OS time in patients with resectable AGE.

Schisandrin treatment suppresses the proliferation, migration, invasion, and inflammatory responses of fibroblast-like synoviocytes from rheumatoid arthritis patients and attenuates synovial inflammation and joint destruction in CIA mice.

BACKGROUND: Rheumatoid arthritis (RA) is a systemic autoimmune disease causing joint dysfunction. As disease-modifying anti-rheumatic drugs (DMARDs) have poor efficacy in 20% to 25% of RA patients, additional novel RA medications are urgently needed. Schisandrin (SCH) has multiple therapeutic effects. However, whether SCH is effective against RA remains unknown. PURPOSE: To investigate how SCH affects the abnormal behaviours of RA fibroblast-like synoviocytes (FLSs) and further elucidate the underlying mechanism of SCH in RA FLSs and collagen-induced arthritis (CIA) mice. METHODS: Cell Counting Kit-8 (CCK8) assays were used to characterize cell viability. EdU assays were performed to assess cell proliferation. Annexin V-APC/PI assays were used to determine apoptosis. Transwell chamber assays were used to measure cell migration and invasion in vitro. RT-qPCR was used to assess proinflammatory cytokine and MMP mRNA expression. Western blotting was used to detect protein expression. RNA sequencing was performed to explore the potential downstream targets of SCH. CIA model mice were used to assess the treatment efficacy of SCH in vivo. RESULTS: Treatments with SCH (50, 100, and 200 µΜ) inhibited RA FLSs proliferation, migration, invasion, and TNF-α-induced IL-6, IL-8, and CCL2 expression in a dose-dependent manner but did not affect RA FLSs viability or apoptosis. RNA sequencing and Reactome enrichment analysis indicated that SREBF1 might be the downstream target in SCH treatment. Furthermore, knockdown of SREBF1 exerted effects similar to those of SCH in inhibiting RA FLSs proliferation, migration, invasion, and TNF-α-induced expression of IL-6, IL-8, and CCL2. Both SCH treatment and SREBF1 knockdown decreased activation of the PI3K/AKT and NF-κB signalling pathways. Moreover, SCH ameliorated joint inflammation and cartilage and bone destruction in CIA model mice. CONCLUSION: SCH controls the pathogenic behaviours of RA FLSs by targeting SREBF1-mediated activation of the PI3K/AKT and NF-κB signalling pathways. Our data suggest that SCH inhibits FLS-mediated synovial inflammation and joint damage and that SCH might have therapeutic potential for RA.

Sustained release of alginate hydrogel containing antimicrobial peptide Chol-37(F34-R) in vitro and its effect on wound healing in murine model of Pseudomonas aeruginosa infection.

BACKGROUND: Antibiotic resistance is a significant public health concern around the globe. Antimicrobial peptides exhibit broad-spectrum and efficient antibacterial activity with an added advantage of low drug resistance. The higher water content and 3D network structure of the hydrogels are beneficial for maintaining antimicrobial peptide activity and help to prevent degradation. The antimicrobial peptide released from hydrogels also hasten the local wound healing by promoting epithelial tissue regeneration and granulation tissue formation. OBJECTIVE: This study aimed at developing sodium alginate based hydrogel loaded with a novel antimicrobial peptide Chol-37(F34-R) and to investigate the characteristics in vitro and in vivo as an alternative antibacterial wound dressing to treat infectious wounds. METHODS: Hydrogels were developed and optimized by varying the concentrations of crosslinkers and subjected to various characterization tests like cross-sectional morphology, swelling index, percent water contents, water retention ratio, drug release and antibacterial activity in vitro, and Pseudomonas aeruginosa infected wound mice model in vivo. RESULTS: The results indicated that the hydrogel C proved superior in terms of cross-sectional morphology having uniformly sized interconnected pores, a good swelling index, with the capacity to retain a higher quantity of water. Furthermore, the optimized hydrogel has been found to exert a significant antimicrobial activity against bacteria and was also found to prevent bacterial infiltration into the wound site due to forming an impermeable barrier between the wound bed and external environment. The optimized hydrogel was found to significantly hasten skin regeneration in animal models when compared to other treatments in addition to strong inhibitory effect on the release of pro-inflammatory cytokines (interleukin-1ß and tumor necrosis factor-α). CONCLUSIONS: Our results suggest that sodium alginate -based hydrogels loaded with Chol-37(F34-R) hold the potential to be used as an alternative to conventional antibiotics in treating infectious skin wounds.