Switch to fixed-dose ainuovirine, lamivudine, and tenofovir DF versus elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in virologically suppressed people living with HIV-1: the 48-week results of the SPRINT trial, a multi-centre, randomised, double-blind, active-controlled, phase 3, non-inferiority trial.

Background: We compared the efficacy and safety profiles of ainuovirine (ANV), a new-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), with boosted elvitegravir (EVG), both coformulated with two nucleoside reverse transcriptase inhibitors (NRTIs), in people living with HIV-1 (PLWH) who had achieved virological suppression on previous NNRTI-based antiretroviral (ARV) regimen. Methods: This study was a multi-centre, randomised, double-blind, active-controlled, non-inferiority trial recruiting PLWH from 10 clinical centres across China. Main inclusion criteria included age of 18-65 years (inclusive), and stably staying on an ARV regimen combining an NNRTI with a two-drug NRTI backbone for at least 12 months. Eligible participants must have maintained plasma HIV-1 ribonucleic acid (RNA) titre below 50 copies per mL confirmed on two successive tests at an interval of at least one month prior to randomisation. Participants were randomly assigned to receive ANV 150 mg plus lamivudine (3TC) 300 mg, and tenofovir disoproxil fumarate (TDF) 300 mg (ANV/3TC/TDF), or cobicistat (Cobi) 150 mg boosted EVG plus emtricitabine (FTC) 200 mg, and tenofovir alafenamide (TAF) 10 mg. The primary efficacy endpoint was the proportion of participants with HIV-1 RNA titre at 50 copies per mL or above at week 48 using the US Food and Drug Administration snapshot algorithm, with a non-inferiority margin of 4 percentage points at a two-side 95% confidence level. This trial is active, but not recruiting, and is registered with Chinese Clinical Trial Registry (ChiCTR), number ChiCTR2100051605. Findings: Between October 2021 and February 2022, 923 patients were screened for eligibility, among whom 762 participants were randomized and had received at least one dose of ANV/3TC/TDF (n = 381) or EVG/Cobi/FTC/TAF (n = 381). At week 48, 7 (1.8%) participants on ANV/3TC/TDF and 6 (1.6%) participants on EVG/Cobi/FTC/TAF had plasma HIV-1 RNA titre at 50 copies per mL or above, including missing virological data within the time window (the Cochran-Mantel-Haenszel method, estimated treatment difference [ETD], 0.3%, 95% CI -1.6 to 2.1), establishing the non-inferiority of ANV/3TC/TDF to EVG/Cobi/FTC/TAF. The proportions of participants experiencing at least one treatment-emergent adverse events (AEs) were comparable between the two arms (97.6% versus 97.6%). A small proportion of participants discontinued study drug due to AEs (0.3% versus 0.3%). Serious AEs occurred in 11 (2.9%) participants on ANV/3TC/TDF and 9 (2.4%) participants on EVG/Cobi/FTC/TAF, respectively, none of which was considered related to study drug at the jurisdiction of the investigator. At week 48, participants on ANV/3TC/TDF showed a significantly less weight gain from baseline compared to those on EVG/Cobi/FTC/TAF (least square mean, 1.16 versus 2.05 kg, ETD -0.90 kg, 95% CI, -1.43 to -0.37). The changes in serum lipids from baseline also favoured ANV/3TC/TDF over EVG/Cobi/FTC/TAF. Interpretation: In virologically suppressed PLWH on previous NNRTI-based ARV regimen, switch to ANV/3TC/TDF resulted in less weight gain, and improved lipid metabolism while maintaining virological suppression non-inferior to that to EVG/Cobi/FTC/TAF. Funding: Jiangsu Aidea Pharmaceutical & the National "Thirteenth Five-year Period" Major Innovative Drugs Research and Development Key Project of the People's Republic of China Ministry of Science and Technology.

Performance assessment of hybrid machine learning approaches for breast cancer and recurrence prediction.

Breast cancer is a major health concern for women everywhere and a major killer of women. Malignant tumors may be distinguished from benign ones, allowing for early diagnosis of this disease. Therefore, doctors need an accurate method of diagnosing tumors as either malignant or benign. Even if therapy begins immediately after diagnosis, some cancer cells may persist in the body, increasing the risk of a recurrence. Metastasis and recurrence are the leading causes of death from breast cancer. Therefore, detecting a return of breast cancer early has become a pressing medical issue. Evaluating and contrasting various Machine Learning (ML) techniques for breast cancer and recurrence prediction is crucial to choosing the best successful method. Inaccurate forecasts are common when using datasets with a large number of attributes. This study addresses the need for effective feature selection and optimization methods by introducing Recursive Feature Elimination (RFE) and Grey Wolf Optimizer (GWO), in response to the limitations observed in existing approaches. In this research, the performance evaluation of methods is enhanced by employing the RFE and GWO, considering the Wisconsin Diagnostic Breast Cancer (WDBC) and Wisconsin Prognostic Breast Cancer (WPBC) datasets taken from the UCI-ML repository. Various preprocessing techniques are applied to raw data, including imputation, scaling, and others. In the second step, relevant feature correlations are used with RFE to narrow down candidate discriminative features. The GWO chooses the best possible combination of attributes for the most accurate result in the next step. We use seven ML classifiers in both datasets to make a binary decision. On the WDBC and WPBC datasets, several experiments have shown accuracies of 98.25% and 93.27%, precisions of 98.13% and 95.56%, sensitivities of 99.06% and 96.63%, specificities of 96.92% and 73.33%, F1-scores of 98.59% and 96.09% and AUCs of 0.982 and 0.936, respectively. The hybrid approach's superior feature selection improved the accuracy of breast cancer performance indicators and recurrence classification.

Upregulation of TCPTP in Macrophages Is Involved in IL-35 Mediated Attenuation of Experimental Colitis.

Ulcerative colitis (UC) is a chronic intestinal inflammatory disease with complex etiology. Interleukin-35 (IL-35), as a cytokine with immunomodulatory function, has been shown to have therapeutic effects on UC, but its mechanism is not yet clear. Therefore, we constructed Pichia pastoris stably expressing IL-35 which enables the cytokines to reach the diseased mucosa, and explored whether upregulation of T-cell protein tyrosine phosphatase (TCPTP) in macrophages is involved in the mechanisms of IL-35-mediated attenuation of UC. After the successful construction of engineered bacteria expressing IL-35, a colitis model was successfully induced by giving BALB/c mice a solution containing 3% dextran sulfate sodium (DSS). Mice were treated with Pichia/IL-35, empty plasmid-transformed Pichia (Pichia/0), or PBS by gavage, respectively. The expression of TCPTP in macrophages (RAW264.7, BMDMs) and intestinal tissues after IL-35 treatment was detected. After administration of Pichia/IL-35, the mice showed significant improvement in weight loss, bloody stools, and shortened colon. Colon pathology also showed that the inflammatory condition of mice in the Pichia/IL-35 treatment group was alleviated. Notably, Pichia/IL-35 treatment not only increases local M2 macrophages but also decreases the expression of inflammatory cytokine IL-6 in the colon. With Pichia/IL-35 treatment, the proportion of M1 macrophages, Th17, and Th1 cells in mouse MLNs were markedly decreased, while Tregs were significantly increased. In vitro experiments, IL-35 significantly promoted the expression of TCPTP in macrophages stimulated with LPS. Similarly, the mice in the Pichia/IL-35 group also expressed more TCPTP than that of the untreated group and the Pichia/0 group.

Impact of Missense Mutations on Spike Protein Stability and Binding Affinity in the Omicron Variant.

The global effort to combat the COVID-19 pandemic faces ongoing uncertainty with the emergence of Variants of Concern featuring numerous mutations on the Spike (S) protein. In particular, the Omicron Variant is distinguished by 32 mutations, including 10 within its receptor-binding domain (RBD). These mutations significantly impact viral infectivity and the efficacy of vaccines and antibodies currently in use for therapeutic purposes. In our study, we employed structure-based computational saturation mutagenesis approaches to predict the effects of Omicron missense mutations on RBD stability and binding affinity, comparing them to the original Wuhan-Hu-1 strain. Our results predict that mutations such as G431W and P507W induce the most substantial destabilizations in the Wuhan-Hu-1-S/Omicron-S RBD. Notably, we postulate that mutations in the Omicron-S exhibit a higher percentage of enhancing binding affinity compared to Wuhan-S. We found that the mutations at residue positions G447, Y449, F456, F486, and S496 led to significant changes in binding affinity. In summary, our findings may shed light on the widespread prevalence of Omicron mutations in human populations. The Omicron mutations that potentially enhance their affinity for human receptors may facilitate increased viral binding and internalization in infected cells, thereby enhancing infectivity. This informs the development of new neutralizing antibodies capable of targeting Omicron's immune-evading mutations, potentially aiding in the ongoing battle against the COVID-19 pandemic.

Intermittent Catheterization Continuity Care on Bladder Function Recovery and Quality of Life in Patients After Radical Hysterectomy for Cervical Cancer: A Quasi-Experimental Study.

Background: Bladder dysfunction is a common complication following radical hysterectomy, affecting patients' QOL. Exploring interventions, particularly IC continuity care, is crucial for identifying strategies to enhance postoperative outcomes. This study aimed to assess the impact of continuous intermittent catheterization (IC) care on bladder function recovery and quality of life (QOL) in patients undergoing radical hysterectomy for cervical cancer. Methods: The primary outcome measured was the time to bladder function recovery, with secondary outcomes comprising EORTC QLQ-C30 assessments at 3 and 6 months post-surgery, as well as EORTC QLQ-CX24 evaluations. Meanwhile, urinary complications, readmissions, and outpatient follow-up were also compared. Results: Among the 128 participants, with 64 in each group, indwelling catheterization durations were similar. However, the IC continuity care group exhibited significantly shorter IC duration and bladder recovery time. This group demonstrated superior QOL, lower occurrence rates post-IC, reduced urethral injuries, and higher readmission and outpatient follow-up rates. Conclusion: This study underscores continuous IC care emerges as a beneficial intervention, facilitating accelerated bladder function recovery and improved QOL in patients following radical hysterectomy for cervical cancer.

GuiErBai: a potent inhibitor, exhibiting broadly antitumor effect against cervical cancer in vitro and in vivo.

Introduction: Cervical cancer (CC) ranks as the fourth most prevalent malignant tumor among women worldwide, and is the fourth leading cause of cancer-related mortality. GuiErBai (GEB), a compound preparation developed by our research team, is derived from the ancient Chinese medicine of the Miao nationality and is comprised of podophyllotoxin (PTOX), imperatorin, isoimperatorin, and A. dahurica alkaloids. These individual components have demonstrated notable efficacy in tumor treatment. However, the specific anti-tumor effect of the compound Chinese medicine GEB in the context of CC has yet to be validated. Methods: HeLa and SiHa cell lines were utilized for in vitro experiments and treated with 5 mg/mL and 10 mg/mL GEB concentrations, respectively. The cell cycle changes after GEB treatment were assessed using flow cytometry. Transmission electron microscopy was employed to observe autophagic bodies and apoptotic bodies, while MDC staining evaluated the occurrence of autophagy. CCK-8 was used to observe the effect of GEB on cell proliferation, and Transwell assays assessed cell migration and invasion. Western blotting detected cell cycle and apoptosis-related protein expression, along with the expression level of autophagy-related protein LC3I/II. Changes in ROS and mitochondrial membrane potential in cervical cancer cells following GEB treatment were determined using ROS detection and mitochondrial membrane potential detection kits. For the in vivo experiment, a nude mouse model of cervical cancer transplantation based on HeLa cells was established. Experimental animals were divided into negative control, positive control, high-dose GEB (10 mg/mL), and low-dose GEB (5 mg/mL) groups. Results: In HeLa and SiHa cell lines, the G0/G1 phase of tumor cells significantly decreased (p < 0.001), while the G2/M phase increased notably (p < 0.001) following various GEB treatments. Electron microscopy showed GEB promoted apoptotic body and autophagosome formation in both cell lines. Compared to untreated HeLa and SiHa cells, GEB-treated cells exhibited significantly reduced caspase3 protein expression, and substantially increased autophagy-related protein LC3I/II expression. GEB treatment significantly reduced migration and invasion capabilities in both cell lines (p < 0.001), while ROS content and mitochondrial membrane potential were significantly elevated (p < 0.001). GEB effectively inhibited cervical cancer cell proliferation, with the optimal concentration being 10 mg/mL. A successful nude mouse model of cervical cancer transplantation was established using HeLa cells. Post-GEB treatment, the tumor volume and weight in nude mice significantly decreased (p < 0.001), with diminished expression of CD34, VEGF, and caspase3 proteins in tumor tissues. Discussion: GEB exhibits a robust antitumor effect against cervical cancer, both in vitro and in vivo, in a concentration-dependent manner, by regulating autophagy and apoptosis of tumor cells.

Sesamol Alleviates Sarcopenia via Activating AKT/mTOR/FoxO1 Signal Pathway in Aged Obese Mice.

Sesamol is a major bioactive component extracted from sesame seeds and has various medicinal properties. However, the effects of sesamol on sarcopenia associated with aging and obesity remains unclear. Therefore, the protective effects and underlying mechanisms of sesamol on sarcopenia was evaluated in aged and obese C57BL/6 J male mouse models fed a high fat diet and C2C12 myotubes co-treated with D-gal and PA in this study. Our in vivo data showed that sesamol activated AKT/mTOR/FoxO1 signal pathway, and then upregulated p-p70S6K and p-4EBP1 to promote myoprotein synthesis, and downregulated Atrogin-1 and MuRF1 to inhibit myoprotein degradation, thus ameliorating sarcopenia related to aging and obesity. Furthermore, our in vitro results confirmed the protective effect and aforementioned mechanisms of sesamol on sarcopenia. Collectively, sesamol could alleviate sarcopenia associated with aging and obesity via activating the AKT/mTOR/FoxO1 signal pathway. Our findings highlight the therapeutic potentials of sesamol for aging and obesity-related metabolic muscular complications.

[The Efficacy and Influencing Factors of Cyclosporine Alone in the Treatment of Children with Acquired Aplastic Anemia].

OBJECTIVE: To analyze the efficacy and influencing factors of cyclosporine (CsA) alone in the treatment of children with acquired aplastic anemia (AA). METHODS: The clinical data of children diagnosed with AA and treated with CsA alone from January 1, 2016 to December 31, 2020 in the Children's Hospital of Chongqing Medical University were collected, and the efficacy and influencing factors of CsA treatment were evaluated. RESULTS: Among the 119 patients, there were 62 male and 57 female, with a median age of 7 years and 1 month. There were 45 cases of very severe AA (VSAA), 47 cases of severe AA (SAA), and 27 cases of non-severe AA (NSAA). At 6 months after treatment, the efficacy of VSAA was lower than that of SAA and NSAA, and there was a statistical difference (P < 0.01). 6 cases died early, 16 cases relapsed, 2 cases progressed to AML and ALL. The results of univariate analysis showed that the high proportion of lymphocyte in the bone marrow at 6 months was an adverse factor for the efficacy of CsA, while high PLT count was a protective factor (P =0.008, P =0.002). The ROC curve showed that the cut-off values of PLT count and the proportion of bone marrow lymphocyte at 6 months were 16.5×109 /L, 68.5%, respectively. Multivariate analysis showed that the high proportion of lymphocyte in bone marrow at 6 months was an independent adverse factor for IST (P =0.020, OR =0.062), and high PLT count was a protective factor (P =0.044, OR =1.038). At 3 months of treatment, CsA response and NSAA were the risk factor for recurrence (P =0.001, 0.031). CONCLUSION: The efficacy of NSAA was higher than that of SAA and VSAA after 6 months of treatment with CsA alone. A high PLT count at the initial diagnosis was a good factor for the effectiveness of CsA, and a high proportion of bone marrow lymphocyte was an unfavorable factor. CsA response at 3 months and NSAA were risk factors for recurrence.

Population pharmacokinetics of Ainuovirine and exposure-response analysis in human immunodeficiency virus-infected individuals.

BACKGROUND: Ainuovirine (ANV) is a new generation of non-nucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus (HIV) type 1 infection. This study aimed to evaluate the population pharmacokinetic (PopPK) profile and exposure-response relationship of ANV among people living with HIV. METHODS: Plasma concentration-time data from phase 1 and phase 3 clinical trials of ANV were pooled for developing the PopPK model. Exposure estimates obtained from the final model were used in exposure-response analysis for virologic responses and safety responses. RESULTS: ANV exhibited a nonlinear pharmacokinetic profile, which was best described by a two-compartment model with first-order elimination. There were no significant covariates correlated to the pharmacokinetic parameters of ANV. The PopPK parameter estimate (relative standard error [%]) for CL/F was 6.46 (15.00) L/h, and the clearance of ANV increased after multiple doses. The exposure-response model revealed no significant correlation between the virologic response (HIV-RNA <50 copies/mL) at 48 weeks and the exposure, but the incidence of adverse events increased with the increasing exposure( P value of steady-state trough concentration and area under the steady-state curve were 0.0177 and 0.0141, respectively). CONCLUSIONS: Our PopPK model supported ANV 150 mg once daily as the recommended dose for people living with HIV, requiring no dose adjustment for the studied factors. Optimization of ANV dose may be warranted in clinical practice due to an increasing trend in adverse reactions with increasing exposure. TRIAL REGISTRATION: Chinese Clinical Trial Registry https://www.chictr.org.cn (Nos. ChiCTR1800018022 and ChiCTR1800019041).

Detection and assessment of immune and stromal related risk genes to predict preeclampsia: A bioinformatics analysis with dataset.

This study aimed to investigate immune score and stromal score-related signatures associated with preeclampsia (PE) and identify key genes for diagnosing PE using bioinformatics analysis. Four microarray datasets, GSE75010, GSE25906, GSE44711, and GSE10588 were obtained from the Gene Expression Omnibus database. GSE75010 was utilized for differential expressed gene (DEGs) analysis. Subsequently, bioinformatic tools such as gene ontology, Kyoto Encyclopedia of Genes and Genomes, weighted gene correlation network analysis, and gene set enrichment analysis were employed to functionally characterize candidate target genes involved in the pathogenesis of PE. The least absolute shrinkage and selection operator regression approach was employed to identify crucial genes and develop a predictive model. This method also facilitated the creation of receiver operating characteristic (ROC) curves, enabling the evaluation of the model's precision. Furthermore, the model underwent external validation through the other three datasets. A total of 3286 DEGs were identified between normal and PE tissues. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed enrichments in functions related to cell chemotaxis, cytokine binding, and cytokine-cytokine receptor interaction. weighted gene correlation network analysis identified 2 color modules strongly correlated with immune and stromal scores. After intersecting DEGs with immune and stromal-related genes, 13 genes were selected and added to the least absolute shrinkage and selection operator regression. Ultimately, 7 genes were screened out to establish the risk model for discriminating preeclampsia from controls, with each gene having an area under the ROC curve >0.70. The constructed risk model demonstrated that the area under the ROC curves in internal and the other three external datasets were all greater than 0.80. A 7-gene risk signature was identified to build a potential diagnostic model and performed well in the external validation group for PE patients. These findings illustrated that immune and stromal cells played essential roles in PE during its progression.

Transfer learned deep feature based crack detection using support vector machine: a comparative study.

Technology offers a lot of potential that is being used to improve the integrity and efficiency of infrastructures. Crack is one of the major concerns that can affect the integrity or usability of any structure. Oftentimes, the use of manual inspection methods leads to delays which can worsen the situation. Automated crack detection has become very necessary for efficient management and inspection of critical infrastructures. Previous research in crack detection employed classification and localization-based models using Deep Convolutional Neural Networks (DCNNs). This study suggests and compares the effectiveness of transfer learned DCNNs for crack detection as a classification model and as a feature extractor to overcome this restriction. The main objective of this paper is to present various methods of crack detection on surfaces and compare their performance over 3 different datasets. Experiments conducted in this work are threefold: initially, the effectiveness of 12 transfer learned DCNN models for crack detection is analyzed on three publicly available datasets: SDNET, CCIC and BSD. With an accuracy of 53.40%, ResNet101 outperformed other models on the SDNET dataset. EfficientNetB0 was the most accurate (98.8%) model on the BSD dataset, and ResNet50 performed better with an accuracy of 99.8% on the CCIC dataset. Secondly, two image enhancement methods are employed to enhance the images and are transferred learned on the 12 DCNNs in pursuance of improving the performance of the SDNET dataset. The results from the experiments show that the enhanced images improved the accuracy of transfer-learned crack detection models significantly. Furthermore, deep features extracted from the last fully connected layer of the DCNNs are used to train the Support Vector Machine (SVM). The integration of deep features with SVM enhanced the detection accuracy across all the DCNN-dataset combinations, according to analysis in terms of accuracy, precision, recall, and F1-score.

Risk factors, impact and treatment of postoperative lymphatic leakage in children with abdominal neuroblastoma operated on by laparotomy.

BACKGROUND: Lymphatic leakage is one of the postoperative complications of neuroblastoma. The purpose of this study is to summarize the clinical characteristics and risk factors of lymphatic leakage and try to find effective prevention and treatment measures. METHODS: A retrospective study included 186 children with abdominal neuroblastoma, including 32 children of lymphatic leakage and 154 children of non-lymphatic leakage. The clinical information, surgical data, postoperative abdominal drainage, treatment of lymphatic leakage and prognosis of the two groups were collected and analyzed. RESULTS: The incidence of lymphatic leakage in this cohort was 14% (32 children). Through univariate analysis of lymphatic leakage group and non-lymphatic leakage group, we found that lymphatic leakage increased the complications, prolonged the time of abdominal drainage and hospitalization, and delayed postoperative chemotherapy (p < 0.05). In this cohort, the median follow-up time was 46 (95% CI: 44-48) months. The follow-up data of 7 children were partially missing. 147 children survived, of which 23 had tumor recurrence (5 children recurred in the surgical area). 37 children died, of which 32 had tumor recurrence (9 children recurred in the operation area). In univariate analysis, there was no statistical difference in overall survival (p = 0.21) and event-free survival (p = 0.057) between lymphatic leakage group and non-lymphatic leakage group, while 3-year cumulative incidence of local progression was higher in lymphatic leakage group (p = 0.015). However, through multivariate analysis, we found that lymphatic leakage did not affect event-free survival, overall survival and cumulative incidence of local progression in children with neuroblastoma. Resection of 5 or more lymphatic regions was an independent risk factor for lymphatic leakage after neuroblastoma surgery. All 32 children with lymphatic leakage were cured by conservative treatment without surgery. Of these, 75% (24/32) children were cured by fat-free diet or observation, 25% (8/32) children were cured by total parenteral nutrition. The median drain output at diagnosis in total parenteral nutrition group was higher than that in non-total parenteral nutrition group (p < 0.001). The cut-off value was 17.2 ml/kg/day. CONCLUSIONS: Lymphatic leakage does not affect the prognosis of children with neuroblastoma, but long-term drain output caused by lymphatic leakage will still adversely affect postoperative complications and follow-up treatment, which requires attention and active treatment measures. More attention should be paid to the children with 5 or more lymphatic regions resection, and the injured lymphatic vessels should be actively found and ligated after tumor resection to reduce the postoperative lymphatic leakage. Early application of total parenteral nutrition is recommended for those who have drain output at diagnosis of greater than 17.2 ml/kg/day. LEVEL OF EVIDENCE: Level III, Treatment study (Retrospective comparative study).

Comparison of the Global Leadership Initiative on Malnutrition and the Patient-Generated Subjective Global Assessment for diagnosing malnutrition in patients undergoing surgery for hepatobiliary and pancreatic malignancies.

OBJECTIVE: to analyse the differences in malnutrition assessment between the Global Leadership Initiative on Malnutrition (GLIM) criteria and the Patient-Generated Subjective Global Assessment (PG-SGA) among patients with hepatobiliary and pancreatic malignancies. METHOD: this study was a cross-sectional study and included 126 hospitalised patients who underwent surgery for hepatobiliary and pancreatic malignancies between November 1, 2019 and August 1, 2020. The patients' clinical data were collected, and malnutrition assessments were completed using the different nutritional assessment tools. The consistency of both tools was analysed using Cohen's kappa coefficient. RESULTS: the prevalence of malnutrition showed a difference in diagnosis results between the GLIM criteria (36.51 %) and the PG-SGA (55.56 %). The two methods had moderate consistency (kappa = 0.590, p < 0.01). The sensitivity of a malnutrition diagnosis using a combination of GLIM and PG-SGA was 65.7 % (53.3 % and 76.4 %, respectively), and specificity was 100 % (92 % and 100 %, respectively). When malnutrition was evaluated using only PG-SGA, sensitivity was 88.9 % (95 % confidence interval (CI) 63.9 % to 98.1 %), whereas when only the GLIM score was used for malnutrition evaluation, sensitivity was 98.2 % (95 % CI, 92.8 % to 99.7 %). In addition, the PG-SGA score and the GLIM score had significant correlations. CONCLUSION: GLIM performed better than PG-SGA in the correlation analysis of nutritional indicators. GLIM is more suitable for patients with hepatobiliary and pancreatic malignancies than PG-SGA.

Extracellular cold-inducible RNA-binding protein mediated neuroinflammation and neuronal apoptosis after traumatic brain injury.

Background: Extracellular cold-inducible RNA-binding protein (eCIRP) plays a vital role in the inflammatory response during cerebral ischaemia. However, the potential role and regulatory mechanism of eCIRP in traumatic brain injury (TBI) remain unclear. Here, we explored the effect of eCIRP on the development of TBI using a neural-specific CIRP knockout (KO) mouse model to determine the contribution of eCIRP to TBI-induced neuronal injury and to discover novel therapeutic targets for TBI. Methods: TBI animal models were generated in mice using the fluid percussion injury method. Microglia or neuron lines were subjected to different drug interventions. Histological and functional changes were observed by immunofluorescence and neurobehavioural testing. Apoptosis was examined by a TdT-mediated dUTP nick end labelling assay in vivo or by an annexin-V assay in vitro. Ultrastructural alterations in the cells were examined via electron microscopy. Tissue acetylation alterations were identified by non-labelled quantitative acetylation via proteomics. Protein or mRNA expression in cells and tissues was determined by western blot analysis or real-time quantitative polymerase chain reaction. The levels of inflammatory cytokines and mediators in the serum and supernatants were measured via enzyme-linked immunoassay. Results: There were closely positive correlations between eCIRP and inflammatory mediators, and between eCIRP and TBI markers in human and mouse serum. Neural-specific eCIRP KO decreased hemispheric volume loss and neuronal apoptosis and alleviated glial cell activation and neurological function damage after TBI. In contrast, eCIRP treatment resulted in endoplasmic reticulum disruption and ER stress (ERS)-related death of neurons and enhanced inflammatory mediators by glial cells. Mechanistically, we noted that eCIRP-induced neural apoptosis was associated with the activation of the protein kinase RNA-like ER kinase-activating transcription factor 4 (ATF4)-C/EBP homologous protein signalling pathway, and that eCIRP-induced microglial inflammation was associated with histone H3 acetylation and the α7 nicotinic acetylcholine receptor. Conclusions: These results suggest that TBI obviously enhances the secretion of eCIRP, thereby resulting in neural damage and inflammation in TBI. eCIRP may be a biomarker of TBI that can mediate the apoptosis of neuronal cells through the ERS apoptotic pathway and regulate the inflammatory response of microglia via histone modification.

Total Synthesis of (±)-Simonsol C.

Total synthesis of simonsol C has been achieved, focusing on the postdearomatization transformations. Our methodology integrates an efficient combination of dearomatization and Zn/AcOH reduction to introduce an allyl group, followed by oxo-Michael addition, to construct the 6/5/6 benzofuran skeleton. It offers a novel method for synthesizing allyl-containing quaternary carbon atoms in a straightforward manner.

[Study on mechanism of inhibiting proliferation of head and neck cancer cells by citral, active ingredient of lemon essential oil].

To explore the active substances exerting anti-tumour effect in lemon essential oil and the molecular mechanism inhibiting the proliferation of head and neck cancer cells SCC15 and CAL33, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay(MTT) was utilized to identify the active component inhibiting the proliferation of head and neck cancer cells, namely citral. The IC_(50) of citral inhibiting the proliferation of head and neck cancer cells and normal cells were also determined. In addition, a 5-ethynyl-2'-deoxyuridine(EdU) staining assay was used to detect the effect of citral on the proliferation rate of head and neck cancer cells, and a colony formation assay was used to detect the effect of citral on tumor sphere formation of head and neck cancer cells in vitro. The cell cycle arrest and apoptosis induction of head and neck cancer cells by citral were evaluated by flow cytometry, and Western blot was used to detect the effect of citral on the expression levels of cell cycle-and apoptosis-related proteins in head and neck cancer cells. The findings indicated that citral could effectively inhibit the proliferation and growth of head and neck cancer cells, with anti-tumor activity, and its half inhibitory concentrations for CAL33 and SCC15 were 54.78 and 25.23 µg·mL~(-1), respectively. Furthermore, citral arrested cell cycle at G_2/M phase by down-regulating cell cycle-related proteins such as S-phase kinase associated protein 2(SKP2), C-MYC, cyclin dependent kinase 1(CDK1), and cyclin B. Moreover, citral increased the cysteinyl aspartate-specific proteinase-3(caspase-3), cysteinyl aspartate-specific proteinase-9(caspase-9), and cleaved poly ADP-ribose polymerase(PARP). It up-regulated the level of autophagy-related proteins including microtubule associated protein 1 light chain 3B(LC3B), sequestosome 1(P62/SQSTM1), autophagy effector protein Beclin1(Beclin1), and lysosome-associate membrane protein 1(LAMP1), suggesting that citral could effectively trigger cell apoptosis and cell autophagy in head and neck cancer cells. Furthermore, the dual-tagged plasmid system mCherry-GFP-LC3 was used, and it was found that citral impeded the fusion of autophagosomes and lysosomes, leading to autophagic flux blockage. Collectively, our findings reveal that the main active anti-proliferation component of lemon essential oil is citral, and this component has a significant inhibitory effect on head and neck cancer cells. Its underlying molecular mechanism is that citral induces apoptosis and autophagy by cell cycle arrest and ultimately inhibits cell proliferation.

Leveraging ANFIS with Adam and PSO optimizers for Parkinson's disease.

Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by motor deficits, including tremor, rigidity, bradykinesia, and postural instability. According to the World Health Organization, about 1 % of the global population has been diagnosed with PD, and this figure is expected to double by 2040. Early and accurate diagnosis of PD is critical to slowing down the progression of the disease and reducing long-term disability. Due to the complexity of the disease, it is difficult to accurately diagnose it using traditional clinical tests. Therefore, it has become necessary to develop intelligent diagnostic models that can accurately detect PD. This article introduces a novel hybrid approach for accurate prediction of PD using an ANFIS with two optimizers, namely Adam and PSO. ANFIS is a type of fuzzy logic system used for nonlinear function approximation and classification, while Adam optimizer has the ability to adaptively adjust the learning rate of each individual parameter in an ANFIS at each training step, which helps the model find a better solution more quickly. PSO is a metaheuristic approach inspired by the behavior of social animals such as birds. Combining these two methods has potential to provide improved accuracy and robustness in PD diagnosis compared to existing methods. The proposed method utilized the advantages of both optimization techniques and applied them on the developed ANFIS model to maximize its prediction accuracy. This system was developed by using an open access clinical and demographic data. The chosen parameters for the ANFIS were selected through a comparative experimental analysis to optimize the model considering the number of fuzzy membership functions, number of epochs of ANFIS, and number of particles of PSO. The performance of the two ANFIS models: ANFIS (Adam) and ANFIS (PSO) focusing at ANFIS parameters and various evaluation metrics are further analyzed in detail and presented, The experimental results showed that the proposed ANFIS (PSO) shows better results in terms of loss and precision, whereas, the ANFIS (Adam) showed the better results in terms of accuracy, f1-score and recall. Thus, this adaptive neural-fuzzy algorithm provides a promising strategy for the diagnosis of PD, and show that the proposed models show their suitability for many other practical applications.

Melatonin pretreatment improves endometrial regenerative cell-mediated therapeutic effects in experimental colitis.

BACKGROUND: Endometrial regenerative cells (ERCs) have been proven to be an effective strategy for attenuating experimental colitis, but the complex in vivo microenvironment such as oxidative stress may largely limit and weaken ERC efficacy. Melatonin (MT) works as an anti-oxidative agent in a variety of preclinical diseases, and has been identified to promote mesenchymal stem cell-mediated therapeutic effects in different diseases. However, the ability of MT to enhance ERC-mediated effects in colitis is currently poorly understood. METHODS: Menstrual blood was collected from healthy female volunteers to obtain ERCs and identified. In vitro, H2O2-induced oxidative stress was introduced to test if MT could prevent ERCs from damage through detection of intracellular reactive oxidative species (ROS) and apoptosis assay. In vivo, dextran sodium sulfate (DSS)-induced acute colitis was treated by ERCs and MT-primed ERCs, therapeutic effects were assayed by the disease activity index (DAI), histological features, and macrophage and CD4+ T cell in the spleen and colon, and cytokine profiles in the sera and colon were also measured. RESULTS: In vitro, ERCs that underwent MT-precondition were found to possess more anti-oxidative potency in comparison to naïve ERCs, which were characterized by decreased apoptosis rate and intracellular ROS under H2O2 stimulation. In vivo, MT pretreatment can significantly enhance the therapeutic effects of ERCs in the attenuation of experimental colitis, including decreased DAI index and damage score. In addition, MT pretreatment was found to promote ERC-mediated inhibition of Th1, Th17, and M1 macrophage and pro-inflammatory cytokines, increase of Treg, and immunomodulation of cytokines in the spleen and colon. CONCLUSIONS: MT pretreatment facilitates the promotion of cell viability under oxidative stress in vitro, while also enhancing ERC-mediated therapeutic effects in experimental colitis.

Phenotypic comparison and the potential antitumor function of immortalized bone marrow-derived macrophages (iBMDMs).

Introduction: Macrophages are an important component of innate immunity and involved in the immune regulation of multiple diseases. The functional diversity and plasticity make macrophages to exhibit different polarization phenotypes after different stimuli. During tumor progression, the M2-like polarized tumor-associated macrophages (TAMs) promote tumor progression by assisting immune escape, facilitating tumor cell metastasis, and switching tumor angiogenesis. Our previous studies demonstrated that functional remodeling of TAMs through engineered-modifying or gene-editing provides the potential immunotherapy for tumor. However, lack of proliferation capacity and maintained immune memory of infused macrophages restricts the application of macrophage-based therapeutic strategies in the repressive tumor immune microenvironment (TIME). Although J2 retrovirus infection enabled immortalization of bone marrow-derived macrophages (iBMDMs) and facilitated the mechanisms exploration and application, little is known about the phenotypic and functional differences among multi kinds of macrophages. Methods: HE staining was used to detect the biosafety of iBMDMs, and real-time quantitative PCR, immunofluorescence staining, and ELISA were used to detect the polarization response and expression of chemokines in iBMDMs. Flow cytometry, scratch assay, real-time quantitative PCR, and crystal violet staining were used to analyze its phagocytic function, as well as its impact on tumor cell migration, proliferation, and apoptosis. Not only that, the inhibitory effect of iBMDMs on tumor growth was detected through subcutaneous tumor loading, while the tumor tissue was paraffin sectioned and flow cytometry was used to detect its impact on the tumor microenvironment. Results: In this study, we demonstrated iBMDMs exhibited the features of rapid proliferation and long-term survival. We also compared iBMDMs with RAW264.7 cell line and mouse primary BMDMs with in vitro and in vivo experiments, indicating that the iBMDMs could undergo the same polarization response as normal macrophages with no obvious cellular morphology changes after polarization. What's more, iBMDMs owned stronger phagocytosis and pro-apoptosis functions on tumor cells. In addition, M1-polarized iBMDMs could maintain the anti-tumor phenotypes and domesticated the recruited macrophages of receptor mice, which further improved the TIME and repressed tumor growth. Discussion: iBMDMs can serve as a good object for the function and mechanism study of macrophages and the optional source of macrophage immunotherapy.