Incorporating machine learning and PPI networks to identify mitochondrial fission-related immune markers in abdominal aortic aneurysms.

Purpose: The aim of this study is to investigate abdominal aortic aneurysm (AAA), a disease characterised by inflammation and progressive vasodilatation, for novel gene-targeted therapeutic loci. Methods: To do this, we used weighted co-expression network analysis (WGCNA) and differential gene analysis on samples from the GEO database. Additionally, we carried out enrichment analysis and determined that the blue module was of interest. Additionally, we performed an investigation of immune infiltration and discovered genes linked to immune evasion and mitochondrial fission. In order to screen for feature genes, we used two PPI network gene selection methods and five machine learning methods. This allowed us to identify the most featrue genes (MFGs). The expression of the MFGs in various cell subgroups was then evaluated by analysis of single cell samples from AAA. Additionally, we looked at the expression levels of the MFGs as well as the levels of inflammatory immune-related markers in cellular and animal models of AAA. Finally, we predicted potential drugs that could be targeted for the treatment of AAA. Results: Our research identified 1249 up-regulated differential genes and 3653 down-regulated differential genes. Through WGCNA, we also discovered 44 genes in the blue module. By taking the point where several strategies for gene selection overlap, the MFG (ITGAL and SELL) was produced. We discovered through single cell research that the MFG were specifically expressed in T regulatory cells, NK cells, B lineage, and lymphocytes. In both animal and cellular models of AAA, the MFGs' mRNA levels rose. Conclusion: We searched for the AAA novel targeted gene (ITGAL and SELL), which most likely function through lymphocytes of the B lineage, NK cells, T regulatory cells, and B lineage. This analysis gave AAA a brand-new goal to treat or prevent the disease.

Efficacy and safety of precision-guided transjugular extrahepatic portosystemic shunt (TEPS) in the management of cavernous transformation of the portal vein with portal hypertension: a case series.

BACKGROUND AND AIMS: Performing a Transjugular intrahepatic portal system shunt (TIPS) in patients with portal vein cavernous transformation (CTPV) poses significant challenges. As an alternative, transjugular extrahepatic portal vein shunt (TEPS) may offer a potential solution for these patients. Nonetheless, the effectiveness and safety of TEPS remain uncertain. This case series study aimed to evaluate the efficacy and safety of TEPS in treating patients with CTPV portal hypertension complications. METHODS: The study encompassed a cohort of 22 patients diagnosed with CTPV who underwent TEPS procedures. Of these, 13 patients manifested recurrent hemorrhagic episodes subsequent to conventional therapies, 8 patients grappled with recurrent or refractory ascites, and 1 patient experienced acute bleeding but refused endoscopic treatment. Comprehensive postoperative monitoring was conducted for all patients to rigorously evaluate both the technical and clinical efficacy of the intervention, as well as long-term outcomes. RESULTS: The overall procedural success rate among the 22 patients was 95.5% (21/22).During the TEPS procedure, nine patients were guided by percutaneous splenic access, three patients were guided by percutaneous hepatic access, five patients were guided by transmesenteric vein access from the abdomen, and two patients were guided by catheter marking from the hepatic artery. Additionally, guidance for three patients was facilitated by pre-existing TIPS stents. The postoperative portal pressure gradient following TEPS demonstrated a statistically significant decrease compared to preoperative values (24.95 ± 3.19 mmHg vs. 11.48 ± 1.74 mmHg, p < 0.01).Although three patients encountered perioperative complications, their conditions ameliorated following symptomatic treatment, and no procedure-related fatalities occurred. During a median follow-up period of 14 months, spanning a range of 5 to 39 months, we observed four fatalities. Specifically, one death was attributed to hepatocellular carcinoma, while the remaining three were ascribed to chronic liver failure. During the follow-up period, no instances of shunt dysfunction were observed. CONCLUSIONS: Precision-guided TEPS appears to be a safe and efficacious intervention for the management of CTPV.

Home-based vs center-based exercise on patient-reported and performance-based outcomes for knee osteoarthritis: a systematic review with meta-analysis.

Background: Home-based exercise (HBE) represents an alternative to increase the accessibility of rehabilitation programs and relieve the burden on the health care system for people with knee osteoarthritis. Objectives: To summarize for the first time the effectiveness of HBE as compared to center-based exercise (CBE), both with and without HBE, on patient-reported and performance-based outcomes in people with KOA. Methods: Searches were conducted on PubMed, Cochrane, Embase, Web of Science, and Scopus until March 10, 2023, without date or language restrictions. Randomized controlled trials investigating HBE versus CBE or HBE combined with CBE for people with KOA were eligible. The primary outcomes were patient-reported: pain, physical disability, and quality of life. The secondary outcomes were performance-based: walking ability, lower limb muscle strength, and balance function. Risk of bias was assessed with the Cochrane Risk of Bias tool and quality of evidence according to the GRADE. Results: Eleven trials involving 956 participants were included. There was no difference in short-term pain (SMD, 0.22 [95% CI, -0.04 to 0.47], p = 0.09; I2 = 0%), physical disability (SMD, 0.17 [95% CI, -0.19 to 0.54], p = 0.35; I2 = 0%), walking ability (SMD, -0.21 [95% CI, -0.64 to 0.22], p = 0.33; I2 = 35%) and lower limb muscle strength (SMD, -0.24 [95% CI, -0.88 to 0.41], p = 0.47; I2 = 69%) between HBE and CBE. HBE combined with CBE has better benefits compared with HBE alone in short-term pain (SMD, 0.89 [95% CI, 0.60 to 1.17], p < 0.001; I2 = 11%) and physical disability (SMD, 0.25 [95% CI, 0.00 to 0.50], p = 0.05; I2 = 0%). Conclusion: Based on limited evidence, HBE is as effective as CBE on short-term pain, physical disability, walking ability, and lower limb muscle strength in people with knee osteoarthritis. Furthermore, combining HBE with CBE may enhance the overall efficacy of the intervention. Systematic review registration: PROSPERO, CRD42023416548.

Immunogenicity of Tetravalent Protein Vaccine SCTV01E-2 against SARS-CoV-2 EG.5 Subvaraint: A Phase 2 Trial.

The Omicron EG.5 lineage of SARS-CoV-2 is currently on a trajectory to become the dominant strain. This phase 2 study aims to evaluate the immunogenicity of SCTV01E-2, a tetravalent protein vaccine, with a specific emphasis on its immunogenicity against Omicron EG.5, comparing it with its progenitor vaccine, SCTV01E (NCT05933512). As of 12 September 2023, 429 participants aged ≥18 years were randomized into the groups SCTV01E (N = 215) and SCTV01E-2 (N = 214). Both vaccines showed increases in neutralizing antibody (nAb) against Omicron EG.5, with a 5.7-fold increase and a 9.0-fold increase in the SCTV01E and SCTV01E-2 groups 14 days post-vaccination, respectively. The predetermined statistical endpoints were achieved, showing that the geometric mean titer (GMT) of nAb and the seroresponse rate (SRR) against Omicron EG.5 were significantly higher in the SCTV01E-2 group than in the SCTV01E group. Additionally, SCTV01E and SCTV01E-2 induced a 5.5-fold and a 5.9-fold increase in nAb against XBB.1, respectively. Reactogenicity was generally mild and transient. No vaccine-related serious adverse events (SAEs), adverse events of special interest (AESIs), or deaths were reported. In summary, SCTV01E-2 elicited robust neutralizing responses against Omicron EG.5 and XBB.1 without raising safety concerns, highlighting its potential as a versatile COVID-19 vaccine against SARS-CoV-2 variants.

Parallel-Forms Reliability and Minimal Detectable Change of the Four Telerehabilitation Version Mobility-Related Function Scales in Stroke Survivors.

OBJECTIVE: To investigate the parallel-forms reliability, minimal detectable change with 95% confidence interval (MDC95), and feasibility of the 4 telerehabilitation version mobility-related function scales: Fugl-Meyer Assessment-lower extremity subscale (Tele-FMA-LE), Berg Balance Scale (Tele-BBS), Tinetti Performance Oriented Mobility Assessment-Gait subscale (Tele-POMA-G), and Rivermead Mobility Index (Tele-RMI). DESIGN: Reliability and agreement study and cross-sectional study. SETTING: Medical center. PARTICIPANTS: Stroke survivors' ability to independently walk 3 meters with assistive devices, age of ≥18 years for participants and their partners, stable physical condition, and absence of cognitive impairment (N=60). INTERVENTIONS: Not applicable. MAIN OUTCOMES MEASURES: Parallel-forms reliability and MDC95 of Tele-FMA-LE, Tele-BBS, Tele-POMA-G, and Tele-RMI. RESULTS: No significant differences (P>.05) were observed among the mean scores of the telerehabilitation version and face-to-face version mobility-related function scales. Intraclass correlation coefficients (ICCs) indicated good reliability for most scales, with Tele-FMA-LE, Tele-BBS, and Tele-RMI scores achieving values of 0.81, 0.78, and 0.84. Tele-POMA-G scores demonstrated moderate reliability (ICC=0.72). Weighted kappa (κw) showed good-to-excellent reliability for most individual items (κw>0.60). The MDCs of the Tele-FMA-LE, Tele-BBS, Tele-POMA-G, and Tele-RMI were 5.84, 8.10, 2.74, and 1.31, respectively. Bland-Altman analysis showed adequate agreement between tele-assessment and face-to-face assessment for all scales. The 5 dimensions affirm the robust feasibility of tele-assessment: assessment time, subjective fatigue perception, overall preference, participant satisfaction, and system usability. CONCLUSIONS: The study demonstrates good parallel-forms reliability, MDC, and promising feasibility of the 4 telerehabilitation version mobility-related function scales (Tele-FMA-LE, Tele-BBS, Tele-POMA-G, and Tele-RMI) in survivors of stroke.

Application of improved GalNAc conjugation in development of cost-effective siRNA therapies targeting cardiovascular diseases.

N-Acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA) therapies have received approval for treating both orphan and prevalent diseases. To improve in vivo efficacy and streamline the chemical synthesis process for efficient and cost-effective manufacturing, we conducted this study to identify better designs of GalNAc-siRNA conjugates for therapeutic development. Here, we present data on redesigned GalNAc-based ligands conjugated with siRNAs against angiopoietin-like 3 (ANGPTL3) and lipoprotein (a) (Lp(a)), two target molecules with the potential to address large unmet medical needs in atherosclerotic cardiovascular diseases. By attaching a novel pyran-derived scaffold to serial monovalent GalNAc units before solid-phase oligonucleotide synthesis, we achieved increased GalNAc-siRNA production efficiency with fewer synthesis steps compared to the standard triantennary GalNAc construct L96. The improved GalNAc-siRNA conjugates demonstrated equivalent or superior in vivo efficacy compared to triantennary GalNAc-conjugated siRNAs.

Measurement method of the RDC for the IPS and FFS-LCD.

The residual direct current (RDC) almost always brings serious image sticking (IS) problems in LCDs and is mainly related to the liquid crystal (LC) and photoaligned polyimide. In this paper, we propose a novel method, to the best of our knowledge, to evaluate the RDC of the FFS-LCDs through an optical measurement system. By this means, the accumulation and release of the ions can be seen distinctly through the transmittance-time curves with the voltage regulation. Hence, it is helpful to compare and analyze the RDC problem of different displays. Moreover, this method possesses the advantage of high efficiency and simplicity in order to benefit the material design in photoaligned polyimide or the LC.

Application of combined preoperative indocyanine green lymphography and ultrasonography for low-pressure vein localization in secondary lymphedema surgery for breast cancer.

BACKGROUND: This study aimed to investigate the value of preoperative indocyanine green (ICG) lymphography combined with ultrasonography for low-pressure vein localization in secondary lymphedema surgery for breast cancer. METHODS: A total of 29 patients who were admitted to the breast surgery department of our hospital from July 2019 to May 2021 were included in this study. All patients received preoperative reverse lymphography and ultrasonography for low-pressure vein in lymphedema surgery. Three arm circumferences were measured before surgery, 6 months after surgery, and 12 months after surgery for comparison with the healthy limb at the same time. RESULTS: Arm circumference at 12 months after surgery was significantly different from those at the preoperative period and 6 months after surgery (P < 0.05). However, this parameter after surgery was still significantly higher than that of the healthy limb (P < 0.05). CONCLUSIONS: The application of preoperative ICG lymphography combined with ultrasonography for low-pressure vein localization before surgery can greatly shorten operation duration by reducing the number of ineffective incisions and improving the probability of vein-lymphatic vessel matching, while ensuring the postoperative efficacy for patients.

Dietary Zinc-Loaded Montmorillonite Supplementation Improves Growth Performance, Diarrhea, Intestinal Barrier Function and Regulating Gut Microbiota in Weaned Piglets.

This experiment was conducted to investigate whether low-dose zinc-loaded montmorillonite (Zn-MMT) could be used as a potential alternative for high-dose conventional ZnO in preventing diarrhea in weaned piglets. In total, 180 piglets were randomly divided to receive either of the three treatments, with six replicates per treatment and 10 piglets per replicate. The treatments were the control group (CT), the Zn-MMT group (ZM), and the ZnO group (ZO). Compared with the CT group, the ZM and ZO groups exhibited increased ADG at 14-28 days and during the whole period (p < 0.05), and a significantly decreased diarrhea rate during the whole period (p < 0.01). The activities of T-AOC and SOD were significantly increased (p < 0.05), whereas the MDA level decreased (p < 0.05) in the serum and colonic mucosa of Zn-MMT- and ZnO-fed piglets. Dietary supplementation with Zn-MMT and ZnO decreased the contents of IFN-γ, TNF-α, IL-1ß, IL-6, DAO, and LPS in the serum and colonic mucosa (p < 0.01), and increased the IL-10 level (p < 0.01). The relative mRNA expressions of TLR-4, claudin 2, Pbd1, and MUC2 were elevated in the colonic mucosa of the Zn-MMT and ZnO groups (p < 0.05). 16S rRNA gene sequencing analysis revealed that the abundances of Proteobacteria and Actinobacteria in the ileum and the populations of Ruminnococcus and Faecalibacterium in the cecum were higher in the CT group than in the other two groups. Collectively, dietary addition of Zn from Zn-MMT was comparable to Zn from ZnO for increasing growth performance, alleviating diarrhea, as well as improving mucosal barrier integrity, and regulating the gut microbiota of weaned piglets.

Accurate prediction of biliary atresia with an integrated model using MMP-7 levels and bile acids.

BACKGROUND: Biliary atresia (BA) is a rare fatal liver disease in children, and the aim of this study was to develop a method to diagnose BA early. METHODS: We determined serum levels of matrix metalloproteinase-7 (MMP-7), the results of 13 liver tests, and the levels of 20 bile acids, and integrated computational models were constructed to diagnose BA. RESULTS: Our findings demonstrated that MMP-7 expression levels, as well as the results of four liver tests and levels of ten bile acids, were significantly different between 86 BA and 59 non-BA patients (P < 0.05). The computational prediction model revealed that MMP-7 levels alone had a higher predictive accuracy [area under the receiver operating characteristic curve (AUC) = 0.966, 95% confidence interval (CI): 0.942, 0.989] than liver test results and bile acid levels. The AUC was 0.890 (95% CI 0.837, 0.943) for liver test results and 0.825 (95% CI 0.758, 0.892) for bile acid levels. Furthermore, bile levels had a higher contribution to enhancing the predictive accuracy of MMP-7 levels (AUC = 0.976, 95% CI 0.953, 1.000) than liver test results. The AUC was 0.983 (95% CI 0.962, 1.000) for MMP-7 levels combined with liver test results and bile acid levels. In addition, we found that MMP-7 levels were highly correlated with gamma-glutamyl transferase levels and the liver fibrosis score. CONCLUSION: The innovative integrated models based on a large number of indicators provide a noninvasive and cost-effective approach for accurately diagnosing BA in children. Video Abstract (MP4 142103 KB).

Muscone inhibits angiotensin II-induced cardiac hypertrophy through the STAT3, MAPK and TGF-ß/SMAD signaling pathways.

BACKGROUND: Muscone is a chemical monomer derived from musk. Although many studies have confirmed the cardioprotective effects of muscone, the effects of muscone on cardiac hypertrophy and its potential mechanisms are unclear.The aim of the present study was to investigate the effect of muscone on angiotensin (Ang) II-induced cardiac hypertrophy. METHODS AND RESULTS: In the present study, we found for the first time that muscone exerted inhibitory effects on Ang II-induced cardiac hypertrophy and cardiac injury in mice. Cardiac function was analyzed by echocardiography measurement, and the degree of cardiac fibrosis was determined by the quantitative real-time polymerase chain reaction (qRT-PCR), Masson trichrome staining and western blot assay. Secondly, qRT-PCR experiment showed that muscone attenuated cardiac injury by reducing the secretion of pro-inflammatory cytokines and promoting the secretion of anti-inflammatory cytokines. Moreover, western blot analysis found that muscone exerted cardio-protective effects by inhibiting phosphorylation of key proteins in the STAT3, MAPK and TGF-ß/SMAD pathways. In addition, CCK-8 and determination of serum biochemical indexes showed that no significant toxicity or side effects of muscone on normal cells and organs. CONCLUSIONS: Muscone could attenuate Ang II-induced cardiac hypertrophy, in part, by inhibiting the STAT3, MAPK, and TGF-ß/SMAD signaling pathways.

The Effect of Web-Based Telerehabilitation Programs on Children and Adolescents With Brain Injury: Systematic Review and Meta-Analysis.

BACKGROUND: Acquired brain injury (ABI) in children and adolescents can lead to motor and executive impairments that often require long-term treatment. The implementation of web-based telerehabilitation therapy at home is a method to improve the functional status of patients. Therefore, we performed a systematic review of the effects of web-based telerehabilitation programs on functional outcomes in children and adolescents with brain injury and supplemented the findings with a meta-analysis. OBJECTIVE: This study evaluated the therapeutic effect of web-based telerehabilitation training on children and adolescents with brain injury to determine whether web-based telerehabilitation therapy improved motor function, executive function, physical activity level, lower limb strength, hand and upper limb function, visual processing skills, and occupational functional performance in children and adolescents with brain injury. METHODS: PubMed, Embase, Scopus, Web of Science, and the Cochrane Library were searched for randomized controlled trials on web-based telerehabilitation programs in children and adolescents with brain injury until December 2022, and the risk of bias was evaluated using the Cochrane Collaboration Tool. Relevant data were extracted, and a meta-analysis was performed using RevMan5.3 software. RESULTS: Overall, 17 studies involving 848 patients were included. Web-based telerehabilitation therapy improved the motor function (standardized mean difference [SMD] 0.29, 95% CI 0.01-0.57; P=.04), physical activity level (SMD 0.42, 95% CI 0.11-0.73; P=.007), lower limb strength (SMD 0.52, 95% CI 0.13-0.90; P=.009), and visual processing skills (SMD 0.26, 95% CI 0.02-0.50; P=.04) of children and adolescents with brain injury. It also improved executive function in letter-number sequencing (SMD 1.26, 95% CI 0.26-2.26; P=.01), attention (SMD 0.38, 95% CI 0.09-0.66; P=.009), and symbol search (SMD 1.18, 95% CI 0.43-1.93, P=.002). CONCLUSIONS: Web-based telerehabilitation therapy improved motor function, physical activity level, lower limb strength, letter-number sequencing, attention, and symbol search, which improved the quality of life in children and adolescents with brain injury. Web-based telerehabilitation programs provide great convenience for children and adolescents with ABI who need long-term treatment and allow them to exercise at home for rehabilitation training. The widespread implementation of remote interventions also provides children and adolescents in remote areas with better access to rehabilitation services. This review provides evidence for the effectiveness of web-based telerehabilitation therapy, but there was heterogeneity in some of the results because of different disease types and intervention programs. Future studies can expand the sample size according to disease type and increase follow-up time according to different exercise prescriptions to further refine the long-term effects of this intervention on various functions of children and adolescents with ABI. TRIAL REGISTRATION: PROSPERO CRD42023421917; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=421917.

Pericyte-derived exosomal miR-210 improves mitochondrial function and inhibits lipid peroxidation in vascular endothelial cells after traumatic spinal cord injury by activating JAK1/STAT3 signaling pathway.

BACKGROUND: Spinal cord injury (SCI) remains a significant health concern, with limited available treatment options. This condition poses significant medical, economic, and social challenges. SCI is typically categorized into primary and secondary injuries. Inflammation, oxidative stress, scar formation, and the immune microenvironment impede axon regeneration and subsequent functional restoration. Numerous studies have shown that the destruction of the blood-brain barrier (BBB) and microvessels is a crucial factor in severe secondary injury. Additionally, reactive oxygen species (ROS)-induced lipid peroxidation significantly contributes to endothelial cell death. Pericytes are essential constituents of the BBB that share the basement membrane with endothelial cells and astrocytes. They play a significant role in the establishment and maintenance of BBB. RESULTS: Immunofluorescence staining at different time points revealed a consistent correlation between pericyte coverage and angiogenesis, suggesting that pericytes promote vascular repair via paracrine signaling. Pericytes undergo alterations in cellular morphology and the transcriptome when exposed to hypoxic conditions, potentially promoting angiogenesis. We simulated an early ischemia-hypoxic environment following SCI using glucose and oxygen deprivation and BBB models. Co-culturing pericytes with endothelial cells improved barrier function compared to the control group. However, this enhancement was reduced by the exosome inhibitor, GW4869. In vivo injection of exosomes improved BBB integrity and promoted motor function recovery in mice following SCI. Subsequently, we found that pericyte-derived exosomes exhibited significant miR-210-5p expression based on sequencing analysis. Therefore, we performed a series of gain- and loss-of-function experiments in vitro. CONCLUSION: Our findings suggest that miR-210-5p regulates endothelial barrier function by inhibiting JAK1/STAT3 signaling. This process is achieved by regulating lipid peroxidation levels and improving mitochondrial function, suggesting a potential mechanism for restoration of the blood-spinal cord barrier (BSCB) after SCI.

Voluntary wheel-running improved pulmonary fibrosis by reducing epithelial mesenchymal transformation.

AIMS: Pulmonary fibrosis seriously affects the health and life quality of patients. Exercise has been shown to have anti-inflammatory and antioxidant effects, but its effect on pulmonary fibrosis is unclear. In this study, the effect and mechanism of exercise on pulmonary fibrosis induced by paraquat were detected. MAIN METHODS: Three data sets were retrieved from GEO data. The biological significance of DEGs generation was determined by GO, KEGG, GSEA, and PPI. Thirty male BALB/C mice were randomly divided into control group, model group and exercise group. H&E staining, Masson staining, Immunohistochemistry and Western blot were used to explore the results. The levels of SOD, CAT, MDA, and GSH in lung tissue were analyzed with detection kits. The levels of inflammatory factors in serum and BALF were measured by ELISA. KEY FINDINGS: Compared with the control group, the infiltration of inflammatory cells and fibrotic lesions were increased in the model group. Compared with the model group, voluntary wheel-running reducing the EMT of alveolar epithelial cells, the activation of the Wnt/ß-catenin signaling pathway and the level of oxidative distress. Moreover, compared to model group, the serum IL-4, IL-10 and IFN-γ were increased, while the serum CXCL1 were decreased, while the levels of CXCL1, IL-6, IL-10, TNF-α and IFN-γ in the bronchoalveolar lavage fluid were decreased in exercise group. SIGNIFICANCE: Voluntary wheel-running reduced inflammatory infiltration and upregulated the expression of antioxidative distress proteins, further to improve the degree of EMT, and ultimately alleviated paraquat induced pulmonary fibrosis.

Advances in immunotherapy for triple-negative breast cancer.

BACKGROUND: Immunotherapy has recently emerged as a treatment strategy which stimulates the human immune system to kill tumor cells. Tumor immunotherapy is based on immune editing, which enhances the antigenicity of tumor cells and increases the tumoricidal effect of immune cells. It also suppresses immunosuppressive molecules, activates or restores immune system function, enhances anti-tumor immune responses, and inhibits the growth f tumor cell. This offers the possibility of reducing mortality in triple-negative breast cancer (TNBC). MAIN BODY: Immunotherapy approaches for TNBC have been diversified in recent years, with breakthroughs in the treatment of this entity. Research on immune checkpoint inhibitors (ICIs) has made it possible to identify different molecular subtypes and formulate individualized immunotherapy schedules. This review highlights the unique tumor microenvironment of TNBC and integrates and analyzes the advances in ICI therapy. It also discusses strategies for the combination of ICIs with chemotherapy, radiation therapy, targeted therapy, and emerging treatment methods such as nanotechnology, ribonucleic acid vaccines, and gene therapy. Currently, numerous ongoing or completed clinical trials are exploring the utilization of immunotherapy in conjunction with existing treatment modalities for TNBC. The objective of these investigations is to assess the effectiveness of various combined immunotherapy approaches and determine the most effective treatment regimens for patients with TNBC. CONCLUSION: This review provides insights into the approaches used to overcome drug resistance in immunotherapy, and explores the directions of immunotherapy development in the treatment of TNBC.

Iguratimod promotes functional recovery after SCI by repairing endothelial cell tight junctions.

Destruction of the blood-spinal cord barrier (BSCB) after spinal cord injury (SCI) is an important factor promoting the progression of the injury. This study addressed how to repair the BSCB in order to promote the repair of injured spinal cords. Iguratimod (IGU), an anti-rheumatic drug, has been approved for clinical use. A spinal cord injury mouse model and TNF-α-stimulated bEnd.3 cells were used to investigate the effect and mechanism of IGU on injured BSCB. An intracerebroventricular osmotic pump was used to administer drugs to the SCI mouse model. The results showed that the SCI mice in the treatment group had better recovery of neurological function than the control group. Examination of the tissue revealed better repair of the BSCB in injured spinal cords after medication. According to the results from the cell model, IGU promoted the expression of tight junction proteins and reduced cell permeability. Further research found that IGU repaired the barrier function by regulating glycolysis levels in the injured endothelial cells. In studying the mechanism, IGU was found to regulate HIF-1α expression through the NF-κB pathway, thereby regulating the expression of the glycolytic enzymes related to endothelial injury. In summary, IGU promoted functional recovery in vivo by repairing the BSCB. In vitro, IGU regulated the level of glycolysis in the damaged endothelium through the NF-κB pathway, thereby repairing the tight junctions between the endothelium. Therefore, IGU may become a potential drug for treating spinal cord injury.

Contributory roles of sarcopenia and myosteatosis in development of overt hepatic encephalopathy and mortality after transjugular intrahepatic portosystemic shunt.

BACKGROUND: Skeletal muscle abnormalities, such as muscle mass depletion (sarcopenia) and fatty infiltration of the muscle (myosteatosis), are frequent complications in cirrhotic patients scheduled for transjugular intrahepatic portosystemic shunt (TIPS). AIM: To investigate the association and predictive value of sarcopenia and myosteatosis for overt hepatic encephalopathy (HE) and mortality after TIPS. METHODS: The records of cirrhotic patients who underwent the TIPS procedure at our hospital between January 2020 and June 2021 were retrospectively retrieved. The transversal psoas muscle thickness (TPMT) and psoas muscle attenuation (PMA) measured from the unenhanced abdominal computed tomography (CT) at the level of the third lumbar vertebrae were used to analyze the sarcopenia and myosteatosis, respectively. The area under curve (AUC) was used to evaluate the discriminative power of TPMT, PMA, and relevant clinical parameters. Fur-thermore, log-rank test was performed to compare the incidence of overt HE and survival between the different groups, and the association of risk factors with overt HE and mortality was analyzed using Cox proportional hazards regression models. RESULTS: A total of 108 patients were collected. Among these patients, 45.4% of patients developed overt HE after TIPS treatment. Furthermore, 32.4% and 28.7% of these patients were identified to have myosteatosis and sarcopenia, respectively. Myosteatosis (51.0% vs 16.9%, P < 0.001) and sarcopenia (40.8 vs 18.6%, P = 0.011) were found to be more frequent in patients with overt HE, when compared to patients without overt HE. The receiver operating characteristics analysis indicated that the predictive power of TPMT and PMA in overt HE (AUC = 0.713 and 0.778, respectively) was higher when compared to the neutrophil lymphocyte ratio (AUC = 0.636). The cumulative incidence of overt HE was the highest in patients with concomitant sarcopenia and myosteatosis, followed by patients with myosteatosis or sarcopenia, while this was the lowest in patients without sarcopenia and myosteatosis. In addition, sarcopenia and myosteatosis were inde-pendently associated with overt HE and mortality after adjusting for confounding factors in post-TIPS patients. CONCLUSION: CT-based estimations for sarcopenia and myosteatosis can be used as reliable predictors for the risk of developing overt HE and mortality in cirrhotic patients after TIPS.

Bioinformatic analysis of the molecular mechanisms underlying the progression of bone defects.

Background: The pathophysiology of bone defects (BDs) is complex, and the treatment for bone defects, in particular massive bone defects, remains a major clinical challenge. Our study was conducted to explore the molecular events related to the progression of bone defects a common clinical condition. Methods: First, microarray data of GSE20980 were obtained from the Gene Expression Omnibus (GEO) database, where 33 samples in total were used to analyze the molecular biological processes related to bone defects. Next, the original data were normalized and differentially expressed genes (DEGs) were identified. Additionally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted. Finally, a protein-protein interaction (PPI) network was constructed and the trends of the different genes were confirmed. Results: Compared with the samples of non-critical size defects (NCSD), the samples of critical size defects (CSD) had 2057, 827, and 1,024 DEGs at 7, 14, and 21 days post injury, respectively. At day 7, the DEGs were significantly enriched in metabolic pathways, at day 14 the DEGs were predominantly enriched in G-protein coupled signaling pathways and the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway, and at day 21 the DEGs were mainly enriched in circadian entrainment and synaptic-related functions. The PPI network showed similar results. Quantitative real-time PCR (qRT-PCR) and western blot (WB) were performed to validate the partial results of sequencing. Conclusion: This study provides some clues about the molecular mechanism behind bone defects, which should contribute to scientific research and clinical treatment of this condition.

α-Stereoselective 3-Deoxy-d-manno-oct-2-ulosonoic Acid (Kdo) O-Glycosylation with a p-Toluenethioglycoside Donor by the (p-Tol)2SO/Tf2O Preactivation Strategy.

A convenient and efficient approach was developed to synthesize α-Kdo O-glycosides based on the Tf2O/(p-Tol)2SO preactivation strategy using peracetylated Kdo thioglycoside as a donor. Under the optimized reaction conditions, several O-glycoside products, including α-(2 → 1)-, α-(2 → 2)-, α-(2 → 3)-, and α-(2 → 6)-Kdo products, were stereoselectively synthesized in high yields. Remarkably, a series of aromatic α-Kdo O-glycosides were first and successfully constructed in high yields. An SN2-like mechanism was revealed by DFT calculations and experimental results.