Effectiveness and safety of early lens extraction during par plana vitrectomy for proliferative diabetes retinopathy with mild cataract: a randomized clinical trial.

AIM: To evaluate the effectiveness and safety of early lens extraction during pars plana vitrectomy (PPV) for proliferative diabetic retinopathy (PDR) compared to those of PPV with subsequent cataract surgery. METHODS: This multicenter randomized controlled trial was conducted in three Chinese hospitals on patients with PDR, aged >45y, with mild cataracts. The participants were randomly assigned to the combined (PPV combined with simultaneously cataract surgery, i.e., phacovitrectomy) or subsequent (PPV with subsequent cataract surgery 6mo later) group and followed up for 12mo. The primary outcome was the change in best-corrected visual acuity (BCVA) from baseline to 6mo, and the secondary outcomes included complication rates and medical expenses. RESULTS: In total, 129 patients with PDR were recruited and equally randomized (66 and 63 in the combined and subsequent groups respectively). The change in BCVA in the combined group [mean, 36.90 letters; 95% confidence interval (CI), 30.35-43.45] was significantly better (adjusted difference, 16.43; 95%CI, 8.77-24.08; P<0.001) than in the subsequent group (mean, 22.40 letters; 95%CI, 15.55-29.24) 6mo after the PPV, with no significant difference between the two groups at 12mo. The overall surgical risk of two sequential surgeries was significantly higher than that of the combined surgery for neovascular glaucoma (17.65% vs 3.77%, P=0.005). No significant differences were found in the photocoagulation spots, surgical time, and economic expenses between two groups. In the subsequent group, the duration of work incapacity (22.54±9.11d) was significantly longer (P<0.001) than that of the combined group (12.44±6.48d). CONCLUSION: PDR patients aged over 45y with mild cataract can also benefit from early lens extraction during PPV with gratifying effectiveness, safety and convenience, compared to sequential surgeries.

Colorectal ALOX15 as a host factor determinant of EPA and DHA effects on colorectal carcinogenesis.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), omega-3 polyunsaturated fatty acids (ω-3 PUFAs) derived from fish oil, are widely used as dietary supplements and FDA-approved treatments for hypertriglyceridemia. However, studies investigating the effects of EPA and DHA on colorectal carcinogenesis (CRC) have yielded conflicting results. The factors that determine these discrepant results remain unknown. Resolvins, oxidative metabolites of EPA and DHA, inhibit key pro-tumorigenic cytokine and chemokine signaling of colorectal cancer (e.g., IL-6, IL-1ß, and CCL2). 15-lipoxygenase-1 (ALOX15), a critical enzyme for resolvin generation is commonly lost during human CRC. Whether ALOX15 expression, as a host factor, modulates the effects of EPA and DHA on CRC remains unknown. Therefore, we evaluated the effects of ALOX15 transgenic expression in colonic epithelial cells on resolvin generation by EPA and DHA and CRC in mouse models representative of human CRC. Our results revealed that 1) EPA and DHA effects on CRC were diverse, ranging from suppressive to promotive, and these effects were occasionally altered by the formulations of EPA and DHA (free fatty acid, ethyl ester, triglyceride); 2) EPA and DHA uniformly suppressed CRC in the presence of intestinal ALOX15 transgenic expression, which induced the production of resolvins, decreased colonic CCL3-5 and CXCL-5 expression and tumor associated macrophages while increasing CD8 T cell abundance in tumor microenvironment; and 3) RvD5, the predominant resolvin produced by ALOX15, inhibited macrophage generation of pro-tumorigenic cytokines. These findings demonstrate the significance of intestinal ALOX15 expression as a host factor in determining the effects of EPA and DHA on CRC. Significance: Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are widely used as dietary supplements and FDA-approved treatments for hypertriglyceridemia. Studies of EPA and DHA effects on colorectal carcinogenesis (CRC) have revealed inconsistencies; factors determining the direction of their impact on CRC have remained unidentified. Our data show that EPA and DHA effects on CRC were divergent and occasionally influenced by their formulations. More importantly, intestinal 15-lipoxgenase-1 (ALOX15) expression modulated EPA and DHA effects on CRC, leading to their consistent suppression of CRC. ALOX15 promoted EPA and DHA oxidative metabolism to generate resolvins, which inhibited key pro-tumorigenic inflammatory cytokines and chemokines, including IL-6. IL-1ß, and CCL2. ALOX15 is therefore an important host factor in determining EPA and DHA effects on CRC.

miR-200b-3p relieved inflammation in patients with heart failure by regulating ZEB1 expression.

BACKGROUND: MicroRNA-200b-3p (miR-200b-3p) plays a pivotal role in inflammatory responses and is implicated in various inflammatory disorders. In this study, we aim to explore the role of miR-200b-3p in the inflammatory response in heart failure (HF). METHODS: Patients diagnosed with heart failure and age-matched healthy controls were studied. Peripheral blood samples from participants were collected for RNA-seq analysis to explore the expression profile of miR-200b-3p. The predictive value of miR-200b-3p and ZEB1 in the prognosis of heart failure was evaluated by analyzing the receiver operating characteristic (ROC) curve. Bioinformatics analysis and double luciferase reporter gene analysis were used to confirm the interaction between miR-200b-3p and ZEB1. Real-time quantitative polymerase chain reaction (QRT-PCR) was used to detect the expression levels of miR-200b-3p and ZEB1 in cardiopulmonary bypass. Additionally, the effects of miR-200b-3p on myocardial cell line (H9c2) injury were evaluated by enzyme-linked immunosorbent assay (ELISA). RESULTS: In the extracardiac circulation of HF patients, miR-200b-3p expression was significantly reduced, while ZEB1 levels were notably elevated. Analysis of the ROC curve revealed that miR-200b-3p and ZEB1 have predictive value in the prognosis of HF patients. The double luciferase reporter experiment demonstrated that miR-200b-3p binds to ZEB1 and inhibits its expression. Overexpression of miR-200b-3p demonstrated a remarkable ability to alleviate inflammation and inhibit the damage to myocardial cells in vivo. CONCLUSION: MiR-200b-3p can target and inhibit ZEB1, reducing the inflammatory reaction of myocardial cells. The miR-200b-3p/ZEB1 network may be helpful in preventing and treating HF.

Regulation of TMEM100 expression by epigenetic modification, effects on proliferation and invasion of esophageal squamous carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a prevalent malignancy with a high morbidity and mortality rate. TMEM100 has been shown to be suppressor gene in a variety of tumors, but there are no reports on the role of TMEM100 in esophageal cancer (EC). AIM: To investigate epigenetic regulation of TMEM100 expression in ESCC and the effect of TMEM100 on ESCC proliferation and invasion. METHODS: Firstly, we found the expression of TMEM100 in EC through The Cancer Genome Atlas database. The correlation between TMEM100 gene expression and the survival of patients with EC was further confirmed through Kaplan-Meier analysis. We then added the demethylating agent 5-AZA to ESCC cell lines to explore the regulation of TMEM100 expression by epigenetic modification. To observe the effect of TMEM100 expression on tumor proliferation and invasion by overexpressing TMEM100. Finally, we performed gene set enrichment analysis using the Kyoto Encyclopaedia of Genes and Genomes Orthology-Based Annotation System database to look for pathways that might be affected by TMEM100 and verified the effect of TMEM100 expression on the mitogen-activated protein kinases (MAPK) pathway. RESULTS: In the present study, by bioinformatic analysis we found that TMEM100 was lowly expressed in EC patients compared to normal subjects. Kaplan-meier survival analysis showed that low expression of TMEM100 was associated with poor prognosis in patients with EC. Then, we found that the demethylating agent 5-AZA resulted in increased expression of TMEM100 in ESCC cells [quantitative real-time PCR (qRT-PCR) and western blotting]. Subsequently, we confirmed that overexpression of TMEM100 leads to its increased expression in ESCC cells (qRT-PCR and western blotting). Overexpression of TMEM100 also inhibited proliferation, invasion and migration of ESCC cells (cell counting kit-8 and clone formation assays). Next, by enrichment analysis, we found that the gene set was significantly enriched in the MAPK signaling pathway. The involvement of TMEM100 in the regulation of MAPK signaling pathway in ESCC cell was subsequently verified by western blotting. CONCLUSION: TMEM100 is a suppressor gene in ESCC, and its low expression may lead to aberrant activation of the MAPK pathway. Promoter methylation may play a key role in regulating TMEM100 expression.

Perioperative versus adjuvant S-1 plus oxaliplatin chemotherapy for stage II/III resectable gastric cancer (RESONANCE): a randomized, open-label, phase 3 trial.

Evidence from Europe shows that perioperative chemotherapy may be beneficial for the treatment of locally advanced gastric cancer, but reliable and robust data is lacking. To rectify this, the phase 3 RESONANCE trial investigated the efficacy and safety of S-1 plus oxaliplatin (SOX) as a perioperative chemotherapy regimen for gastric cancer. This randomized, open-label trial enrolled patients from 19 medical centers with stage II/III resectable gastric cancer who were centrally randomly assigned to either perioperative chemotherapy (PC) arm or adjuvant chemotherapy (AC) arm. Patients in the PC arm received two to four cycles of SOX followed by surgery and four to six cycles of SOX. Patients in the AC arm received upfront surgery and eight cycles of SOX. 386 patients in each group were enrolled and 756 (382 in PC and 374 in AC) were included in the mITT population. The three-year DFS rate was 61.7% in the PC arm and 53.8% in the AC arm (log-rank p = 0.019). The R0 resection rate in the PC arm was significantly higher than that in the AC arm (94.9% vs. 83.7%, p < 0.0001). There was no difference between two arms in surgical outcomes or postoperative complications. Safety-related data were like the known safety profile. In conclusion, from a clinical perspective, this trial indicated a trend towards higher three-year disease-free survival rate with perioperative SOX in stage II/III resectable gastric cancer with well-tolerated toxicity compared to adjuvant SOX, which might provide a theoretical basis for applying perioperative SOX in advanced gastric cancer patients. (ClinicalTrials.gov NCT01583361).

Explaining how childhood physical abuse and physical neglect influence adult depression: An analysis with multiple sequential mediators.

BACKGROUND: Substantial evidence indicates that experiencing physical abuse and neglect during childhood significantly elevates the likelihood of developing depression in adulthood. Nevertheless, there remains a dearth of understanding regarding the mechanisms underpinning this correlation. OBJECTIVE: In this study, we aimed to examine the associations of childhood physical abuse and physical neglect with depression using follow-up data from UK Biobank and quantified the contribution of smoking, insomnia, and BMI in these associations. PARTICIPANTS AND SETTINGS: This study included 144,704 participants (64,168 men and 80,536 women) from UK Biobank, most of whom were white (97 %). METHODS: Physical abuse and physical neglect were measured using two items of Childhood Trauma Screener (CTS). Data on the incidence of depression were obtained from primary care, hospital inpatient records, self-reported medical conditions, and death registries. We used a sequential mediation analysis based on the "g-formula" approach to explore the individual and joint effects of potential mediators. RESULTS: The depression incidence rate was 1.85 per 1000 person-years for men and 2.83 per 1000 person-years for women, respectively. Results of Cox proportional risk regression showed that physical abuse (HRs: 1.39-1.53, P < 0.001) and physical neglect (HRs: 1.43-1.60, P < 0.001) are associated with depression. Smoking, insomnia, and BMI together mediated 3 %-26 % of the associations. CONCLUSIONS: These findings contribute to our understanding of how physical abuse and physical neglect influence depression. Furthermore, a more effective reduction in the burden of depression can be achieved by managing modifiable mediators.

An injectable active hydrogel based on BMSC-derived extracellular matrix for cartilage regeneration enhancement.

Articular cartilage injury impairs joint function and necessitates orthopedic intervention to restore the structure and function of the cartilage. Extracellular matrix (ECM) scaffolds derived from bone marrow mesenchymal stem cells (BMSCs) can effectively promote cell adhesion, proliferation, and chondrogenesis. However, pre-shaped ECM scaffolds have limited applicability due to their poor fit with the irregular surface of most articular cartilage defects. In this study, we fabricated an injectable active ECM hydrogel from autologous BMSCs-derived ECM by freeze-drying, liquid nitrogen milling, and enzymatic digestion. Moreover, our in vitro and in vivo results demonstrated that the prepared hydrogel enhanced chondrocyte adhesion and proliferation, chondrogenesis, cartilage regeneration, and integration with host tissue, respectively. These findings indicate that active ECM components can provide trophic support for cell proliferation and differentiation, restoring the structure and function of damaged cartilage.

Tumor Necrosis Factor α-Induced Protein 8-Like 1 Binds to Protein Arginine Methyltransferase 1 to Suppress the Methylation of Signal Transducer and Activator of Transcription 3 and Cell Growth in Oral Squamous Cell Carcinoma.

The tumor necrosis factor α-induced protein 8 (TIPE, also TNFAIP8 or OXi-α) family is a newly discovered series of proteins involved in immune regulation and tumorigenesis. TIPE1, a member of the TIPE/TNFAIP8/OXi-α family, has emerged as an anticancer-drug target, as it promotes cancer cell apoptosis and inhibits cell proliferation. The current study aimed to systematically reveal that TIPE1 regulates the activity of protein arginine methyltransferase (PRMT)-1 and the subsequent methylation of signal transducer and activator of transcription (STAT)-3 to suppress oral squamous cell carcinoma (OSCC) growth. TIPE1 was down-regulated in the OSCC cell lines (Tca8113, SCC25, Cal27, SCC15, and HSC27). TIPE1 overexpression significantly inhibited cell proliferation, colony formation, in vivo tumorgenicity, and Ki-67 expression in OSCC. TIPE1 interacted with the catalytic region of PRMT1 and inhibited STAT3 methylation. The effects of TIPE1 on OSCC cells were alleviated after PRMT1 overexpression, confirming the importance of this interaction to the tumor-suppressive effects of TIPE1. Together, these findings confirmed that TIPE1 mediated PRMT1 suppression through direct binding to its catalytic domain and subsequently inhibited the methylation and expression of STAT3 in OSCC cells, thereby inhibiting cell growth and tumorgenicity.

Effect of electroacupuncture on behavior and hippocampal inflammatory factors in rats with chronic fatigue syndrome. / ç”µé’ˆå¯¹æ ¢æ€§ç–²åŠ³ç»¼åˆå¾å¤§é¼ è¡Œä¸ºå­¦åŠæµ·é©¬ç‚Žæ€§å› å­çš„å½±å“.

OBJECTIVES: To observe the effect of electroacupuncture (EA) on the changes of behavior and hippocampal inflammatory factors in rats with chronic fatigue syndrome (CFS), so as to explore its possible mechanisms in the treatment of CFS. METHODS: Twenty-seven SD rats were randomly divided into control, model and electroacupuncture (EA) groups (n=9 rats in each group). The CFS model was established by multi-factor compound stress stimulation method. Rats of the EA group received EA (10 Hz) at "Shenting" (GV24) penetrating "Baihui" (GV20), "Dazhui" (GV14) for 15 min, twice a day for 14 days. The general conditions, Morris water maze test, open field test, the exhausted running platform were conducted for determining the rats' locomotor and learning-memory activities. H.E. staining was used to observe the morphological structure of neurons in hippocampal CA1 region. The contents of interleukin (IL)-10, IL-17 and transforming growth factor (TGF) ß1 in hippocampus and serum of rats were detected by ELISA, and the positive expressions of IL-10, IL-17 and TGF-ß1 in hippocampal CA1 region were detected by immunofluorescence staining. RESULTS: Compared with the control group, the score of general condition was increased (P<0.05), the escape latency was prolonged (P<0.05), the number of crossing the original platform was decreased (P<0.05), the numbers of crossing the grid and entering the central area were increased (P<0.05), and the exhaustive treadmill time was shortened (P<0.05) in the model group. The contents of IL-10 in the hippocampus and serum were decreased (P<0.05), while IL-17 and TGF-ß1 contents were increased (P<0.05). The immunofluorescence intensity of IL-10 in the hippocampus was decreased (P<0.05), while the intensity of IL-17 and TGF-ß1 were increased (P<0.05). After treatment, compared with the model group, the score of general condition was decreased (P<0.05), the escape latency was shortened (P<0.05), the number of crossing the original platform was increased (P<0.05), the numbers of crossing the grid and entering the central area were decreased (P<0.05), and the exhaustive treadmill time was prolonged (P<0.05) in the EA group. The contents of IL-10 in the hippocampus and serum were increased (P<0.05), while IL-17 and TGF-ß1 levels were decreased (P<0.05). The immunofluorescence intensity of IL-10 in the hippocampus was increased (P<0.05), while the intensity of IL-17 and TGF-ß1 were decreased (P<0.05). H.E. staining showed that in the model group, the number of neurons in the hippocampus decreased, with disordered arrangement and loose structure, and a small numbers of neuronal nuclei were missing. The degree of tissue damage of the EA group was milder than that of the model group. CONCLUSIONS: EA can alleviate fatigue and spatial learning and memory impairment in CFS rats, which may be related to the regulation of peripheral and central inflammation.

A multifunctional biomimetic nanoplatform for image-guideded photothermal-ferroptotic synergistic osteosarcoma therapy.

Much effort has been devoted to improving treatment efficiency for osteosarcoma (OS). However, most current approaches result in poor therapeutic responses, thus indicating the need for the development of other therapeutic options. This study developed a multifunctional nanoparticle, PDA-MOF-E-M, an aggregation of OS targeting, programmed death targeting, and near-infrared (NIR)-aided targeting. At the same time, a multifunctional nanoparticle that utilises Fe-MOFs to create a cellular iron-rich environment and erastin as a ferroptosis inducer while ensuring targeted delivery to OS cells through cell membrane encapsulation is presented. The combination of PDA-MOF-E-M and PTT increased intracellular ROS and LPO levels and induced ferroptosis-related protein expression. A PDA-based PTT combined with erastin showed significant synergistic therapeutic improvement in the anti-tumour efficiency of the nanoparticle in vitro and vivo. The multifunctional nanoparticle efficiently prevents the osteoclasia progression of OS xenograft bone tumors in vivo. Finally, this study provides guidance and a point of reference for clinical approaches to treating OS.

Caspase-1 activates gasdermin A in non-mammals.

Gasdermins oligomerize to form pores in the cell membrane, causing regulated lytic cell death called pyroptosis. Mammals encode five gasdermins that can trigger pyroptosis: GSDMA, B, C, D, and E. Caspase and granzyme proteases cleave the linker regions of and activate GSDMB, C, D, and E, but no endogenous activation pathways are yet known for GSDMA. Here, we perform a comprehensive evolutionary analysis of the gasdermin family. A gene duplication of GSDMA in the common ancestor of caecilian amphibians, reptiles, and birds gave rise to GSDMA-D in mammals. Uniquely in our tree, amphibian, reptile, and bird GSDMA group in a separate clade than mammal GSDMA. Remarkably, GSDMA in numerous bird species contain caspase-1 cleavage sites like YVAD or FASD in the linker. We show that GSDMA from birds, amphibians, and reptiles are all cleaved by caspase-1. Thus, GSDMA was originally cleaved by the host-encoded protease caspase-1. In mammals the caspase-1 cleavage site in GSDMA is disrupted; instead, a new protein, GSDMD, is the target of caspase-1. Mammal caspase-1 uses exosite interactions with the GSDMD C-terminal domain to confer the specificity of this interaction, whereas we show that bird caspase-1 uses a stereotypical tetrapeptide sequence to confer specificity for bird GSDMA. Our results reveal an evolutionarily stable association between caspase-1 and the gasdermin family, albeit a shifting one. Caspase-1 repeatedly changes its target gasdermin over evolutionary time at speciation junctures, initially cleaving GSDME in fish, then GSDMA in amphibians/reptiles/birds, and finally GSDMD in mammals.

Safety and feasibility of minimally invasive gastrectomy after neoadjuvant immunotherapy for locally advanced gastric cancer: a propensity score-matched analysis in China.

Background: The effect of neoadjuvant immunotherapy on minimally invasive gastrectomy (MIG) for locally advanced gastric cancer (LAGC) remains controversial. This study aimed to compare short-term outcomes between MIG after neoadjuvant chemo-immunotherapy (NICT-MIG) and MIG after neoadjuvant chemotherapy alone (NCT-MIG), and determine risk factors for post-operative complications (POCs). Methods: This retrospective study included clinicopathologic data from 193 patients who underwent NCT-MIG or NICT-MIG between January 2020 and February 2023 in the Department of General Surgery, Chinese People's Liberation Army General Hospital First Medical Center (Beijing, China). Propensity score-matched analysis at a ratio of 1:2 was performed to reduce bias from confounding patient-related variables and short-term outcomes were compared between the two groups. Results: The baseline characteristics were comparable between 49 patients in the NICT-MIG group and 86 patients in the NCT-MIG group after propensity score matching. Objective and pathologic complete response rates were significantly higher in the NICT-MIG group than in the NCT-MIG group (P < 0.05). The overall incidence of treat-related adverse events, intraoperative bleeding, operation time, number of retrieved lymph nodes, time to the first flatus, post-operative duration of hospitalization, overall morbidity, and severe morbidity were comparable between the NCT-MIG and NICT-MIG groups (P > 0.05). By multivariate logistic analysis, estimated blood loss of >200 mL (P = 0.010) and prognostic nutritional index (PNI) score of <45 (P = 0.003) were independent risk factors for POCs after MIG following neoadjuvant therapy. Conclusions: Safety and feasibility of NICT were comparable to those of NCT in patients undergoing MIG for LAGC. Patients with an estimated blood loss of >200 mL or a PNI score of <45 should be carefully evaluated for increased POCs risk.

Nanodrug modified with engineered cell membrane targets CDKs to activate aPD-L1 immunotherapy against liver metastasis of immune-desert colon cancer.

Immunotherapy based on the PD-1/PD-L1 axis blockade has no benefit for patients diagnosed with colon cancer liver metastasis (CCLM) for the microsatellite stable/proficient mismatch repair (MSS/pMMR)) subtype, which is known as an immune-desert cancer featuring poor immunogenicity and insufficient CD8+ T cell infiltration in the tumor microenvironment. Here, a multifunctional nanodrug carrying a cyclin-dependent kinase (CDK)1/2/5/9 inhibitor and PD-L1 antibody is prepared to boost the immune checkpoint blockade (ICB)-based immunotherapy against MSS/pMMR CCLM via reversing the immunosuppressive tumor microenvironment. To enhance the MSS/pMMR CCLM-targeting efficacy, we modify the nanodrug with PD-L1 knockout cell membrane of this colon cancer subtype. First, CDKs inhibitor delivered by nanodrug down-regulates phosphorylated retinoblastoma and phosphorylated RNA polymerase II and meanwhile arrests the G2/M cell cycle in CCLM to promote immunogenic signal release, stimulate dendritic cell maturation, and enhance CD8+ T cell infiltration. Moreover, CDKi suppresses the secretion of immunosuppressive cytokines in tumor-associated myeloid cells sensitizing ICB therapy in CCLM. Notably, the great efficacy to activate immune responses is demonstrated in the patient-derived xenograft model and the patient-derived organoid model as well, revealing a clinical application potential. Overall, our study represents a promising therapeutic approach for targeting liver metastasis, remolding the tumor immune microenvironment (TIME), and enhancing the response of MSS/pMMR CCLM to boost ICB immunotherapy.

Comparison of Clinical Characteristics, Therapy, and Short-Term Prognosis between Blunt and Penetrating Abdominal Trauma: A Multicentric Retrospective Cohort Study.

Objective: Large-scale studies on the characteristics and management of abdominal trauma in megacities in China are lacking. The aim of this study was to analyze and present the clinical patterns and treatment status of abdominal trauma in regional medical centers. Methods: Cases of abdominal trauma treated at seven medical centers in Beijing from 2010 to 2021 were collected. Clinical information about age, sex, injury cause, geographic distribution, abbreviated injury scale/injury severity score (AIS/ISS) value, injury-hospital time, preoperative time, surgically identified organ injuries, type of surgery, causes of reoperation and 90-day mortality was included in this study. Clinical characteristics, treatment methods, and short-term prognoses (90-days survival) were compared between blunt abdominal trauma (BAT) and penetrating abdominal trauma (PAT) cases. Non-normally distributed data are described as medians (IQR), and the Mann‒Whitney U test was performed; qualitative data were analyzed using the X2 test. Univariate and multivariate survival analyses were performed by the Cox proportional hazards model. Results: A total of 553 patients (86.98% male) with a median age of 36.50 (27.00-48.00) years were included. The BAT group had a significantly higher proportion of serious injury (P=0.001), lower initial hemoglobin level (P=0.001), and a lower laparoscopy surgery rate (P=0.044) compared to the PAT group. Additionally, more BAT cases were from the area around Beijing (P=0.008) and a longer injury-regional hospital time (10.47 (5.18-22.51) hours vs. 7.00 (3.80-15.38) hours, P=0.001). In the hollow viscus injury subgroup, the BAT group had a significantly longer injury-regional hospital time and preoperative time compared to the PAT group (injury-regional hospital time: 10.23 (6.00-21.59) hours vs. 7.07 (3.99-13.85) hours, P=0.002; preoperative time: 3.02 (2.01-5.58) hours vs. 2.81 (1.85-3.63) hours, P=0.047). The overall 90-day mortality was 11.9%, and longer injury-regional hospital time (HR: 1.01, 95% CI: 1.00-1.02, P=0.008), receipt of ICU treatment (HR: 4.69, 95% CI: 2.54-8.65, P=0.001), and severe ISSs (ISS > 25 vs. ISS < 16, HR: 2.78, 95% CI: 1.38-5.601, P=0.004) had a worse impact on survival. Conclusion: More patients with BAT were transferred to higher-level hospital, leading to significantly longer prehospital and preoperation time. In the subgroup of hemodynamically stable individuals, more patients with BAT experienced hollow viscus injuries. For those patients, aggressive diagnostic laparoscopic exploration may be beneficial. Patients with longer injury-regional hospital intervals, the need for ICU care, and higher injury severity scores (ISSs) suffered from worse prognoses.

Profiling of aberrant sialylated N-glycans in hepatocellular carcinoma by liquid chromatography mass spectrometry.

BACKGROUND: Aberrant sialylation is closely associated with the tumorigenesis, progression, and metastasis, and may be of importance for disease diagnosis. However, the analysis of altered expression of sialylated glycans (SGs) in blood is particularly challenging due to the low content and poor ionization efficiency of sialylated glycans in mass spectrometry. METHODS: An analytical strategy based on enrichment of SGs, liquid chromatography-high resolution mass spectrometric detection, and automatic glycan annotation was developed to profile the sialylated N-glycome in serum. The enrichment of sialylated glycans was accomplished using cationic cotton via electrostatic and hydrogen interaction. Using partial least squares-discriminant analysis (PLS-DA), the approach was applied for nontarget screening and profiling of aberrant sialylated N-glycans in hepatocellular carcinoma (HCC). RESULTS: 55 SGs were identified in human serum, and three important SGs (SG35, SG45, and SG46) were screened to have good diagnostic specificity for HCC. Their areas under the receiver operating characteristic (ROC) curve (AUC) were higher than α-fetoprotein (AFP)'s (AUC = 0.85), at 0.88, 0.87, and 0.91, respectively. When three SGs are combined, the diagnostic specificity for HCC may increase to 94 %. The fact that SGs biomarkers are sensitive to AFP-Negative HCC is very noteworthy. CONCLUSIONS: The method significantly advanced the search for sialylated glycan-based cancer biomarkers. In comparison to traditional indicators like AFP and imaging tools, SGs showed a higher diagnostic sensitivity for HCC.

Evaluation of the Protective Effect of Compound Kushen Injection Against Radiation- induced Pneumonitis in Mice.

Background Radiation-induced lung injury (RILI) via inflammation is a common adverse effect of thoracic radiation that negatively impacts patient quality of life and survival. Compound kushen injection (CKI), a botanical drug treatment, was examined for its ability to reduce RILI, and inflammatory responses and improve survival in mice exposed total lung irradiation (TLI). CKI's specific mechanisms of action were also evaluated. Methods C3H mice underwent TLI and were treated with CKI (2, 4, or 8 mL/kg) intraperitoneally once a day for 8 weeks. The effects of CKI on survival were estimated by Kaplan-Meier survival analysis and compared by log-rank test. RILI damage was evaluated by histopathology and micro-computed tomography (CT). Inflammatory cytokines and cyclooxygenase metabolites were examined by IHC staining, western blot, and ELISA. Results Pre-irradiation treatment with 4 or 8 mL/kg CKI starting 2 weeks before TLI or concurrent treatment with 8 mL/kg CKI were associated with a significantly longer survival compared with TLI vehicle-treated group ( P < 0.05). Micro-CT images evaluations showed that concurrent treatment with 8 mL/kg CKI was associated with significantly lower incidence of RILI ( P < 0.05). Histological evaluations revealed that concurrent TLI treatment of CKI (4 and 8 mL/kg) significantly reduced lung inflammation (p < 0.05). Mechanistic investigation showed that at 72 hours after radiation, TLI plus vehicle mice had significantly elevated serum IL6, IL17A, and TGF-ß levels compared with non-irradiated, age-matched normal mice; in contrast, levels of these cytokines in mice that received TLI plus CKI treatment were lower than those in the TLI plus vehicle-treated mice ( P < 0.05) and similar to the nonirradiated mice. IHC staining showed that the CKI treatment led to a reduction of TGF-ß positive cells in the lung tissues of TLI mice (P < 0.01). The concurrent CKI with TLI treatment group had a significant reduction in COX-2 activity and COX-2 metabolites compared with the TLI vehicle-treated group ( P < 0.05). Conclusions These data suggest that CKI treatment was associated with reduced radiation-induced inflammation in lung tissues, reduced RILI, and improved survival. Further investigation of CKI in human clinical trials as a potential radioprotector against RILI to improve patients' quality of life and survival is warranted.

The STING-mediated antiviral effect of fucoidan from Durvillaea antarctica.

Fucoidans have attracted increasing attention due to their minimal toxicity and various biological activities, such as antioxidant, anti-inflammatory, anti-tumor and immunomodulatory effects. In this study, the antiviral effect and mechanism of fucoidan (FU) derived from Durvillaea antarctica were explored in vitro. The results demonstrated that FU effectively inhibited the infection of both RNA virus (VSV) and DNA virus (HSV-1). The potential antiviral mechanism of FU is to trigger the production of type I IFN (IFN-I) and IFN-stimulated genes dependent on the cytoplasmic DNA adaptor STING (stimulator of interferon genes), and to enhance innate immune response via activating the STING-TBK1-IRF3 pathway. FU possesses the potential to be an antiviral and immunomodulatory agent in the future.

Exploration of anti­osteosarcoma activity of asiatic acid based on network pharmacology and in vitro experiments.

Osteosarcomas are malignant bone tumors that typically originate in the epiphyses of the long bones of the extremities in adolescents. Asiatic acid has been reported to possess anti­inflammatory, neuroprotective, antidiabetic, antitumor and antimicrobial activities. The present study used a combination of network pharmacological prediction and in vitro experimental validation to explore the potential pharmacological mechanism of asiatic acid against osteosarcoma. A total of 78 potential asiatic acid targets in osteosarcoma were identified using databases. Kyoto Encyclopedia of Genes and Genomes analysis indicated that the PI3K/AKT and MAPK signaling pathways are essential in the treatment of osteosarcoma with asiatic acid. Molecular docking revealed binding of asiatic acid to EGFR, Caspase­3, ESR1, HSP90AA1, IL­6 and SRC proteins. asiatic acid inhibited proliferation through G2/M cell cycle arrest in osteosarcoma cells. In addition, asiatic acid induced mitochondria­dependent apoptosis as demonstrated by increases in Bax and VDAC1 expression, and a decrease in Bcl­2 protein expression. The increased autophagosomes, increased LC3­II/I ratios and decreased p62 expression in the treatment group indicated that asiatic acid triggered autophagy. In addition, asiatic acid decreased the levels of phosphorylated (p­)PI3K/PI3K and p­AKT/AKT, increased reactive oxygen species (ROS) and upregulated the levels of p­ERK1/2/ERK1/2, p­p38/p38 and p­JNK/JNK in osteosarcoma cells. These results demonstrated that asiatic acid inhibited osteosarcoma cells proliferation by inhibiting PI3K/AKT and activating ROS/MAPK signaling pathways, suggesting asiatic acid is a potential agent against osteosarcoma.