Gut bacteria-driven homovanillic acid alleviates depression by modulating synaptic integrity.

The gut-brain axis is implicated in depression development, yet its underlying mechanism remains unclear. We observed depleted gut bacterial species, including Bifidobacterium longum and Roseburia intestinalis, and the neurotransmitter homovanillic acid (HVA) in individuals with depression and mouse depression models. Although R. intestinalis does not directly produce HVA, it enhances B. longum abundance, leading to HVA generation. This highlights a synergistic interaction among gut microbiota in regulating intestinal neurotransmitter production. Administering HVA, B. longum, or R. intestinalis to mouse models with chronic unpredictable mild stress (CUMS) and corticosterone (CORT)-induced depression significantly improved depressive symptoms. Mechanistically, HVA inhibited synaptic autophagic death by preventing excessive degradation of microtubule-associated protein 1 light chain 3 (LC3) and SQSTM1/p62 proteins, protecting hippocampal neurons' presynaptic membrane. These findings underscore the role of the gut microbial metabolism in modulating synaptic integrity and provide insights into potential novel treatment strategies for depression.

Enterovirus 71 Activates Plasmacytoid Dendritic Cell-Dependent PSGL-1 Binding Independent of Productive Infection.

Enterovirus 71 (EV71) is a significant causative agent of hand, foot, and mouth disease, with potential serious neurologic complications or fatal outcomes. The lack of effective treatments for EV71 infection is attributed to its elusive pathogenicity. Our study reveals that human plasmacytoid dendritic cells (pDCs), the main type I IFN-producing cells, selectively express scavenger receptor class B, member 2 (SCARB2) and P-selectin glycoprotein ligand 1 (PSGL-1), crucial cellular receptors for EV71. Some strains of EV71 can replicate within pDCs and stimulate IFN-α production. The activation of pDCs by EV71 is hindered by Abs to PSGL-1 and soluble PSGL-1, whereas Abs to SCARB2 and soluble SCARB2 have a less pronounced effect. Our data suggest that only strains binding to PSGL-1, more commonly found in severe cases, can replicate in pDCs and induce IFN-α secretion, highlighting the importance of PSGL-1 in these processes. Furthermore, IFN-α secretion by pDCs can be triggered by EV71 or UV-inactivated EV71 virions, indicating that productive infection is not necessary for pDC activation. These findings provide new insights into the interaction between EV71 and pDCs, suggesting that pDC activation could potentially mitigate the severity of EV71-related diseases.

Identification and Verification of Novel Biomarkers Involving Rheumatoid Arthritis with Multimachine Learning Algorithms: An In Silicon and In Vivo Study.

Background: Rheumatoid arthritis (RA) remains one of the most prevalent chronic joint diseases. However, due to the heterogeneity among RA patients, there are still no robust diagnostic and therapeutic biomarkers for the diagnosis and treatment of RA. Methods: We retrieved RA-related and pan-cancer information datasets from the Gene Expression Omnibus and The Cancer Genome Atlas databases, respectively. Six gene expression profiles and corresponding clinical information of GSE12021, GSE29746, GSE55235, GSE55457, GSE77298, and GSE89408 were adopted to perform differential expression gene analysis, enrichment, and immune component difference analyses of RA. Four machine learning algorithms, including LASSO, RF, XGBoost, and SVM, were used to identify RA-related biomarkers. Unsupervised cluster analysis was also used to decipher the heterogeneity of RA. A four-signature-based nomogram was constructed and verified to specifically diagnose RA and osteoarthritis (OA) from normal tissues. Consequently, RA-HFLS cell was utilized to investigate the biological role of CRTAM in RA. In addition, comparisons of diagnostic efficacy and biological roles among CRTAM and other classic biomarkers of RA were also performed. Results: Immune and stromal components were highly enriched in RA. Chemokine- and Th cell-related signatures were significantly activated in RA tissues. Four promising and novel biomarkers, including CRTAM, PTTG1IP, ITGB2, and MMP13, were identified and verified, which could be treated as novel treatment and diagnostic targets for RA. Nomograms based on the four signatures might aid in distinguishing and diagnosing RA, which reached a satisfactory performance in both training (AUC = 0.894) and testing (AUC = 0.843) cohorts. Two distinct subtypes of RA patients were identified, which further verified that these four signatures might be involved in the immune infiltration process. Furthermore, knockdown of CRTAM could significantly suppress the proliferation and invasion ability of RA cell line and thus could be treated as a novel therapeutic target. CRTAM owned a great diagnostic performance for RA than previous biomarkers including MMP3, S100A8, S100A9, IL6, COMP, LAG3, and ENTPD1. Mechanically, CRTAM could also be involved in the progression through immune dysfunction, fatty acid metabolism, and genomic instability across several cancer subtypes. Conclusion: CRTAM, PTTG1IP, ITGB2, and MMP13 were highly expressed in RA tissues and might function as pivotal diagnostic and treatment targets by deteriorating the immune dysfunction state. In addition, CRTAM might fuel cancer progression through immune signals, especially among RA patients.

The active components and potential mechanisms of Wuji Wan in the treatment of ethanol-induced gastric ulcer: An integrated metabolomics, network pharmacology and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Wuji Wan (WJW) is a traditional Chinese medicine formula that can be found in the "Prescriptions of Taiping Benevolent Dispensary" that has been employed in treating gastric discomfort, burning epigastric pain, and gastric reflux for hundreds of years and has shown promise for treating gastric ulcers (GUs). However, the active components and mechanism of action against GUs remain unclear. AIM OF THE STUDY: The aim of this study was to explore the active components of WJW and elucidate the underlying mechanism involved in treating GUs. MATERIALS AND METHODS: Initially, cell viability was measured by a cell counting kit 8 (CCK-8) assay to evaluate the efficacy of WJW-containing serum in vitro. The gastric ulcer index, ulcer inhibition rate, hematoxylin and staining (H&E), and periodic acid-Schiff (PAS) staining were used to evaluate the therapeutic effect of WJW in vivo. Subsequently, the levels of inflammatory factors and oxidative stress factors were determined using an enzyme-linked immunosorbent assays (ELISA) on in vitro and in vivo samples. Additionally, UPLC-Q Exactive Plus Orbitrap HRMS was used to analyze the components that were absorbed into the blood of WJW and its metabolites. Network pharmacology and metabolomics were subsequently used to identify the targets and pathways. Real-time quantitative PCR (RT‒qPCR) and Western blotting were used to verify the mRNA and protein levels of the key targets and pathways. Finally, the active components were identified by molecular docking to verify the binding stability of the components and key targets. RESULTS: WJW-containing serum ameliorated ethanol-induced damage in GES-1 cells and promoted cell healing. WJW-containing serum reduced IL-6, TNF-α, MDA, and LDH levels while increasing IL-10, SOD, and T-AOC levels in the cells. Moreover, WJW treatment resulted in decreased IL-6, TNF-α, and MDA levels and increased IL-10, SOD, PGE2, and NO levels in GUs rats. In addition, eight components of WJW were absorbed into the blood. The network pharmacology results revealed 192 common targets for blood entry components and GUs, and KEGG analysis revealed that apoptosis signaling pathways were the main pathways involved in WJW activity against GUs. Metabolomic screening was used to identify 13 differential metabolites. There were 23 common targets for blood entry components, GUs, and differential metabolites, with the key targets TNF (TNF-α), AKT1, PTGS2 (COX2) and MAPK1. WJW significantly inhibited the expression of Bax, Caspase-9, Caspase-3, cleaved Caspase-9, cleaved Caspase-3, TNF-α, COX2, and p-p44/42 MAPK while promoting the expression of Bcl-2 and p-AKT1. Molecular docking revealed that the active components of WJW for the treatment of GUs are berberine, palmatine, coptisine, evodiamine, rutaecarpine, evocarpine, and paeoniflorin. CONCLUSIONS: WJW treatment reduces inflammation and oxidative stress injury and inhibits apoptosis signaling pathways. The main active components are berberine, palmatine, coptisine, evodiamine, rutaecarpine, evocarpine, and paeoniflorin. In this paper, we provide a new strategy for exploring the active components of traditional Chinese medicine formulas for the treatment of diseases based on target mechanisms.

Hyodeoxycholic acid alleviates non-alcoholic fatty liver disease through modulating the gut-liver axis.

Non-alcoholic fatty liver disease (NAFLD) is regarded as a pandemic that affects about a quarter of the global population. Recently, host-gut microbiota metabolic interactions have emerged as distinct mechanistic pathways implicated in the development of NAFLD. Here, we report that a group of gut microbiota-modified bile acids (BAs), hyodeoxycholic acid (HDCA) species, are negatively correlated with the presence and severity of NAFLD. HDCA treatment has been shown to alleviate NAFLD in multiple mouse models by inhibiting intestinal farnesoid X receptor (FXR) and upregulating hepatic CYP7B1. Additionally, HDCA significantly increased abundances of probiotic species such as Parabacteroides distasonis, which enhances lipid catabolism through fatty acid-hepatic peroxisome proliferator-activated receptor alpha (PPARα) signaling, which in turn upregulates hepatic FXR. These findings suggest that HDCA has therapeutic potential for treating NAFLD, with a unique mechanism of simultaneously activating hepatic CYP7B1 and PPARα.

Multi-omics studies reveal ameliorating effects of physical exercise on neurodegenerative diseases.

Introduction: Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, are heavy burdens to global health and economic development worldwide. Mounting evidence suggests that exercise, a type of non-invasive intervention, has a positive impact on the life quality of elderly with neurodegenerative diseases. X-omics are powerful tools for mapping global biochemical changes in disease and treatment. Method: Three major databases were searched related to current studies in exercise intervention on neurodegenerative diseases using omics tools, including metabolomics, metagenomics, genomics, transcriptomics, and proteomics. Result: We summarized the omics features and potential mechanisms associated with exercise and neurodegenerative diseases in the current studies. Three main mechanisms by which exercise affects neurodegenerative diseases were summed up, including adult neurogenesis, brain-derived neurotrophic factor (BDNF) signaling, and short-chain fatty acids (SCFAs) metabolism. Conclusion: Overall, there is compelling evidence that exercise intervention is a feasible way of preventing the onset and alleviating the severity of neurodegenerative diseases. These studies highlight the importance of exercise as a complementary approach to the treatment and intervention of neurodegenerative diseases in addition to traditional treatments. More mechanisms on exercise interventions for neurodegenerative diseases, the specification of exercise prescriptions, and differentiated exercise programs should be explored so that they can actually be applied to the clinic.

Investigation and analysis of four countries' recalls of osteosynthesis implants and joint replacement implants from 2011 to 2021.

BACKGROUND: Medical devices are used in almost all orthopedic surgical subspecialties, and the frequency of adverse events is increasing, which should not be ignored. To provide suggestions on how to avoid implant recalls from the perspective of manufacturers, medical institutions and supervisions, as well as how to respond promptly to adverse events. METHODS: The research extracted recalls of osteosynthesis implants and joint replacement implants from January 1, 2011, to June 30, 2021, in the CNMPA, FDA, HC and ATGA websites and collected the information on device name, recall time, recall class, recall manufacturer, device classification and affected areas. Moreover, the McKinsey 7S model and fishbone diagram were used to analyze recall reasons. RESULTS: A total of 315 cases of osteosynthesis implants and 286 cases of joint replacement implants were reported in China, the USA, Canada and Australia. The recalls number from 2016 to 2021 was more than that from 2011 to 2015 for osteosynthesis implant (p = 0.012) and joint replacement implant (p = 0.002), and both mainly focused on class II (76.19% and 78.32%). There were statistical differences in the four countries for both implants (p = 0.000), especially osteosynthesis implant between China and the USA (p = 0.000), China and Canada (p = 0.001), the USA and Australia (p = 0.002), and joint replacement implant between China and Australia (p = 0.000). CONCLUSIONS: To avoid the recalls of such implants, manufacturers should strictly select implant materials and components, develop detailed labels and instructions, severely control the packaging process and establish the integrity of medical device data. Medical institutions should standardize procurement procedures, use qualified equipment and train medical workers. It also requires supervisions to conduct premarket safety assessments. In addition, regulators should strengthen supervision and establish reporting systems to deal with the occurrence of adverse events promptly.

Mesenchymal stem cells improve liver fibrosis and protect hepatocytes by promoting microRNA-148a-5p-mediated inhibition of Notch signaling pathway.

BACKGROUND: Mesenchymal stem cells (MSCs) are considered to be a potential therapeutic tool for liver fibrosis. Inhibiting the activation of hepatic stellate cells (HSCs) and protecting hepatocytes are important mechanisms for the anti-fibrotic effect of MSCs. However, how MSCs inhibit liver fibrosis by regulating the expression of microRNAs (miRNAs) has not been fully clarified. METHODS: Transforming growth factor-ß1 (TGF-ß1)-activated HSCs LX-2 were single cultured or co-cultured with human umbilical cord mesenchymal stem cells (HUC-MSCs). High-throughput sequencing was used to evaluate the differentially expressed microRNAs (DEMs) between the two groups. Quantitative real-time PCR (qRT-PCR), Western blot, and transfection experiments were used to investigate and screen the most significantly up-regulated DEM. Bioinformatics analysis was used to predict the target mRNAs and the potential functions of the DEM. The possible mechanism of HUC-MSCs against liver fibrosis was analyzed by co-culture experiment of HUC-MSCs with LX-2 cells, and HUC-MSCs treatment of Bile duct ligation (BDL)-induced liver fibrosis in mice. Finally, the mechanism of the DEM regulating liver fibrosis was confirmed in human liver fibrosis specimens. RESULTS: MicroRNA-148a-5p (miR-148a-5p) was the most significantly up-regulated DEM in activated LX-2 cells co-cultured with HUC-MSCs compared with LX-2 cells single cultured. Up-regulation of the expression of miR-148a-5p in activated LX-2 cells could significantly inhibit the expression of hepatic fibrosis markers α-SMA and Col1α1. Notch2 was one target gene of miR-148a-5p. Co-cultured with HUC-MSCs could inhibit the activation of LX-2 cells by inhibiting the expression of the Notch2 and the Notch signaling pathway. In addition, HUC-MSCs treatment could up-regulate the expression of miR-148a-5p in liver tissue and hepatocytes, promote the proliferation and avoid the apoptosis of hepatocytes, and reduce the degree of fibrosis by inhibiting expression of the Notch2 and the Notch signaling pathway in BDL-induced liver fibrosis mice. Moreover, miR-148a-5p was down-regulated and Notch2 was up-regulated in fibrotic human liver tissues compared with the normal livers. CONCLUSIONS: HUC-MSCs treatment could inhibit HSCs activation, protect hepatocytes, and alleviate BDL-induced liver fibrosis in mice by up-regulating the expression of miR-148-5p and inhibiting the Notch signaling pathway. The down-regulation of miR-148-5p and up-regulation of Notch2 could be used as biomarkers to monitor the progression of liver fibrosis.

Efficacy of Endoscopic Intervention plus Growth Inhibitor and Patient Self-Management in the Treatment of Esophagogastric Variceal Bleeding in Cirrhosis.

Objective: To assess the efficacy of endoscopic intervention plus growth inhibitor and patient self-management in the treatment of esophagogastric variceal bleeding. Methods: Between January 2019 and December 2021, 60 patients with esophagogastric variceal bleeding treated in our hospital were assessed for eligibility and randomly recruited. They were concurrently and randomly assigned at a ratio of 1 : 1 to receive either endoscopic intervention plus growth inhibitor (control group) or endoscopic intervention plus growth inhibitor and patient self-management (observation group). The endpoint is clinical efficacy. Results: All eligible patients showed a similar time of hemostasis, success rate of hemostasis, rebleeding rate, and disappearance rate of varicose veins (P > 0.05). Endoscopic intervention plus growth inhibitor and patient self-management were associated with a lower incidence of complication (6.67%, including 1 (3.34%) case of ulcer and 1 (3.34%) case of fever) than endoscopic intervention plus growth inhibitor (26.67%, including 3 (10.00%) cases of ulcer, 2 (6.67%) cases of retrosternal pain, and 3 (10.00%) cases of fever) (P < 0.05). Patients in the observation group had significantly higher life satisfaction scores (25.17 ± 4.28 and 23.68 ± 5.17) than those in the control group (22.13 ± 2.24 and 18.12 ± 3.28) (P < 0.05). A decrease in life satisfaction scores was observed at 6 months after treatment, and the patients given patient self-management showed a higher satisfaction (P < 0.05). Conclusion: Endoscopic intervention plus growth inhibitor and patient self-management yielded remarkable clinical efficacy in the treatment of esophagogastric variceal bleeding as it reduces the incidence of complication and enhances the life satisfaction of patients, and so it is worthy of clinical promotion.

A Sternoclavicular Joint-Specific Plate for the Displaced Medial-End Clavicle Fracture.

Objectives: This study aimed to introduce a sternoclavicular joint (SCJ)-specific plate for the treatment of medial-end clavicle fracture and evaluate the clinical and radiological results of this method. Methods: From January 2006 to December 2020, 31 patients with displaced medial-end clavicle fractures were included in this study, with 8 patients with accompanying SCJ dislocation. Abduction and forward elevation of the shoulder, the Visual Analogue Scale (VAS), and the American Shoulder and Elbow Surgeons Score (ASES) were used for evaluation before index surgery and at the latest follow-up. Results: After an average of 98.5 (range, 13 to 171) months, the mean VAS significantly decreased from 6.8 ± 1.0 preoperatively to 0.9 ± 0.8 at the latest follow-up (P < 0.001). The mean ASES score significantly increased from 34.3 ± 7.8 preoperatively to 90.2 ± 4.9 at the latest follow-up (P < 0.001). The mean abduction of the shoulder significantly increased from 72.1 ± 6.6 preoperatively to 169.5 ± 8.5 at the latest follow-up (P < 0.001). The mean forward elevation of the shoulder significantly increased from 97.1 ± 11.0 preoperatively to 163.1 ± 11.5 at the latest follow-up (P < 0.001). The union of all fractures was achieved, and all implants were removed. No loose or breakage of implants was observed. No vascular or nerve damage occurred during the operation. Conclusions: This SCJ-specific plate provided excellent long-term results for the treatment of displaced medial-end clavicle fractures and was an alternative implant for medial-end clavicle fractures with or without small or comminuted medial fragments, especially those associated with SCJ dislocation.

Gut microbiota-bile acid crosstalk contributes to the rebound weight gain after calorie restriction in mice.

Calorie restriction (CR) and fasting are common approaches to weight reduction, but the maintenance is difficult after resuming food consumption. Meanwhile, the gut microbiome associated with energy harvest alters dramatically in response to nutrient deprivation. Here, we reported that CR and high-fat diet (HFD) both remodeled the gut microbiota with similar microbial composition, Parabacteroides distasonis was most significantly decreased after CR or HFD. CR altered microbiota and reprogramed metabolism, resulting in a distinct serum bile acid profile characterized by depleting the proportion of non-12α-hydroxylated bile acids, ursodeoxycholic acid and lithocholic acid. Downregulation of UCP1 expression in brown adipose tissue and decreased serum GLP-1 were observed in the weight-rebound mice. Moreover, treatment with Parabacteroides distasonis or non-12α-hydroxylated bile acids ameliorated weight regain via increased thermogenesis. Our results highlighted the gut microbiota-bile acid crosstalk in rebound weight gain and Parabacteroides distasonis as a potential probiotic to prevent rapid post-CR weight gain.

Bile Acid-Microbiome Interaction Promotes Gastric Carcinogenesis.

Bile reflux gastritis (BRG) is associated with the development of gastric cancer (GC), but the specific mechanism remains elusive. Here, a comprehensive study is conducted to explore the roles of refluxed bile acids (BAs) and microbiome in gastric carcinogenesis. The results show that conjugated BAs, interleukin 6 (IL-6), lipopolysaccharide (LPS), and the relative abundance of LPS-producing bacteria are increased significantly in the gastric juice of both BRG and GC patients. A secondary BA, taurodeoxycholic acid (TDCA), is significantly and positively correlated with the LPS-producing bacteria in the gastric juice of these patients. TDCA promotes the proliferation of normal gastric epithelial cells (GES-1) through activation of the IL-6/JAK1/STAT3 pathway. These results are further verified in two mouse models, one by gavage of TDCA, LPS, and LPS-producing bacteria (Prevotella melaninogenica), respectively, and the other by bile reflux (BR) surgery, mimicking clinical bile refluxing. Moreover, the bile reflux induced gastric precancerous lesions observed in the post BR surgery mice can be prevented by treatment with cryptotanshinone, a plant-derived STAT3 inhibitor. These results reveal an important underlying mechanism by which bile reflux promotes gastric carcinogenesis and provide an alternative strategy for the prevention of GC associated with BRG.

Corrigendum: Utility of S100A12 as an Early Biomarker in Patients With ST-Segment Elevation Myocardial Infarction.

[This corrects the article DOI: 10.3389/fcvm.2021.747511.].

Three-Dimensional Silk Fibroin/Chitosan Based Microscaffold for Anticancer Drug Screening.

Traditional monolayer cell cultures often fail to accurately predict the anticancer activity of drug candidates, as they do not recapitulate the natural microenvironment. Recently, three-dimensional (3D) culture systems have been increasingly applied to cancer research and drug screening. Materials with good biocompatibility are crucial to create a 3D tumor microenvironment involved in such systems. In this study, natural silk fibroin (SF) and chitosan (CS) were selected as the raw materials to fabricate 3D microscaffolds; Besides, sodium tripolyphosphate (TPP), and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) were used as cross-linking agents. The physicochemical properties of obtained scaffolds were characterized with kinds of testing methods, including emission scanning electron microscopy, x-ray photoelectron spectroscopy, fourier transform infrared spectroscopy, water absorption, and swelling ratio analysis. Cancer cell lines (LoVo and MDA-MB-231) were then seeded on scaffolds for biocompatibility examination and drug sensitivity tests. SEM results showed that EDC cross-linked scaffolds had smaller and more uniform pores with great interconnection than the TPP cross-linked scaffolds, and the EDC cross-linked scaffold exhibited a water absorption ratio around 1000% and a swelling ratio of about 72%. These spatial structures and physical properties could provide more adhesion sites and sufficient nutrients for cell growth. Moreover, both LoVo and MDA-MB-231 cells cultured on the EDC cross-linked scaffold exhibited good adhesion and spreading. CCK8 results showed that increased chemotherapeutic drug sensitivity was observed in 3D culture compared with 2D culture, particularly in the condition of low drug dose (<1  µ M). The proposed SF/CS microscaffold can provide a promising in vitro platform for the efficacy prediction and sensitivity screening of anticancer drugs.

HPV-Related Promoter Methylation-Based Gene Signature Predicts Clinical Prognosis of Patients With Cervical Cancer.

Persistent high-risk HPV infection drives tumorigenesis in various human malignancies, including cervical, oropharyngeal, anal, and vulvar carcinomas. Although HPV-related tumors arise in several different sites, they share many common genetic and epigenetic events. Complex and heterogeneous genomic aberrations and mutations induced by high-risk HPV contribute to the initiation and progression of cervical cancer (CC). However, the associations between high-risk HPV infection and DNA methylation have not been clearly investigated. In the present study, HPV-related gene promoter methylation signature was comprehensively analyzed using multiple interactive platforms. CC patients were successfully classified into high-risk and low-risk groups with significant differences in clinical outcomes based on the HPV-related gene promoter methylation signature. Moreover, the protein levels of ALDH1A2 and clinical prognostic value were confirmed in the CC patients cohort. In summary, our study provides compelling evidence that HPV-related gene promoter methylation signature serves as a strong prognostic signature for CC patients. Clinical investigations in large CC patient cohorts are greatly needed to pave the way to implement epigenetic biomarkers into better clinical management.

Expression and prognostic value of E2F3 transcription factor in non-small cell lung cancer.

E2F transcription factor 3 (E2F3) plays a vital role in the development of various types of cancer. To verify whether E2F3 is a suitable biomarker for the prognosis of lung cancer, bioinformatics analysis was performed to determine the differential expression level of E2F3 in lung cancer and the surrounding non-tumor tissues, and the results were confirmed in a NSCLC cell line and a tissue microarray (TMA). The relevance of E2F3 in non-small cell lung cancer (NSCLC) was investigated in 19 studies from the Oncomine database and confirmed in The Cancer Genome Atlas database. In the lung cancer cell line A549, the inhibition of E2F3 mRNA expression level led to decreased tumor cell viability and cell migration, which was determined by a Cell Counting Kit-8 and wound healing assays, respectively. Immunohistochemistry analyses of E2F3, Bcl-2, Bax and caspase-3 were performed in the NSCLC TMA (n=50). The assessment of TMA detected the increase of E2F3 protein expression level in the tumor tissues, as compared with that in the non-tumor tissues, which was also correlated with the increase in expression of Bcl-2 in tumors. Analysis of the clinical data from patients with NSCLC revealed that the overexpression of E2F3 was associated with early lymphatic spreading, and poor patient survival time. The OncomiR website was used to predict the E2F3 upstream microRNAs and determine their prognostic value in patients with NSCLC. The results from the present study revealed that E2F3 was overexpressed at both the transcriptional and translational levels in NSCLC tissues, as compared with that in non-tumor tissues. The overexpression of E2F3 was associated with the upregulation of the anti-apoptotic factor, Bcl-2, which may contribute to uncontrolled tumor growth. Thus, E2F3 was shown to have important oncogenic properties in the development of NSCLC, and it may become a potential biomarker for patients with NSCLC.

Hyocholic acid species as novel biomarkers for metabolic disorders.

Hyocholic acid (HCA) is a major bile acid (BA) species in the BA pool of pigs, a species known for its exceptional resistance to spontaneous development of diabetic phenotypes. HCA and its derivatives are also present in human blood and urine. We investigate whether human HCA profiles can predict the development of metabolic disorders. We find in the first cohort (n = 1107) that both obesity and diabetes are associated with lower serum concentrations of HCA species. A separate cohort study (n = 91) validates this finding and further reveals that individuals with pre-diabetes are associated with lower levels of HCA species in feces. Serum HCA levels increase in the patients after gastric bypass surgery (n = 38) and can predict the remission of diabetes two years after surgery. The results are replicated in two independent, prospective cohorts (n = 132 and n = 207), where serum HCA species are found to be strong predictors for metabolic disorders in 5 and 10 years, respectively. These findings underscore the association of HCA species with diabetes, and demonstrate the feasibility of using HCA profiles to assess the future risk of developing metabolic abnormalities.

Long-term results for traumatic sternoclavicular joint dislocation treated with a sternoclavicular joint-specific plate.

BACKGROUND: The treatment of traumatic sternoclavicular joint (SCJ) dislocation (SCJD) with internal fixation has been reported with good short-term results, but data on its long-term results are scarce. METHODS: Patients with traumatic SCJD treated with an SCJ-specific plate between January 2003 and January 2018 were evaluated retrospectively. All implants were routinely removed. Data from radiography, the American Shoulder and Elbow Surgeons score, the visual analogue scale and abduction and forward elevation of the shoulder were collected and evaluated before the index surgery, at implant removal and at the latest follow-up. RESULTS: A total of 22 patients were included in this study with a mean follow-up period of 94.8 months. All patients maintained good reduction after the index surgery and implant removal. The visual analogue scale significantly improved from 7.1 ± 1.3 before the index surgery to 0.9 ± 1.0 at implant removal (P < 0.001) and to 1.0 ± 1.1 at the latest follow-up (P < 0.001); the American Shoulder and Elbow Surgeons score significantly improved from 37.9 ± 10.1 to 90.8 ± 7.8 (P < 0.001) and to 86.7 ± 8.6; and both abduction and forward elevation of the shoulder significantly improved at the latest follow-up (P < 0.001). There was no significant difference in the clinical results after implant removal. CONCLUSION: Traumatic SCJD treated with an SCJ-specific plate appeared to be efficient, with satisfactory clinical and radiological results at long-term follow-up.

microRNA­196a­3p inhibits cell proliferation and promotes cell apoptosis by targeting ADP ribosylation factor 4 in diffuse large B­cell lymphoma.

Diffuse large B­cell lymphoma (DLBCL) is the most prevalent type of non­Hodgkin's lymphoma with a heterogeneous molecular pathogenesis and aggressive clinical manifestations. The aim of the present study was to investigate the role of miR­196a­3p and its target gene in the development and progression of DLBCL. RT­qPCR was used to detect the miR­196a­3p expression level in human DLBCL cell lines and DLBCL pathological tissues and compare them with the normal control. The clinical significance of the miR­196a­3p expression was also analyzed in DLBCL patients. Next, the effect of miR­196a­3p overexpression on the cell cycle, apoptosis, and proliferation of DLBCL cells was evaluated. To explore its underlying mechanism, the target gene of miR­196a­3p was predicted and validated using bioinformatics and molecular biological approaches. Finally, the expression of this target gene in clinical specimens and its correlation with clinicopathological characteristics were determined. The decreased expression of miR­196a­3p was validated in DLBCL, with further analysis proving that it was correlated with poor prognosis. It was shown that the overexpression of miR­196a­3p was associated with cell cycle arrest, enhanced apoptosis, and inhibited proliferation in DLBCL cells. Furthermore, ADP ribosylation factor 4 (ARF4) was verified as the downstream target gene of miR­196a­3p. Similar to miR­196a­3p restoration in vitro, endogenous ARF4­knockdown was proven to inhibit cell proliferation through cell cycle arrest and elevate apoptosis in DLBCL. The present results indicated that miR­196a­3p downregulation contributed to the tumorigenesis of DLBCL by targeting ARF4 expression, which may be used as a novel prognostic marker or potential molecular therapeutic target for DLBCL management in the future.