Deep learning based digital pathology for predicting treatment response to first-line PD-1 blockade in advanced gastric cancer.

BACKGROUND: Advanced unresectable gastric cancer (GC) patients were previously treated with chemotherapy alone as the first-line therapy. However, with the Food and Drug Administration's (FDA) 2022 approval of programmed cell death protein 1 (PD-1) inhibitor combined with chemotherapy as the first-li ne treatment for advanced unresectable GC, patients have significantly benefited. However, the significant costs and potential adverse effects necessitate precise patient selection. In recent years, the advent of deep learning (DL) has revolutionized the medical field, particularly in predicting tumor treatment responses. Our study utilizes DL to analyze pathological images, aiming to predict first-line PD-1 combined chemotherapy response for advanced-stage GC. METHODS: In this multicenter retrospective analysis, Hematoxylin and Eosin (H&E)-stained slides were collected from advanced GC patients across four medical centers. Treatment response was evaluated according to iRECIST 1.1 criteria after a comprehensive first-line PD-1 immunotherapy combined with chemotherapy. Three DL models were employed in an ensemble approach to create the immune checkpoint inhibitors Response Score (ICIsRS) as a novel histopathological biomarker derived from Whole Slide Images (WSIs). RESULTS: Analyzing 148,181 patches from 313 WSIs of 264 advanced GC patients, the ensemble model exhibited superior predictive accuracy, leading to the creation of ICIsNet. The model demonstrated robust performance across four testing datasets, achieving AUC values of 0.92, 0.95, 0.96, and 1 respectively. The boxplot, constructed from the ICIsRS, reveals statistically significant disparities between the well response and poor response (all p-values < = 0.001). CONCLUSION: ICIsRS, a DL-derived biomarker from WSIs, effectively predicts advanced GC patients' responses to PD-1 combined chemotherapy, offering a novel approach for personalized treatment planning and allowing for more individualized and potentially effective treatment strategies based on a patient's unique response situations.

Resveratrol Delays Diabetic Cardiomyopathy Fibrosis by Regulating Mitochondrial Autophagy.

Objective: To explore whether resveratrol can postpone the fibrosis associated with diabetic cardiomyopathy (DCM) by modulating the mitochondrial autophagy response through the AMPK/SIRT1-mediated IRE1α/PINK signaling pathway. Methods: A DCM mouse model was established using a high-sugar high-fat diet and streptozotocin. Resveratrol was administered to a subset of the DCM mouse models for comparison. Echocardiography, Masson staining, TNUEL assay, and transmission electron microscopy were employed to evaluate the cardiac status, myocardial fibrosis, myocardial cell apoptosis, and morphological changes of myocardial cells and their internal mitochondria in each group of mice. Western blot staining was performed on myocardial tissues to assess the protein expression levels of p-AMPK, SIRT1, SIRT3, p22, GP91, p-IRE1α, XBP1s PINK, Parkin, LC3I, and Beclin. Mouse myocardial cells were cultured in vitro and intervened with a high-sugar high-fat diet, resveratrol, and GSK690693 (an AMPK inhibitor) to observe the protein expression levels of p-AMPK, p22, XBP1s, and PINK in mouse myocardial cells in each group. Results: Results from echocardiography, Masson staining, TNUEL assay, and transmission electron microscopy showed that resveratrol administration alleviated cardiac damage, myocardial fibrosis, myocardial cell apoptosis, and mitochondrial autophagy in DCM mice. Resveratrol administration promoted the expression of phosphorylated AMP-activated protein kinase (p-AMPK), sirtuin 1 (SIRT1), and sirtuin 3 (SIRT3) in the myocardial tissue of mice, while lowering the elevated protein expression levels of p22 subunit (p22), guanine nucleotide-binding protein q polypeptide 1 (GP91), phosphorylated inositol-requiring enzyme 1 alpha (p-IRE1α), X-box binding protein 1 spliced form (XBP1s), PTEN-induced putative kinase 1 (PINK), Parkin, microtubule-associated proteins light chain 3 isoform I (LC3I), and Beclin (Bcl-2 interacting protein) caused by DCM. GSK690693 (an AMPK inhibitor) suppressed the expression of p-AMPK, SIRT1, and SIRT3 and enhanced the protein expression of p22, XBP1s, and PINK. Conclusion: Resveratrol postpones dilated cardiomyopathy fibrosis by regulating the mitochondrial autophagy response through the AMP-activated protein kinase (AMPK)/silent mating type information regulation 2 homolog 1 (SIRT1)-mediated inositol-requiring enzyme 1 alpha (IRE1α)/PTEN-induced putative kinase 1 (PINK) signaling pathway.

Digital histopathological images of biopsy predict response to neoadjuvant chemotherapy for locally advanced gastric cancer.

BACKGROUND: Neoadjuvant chemotherapy (NAC) has been recognized as an effective therapeutic option for locally advanced gastric cancer as it is expected to reduce tumor size, increase the resection rate, and improve overall survival. However, for patients who are not responsive to NAC, the best operation timing may be missed together with suffering from side effects. Therefore, it is paramount to differentiate potential respondents from non-respondents. Histopathological images contain rich and complex data that can be exploited to study cancers. We assessed the ability of a novel deep learning (DL)-based biomarker to predict pathological responses from images of hematoxylin and eosin (H&E)-stained tissue. METHODS: In this multicentre observational study, H&E-stained biopsy sections of patients with gastric cancer were collected from four hospitals. All patients underwent NAC followed by gastrectomy. The Becker tumor regression grading (TRG) system was used to evaluate the pathologic chemotherapy response. Based on H&E-stained slides of biopsies, DL methods (Inception-V3, Xception, EfficientNet-B5, and ensemble CRSNet models) were employed to predict the pathological response by scoring the tumor tissue to obtain a histopathological biomarker, the chemotherapy response score (CRS). The predictive performance of the CRSNet was evaluated. RESULTS: 69,564 patches from 230 whole-slide images of 213 patients with gastric cancer were obtained in this study. Based on the F1 score and area under the curve (AUC), an optimal model was finally chosen, named the CRSNet model. Using the ensemble CRSNet model, the response score derived from H&E staining images reached an AUC of 0.936 in the internal test cohort and 0.923 in the external validation cohort for predicting pathological response. The CRS of major responders was significantly higher than that of minor responders in both internal and external test cohorts (both p < 0.001). CONCLUSION: In this study, the proposed DL-based biomarker (CRSNet model) derived from histopathological images of the biopsy showed potential as a clinical aid for predicting the response to NAC in patients with locally advanced GC. Therefore, the CRSNet model provides a novel tool for the individualized management of locally advanced gastric cancer.

The effects of hyperuricemia on endothelial cells are mediated via GLUT9 and the JAK2/STAT3 pathway.

BACKGROUND: Uric acid (UA) transporters mediate the uptake and outflow of UA, and are greatly involved in the control of UA concentrations. Glucose transporter 9 (GLUT9), one of the UA transporters, has been confirmed to be expressed in human umbilical vein endothelial cells (HUVECs). This study aimed to characterize GLUT9's effect on intracellular UA accumulation in HUVECs in a high-UA environment and to explore the mechanism of cellular dysfunction. METHODS AND RESULTS: HUVECs were treated with UA to establish a model of cellular dysfunction. Then, UA uptake, GLUT9 expression and endothelial nitric oxide synthase (eNOS) and reactive oxygen species (ROS) amounts were measured. UA uptake was concentration- and time-dependent, and UA treatment significantly reduced nitric oxide (NO) levels and eNOS activity. UA also upregulated pro-inflammatory molecules and GLUT9, and increased intracellular ROS amounts in HUVECs. GLUT9 knockdown reduced UA uptake and ROS content, but antioxidant treatment did not reduce GLUT9 expression. To assess the function of JAK2/STAT3 signaling, HUVECs were treated with UA, and the phosphorylation levels of JAK2, STAT3, IL-6 and SOCS3 were increased by a high concentration of UA. In addition, GLUT9 knockdown reduced the phosphorylation of JAK2/STAT3 intermediates and increased p-eNOS amounts. CONCLUSIONS: GLUT9 mediated the effects of high UA levels on HUVECs by increasing the cellular uptake of UA, activating JAK2/STAT3 signaling, and reduced the production of active eNOS and NO in HUVECs.

Perioperative blood transfusion is one of the factors that affect the prognosis of gastric cancer.

PURPOSE: To demonstrate the potential significance of perioperative blood transfusion on the prognosis of gastric cancer. METHODS: Data from 234 patients who were subjected to radical gastrectomy in our hospital were obtained and retrospectively analyzed. Patients' age, gender, preoperative anemia, tumor size, location, invasion depth, lymph node metastasis, TNM stage, presence or absence of blood transfusion and blood transfusion volume were observed and analyzed. RESULTS: The difference of tumor recurrence in patients whose blood transfusion volume was greater than 2U was significant (p<0.001). The tumor recurrence in patients whose blood transfusion was less than 2U was significantly shorter than in those whose transfusion volume was greater than 4U (p=0.03). The survival in the blood transfusion group was significantly lower in comparison with the nonblood transfusion group (p=0.002). The survival of transfusion group in TNM stage III and IV was significantly shorter than that in non-transfusion group (p=0.03). Statistical significance was found in survival between the transfusion group and non-transfusion group when the tumor size was less than 5 cm and greater than 5 cm (p=0.006, p=0.04, respectively). CONCLUSIONS: Perioperative transfusion is one of the factors for predicting the prognosis of postoperative gastric cancer patients, and the larger the perioperative transfusion, the shorter the tumor recurrence, the worse the prognosis. Therefore, it is of great significance reducing the intraoperative blood loss and strict controlling blood transfusion indications.

Expression and role of oncogenic miRNA-224 in esophageal squamous cell carcinoma.

BACKGROUND: Aberrant expression of miR-224 is associated with tumor development and progression. This study investigated the role of miR-224 in esophageal squamous cell carcinoma (ESCC) ex vivo and in vitro. METHODS: A total of 103 esophageal intraepithelial neoplasia, ESCC tissue specimens, and their matched distant normal tissues were collected to test miR-224 expression using qRT-PCR analysis. Western blot was used to quantify the level of PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1) and PHLPP2 in ESCC tissues. Cell viability, apoptosis, invasion, and colony formation assays were used to assess the altered phenotypes of esophageal cancer cell lines after miR-224 expression or inhibition. A luciferase reporter assay was used to confirm miR-224 binding to PHLPP1 and PHLPP2 mRNA. RESULTS: miR-224 was significantly overexpressed in esophageal intraepithelial neoplasia and ESCC tissues, while the expression of PHLPP1 and PHLPP2 proteins, the target genes of miR-224, was downregulated in ESCC tissues. miR-224 expression was associated with advanced clinical TNM stage, pathologic grade, and the level of PHLPP1 and PHLPP2 proteins in ESCC tissues. Ectopic overexpression of miR-224 promoted proliferation, migration, and invasion, but suppressed apoptosis of ESCC cells. miR-224 was able to bind to the 3' untranslated region (3'-UTR) of PHLPP1 and PHLPP2 mRNA to suppress their expression. CONCLUSIONS: The current study demonstrated that miR-224 acts as an oncogenic miRNA in ESCC, possibly by targeting PHLPP1 and PHLPP2.

Immune function of Chinese formula Qingwen Baidu granule in broilers.

This study was to investigate the effects of Qingwen Baidu granules on the antibody level, immune organ index and the lymphocyte transformation of broilers. Hy-line variety white cocks of 30 days were used to evaluate the antibody titer of Newcastle Disease in each serum group, and MTT method was used to determine the T lymphocyte proliferation, and organ weighing methods to measure the immune organ index 21 days after immunization. The results showed that Qingwen Baidu granules could prolong the residue time in the body, improve the lymphocyte conversion ratio, increase the bursa, thymus and spleen index and promote immune organ development. These results suggested that Qingwen Baidu granules could improve the serum Newcastle disease antibody level, improve peripheral blood lymphocyte proliferation, enhance the cellular immune function, and elevate the immune organ index and growth, in order to raise the immune function in chicken. The above demonstrates that the Qingwen Baidu granules have significant effects on the cytoimmunity and humoral immunity, and the potentiation of the immune function in broilers.

Fatigue Life Prediction Model of FRP-Concrete Interface Based on Gene Expression Programming.

Under fatigue loading, the interfacial fatigue life of fiber-reinforced polymer(FRP)-concrete is an important index for the analysis of the fatigue performance of reinforced concrete beams strengthened with FRP materials and the evaluation of the reinforcement effect. To solve the problems of the inconsistent and limited accuracy of existing fatigue life prediction models, gene expression programming (GEP) was used to study the interfacial fatigue life of FRP-concrete. Firstly, 219 sets of interfacial fatigue test data were collected, which included two kinds of reinforcement methods, namely, externally bonded (EB) reinforcement and near-surface-mounted (NSM) reinforcement; secondly, Pearson correlation analysis was used to determine the key factors affecting the fatigue life, and then GEP was used to explore the influence of different input forms on the prediction accuracy of the model. Fatigue life calculation formulas applicable to the two kinds of reinforcement methods, i.e., EB and NSM, were established, and a specific calculation formula was established. The model was subjected to parameter sensitivity analysis and variable importance analysis and was found to reflect the intrinsic relationship between the fatigue life and various factors. Finally, the GEP model was compared with the models proposed by other researchers. Five statistical indices, such as the coefficient of determination and the average absolute error, were selected to assess the model, and the results show that the GEP model has higher prediction accuracy than other models, with a coefficient of determination of 0.819, and indicators such as the average absolute error are also lower than those of the rest of the models.

SIRT3 rs11246020 Polymorphism Associated Postprandial Triglyceride Dysmetabolism.

Purpose: Energy metabolism is regulated by SIRT3, no research has been done on the connection between lipid metabolism in the oral fat test and SIRT3 polymorphism. Thus, we conducted a case-control study to investigate the connection between postprandial lipid and SIRT3 polymorphism. Patients and Methods: 402 non-obese Chinese subjects were enrolled and their postprandial lipid response to oral fat tolerance test (OFTT) was observed to understand the relationship between rs11246020 gene and postprandial triglyceride metabolism. Results: In a binary logic regression model, a protective effect of the T allele of the rs11246020 SIRT3 for postprandial hypertriglyceridemia was shown (OR=0.417, 95% CI = 0.219-0.794, p=0.008). Compared to the CC genotype, individuals with the TT+CT variant of the rs11246020 SIRT3 gene demonstrated significantly lower levels of homeostasis model assessment of insulin resistance (HOMA-IR) (p=0.04), postprandial plasma glucose (PPG) (p=0.037), fasting plasma glucose (FPG) (p=0.02), and 4-hour triglyceridemia (Tg) (p=0.032). Conclusion: The C allele of rs11246020 SIRT3 gene may be a risk factor to increased possibility of postprandial triglyceridemia after an oral fat test, which involved in the mechanism of glucose and insulin metabolism.

Pharmacological Inhibition or Silencing of TREM1 Restrains HCC Cell Metastasis by Inactivating TLR/PI3K/AKT Signaling.

Hepatocellular carcinoma (HCC), a widely prevalent malignancy strongly linked to inflammation, remains a significant public health concern. Triggering receptor expressed on myeloid cells 1 (TREM1), a modulator of inflammatory responses identified in recent years, has emerged as a crucial facilitator in cancer progression. Despite its significance, the precise regulatory mechanism of TREM1 in HCC metastasis remains unanswered. In the present investigation, we observed aberrant upregulation of TREM1 in HCC tissues, which was significantly linked to poorer overall survival. Inhibition of TREM1 expression resulted in a significant reduction in HCC Huh-7 and MHCC-97H cell proliferation, invasion, and epithelial-mesenchymal transition (EMT) process. Furthermore, inhibiting TREM1 decreased protein expressions of toll-like receptor 2/4 (TLR2/4) and major myeloid differentiation response gene 88 (MyD88), leading to the inactivation of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) in HCC cells. Notably, these effects were reversed by treatment with TLR2-specific agonist (CU-T12-9), indicating a potential crosstalk between TREM1 and TLR2/4. Mechanistic studies revealed a direct interaction between TREM1 and both TLR2 and TLR4. In vivo studies demonstrated that inhibition of TREM1 suppressed the growth of HCC cells in the orthotopic implant model and its metastatic potential in the experimental lung metastasis model. Overall, our findings underscore the role of TREM1 inhibition in regulating EMT and metastasis of HCC cells by inactivating the TLR/PI3K/AKT signaling pathway, thereby providing deeper mechanistic insights into how TREM1 regulates metastasis during HCC progression.

Metformin modifies plasma microbial-derived extracellular vesicles in polycystic ovary syndrome with insulin resistance.

INTRODUCTION: This study investigated changes in plasma microbial-derived extracellular vesicles (EVs) in patients with polycystic ovary syndrome and insulin resistance (PCOS-IR) before and after metformin treatment, and aimed to identify bacterial taxa within EVs that were biologically and statistically significant for diagnosis and treatment. METHODS: The case-control study was conducted at Xiamen Chang Gung Hospital, Hua Qiao University. Plasma samples were collected from five PCOS-IR patients of childbearing age before and after 3 months of metformin treatment, and the samples were sequenced. The diversity and taxonomic composition of different microbial communities were analyzed through full-length 16 S glycosomal RNA gene sequencing. RESULTS: After metformin treatment, fasting plasma glucose levels and IR degree of PCOS-IR patients were significantly improved. The 16 S analysis of plasma EVs from metformin-treated patients showed higher microbial diversity. There were significant differences in EVs derived from some environmental bacteria before and after metformin treatment. Notably, Streptococcus salivarius was more abundant in the metformin-treated group, suggesting it may be a potential probiotic. DISCUSSION: The study demonstrated changes in the microbial composition of plasma EVs before and after metformin treatment. The findings may offer new insights into the pathogenesis of PCOS-IR and provide new avenues for research.

Retrospective study of endoscopic submucosal tunnel dissection (ESTD) for surgical resection of esophageal leiomyoma.

BACKGROUND: Esophageal leiomyoma is benign and often asymptomatic, but if the tumor is too large or obstructive, it should be resected. The aim of this study was to compare a novel approach, endoscopic submucosal tunnel dissection (ESTD), with a more established method, endoscopic submucosal dissection (ESD). METHODS: This was a retrospective study of 39 patients in Chongqing Xinqiao Hospital, China, undergoing resection for leiomyoma >2 cm in diameter, or 1.5-2.0 cm in diameter with symptoms of obstructive dysphagia. Epidemiological data, presenting symptoms, diagnostic investigations, tumor location, histopathological findings, and safety and efficacy of surgical resection were analyzed. RESULTS: Mean tumor sizes in the ESTD (n = 18; mean age = 36.7 ± 6.3 years) and ESD (n = 21; age = 41.0 ± 4.4 years) groups were 3.3 ± 0.7 and 3.0 ± 0.4 cm, respectively. The male:female ratio was 25:14, with a distribution of lesions among the lower, middle, and upper esophagus of 22:14:3. Operating time was significantly shorter (p < 0.05) for ESTD (67.5 ± 9.5 min) than for ESD (87.2 ± 7.7 min), while incision healing was faster (p < 0.05) for ESTD (14.7 ± 2.5 days) than for ESD (57.9 ± 7.5 days). Hospital stay was also shorter (p < 0.05) for ESTD (2.3 ± 0.5 days) than for ESD (5.7 ± 1.0 days). Bleeding was the only complication with ESTD (3/18 patients), with no significant difference in the incidence of complications between groups. ESTD was rapidly learned by surgeons. CONCLUSION: ESTD is a safe and effective treatment for esophageal leiomyoma, with advantages over ESD.

Wetland ecological index and assessment of spatial-temporal changes of wetland ecological integrity.

Long-term, quantitative, and dynamic monitoring of regional ecological integrity using remote sensing can provide powerful decision-making support for sustainable regional development. However, existing methods are unable to accurately evaluate the quality of the surface ecological integrity because they do not consider vegetation saturation and salinization of wetlands. In addition, the ecological fragility of wetlands is characterized by a high frequency of changes in ecological conditions over time, leading to a lack of directionality in the analysis of ecological changes over long time series. To accurately assess the surface ecological integrity, this study integrates environmental salinity (Baseline-based Soil Salinity Index, BSSI) and a new vegetation element (Improved Hyperspectral Image-based Vegetation Index, IHSVI), and proposes the wetland ecological index (WEI) for the ecological integrity assessment system. Combined with the annual ecological integrity assessment using the WEI, the Mann-Kendall test was used to obtain the nodes of long-term changes. The WEI-Mann Kendall (WEI-MK) framework indicates the direction of analysis and realizes clear long-term series change monitoring. In this study, we analyzed the spatial and temporal changes in ecological integrity in the Yellow River Delta from 1991 to 2020 based on the WEI-MK framework. The results showed that: 1) Compared with Remote Sensing-based Ecological Index (RSEI), the WEI improved the accuracy of wetland integrity evaluation to 89 %. The WEI also improved accuracy of assessments in other typical regions by approximately 10 %. 2) The selection of nodes based on the WEI-MK framework clarified the direction of environmental change analysis. The results show that although the quality of the terrestrial ecological environment has improved over the past 30 years in the Yellow River Delta, that of the marine ecological environment has gradually declined. In particular, the state of the marine ecological environment after 2016 should be of concern.

Evaluation of Mucosal Healing in Ulcerative Colitis by Fecal Calprotectin vs. Fecal Immunochemical Test: A Systematic Review and Meta-analysis.

Mucosal healing has been considered a treatment goal for patients with inflammatory bowel disease. To compare the accuracy of fecal immunochemical test and fecal calprotectin in the judgment of mucosal healing in ulcerative colitis, a meta-analysis was performed. We searched the PubMed, Cochrane Library, Web of Science, and Embase for the studies on fecal immunochemical test and fecal calprotectin predicting mucosal healing in ulcerative colitis. The comprehensive sensitivity, specificity, diagnostic odds ratio, positive likelihood ratio, and negative likelihood ratio were calculated to evaluate the accuracy. By analyzing 22 publications, we found that the combined sensitivity and specificity of fecal immunochemical test were 0.87 (95% CI, 0.80-0.92) and 0.73 (95% CI, 0.62-0.81), respectively. The combined sensitivity and specificity of fecal calprotectin were 0.76 (95% CI, 0.70-0.80) and 0.80 (95% CI, 0.76-0.84), respectively. The area under the curve values of the fecal immunochemical test and fecal calprotectin summary receiver operating characteristic (SROC) curves were 0.88 and 0.85, respectively. Consequently, fecal immunochemical test had higher sensitivity in predicting mucosal healing in ulcerative colitis patients, while fecal calprotectin had higher specificity. Compared with fecal calprotectin, fecal immunochemical test was more accurate in judging mucosal healing in ulcerative colitis.

Primer Exchange Reaction Coupled with DNA-Templated Silver Nanoclusters for Label-Free and Sensitive Detection of MicroRNA.

MicroRNAs (MiRNAs) play pivotal roles in regulating gene expression, and serve as crucial biomarkers for diagnosis of a variety of disease. However, label-free and sensitive miRNA detection remains a huge challenge due to the low abundance. Herein, we developed an approach through integrating primer exchange reaction (PER) with DNA-templated silver nanoclusters (AgNCs) for label-free and sensitive miRNA detection. In this method, PER was used to amplify miRNA signals and produce single-strand DNA (ssDNA) sequences. The produced ssDNA sequences mediated DNA-templated AgNCs based signal generation by unfolding the designed hairpin probe (HP). The generated AgNCs signal was correlated with the dosage of target miRNA. Eventually, the established approach exhibited a low detection of limit of 47 fM with a great dynamic range of more than five orders of magnitude. In addition, the method was also utilized to detect the miRNA-31 expression in collected clinical samples from pancreatitis patients and demonstrated that miRNA-31 was upregulated in patients, showing a great promising of the method in clinical application.

Resveratrol improves palmitic acid­induced insulin resistance via the DDIT4/mTOR pathway in C2C12 cells.

The present study aimed to establish a model of palmitic acid (PA)­induced insulin resistance (IR) in C2C12 cells and to determine the mechanism underlying how resveratrol (RSV) improves IR. C2C12 cells were divided into the control (CON), PA, PA + RSV, PA + RSV + DNA damage­inducible transcript 4 (DDIT4)­small interfering (si)RNA and PA + RSV + MHY1485 (mTOR agonist) groups. Glucose contents in culture medium and triglyceride contents in cells were determined. Oil red O staining was performed to observe the pathological changes in the cells. Reverse transcription­quantitative PCR and western blotting were conducted to evaluate the mRNA and protein expression levels, respectively, of DDIT4, mTOR, p70 ribosomal protein S6 kinase (p70S6K), insulin receptor substrate (IRS)­1, PI3K, AKT and glucose transporter 4 (GLUT4). Compared with in the CON group, glucose uptake was decreased, cellular lipid deposition was increased, phosphorylated (p)­IRS­1, p­mTOR and p­p70S6K protein expression levels were increased, and p­PI3K, p­AKT, GLUT4 and DDIT4 protein expression levels were decreased in the PA group. By contrast, compared with in the PA group, culture medium glucose content and cellular lipid deposition were decreased, p­PI3K, p­AKT, GLUT4 and DDIT4 protein expression levels were increased, p­IRS­1 protein expression levels were decreased, and mTOR and p70S6K mRNA and protein expression levels were decreased in the PA + RSV group. Compared with in the PA + RSV group, DDIT4 protein and mRNA expression levels were reduced in the PA + RSV + DDIT4­siRNA group, but showed no change in the PA + RSV + MHY1485 group. Following transfection with DDIT4­siRNA or treatment with MHY1485, the effects of RSV on improving IR and lipid metabolism were weakened, mTOR and p70S6K protein expression levels were upregulated, p­PI3K, p­AKT and GLUT4 protein expression levels were down­regulated, p­IRS­1 protein expression levels were upregulated, and culture medium glucose content and cellular lipid deposition were increased. In conclusion, RSV may improve PA­induced IR in C2C12 cells through the DDIT4/mTOR/IRS­1/PI3K/AKT/GLUT4 signaling pathway, as well as via improvements in glucose and lipid metabolism.

Asymptomatic gastric tuberculosis in the gastric body mimicking an isolated microscopic erosion: A rare case report.

INTRODUCTION: Gastric tuberculosis is rarely seen in clinical practice, which occurs mostly secondary to lung tuberculosis, intestinal tuberculosis, and other common tuberculosis. Gastric tuberculosis rarely presents as a single microscopic superficial erosion. We recently diagnosed such a case, hence reporting it herein. PATIENT CONCERNS: A 40-year-old female patient was admitted with a chief complaint of painful enlarged cervical lymph nodes. She had no other symptoms or any previous history of remarkable diseases. DIAGNOSIS: Physical examination found multiple enlarged cervical lymph nodes. Computer tomography revealed multiple circular well-defined soft tissue masses in the bilateral carotid sheath spaces. A cervical lymph node biopsy showed caseous necrosis with infiltration of neutrophils and lymphocytes, and most importantly, mycobacteria through staining for acid fast bacilli. Routine gastroscopy showed a 0.5 cm × 0.5 cm well-defined erosion on the large curvature of the gastric body. Gastric biopsy revealed chronic granulomatous inflammation with mycobacteria through staining for acid fast bacilli. The patient was diagnosed as having cervical lymph node tuberculosis and gastric tuberculosis. INTERVENTIONS AND OUTCOMES: She received 6 months of standard anti-tuberculosis therapy. The enlarged cervical lymph nodes shrank in size and the pain was relieved. CONCLUSIONS: Gastroscopy should be performed to look for gastric tuberculosis if the patient presents primary tuberculosis in other organs/tissues such as cervical lymph nodes. If any small erosion is found, a biopsy is justified for checking the possibility of gastric tuberculosis.

Resveratrol Alleviates Skeletal Muscle Insulin Resistance by Downregulating Long Noncoding RNA.

Long noncoding RNA (lncRNA) is a crucial factor in the progression of insulin resistance (IR). Resveratrol (RSV) exhibits promising therapeutic potential for IR. However, there are few studies on whether RSV improves IR through lncRNA. This study aimed to determine whether RSV could influence the expression of lncRNA and to elucidate the underlying mechanism. Mice were divided into three groups: control group, high-fat diet (HFD) group, and HFD + RSV group. We conducted a high-throughput sequencing analysis to detect lncRNA and mRNA expression signatures and the ceRNA-network in the skeletal muscles of mice that were fed an HFD to induce IR. Hierarchical clustering, gene enrichment, and gene ceRNA-network analyses were subsequently conducted. Differentially expressed lncRNAs were selected and validated via reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The biological functions of the selected lncRNAs were investigated by silencing the target genes via lentivirus transfection of C2C12 mouse myotube cells. RSV treatment reversed the expression of 338 mRNAs and 629 lncRNAs in the skeletal muscles of mice with HFD-induced IR. The results of the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes database analyses indicated that the differentially expressed mRNAs modulated type II diabetes mellitus. After validating randomly selected lncRNAs via RT-qPCR, we identified a novel lncRNA, NONMMUT044897.2, which was upregulated in the HFD group and reversed with RSV treatment. Additionally, NONMMUT044897.2 was proven to function as a ceRNA of microRNA- (miR-) 7051-5p. Suppressor of Cytokine Signaling 1 (SOCS1) was confirmed as a target of miR-7051-5p. We further performed lentivirus transfection to knock down NONMMUT044897.2 in vitro and found that NONMMUT044897.2 silenced SOCS1 and potentiated the insulin signaling pathway. Hence, RSV mimicked the silencing effect of lentivirus transfection on NONMMUT044897.2. Our study revealed that RSV reduced IR in mouse skeletal muscles via the regulation of NONMMUT044897.2.

Association Between Triglyceride-Glucose Index and Serum Uric Acid Levels: A Biochemical Study on Anthropometry in Non-Obese Type 2 Diabetes Mellitus Patients.

Purpose: The triglyceride-glucose index (TyG) is positively correlated with serum uric acid (SUA) in patients with type 2 diabetes mellitus (T2DM). However, whether this relationship exists in non-obese T2DM patients remains unknown. The study investigated the relationship between TyG and SUA in Chinese non-obese T2DM patients and examined the prognostic value of TyG in hyperuricemia (HUA). Patients and Methods: In total, 719 T2DM patients who were not obese were enrolled from among those who visited the Hebei General Hospital. The patients were categorized into groups according to their SUA levels. The relationship between TyG and clinical parameters was examined through correlation analysis. To consider covariates and examine the independent impact of TyG on HUA, logistic regression was performed. The receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic value of TyG and homeostasis model assessment of insulin resistance (HOMA-IR) for HUA. Results: The HUA prevalence was 12.10%. TyG was statistically different among the four SUA groups, with lower TyG levels in the Q1, Q2, and Q3 groups than that in the Q4 group. TyG was positively correlated with SUA (r = 0.176, P < 0.001). Logistic regression exhibited that TyG and SUA were independently correlated (OR = 2.427, 95% CI = 1.134-5.195, P = 0.022) even after adjustment for confounding factors. The ROC curve showed that the predictive value of TyG for HUA was higher than that of HOMA-IR (AUROC = 0.613, P = 0.001). Conclusion: TyG was positively correlated with SUA in non-obese T2DM patients. TyG may better predict HUA in non-obese T2DM patients than HOMA-IR.

Circulating levels of DDIT4 and mTOR, and contributions of BMI, inflammation and insulin sensitivity in hyperlipidemia.

Evidence shows a high incidence of insulin resistance, inflammation and excess body mass index (BMI) in adults with hyperlipidemia. The present study aimed to determine the circulating levels of DNA damage inducible transcript 4 (DDIT4) and mTOR and assess the contributions of lipids, inflammatory markers, insulin sensitivity and BMI in hyperlipidemia. The study subjects were divided into a hyperlipidemia group and a normal control group (n=55 per group). Sex, age, blood pressure, waist circumference (WC), height, weight and BMI were recorded. Fasting venous blood samples were collected and an automatic biochemical analyzer was used to detect fasting blood glucose (FBG), fasting insulin (FINS), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C). Quantitative ELISA kits were used to determine the levels of DDIT4, mTOR and inflammatory markers and calculate the homeostatic model assessment of insulin resistance (HOMA-IR). Compared with the normal control group, the hyperlipidemia group had significantly increased blood pressure, WC, weight, BMI, FBG, FINS, HOMA-IR, mTOR and inflammatory markers, but significantly reduced DDIT4. A concurrent correlation analysis showed that insulin resistance was positively correlated with blood pressure, BMI, lipid profiles (TG, TC, LDL-C), mTOR and inflammatory markers, but negatively correlated with HDL-C and DDIT4. Lipid profiles were positively correlated with BMI, mTOR and inflammatory markers, but negatively correlated with DDIT4. A factor analysis identified four domains in hyperlipidemia (inflammation-lipid 1 domain, 44.429%; overweight domain, 21.695%; insulin sensitivity domain, 11.782%; lipid 2 domain, 6.723%). In conclusion, people with hyperlipidemia have elevated mTOR and reduced DDIT4 and are accompanied by abnormal indicators such as insulin sensitivity, BMI and inflammatory factors. The identified domains may be applied to predict the outcomes of cardiovascular diseases and metabolic diseases in the future.