STAMarker: determining spatial domain-specific variable genes with saliency maps in deep learning.

Spatial transcriptomics characterizes gene expression profiles while retaining the information of the spatial context, providing an unprecedented opportunity to understand cellular systems. One of the essential tasks in such data analysis is to determine spatially variable genes (SVGs), which demonstrate spatial expression patterns. Existing methods only consider genes individually and fail to model the inter-dependence of genes. To this end, we present an analytic tool STAMarker for robustly determining spatial domain-specific SVGs with saliency maps in deep learning. STAMarker is a three-stage ensemble framework consisting of graph-attention autoencoders, multilayer perceptron (MLP) classifiers, and saliency map computation by the backpropagated gradient. We illustrate the effectiveness of STAMarker and compare it with serveral commonly used competing methods on various spatial transcriptomic data generated by different platforms. STAMarker considers all genes at once and is more robust when the dataset is very sparse. STAMarker could identify spatial domain-specific SVGs for characterizing spatial domains and enable in-depth analysis of the region of interest in the tissue section.

Transcriptome analysis of mesenteric arterioles changes and its mechanisms in cirrhotic rats with portal hypertension.

Portal hypertension (PHT) is a major cause of liver cirrhosis. The formation of portosystemic collateral vessels and splanchnic vasodilation contribute to the development of hyperdynamic circulation, which in turn aggravates PHT and increases the risk of complications. To investigate the changes in mesenteric arterioles in PHT, cirrhotic rat models were established by ligating the common bile ducts. After 4 weeks, the cirrhotic rats suffered from severe PHT and splanchnic hyperdynamic circulation, characterized by increased portal pressure (PP), cardiac output (CO), cardiac index (CI), and superior mesenteric artery (SMA) flow. Mesenteric arterioles in cirrhotic rats displayed remarkable vasodilation, vascular remodeling, and hypocontractility. RNA sequencing was performed based on these findings. A total of 1,637 differentially expressed genes (DEGs) were detected, with 889 up-regulated and 748 down-regulated genes. Signaling pathways related to vascular changes were enriched, including the vascular endothelial growth factor (VEGF), phosphatidylinositol-3-kinase-AKT (PI3K-AKT), and nuclear factor kappa light chain enhancer of activated B cells (NF-κB) signaling pathway, among others. Moreover, the top ten hub genes were screened according to the degree nodes in the protein-protein interaction (PPI) network. Functional enrichment analyses indicated that the hub genes were involved in cell cycle regulation, mitosis, and cellular response to oxidative stress and nitric oxide (NO). In addition, promising candidate drugs for ameliorating PHT, such as resveratrol, were predicted based on hub genes. Taken together, our study highlighted remarkable changes in the mesenteric arterioles of cirrhotic rats with PHT. Transcriptome analyses revealed the potential molecular mechanisms of vascular changes in splanchnic hyperdynamic circulation.

Laparoscopic total extraperitoneal (TEP) inguinal hernia repair with preperitoneal closed-suction drainage reduced postoperative complications.

BACKGROUND: Although laparoscopic total extraperitoneal (TEP) inguinal hernia repair has the advantages of less bleeding, less trauma, less pain, and fast recovery, there are several issues that need to be addressed. This study aims to evaluate the effectiveness of preperitoneal closed­suction drainage on reducing postoperative complications in TEP inguinal hernia repair. METHODS: A retrospective analysis of 122 patients who underwent TEP inguinal hernia repair between June 2018 and June 2021 was performed. The patients were divided into the drainage group and the non-drainage group according to whether the drainage tube was placed or not. Clinical data, surgical procedures and outcome of these patients were collected and analyzed to assess the effectiveness of drainage. RESULTS: A total of 122 patients undergoing TEP surgery were screened, of which 22 were excluded. Most of the patients were male with right indirect inguinal hernia. There was no difference in the mean length of hospital stay between the two groups. Postoperative pain was alleviated by preperitoneal closed­suction drainage 24 h after operation (p = 0.03). The rate of complications such as scrotal edema, seroma and urinary retention in the drainage group was significantly lower than that in the non-drainage group (p < 0.05). Multivariate regression analysis showed that drainage was beneficial to reduce postoperative complications (OR, 0.015; 95% CI, 0.002-0.140; p < 0.01). In addition, it was worth noting that in subgroup analysis, patients with hernia sac volume > 10 cm3 might receive more clinical benefits by placing drainage tube. CONCLUSION: In TEP inguinal hernia repair, placing drainage tube is a simple and feasible traditional surgical treatment, which can promote postoperative recovery without increasing the risk of infection, especially in patients with large hernia sac volume.

Enhanced Meningeal Lymphatic Drainage Ameliorates Neuroinflammation and Hepatic Encephalopathy in Cirrhotic Rats.

BACKGROUND & AIMS: Hepatic encephalopathy (HE) is a serious neurologic complication in patients with liver cirrhosis. Very little is known about the role of the meningeal lymphatic system in HE. We tested our hypothesis that enhancement of meningeal lymphatic drainage could decrease neuroinflammation and ameliorate HE. METHODS: A 4-week bile duct ligation model was used to develop cirrhosis with HE in rats. Brain inflammation in patients with HE was evaluated by using archived GSE41919. The motor function of rats was assessed by the rotarod test. Adeno-associated virus 8-vascular endothelial growth factor C (AAV8-VEGF-C) was injected into the cisterna magna of HE rats 1 day after surgery to induce meningeal lymphangiogenesis. RESULTS: Cirrhotic rats with HE showed significantly increased microglia activation in the middle region of the cortex (P < .001) as well as increased neuroinflammation, as indicated by significant increases in interleukin 1ß, interferon γ, tumor necrosis factor α, and ionized calcium binding adaptor molecule 1 (Iba1) expression levels in at least 1 of the 3 regions of the cortex. Motor function was also impaired in rats with HE (P < .05). Human brains of patients with cirrhosis with HE also exhibited up-regulation of proinflammatory genes (NFKB1, IbA1, TNF-α, and IL1ß) (n = 6). AAV8-VEGF-C injection significantly increased meningeal lymphangiogenesis (P = .035) and tracer dye uptake in the anterior and middle regions of the cortex (P = .006 and .003, respectively), their corresponding meninges (P = .086 and .006, respectively), and the draining lymph nodes (P = .02). Furthermore, AAV8-VEGF-C decreased microglia activation (P < .001) and neuroinflammation and ameliorated motor dysfunction (P = .024). CONCLUSIONS: Promoting meningeal lymphatic drainage and enhancing waste clearance improves HE. Manipulation of meningeal lymphangiogenesis could be a new therapeutic strategy for the treatment of HE.

Serum GGT/ALT ratio predicts vascular invasion in HBV-related HCC.

BACKGROUND: The gamma-glutamyl transferase (GGT) to alanine aminotransferase (ALT) ratio has been reported as an effective predictor of the severity of hepatitis and HCC. The purpose of this study was to determine the role of the GGT/ALT ratio in the prediction of vascular invasion and survival outcomes in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). METHODS: The risk factors for vascular invasion were determined by univariate/multivariate logistic analysis. The cut-off value of GGT/ALT in predicting vascular invasion was calculated using the receiver operating characteristic (ROC) curve. The prognostic value of GGT/ALT was examined by Cox analysis and Kaplan-Meier curves. Sensitivity analysis, such as subgroup analysis and propensity score matching (PSM), was performed to reduce potential confounding bias. RESULTS: A high GGT/ALT ratio was identified as an independent risk factor for vascular invasion (P = 0.03). The correlation analysis suggested that higher GGT/ALT was associated with more severe tumour burdens, including vascular invasion (P < 0.001), tumour volume > 5 cm (P < 0.001), poor pathological differentiation (P = 0.042), more severe BCLC (P < 0.001) and ALBI grade (P = 0.007). In the survival analysis, a high GGT/ALT ratio was associated with poor overall survival (OS) (HR: 1.38; 95% CI 1.03, 1.87; P < 0.0001) and disease-free survival (DFS) (HR: 1.32; 95% CI 1.03, 1.87; P < 0.0001). In the subgroup analysis, similar results were consistently observed across most subgroups. In PSM analysis, GGT/ALT remained independently associated with vascular invasion (OR, 186; 95% CI 1.23, 3.33). CONCLUSION: The GGT/ALT ratio was a potential effective factor in the prediction of vascular invasion and prognosis in patients with HBV-related HCC.

Population-based analysis on predictors for lymph node metastasis in T1 colon cancer.

BACKGROUND: In this study, we aimed to identify independent predictive factors for lymph node metastasis (LNM) in T1 colon cancer. METHODS: Data of 8056 eligible patients were retrospectively collected from the Surveillance, Epidemiology, and End Results (SEER) database during 2004-2012. We performed logistic regression analysis to identify predictive factors for LNM. Both unadjusted and adjusted Cox regression analyses were used to determine the association between LNM and patient survival. Finally, we used competing risks analysis and the cumulative incidence function (CIF) to further confirm the prognostic role of LNM in cancer-specific survival (CSS). RESULTS: The overall risk of LNM in patients with T1 colon cancer was 12.0% (N = 967). Adjusted logistic regression models revealed that mucinous carcinoma [odds ratio (OR) = 2.26, P < 0.001], moderately differentiated (OR 1.74, P < 0.001), poorly differentiated (OR 5.16, P < 0.001), and undifferentiated carcinoma (OR 3.01, P = 0.003); older age (OR 0.66, P < 0.001 for age 65-79 years, OR 0.44, P < 0.001 for age over 80 years); and carcinoma located in the ascending colon (OR 0.77, P = 0.018) and sigmoid colon (OR 1.24, P = 0.014) were independent predictive factors for LNM. Adjusted Cox regression analysis showed that positive lymph node involvement was significantly associated with CSS [hazard ratio (HR) = 3.02, P < 0.001], which was further robustly confirmed using a competing risks model and the CIF. CONCLUSIONS: This population-based study showed that mucinous carcinoma, tumor grade, age, and primary tumor location were independent predictive factors for LNM in T1 colon cancer. The risk of LNM should be carefully evaluated in patients with T1 colon cancer, before clinical management.

Assessment of a biofluid mechanics-based model for calculating portal pressure in canines.

BACKGROUND: Portal hypertension is a severe complication caused by various chronic liver diseases. The standard methods for detecting portal hypertension (hepatic venous pressure gradient and free portal pressure) are available in only a few hospitals due to their technical difficulty and invasiveness; thus, non-invasive measuring methods are needed. This study aimed to establish and assess a novel model to calculate free portal pressure based on biofluid mechanics. RESULT: Comparison of each dog's virtual and actual free portal pressure showed that a biofluid mechanics-based model could accurately predict free portal pressure (mean difference: -0.220, 95% CI: - 0.738 to 0.298; upper limit of agreement: 2.24, 95% CI: 1.34 to 3.14; lower limit of agreement: -2.68, 95% CI: - 3.58 to - 1.78; intraclass correlation coefficient: 0.98, 95% CI: 0.96 to 0.99; concordance correlation coefficient: 0.97, 95% CI: 0.93 to 0.99) and had a high AUC (0.984, 95% CI: 0.834 to 1.000), sensitivity (92.3, 95% CI: 64.0 to 99.8), specificity (91.7, 95% CI: 61.5 to 99.8), positive likelihood ratio (11.1, 95% CI: 1.7 to 72.8), and low negative likelihood ratio (0.08, 95% CI: 0.01 to 0.6) for detecting portal hypertension. CONCLUSIONS: Our study suggests that the biofluid mechanics-based model was able to accurately predict free portal pressure and detect portal hypertension in canines. With further research and validation, this model might be applicable for calculating human portal pressure, detecting portal hypertensive patients, and evaluating disease progression and treatment efficacy.

Prognostic value of the creatinine-albumin ratio in acute pancreatitis debridement.

BACKGROUND: Increases in the levels of serum C-reactive protein (CRP) and creatinine (Cr) and decreases in those of albumin (Alb) are commonly observed in acute pancreatitis (AP). We aimed to evaluate the efficacy of the Cr/Alb and CRP/Alb ratios in the prediction of surgical treatment effect in AP patients. METHODS: This study retrospectively analyzed clinical data obtained from 140 AP patients who underwent debridement from January 2008 to November 2018 in Shanghai Ruijin Hospital. The Cr/Alb and CRP/Alb ratios at admission and before surgery were assessed in the analysis of clinical statistics, prediction of prognoses, and logistic regression analysis. RESULTS: The admission Cr/Alb had the best predictive value of the four ratios. This value was significantly higher in patients with re-operation and those who died (P < 0.05) and was correlated with the Acute Physiology and Chronic Health Evaluation (APACHE II) score, admission CRP/Alb, preoperative Cr/Alb, and post-operative complications. The admission Cr/Alb could predict the risk of AP-related re-operation and mortality with sensitivities, specificities and areas under the curve of 86.3%, 61.7% and 0.824, and 73.4%, 81.3% and 0.794, respectively. At a cut-off value of 3.43, admission Cr/Alb values were indicative of a worse clinical state, including impaired laboratory test values, APACHE II scores, rates of post-operative complications and re-operation, and mortality (P < 0.05). In the logistic regression analysis, admission Cr/Alb values were independently related to the APACHE II score, post-operative renal failure, and mortality. CONCLUSION: Cr/Alb is a novel but promising, easy-to-measure, reproducible, non-invasive prognostic score for the prediction of the effect of debridement in AP patients.

Comparable rates of lymph node metastasis and survival between diffuse type and intestinal type early gastric cancer patients: a large population-based study.

BACKGROUND AND AIMS: Limited evidence and contradictory results exist regarding the impact of Lauren type, namely diffuse and intestinal types, of lymph node metastasis (LNM) and prognosis for early gastric cancer (EGC). We aimed to compare LNM and prognosis between diffuse and intestinal type EGCs using comprehensive statistical analysis. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify all patients with surgically resected, histologically diagnosed, intestinal or diffuse type EGC. Multivariate logistic regression, multivariate Cox regression, multivariate competing risk model, and propensity score matching were used to analyze association the Lauren type and LNM or prognosis. RESULTS: We identified 5593 EGCs from the SEER database, including 4376 intestinal types and 1217 diffuse types. No positive association was found between LNM and Lauren type (odds ratio, .93; 95% confidence interval [CI], .70-1.24; P = .62) after adjustment for other risk factors. Moreover, diffuse-type EGCs showed a similar prognosis to intestinal type EGCs in both multivariate Cox regression (HR [hazard ratio], .95; 95% CI, .77-1.18; P = .66) and the multivariate competing risk model (subdistribution HR [SHR], .99; 95% CI, .80-1.22; P = .926). Propensity score matching was used, and 733 diffuse types were matched with 733 intestinal types. We did not find any association between the Lauren type and LNM (odds ratio, .98; 95% CI, .71-1.37; P = .934) or prognosis in the univariate Cox regression (HR, .98; 95% CI, .76-1.26; P = .893) and univariate competing risk model (SHR, .98; 95% CI, .76-1.26; P = .893). CONCLUSIONS: Diffuse-type EGC may have a comparable risk of LNM and prognosis to intestinal-type EGC. Nevertheless, these results should be carefully interpreted with caution when choosing endoscopic resection instead of surgery, because the treatment choice for EGC depends on the risk of lymphovascular invasion rather than LNM rate or prognosis.

Effects of NLRP6 on the proliferation and activation of human hepatic stellate cells.

Nod-like receptor pyrin domain-containing proteins (NLRPs) are known to take part in the pathogenesis of chronic liver diseases, including liver fibrosis. However, no known direct role of NLRP6, a member of NLRPs, has been reported in liver fibrosis. Here, we found that NLRP6 expression was decreased in fibrotic and cirrhotic livers. In a human hepatic stellate cell line, LX-2, overexpression of NLRP6 suppressed cell proliferation, hydroxyproline accumulation, as well as the expression of type I and type III collagens (Col-I and Col-III), α-smooth muscle actin (α-SMA) and matrix metalloproteinases (MMP2 and MMP9), whereas NLRP6 knockdown displayed reverse effects. Furthermore, NLRP6 significantly suppressed the phosphorylation of Smad2/3 (p-Smad2/3) and enhanced the expression of protein phosphatase magnesium dependent 1 A (PPM1A), the only phosphatase for Smad2/3. NLRP6 overexpression abrogated TGF-ß1-stimulated hydroxyproline accumulation and p-Smad2/3. Co-immunoprecipitation assay demonstrated that NLRP6 was able to form a complex with PPM1A. NLRP6 overexpression did not change the level of p-Smad2/3 in LX-2 cells with PPM1A knockdown. These data indicated that PPM1A was required for the inhibitory effects of NLRP6 on TGF-ß1/Smad2/3 signaling. In conclusion, our results suggest that NLRP6 exerts anti-fibrotic effects in LX-2 cells via regulating PPM1A/Smad2/3 and that NLRP6 may be an effective target in the treatment of liver fibrosis.

Transforming growth factor beta induced (TGFBI) is a potential signature gene for mesenchymal subtype high-grade glioma.

Previous study revealed that higher expression of transforming growth factor beta induced (TGFBI) is correlated to poorer cancer-specific survival and higher proportion of tumor necrosis and Fuhrman grades III and IV in clear cell renal cell carcinomas. However, the relationships between TGFBI expression and malignant phenotypes of gliomas remain unclear. We downloaded and analyzed data from seven GEO datasets (GSE68848, GSE4290, GSE13041, GSE4271, GSE83300, GSE34824 and GSE84010), the TCGA database and the REMBRANDT database to investigate whether TGFBI could be a biomarker of glioma. From microarray data (GSE68848, GSE4290) and RNA-seq data (TCGA), TGFBI expression levels were observed to correlate positively with pathological grade, and TGFBI expression levels were significantly higher in gliomas than in normal brain tissues. Furthermore, in GSE13041, GSE4271 and the TCGA cohort, TGFBI expression in the mesenchymal (Mes) subtype high-grade glioma (HGG) was significantly higher than that in the proneural subtype. Kaplan-Meier survival analysis of GBM patients in the GSE83300 dataset, REMBRANDT and TCGA cohort revealed that patients in the top 50% TGFBI expression group survived for markedly shorter periods than those in the bottom 50%. Analysis of grade III gliomas showed that the median survival time was significantly shorter in the TGFBI high expression group than in the TGFBI low expression group. In addition, we found that TGFBI expression levels might relate to several classical molecular characterizations of glioma, such as, IDH mutation, TP53 mutation, EGFR amplification, etc. These results suggest that TGFBI expression positively correlates with glioma pathological grades and that TGFBI is a potential signature gene for Mes subtype HGG and a potential prognostic molecule.

Inhibition of soluble epoxide hydrolase lowers portal hypertension in cirrhotic rats by ameliorating endothelial dysfunction and liver fibrosis.

Epoxyeicostrienoic acids (EETs) are arachidonic acid derived meditators which are catalyzed by soluble epoxide hydrolase (sEH) to less active dihydroeicostrienoics acids (DHETS). The aim of our study is to investigate the effects of sEH inhibition on hepatic and systemic hemodynamics, hepatic endothelial dysfunction, and hepatic fibrosis in CCl4 cirrhotic rats. The sEH inhibitor,trans-4-{4-[3-(4-trifluoromethoxyphenyl)-ureido]cyclohexyloxy}benzoic acid (t-TUCB) was administered to stabilize hepatic EETs by gavage at a dose of 1mg/kg/d. Our results showed that hepatic sEH expression was markedly increased in portal hypertension, and led to a lower ratio of EETs/DHETs which was effectively reversed by t-TUCB administration. t-TUCB significantly decreased portal pressure without significant changes in systemic hemodynamics, which was associated with the attenuation of intrahepatic vascular resistance (IHVR) and liver fibrosis. t-TUCB ameliorated endothelial dysfunction, increased hepatic endothelial nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) production. In addition, t-TUCB significantly reduced alpha-Smooth Muscle Actin (α-SMA) expression and liver fibrosis, which was associated with a decrease in NF-κB signaling. Taken together, inhibition of sEH reduces portal pressure, liver fibrosis and attenuates hepatic endothelial dysfunction in cirrhotic rats. Our results indicate that sEH inhbitors may be useful in the treatment of portal hypertension in patients with cirrhosis.

Inhibition of soluble epoxide hydrolase reduces portal pressure by protecting mesenteric artery myogenic responses in cirrhotic rats.

Hyperdynamic circulation contributes to the progress of portal hypertension in liver cirrhosis. We investigated the effects of soluble epoxide hydrolase (sEH) inhibition on portal pressure and the myogenic response of mesenteric arteries isolated from cirrhotic rats using the sEH inhibitor t-TUCB (trans-4-{4-[3-(4-trifluoromethoxyphenyl)-ureido]cyclohexyloxy}benzoic acid). Cirrhotic tissues had a higher ratio of epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs) following increased CYP2C11 expression, which may be a protective response. In comparison with controls, myogenic responses of mesenteric arteries from cirrhotic rats were attenuated at 80-140mmHg, while inhibition of sEH partly reversed the impaired myogenic constriction at 100-140mmHg and exhibited better feedback of vascular smooth muscle to pressure variation. Inhibition of sEH reduced portal pressure by decreasing endothelial synthesis of nitric oxide. An imbalance between EETs and nitric oxide may account for hyperdynamic circulation. sEH inhibitors may provide a novel approach for treating cirrhosis of the liver.

Imperatorin attenuates CCl4-induced cirrhosis and portal hypertension by improving vascular remodeling and profibrogenic pathways.

BACKGROUND: Cirrhosis leads to portal hypertension (PHT), affecting survival with limited treatment options. This study investigated Imperatorin (IMP), a furanocoumarin with anti-inflammatory and hypotensive properties, for its therapeutic role and mechanisms in cirrhotic PHT. METHODS: Hepatic stellate cells (HSCs) inhibition by IMP was evaluated using LX-2 cell line. Rat cirrhosis was induced via CCl4 for 16 weeks. Experimental group were orally administered IMP (15/25 mg/kg/day) for 4 weeks. We subsequently examined portal pressure (PP), cirrhosis, inflammation, angiogenesis, and vascular remodeling. Network pharmacology was employed for mechanistic insights. RESULTS: IMP significantly inhibited the fibrogenesis in HSCs and suppressed cell viability. CCl4 exposure induced cirrhosis, inflammation, angiogenesis, vascular remodeling and PHT. IMP significantly reduced PP from 22.85±3.88 mmHg to 6.67±0.6 mmHg, diminished collagen deposition and pro-fibrotic factor expression, alleviated inflammation, and improved liver function. Vessel wall thickness in superior mesenteric arteries was restored, and intra-/extrahepatic angiogenesis was inhibited via VEGF and vWF. Furthermore, IMP induced sinusoidal vasodilation by upregulating eNOS and GCH1. Enrichment analysis indicated that IMP was involved in various biological processes associated with cirrhosis, such as the regulation of blood pressure, tissue remodeling, response to inflammation, and regulation of angiogenesis, etc. Additionally, IMP suppressed hepatic expression of TGF-ß both in vitro and in vivo, which was further supported by KEGG analysis. CONCLUSION: Our research demonstrated that IMP significantly mitigated cirrhosis PHT by reducing hepatic fibrosis and inflammation, curbing angiogenesis and vascular remodeling, and promoting vasodilation. This protective mechanism appears to be facilitated through the downregulation of TGF-ß.

A Python Package itca for Information-Theoretic Classification Accuracy: A Criterion That Guides Data-Driven Combination of Ambiguous Outcome Labels in Multiclass Classification.

The itca Python package offers an information-theoretic criterion to assist practitioners in combining ambiguous outcome labels by balancing the tradeoff between prediction accuracy and classification resolution. This article provides instructions for installing the itca Python package, demonstrates how to evaluate the criterion, and showcases its application in real-world scenarios for guiding the combination of ambiguous outcome labels.

Identification of significant modules and hub genes involved in hepatic encephalopathy using WGCNA.

BACKGROUND: Hepatic encephalopathy (HE) is a reversible syndrome of brain dysfunction caused by advanced liver disease. Weighted gene co-expression network analysis (WGCNA) could establish a robust co-expression network to identify the hub genes and underlying biological functions. This study was aimed to explore the potential therapeutic targets in HE by WGCNA. RESULTS: The green and brown modules were found to be significantly associated with the development of HE. Functional enrichment analyses suggested the neuroinflammation, neuroimmune, extracellular matrix (ECM), and coagulation cascade were involved in HE. CYBB and FOXO1 were calculated as hub genes, which were upregulated in the HE patients. Tamibarotene and vitamin E were suggested as possible drug candidates to alleviate HE. CONCLUSIONS: It is the first time to analyze transcriptomic data of HE by WGCNA. Our study not only promoted the current understanding of neuroinflammation in HE, but also provided the first evidence that CYBB and FOXO1 played pivotal roles in the pathogenesis of HE, which might be potential biomarkers and therapeutic targets. Tamibarotene might be a novel drug compound against HE.

Construction and comprehensive analysis of a lncRNA-mRNA interactive network to reveal a potential lncRNA for hepatic encephalopathy development.

Little is known about the role of lncRNA-mRNA regulatory relationships in hepatic encephalopathy (HE). Here, we aimed to construct the potential lncRNA and mRNA interactive network in forecasting HE development in patients with liver cirrhosis using different bioinformatic analysis method. Through analyses, we found that AL137857.1 had the most connections with other mRNAs and was deemed as a hub lncRNA. It was obviously upregulated in HE patients, which was also validated by another independent dataset. GO and KEGG analyses suggested that AL137857.1 was involved in microglial cell activation, phagocytosis, cytokine biosynthetic process, interleukin-6 production and tumor necrosis factor production. In vitro experiments suggested LPS could stimulate microglia to generate AL137857.1. In addition, we found that inhibition of AL137857.1 suppressed the expression of a series of inflammatory cytokines, including IL-1, IL-6, TNF-α, Cox2 and iNOS. Conversely, AL137857.1 over-expression induced a marked increase in these factors. Finally, AL137857.1 was demonstrated to be highly associated with the ability of microglial phagocytosis. Taken together, we have constructed a lncRNA-mRNA regulatory network associated with HE and explored the biological significance of mRNAs in the network, then discovered a novel lncRNA AL137857.1 in HE that might act as a potential regulator of the downstream inflammatory cytokines.

Salivary biomarkers-assisted ultrasound-based differentiation of malignant and benign thyroid nodules.

BACKGROUND: The incidence of papillary thyroid cancer (PTC) is increasing annually. ultrasonography (US) is the current primary method for evaluating thyroid nodules; however, there have been persisting challenges in diagnosing borderline malignancies. This paper aimed to establish the differential diagnostic value of salivary biomarkers for thyroid nodules geared towards improving the efficacy of US. METHODS: We recruited a total of 44 PTC patients and 42 benign thyroid tumor (BTT) patients to this study. The distribution of tumor markers and thyroid hormones in saliva and serum were compared between groups; then, uni-/multi-variate logistic analyses were used to determine the risk factors of PTC. Further, we estimated the differential diagnostic value of biomarkers in thyroid nodules, especially in borderline scenarios. Finally, a multi-index diagnostic model was constructed constituting biomarkers and US. RESULTS: The distributions of serum thyroglobulin (TG), salivary triiodothyronine (T3), free-triiodothyronine (FT3), and free-thyroxine (FT4) were significantly different in BTT and PTC (P<0.05); salivary FT3 was identified as an independent risk factor for PTC. By analyzing the diagnostic accuracy of various Thyroid Imaging Reporting and Data System (TI-RADS) categories, category 4A was shown to have the lowest diagnostic accuracy (48.39%) with the largest proportion (31 people, 36.05%). In 4A patients, the K-nearest neighbor (KNN) algorithm attained the highest sensitivity of 87.50% and specificity of 100.00% among the machine learning-based multi-biomarkers models. Eventually, by combing the US with the KNN-based biomarkers model, the sensitivity and specificity reached 90.91% and 83.33%, respectively. CONCLUSIONS: Salivary biomarkers exhibit good potential in the differential diagnosis of borderline thyroid nodules and they significantly improve the prediction accuracy of the US. Additionally, we found that salivary FT3 is an independent risk factor for PTC and may be used as a key marker for PTC diagnosis.

Bayesian Joint Matrix Decomposition for Data Integration with Heterogeneous Noise.

Matrix decomposition is a popular and fundamental approach in machine learning and data mining. It has been successfully applied into various fields. Most matrix decomposition methods focus on decomposing a data matrix from one single source. However, it is common that data are from different sources with heterogeneous noise. A few of the matrix decomposition methods have been extended for such multi-view data integration and pattern discovery while only a few methods were designed to consider the heterogeneity of noise in such multi-view data for data integration explicitly. To this end, in this article, we propose a joint matrix decomposition framework (BJMD), which models the heterogeneity of noise by the Gaussian distribution in a Bayesian framework. We develop two algorithms to solve this model: one is a variational Bayesian inference algorithm, which makes full use of the posterior distribution; and another is a maximum a posterior algorithm, which is more scalable and can be easily paralleled. Extensive experiments on synthetic and real-world datasets demonstrate that BJMD is superior or competitive to the state-of-the-art methods.

Bioinformatics-Based Analysis of lncRNA-mRNA Interaction Network of Mild Hepatic Encephalopathy in Cirrhosis.

BACKGROUNDS: Serum long noncoding RNAs (lncRNAs) and messenger RNAs (mRNAs) interaction network was discovered to exert an important role in liver cirrhosis while little is known in mild hepatic encephalopathy (MHE). Therefore, we aim to systematically evaluate the serum lncRNA-mRNA network and its regulatory mechanism in MHE. METHODS: The data of serum mRNAs and lncRNAs were derived from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were calculated between 11 cirrhotic patients with and without MHE. Next, the biological functions and underlined pathways of DEGs were determined through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Finally, an interactive network between lncRNAs and mRNAs was built, and hub genes were identified, respectively. RESULTS: A total of 64 differentially expressed lncRNAs (dif-lncRNAs) were found between patients with and without MHE, including 30 up- and 34 downregulated genes. 187 differentially expressed mRNAs (dif-mRNAs) were identified, including 84 up- and 103 downregulated genes. Functional enrichment analysis suggested that the regulatory pathways involved in MHE mainly consisted of a series of immune and inflammatory responses. Several hub mRNAs involved in regulatory network were identified, including CCL5, CCR5, CXCR3, CD274, STAT1, CXCR6, and EOMES. In addition, lnc-FAM84B-8 and lnc-SAMD3-1 were found to regulate these above hub genes through building a lncRNA-mRNA network. CONCLUSION: This is the first study to construct the serum lncRNA-mRNA network in MHE, demonstrating the critical role of lncRNAs in regulating inflammatory and immunological profiles in the developing of MHE, suggesting a latent mechanism in this pathophysiological process.