Improving diagnosis and outcome prediction of gastric cancer via multimodal learning using whole slide pathological images and gene expression.

For the diagnosis and outcome prediction of gastric cancer (GC), machine learning methods based on whole slide pathological images (WSIs) have shown promising performance and reduced the cost of manual analysis. Nevertheless, accurate prediction of GC outcome may rely on multiple modalities with complementary information, particularly gene expression data. Thus, there is a need to develop multimodal learning methods to enhance prediction performance. In this paper, we collect a dataset from Ruijin Hospital and propose a multimodal learning method for GC diagnosis and outcome prediction, called GaCaMML, which is featured by a cross-modal attention mechanism and Per-Slide training scheme. Additionally, we perform feature attribution analysis via integrated gradient (IG) to identify important input features. The proposed method improves prediction accuracy over the single-modal learning method on three tasks, i.e., survival prediction (by 4.9% on C-index), pathological stage classification (by 11.6% on accuracy), and lymph node classification (by 12.0% on accuracy). Especially, the Per-Slide strategy addresses the issue of a high WSI-to-patient ratio and leads to much better results compared with the Per-Person training scheme. For the interpretable analysis, we find that although WSIs dominate the prediction for most samples, there is still a substantial portion of samples whose prediction highly relies on gene expression information. This study demonstrates the great potential of multimodal learning in GC-related prediction tasks and investigates the contribution of WSIs and gene expression, respectively, which not only shows how the model makes a decision but also provides insights into the association between macroscopic pathological phenotypes and microscopic molecular features.

Huanglian Jiedu Wan intervened with "Shi-Re Shanghuo" syndrome through regulating immune balance mediated by biomarker succinate.

With increasing stress in daily life and work, subhealth conditions induced by "Shi-Re Shanghuo" syndrome was gradually universal. "Huanglian Jiedu Wan" (HLJDW) was the first new syndrome Chinese medicine approved for the treatment of "Shi-Re Shanghuo" with promising clinical efficacy. Preliminary small-sample clinical studies have identified some notable biomarkers (succinate, 4-hydroxynonenal, etc.). However, the correlation and underlying mechanism between these biomarkers of HLJDW intervention on "Shi-Re Shanghuo" syndrome remained ambiguous. Therefore, this study was designed as a randomized, double-blind, multicenter, placebo-controlled Phase II clinical trial, employing integrated analysis techniques such as non-targeted and targeted metabolomics, salivary microbiota, proteomics, parallel peaction monitoring, molecular docking and surface plasmon resonance (SPR). The results of the correlation analysis indicated that HLJDW could mediate the balance between inflammation and immunity through succinate produced via host and microbial source to intervene "Shi-Re Shanghuo" syndrome. Further through the HIF1α/MMP9 pathway, succinate regulated downstream arachidonic acid metabolism, particularly the lipid peroxidation product 4-hydroxynonenal. Finally, an animal model of recurrent oral ulcers induced by "Shi-Re Shang Huo" was established and HLJDW was used for intervention, key essential indicators (succinate, glutamine, 4-hydroxynonenal, arachidonic acid metabolism) essential in the potential pathway HIF1α/MMP9 discovered in clinical practice were validated. The results were found to be consistent with our clinical findings. Taken together, succinate was observed as an important signal that triggered immune responses, which might serve as a key regulatory metabolic switch or marker of "Shi-Re Shanghuo" syndrome treated with HLJDW.

DBLiPro: A Database for Lipids and Proteins in Human Lipid Metabolism.

To help researchers in the field of biology, medicine, chemistry, and materials science to use lipidomic data conveniently, there is an urgent need to develop a platform that provides a systematic knowledgebase of human lipid metabolism and lipidome-centric omics analysis tools. DBLiPro is a user-friendly webserver allowing for access to human metabolism-related lipids and proteins knowledge database and an interactive bioinformatics integrative analysis workflow for lipidomics, transcriptomics, and proteomics data. In DBLiPro, there are 3109 lipid-associated proteins (LAPs) and 2098 lipid metabolites in the knowledge base section, which were obtained from Uniprot, Kyoto Encyclopedia of Genes and Genomes (KEGG) and were further annotated by information from other public resources in the knowledge base section, such as RaftProt and PubChem. DBLiPro offers a step-by-step interactive analysis workflow for lipidomics, transcriptomics, proteomics, and their integrating multi-omics analysis focusing on the human lipid metabolism. In summary, DBLiPro is capable of helping users discover key molecules (lipids and proteins) in human lipid metabolism and investigate lipid-protein functions underlying mechanisms based on their own omics data. The DBLiPro is freely available at http://lipid.cloudna.cn/home.

Betulinic acid mitigates zearalenone-induced liver injury by ERS/MAPK/Nrf2 signaling pathways in mice.

Zearalenone (ZEA) is a mycotoxin commonly found in cereals and feedstuffs, which can induce oxidative stress and inflammation to cause liver damage in humans and animals. Betulinic acid (BA) is extracted from pentacyclic triterpenoids of many natural plants and has anti-inflammatory, and anti-oxidation biological activities in many studies. However, the protective effect of BA on liver injury induced by ZEA has not been reported. Therefore, this study aims to explore the protective effect of BA on ZEA-induced liver injury and its possible mechanism. In the mice experiment, ZEA exposure increased the liver index and caused histopathological impairment, oxidative damage, hepatic inflammatory responses, and increased hepatocyte apoptosis. However, when combined with BA, it could inhibit the production of ROS, up-regulate the proteins expression of Nrf2 and HO-1 and down-regulate the expression of Keap1, and alleviate oxidative damage and inflammation in the liver of mice. In addition, BA could alleviate ZEA-induced apoptosis and liver injury in mice by inhibiting the endoplasmic reticulum stress (ERS) and MAPK signaling pathways. In conclusion, this study revealed the protective effect of BA on the hepatotoxicity of ZEA for the first time, providing a new perspective for the development of ZEA antidote and the application of BA.

[Clinical application value of Huanglian Jiedu Pills in improving syndrome of excess heat and fire toxin based on phase â ¡ clinical trial study on plasma ATP, 4-HNE, and ACTH levels].

A randomized, double-blind, placebo-controlled, multi-center phase Ⅱ clinical trial design was used in this study to recruit subjects who were in line with the syndrome of excess heat and fire toxin, and were diagnosed as recurrent oral ulcers, gingivitis, and acute pharyngitis. A total of 240 cases were included and randomly divided into a placebo group and a Huanglian Jiedu Pills group. The clinical efficacy of Huanglian Jiedu Pills in treating the syndrome of excess heat and fire toxin was evaluated by using the traditional Chinese medicine(TCM) syndrome scale. Enzyme-linked immunosorbent assay(ELISA) was used to determine and evaluate the levels of adenosine triphosphate(ATP), 4-hydroxynonenal(4-HNE), and adrenocorticotropic hormone(ACTH) in plasma of the two groups before and after administration and to predict their application value as clinical biomarkers. The results showed that the disappearance rate of main symptoms in the Huanglian Jiedu Pills group was 69.17%, and that in the placebo group was 50.83%. The comparison between the Huanglian Jiedu Pills group and the placebo group showed that 4-HNE before and after administration was statistically significant(P<0.05). The content of 4-HNE in the Huanglian Jiedu Pills group decreased significantly after administration(P<0.05), but that in the placebo group had no statistical significance and showed an upward trend. After administration, the content of ATP in both Huanglian Jiedu Pills group and placebo group decreased significantly(P<0.05), indicating that the energy metabolism disorder was significantly improved after administration of Huanglian Jiedu Pills and the body's self-healing ability also alleviated the increase in ATP level caused by the syndrome of excess heat and fire toxin to a certain extent. ACTH in both Huanglian Jiedu Pills group and placebo group decreased significantly after administration(P<0.05). It is concluded that Huanglian Jiedu Pills has a significant clinical effect, and can significantly improve the abnormal levels of ATP and 4-HNE in plasma caused by the syndrome of excess heat and fire toxin, which are speculated to be the effective clinical biomarkers for Huanglian Jiedu Pills to treat the syndrome of excess heat and fire toxin.

Betulinic acid alleviates zearalenone-induced uterine injury in mice.

Zearalenone (ZEA) is a mycotoxin with estrogen-like biological activity, which widely present in feed and raw materials, with strong reproductive system toxicity and a major threat to animal reproduction. Betulinic acid (BA) is a natural plant compound with antioxidant, anti-inflammatory and other pharmacological activities. However, the mechanism of ZEA-induced uterine injury and the protective effect of BA have not been reported. Our results show that ZEA could cause uterine histopathological damage and cellular ultrastructural damage, affecting the secretion of sex hormones, such as estradiol (E2) and progesterone (P4), and increase the mRNA and protein expression of estrogen receptor α (ERα). ZEA could inhibit the activities of catalase (CAT) and superoxide dismutase (SOD), increase the production of malondialdehyde (MDA) and reactive oxygen species (ROS), and cause uterine oxidative stress. Furthermore, ZEA affected the homeostasis of uterine cell proliferation and death by regulating the expression of proliferating cell nuclear antigen (PCNA) and activating the mitochondrial apoptotic pathway. ZEA-induced uterine injury might be related to the activation of p38/ERK MAPK signaling pathway. However, the regulatory effect of ZEA on the uterus was reversed after BA treatment. In conclusion, the uterus is an important target organ attacked by ZEA, and BA showed a good therapeutic effect.

Identification of prognostic gene expression signatures based on the tumor microenvironment characterization of gastric cancer.

Increasing evidence has elucidated that the tumor microenvironment (TME) shows a strong association with tumor progression and therapeutic outcome. We comprehensively estimated the TME infiltration patterns of 111 gastric cancer (GC) and 21 normal stomach mucosa samples based on bulk transcriptomic profiles based on which GC could be clustered as three subtypes, TME-Stromal, TME-Mix, and TME-Immune. The expression data of TME-relevant genes were utilized to build a GC prognostic model-GC_Score. Among the three GC TME subtypes, TME-Stomal displayed the worst prognosis and the highest GC_Score, while TME-Immune had the best prognosis and the lowest GC_Score. Connective tissue growth factor (CTGF), the highest weighted gene in the GC_Score, was found to be overexpressed in GC. In addition, CTGF exhibited a significant correlation with the abundance of fibroblasts. CTGF has the potential to induce transdifferentiation of peritumoral fibroblasts (PTFs) to cancer-associated fibroblasts (CAFs). Beyond characterizing TME subtypes associated with clinical outcomes, we correlated TME infiltration to molecular features and explored their functional relevance, which helps to get a better understanding of carcinogenesis and therapeutic response and provide novel strategies for tumor treatments.

Profound Hypothermia Concomitant With Severe Coagulation Dysfunction and Leukopenia in a Preterm Infant: A Case Report and Literature Review.

BACKGROUND: Neonatal hypothermia is common around the world; however, profound hypothermia is a very rare-but life-threatening-event. CLINICAL FINDINGS: This was a very rare case involving a 15-day old preterm infant diagnosed with profound hypothermia (rectal temperature, 27°C) concomitant with severe coagulation dysfunction and leukopenia on admission. PRIMARY DIAGNOSIS: Profound hypothermia together with severe coagulopathy, leukopenia, late-onset sepsis, and pneumonia. INTERVENTIONS: The patient was rewarmed slowly, with a rectal temperature rising at a rate of 0.5°C/h < R < 1°C/h. Vital signs were closely monitored. Coagulation factors were supplemented by intravenous infusion of fresh frozen plasma. Supportive treatment with intravenous infusion of immunoglobulin was provided, and antibiotics were used empirically. Nil per os and intravenous rehydration were also implemented. OUTCOMES: The condition of the preterm infant gradually improved and was successfully discharged. PRACTICE RECOMMENDATIONS: Profound hypothermia is very rare in preterm infants. However, once it occurs, it may be concomitant with severe coagulopathy and leukopenia. Successful management involves slow rewarming, prompt supplementation of coagulation factors, empirical antibiotics, and supportive treatment.

Homozygous familial hypercholesterolemia in China: Genetic and clinical characteristics from a real-world, multi-center, cohort study.

BACKGROUND: There is a lack of large-scale data on the clinical and genotype characteristics of homozygous familial hypercholesterolemia (HoFH) patients in Asia. OBJECTIVE: To define the characteristics of phenotypic and genetic HoFH probands from mainland China. METHODS: We collected data from patients with suspected HoFH from ten clinical hospitals across mainland China from 2003 to 2019. Clinical data and DNA testing were obtained in all patients. The Kaplan-Meier method was used to generate survival curves, and the groups were compared with the log-rank test. RESULTS: A total of 108 unrelated probands with suspected HoFH (mean age 14.9 years) were included. The three most common variants were W483X (c.1448 G>A), A627T (c.1879 G>A), H583Y (c.1747 C>T). The majority (64.8%) were compound heterozygotes (n = 70), 23 (21.3%) were true HoFH patients. True HoFH showed higher LDL-C levels compared to compound HoFH (16.8±3.6 mmol/L vs. 15.0±3.1 mmol/L, P = 0.022). During follow-up, only 21.2% patients exhibited an LDL-C reduction of more than 50%. Kaplan-Meier analysis showed that the true HoFH probands had significantly worse survival rates compared to other genotype probands (13-year survival; 20.3% vs. 76.7%, respectively; P = 0.016). In addition, true HoFH shows that 2.8-fold (P = 0.022) increase any death and 3.0-fold (P = 0.023) increase cardiovascular death risk in relative to other FH. CONCLUSIONS: This report shows that HoFH has devastating consequences, and that patients are often only diagnosed after they have been exposed to severely elevated LDL-C for years. Systematic screening and early intensive treatment are an absolute requirement for these young individuals with HoFH.

Effect of thyroid function on pre-ß1 high-density lipoprotein levels in patients with Graves' disease undergoing radioiodine treatment.

CONTEXT: The metabolism of HDL is altered in thyroid dysfunctions. Preß-1 HDL is a very small discoidal precursor HDL and promotes cholesterol efflux via ABCA1. The effects of thyroid dysfunctions on pre-ß1 HDL are unknown. Thyroid hormone regulates ANGPTL3 expression, which may participate in HDL metabolism in thyroid dysfunctions. OBJECTIVE: To determine the variation of HDL subfractions, especially preß-1 HDL in thyroid dysfunctions, and whether ANGPTL3 mediates the effect of thyroid function on HDL metabolism. METHODS: We recruited 26 patients with Graves' disease undergoing radioiodine treatment. They were evaluated at three time points: at baseline, when they were hypothyroid after radioiodine treatment, and when they were on stable levothyroxine replacement and euthyroid. RESULTS: The concentrations of smaller HDL particles Preß-1 HDL and HDL3 were highest at the hyperthyroid state, and lowest at the hypothyroid state. While the larger HDL particles HDL2 and HDL1 changed just the opposite. Preß1-HDL and HDL3 were positively correlated to fT3 and fT4, while were negatively correlated to TSH. In contrast, HDL1 was negatively associated with fT3 and fT4, while was positively associated with TSH. The correlations between thyroid hormones and HDL subfractions remained significant after adjusting for ANGPTL3. CONCLUSIONS: There is a shift form smaller HDL particles pre-ß1 HDL and HDL3 to larger HDL particles HDL2 and HDL1 in hypothyroidism, while the change is just the opposite in hyperthyroidism. In future, cholesterol efflux capacity should be measured to determine if the function of HDL particles also changes with the shifting of HDL subfractions.

Oxidized LDL but not angiotensin II induces cardiomyocyte hypertrophic responses through the interaction between LOX-1 and AT1 receptors.

It is well known that lectin-like oxidized low-density lipoprotein (ox-LDL) and its receptor LOX-1, angiotensin II (AngII) and its type 1 receptor (AT1-R) play an important role in the development of cardiac hypertrophy. However, the molecular mechanism is not clear. In this study, we found that ox-LDL-induced cardiac hypertrophy was suppressed by inhibition of LOX-1 or AT1-R but not by AngII inhibition. These results suggest that the receptors LOX-1 and AT1-R, rather than AngII, play a key role in the role of ox-LDL. The same results were obtained in mice lacking endogenous AngII and their isolated cardiomyocytes. Ox-LDL but not AngII could induce the binding of LOX-1 and AT1-R; inhibition of LOX-1 or AT1-R but not AngII could abolish the binding of these two receptors. Overexpression of wild type LOX-1 with AT1-R enhanced ox-LDL-induced binding of two receptors and phosphorylation of ERKs, however, transfection of LOX-1 dominant negative mutant (lys266ala / lys267ala) or an AT1-R mutant (glu257ala) not only reduced the binding of two receptors but also inhibited the ERKs phosphorylation. Phosphorylation of ERKs induced by ox-LDL in LOX-1 and AT1-R-overexpression cells was abrogated by an inhibitor of Gq protein rather than Jak2, Rac1 or RhoA. Genetically, an AT1-R mutant lacking Gq protein coupling ability inhibited ox-LDL induced ERKs phosphorylation. Furthermore, through bimolecular fluorescence complementation analysis, we confirmed that ox-LDL rather than AngII stimulation induced the direct binding of LOX-1 and AT1-R. We conclude that direct binding of LOX-1 and AT1-R and the activation of downstream Gq protein are important mechanisms of ox-LDL-induced cardiomyocyte hypertrophy.

Integrative Analysis Identified a 6-miRNA Prognostic Signature in Nasopharyngeal Carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated epithelial malignancy, which is rare in America but endemic in China. The current clinical gold TNM-based standard for prognosis may not be enough. Although some studies have reported that some miRNAs have a prognostic power in NPC, there is a scarcity of independent validation for these miRNAs. METHODS: In this work, we firstly conducted a literature review of all miRNA profiling datasets with survival information, then integrated miRNA expression data across different profiling platforms and built prognostic models using machine learning methods. The Kaplan-Meier method and log-rank tests were applied to estimate correlations of the miRNA signature with survival, and the area under the time-dependent ROC curve (AUC) and concordance index (C-index) were used to assess the predictive power of prognostic models. We also investigated the biological roles of the prognostic miRNAs through identifying their regulated genes and association with immune infiltration. RESULTS: We constructed a prognostic model based on 6-miRNA signature (ebv-miR-BART12, ebv-miR-BART15, miR-29c-3p, miR-30e-5p, hsa-miR-375-3p, has-miR-93-5p) using the elastic net penalized Cox regression model. The AUCs of our model predicting 1-, 3-, and 5-year overall survival rates were 0.90, 0.73, and 0.70 for the external validation dataset and showed better prognostic power than models using previously reported miRNA signatures. The 6-miRNA risk score was an independent prognostic predictor for overall survival (OS), disease-free survival (DFS), and metastasis-free survival (MFS). It could stratify patients into low-risk and high-risk groups; patients in the low-risk group treated with concurrent chemotherapy had a better survival. On the basis that the 6-miRNA risk score improved the current clinical gold standard for prognosis, we built a nomogram integrating both clinical characterizations and the risk score to predict 3-, 5-, and 10-year overall survival. Functional analysis suggested that the six miRNAs mainly play roles in virus infection pathways and oncogenic signaling pathways and associated with B-cell expression. CONCLUSION: We identified a 6-miRNA prognostic signature in nasopharyngeal carcinoma across miRNA profiling platforms and patient geographical difference, which showed good prediction capability in terms of OS, DFS, and MFS. The 6-miRNA risk score might be helpful for clinicians to make treatment strategies and predict patient outcomes.

Tannic acid repair of zearalenone-induced damage by regulating the death receptor and mitochondrial apoptosis signaling pathway in mice.

Zearalenone (ZEA) is an estrogenic toxin produced by Fusarium strains, that is widely present in crops, and endangers the reproductive system of animals. Tannic acid (TA) is a natural polyphenolic substance that is widespread in the roots, stems, and leaves of plants, and has special pharmacological activity. This study was designed to investigate the therapeutic effect of TA on ZEA-induced ovarian damage in mice and to explore the molecular mechanism involved. Ninety healthy Kunming female mice were divided into six equal groups. All the groups but the control group were administered daily with ZEA [10 mg/kg body weight (bw)] orally, for 7 days, to induce damage to the reproductive system. Some groups were also administered with TA (50, 100, and 200 mg/bw) for 7 days. Mice were euthanized 24 h later to allow for collection of serum and ovaries. TA can effectively alleviate the appearance of congestion and redness of the ovary, caused by ZEA, and increase the number of healthy growing follicles. Moreover, the estrogen content and the levels of MDA and ROS in the ovaries can be effectively reduced by TA. It can also reduce the apoptosis of ovarian cells, decreases the protein expression of the estrogen receptor, Fas, Fasl, caspase-3, caspase-8, caspase-9, and Bax, and increases the protein expression of Bcl-2. Our study indicates that TA reduces the strong estrogen and oxidative damage induced by ZEA, and these therapeutic effects may be partially mediated by the death receptor and mitochondrial apoptosis signaling pathway.

Inducible phospholipid transfer protein deficiency ameliorates atherosclerosis.

BACKGROUND AND AIMS: Atherosclerosis progression and regression studies are related to its prevention and treatment. Although we have gained extensive knowledge on germline phospholipid transfer protein (PLTP) deficiency, the effect of inducible PLTP deficiency in atherosclerosis remains unexplored. METHODS: We generated inducible PLTP (iPLTP)-knockout (KO) mice and measured their plasma lipid levels after feeding a normal chow or a Western-type diet. Adenovirus associated virus-proprotein convertase subtilisin/kexin type 9 (AAV-PCSK9) was used to induce hypercholesterolemia in the mice. Collars were placed around the common carotid arteries, and atherosclerosis progression and regression in the carotid arteries and aortic roots were evaluated. RESULTS: On a normal chow diet, iPLTP-KO mice exhibited decreased cholesterol, phospholipid, apoA-I, and apoB levels compared with control mice. Furthermore, the overall amount of high-density lipoprotein (HDL) particles was reduced in these mice, but this effect was more profound for larger HDL particles. On a Western-type diet, iPLTP-KO mice again exhibited reduced levels of all tested lipids, even though the basal lipid levels were increased. Additionally, these mice displayed significantly reduced atherosclerotic plaque sizes with increased plaque stability. Importantly, inducible PLTP deficiency significantly ameliorated atherosclerosis by reducing the size of established plaques and the number of macrophages in the plaques without causing lipid accumulation in the liver. CONCLUSIONS: Induced PLTP deficiency in adult mice reduces plasma total cholesterol and triglycerides, prevents atherosclerosis progression, and promotes atherosclerosis regression. Thus, PLTP inhibition is a promising therapeutic approach for atherosclerosis.

Effect of liver total sphingomyelin synthase deficiency on plasma lipid metabolism.

Sphingomyelin (SM) is one major phospholipids on lipoproteins. It is enriched on apolipoprotein B-containing particles, including very low-density lipoprotein (VLDL) and its catabolites, low-density lipoprotein (LDL). SM is synthesized by sphingomyelin synthase 1 and 2 (SMS1 and SMS2) which utilizes ceramide and phosphatidylcholine, as two substrates, to produce SM and diacylglyceride. SMS1 and SMS2 activities are co-expressed in all tested tissues, including the liver where VLDL is produced. Thus, neither Sms1 gene knockout (KO) nor Sms2 KO approach is sufficient to evaluate the effect of SMS on VLDL metabolism. We prepared liver-specific Sms1 KO/global Sms2 KO mice to evaluate the effect of hepatocyte SM biosynthesis in lipoprotein metabolism. We found that hepatocyte total SMS depletion significantly reduces cellular sphingomyelin levels. Also, we found that the deficiency induces cellular glycosphingolipid levels which is specifically related with SMS1 but not SMS2 deficiency. To our surprise, hepatocyte total SMS deficiency has marginal effect on hepatocyte ceramide, diacylglyceride, and phosphatidylcholine levels. Importantly, total SMS deficiency decreases plasma triglyceride but not apoB levels and reduces larger VLDL concentration. The reduction of triglyceride levels also was observed when the animals were on a high fat diet. Our results show that hepatocyte total SMS blocking can reduce VLDL-triglyceride production and plasma triglyceride levels. This phenomenon could be related with a reduction of atherogenicity.

Identifying Key Genes for Nasopharyngeal Carcinoma by Prioritized Consensus Differentially Expressed Genes Caused by Aberrant Methylation.

Background: Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated epithelial malignancy. Large-scale genetics or epigenetics studies of NPC have been relatively scarce and sporadic, and there are no effective targeted drugs for NPC. Integrative analysis of multiple different omics profiles has been proved to be an effective approach to shed new light on cancer. Methods: We developed a pipeline to aggregate consensus differentially expressed genes (DEGs) from multiple expression datasets from different platforms. Integrated bioinformatics analysis of DNA methylation and gene expression was used to prioritize key genes in NPC. We explored the biological and clinical importance of key genes, combining differential co-expression analysis, network analysis of protein-protein and microRNA (miRNA)-target interactions, and pan-cancer survival analysis. Results: We obtained 668 upregulated and 594 downregulated consensus DEGs, which enriched in the PI3K-AKT, NF-κB and immune-related pathways. In NPC, 98% of 3364 differentially methylated sites were hypermethylated. Actively expressed EBV gene EBNA1 was positively correlated with over-expressed genes coding DNA methyltransferase and Polycomb group proteins, suggesting that EBV infection may have an important role in the hypermethylation of NPC. Through integrated analysis of DNA methylation and mRNA and miRNA expression profiles, we prioritized 56 hypermethylated downregulated genes, including 7 tumor suppressor genes, and constructed a miRNA-target regulation network consisting of 12 hypermethylated miRNAs and 25 upregulated oncogenes. The promoter hypermethylation of PRKCB causing its downregulation was validated by experimental results and higher PRKCB expression was associated with longer overall survival in head-neck squamous cell carcinoma, suggesting the potential of PRKCB as a promising disease biomarker for NPC. Conclusions: Our integrative analysis provides reliable key genes for candidate biomarkers for diagnosis and prognosis in NPC. Based on the combined evidence of promoter hypermethylation, expression up-regulation, and association with overall survival, genes such as SCUBE2, PRKCB, IKZF1, MAP4K1, and GATA6 could be promising novel diagnostic biomarkers, and miRNAs including MIR150, MIR152, and MIR34 could be candidate prognosis biomarkers.

The relationship between umbilical cord blood vitamin A levels and late preterm infant morbidities: a prospective cohort study.

The aim of this study is to explore the association between umbilical cord blood (UCB) vitamin A levels and late preterm infants morbidities. We conducted a prospective cohort study of 208 late-preterm infants(from 34 0/7 to 36 6/7 weeks gestational age) between January 1, 2014 and June 30, 2015. UCB specimens were collected shortly after birth, and vitamin A levels were determined by enzyme-linked immunosorbent assay. Prevalence of low UCB vitamin A level < 0.7 µmol/L was 37.5% in late preterm infants. In comparison to vaginal delivery, cesarean section was associated with UCB vitamin A level < 0.7 µmol/L (P < 0.001). Nevertheless, UCB vitamin A levels did not correlate with gestational age, birth weight, and gender. UCB vitamin A level < 0.7 µmol/L was not an independent risk factor for hospitalization, oxygen supplementation, hyperbilirubinemia, sepsis, and respiratory distress syndrome.Conclusions: Low umbilical cord blood vitamin A levels are common among late-preterm infants. Cesarean section delivery is associated with low umbilical cord blood vitamin A level. Low umbilical cord blood vitamin A levels at birth do not increase morbidity of late-preterm infants, including hyperbilirubinemia, sepsis, and respiratory distress syndrome. What is Known: • Late preterm infants have a higher morbidity and mortality rates when compared to term infants. • Low plasma vitamin A levels increase the risk of preterm infants' morbidity. What is New: • Late preterm infants commonly have low level of umbilical cord blood vitamin A. • Low umbilical cord blood vitamin A level at birth appears to be not associated with the morbidity of late-preterm infants. • Cesarean section is associated with low umbilical cord blood vitamin A level < 0.7 µmol/L compared with vaginal delivery.

Indoxyl sulfate and high-density lipoprotein cholesterol in early stages of chronic kidney disease.

BACKGROUND: High IS level has been demonstrated to be associated with vascular calcification and lymphocyte functional disorders, which are both risk factors of CVD. Low HDL-c level is a risk factor of CVD in CKD patients. This study was designed to explore the potential relationship between IS and HDL-c levels in early stages of CKD population. METHODS: Patients of CKD stage 1-3 were enrolled in this cross-sectional study. Correlations between HDL-c and IS levels were investigated among various clinicopathological variables through independent samples t test and multivariate logistic regression. RESULTS: A total of 205 CKD patients (96 men) aged 43.27 ± 13.80 years old were included in this research. There were 96 patients (46 men) in CKD stage1 and 109 (50 men) in CKD stage 2 or stage 3. IS levels were significantly higher in CKD 2 + 3 group (1.50 ± 1.74 µg/ml vs. 0.94 ± 0.66 µg/ml, p = 0.007), while HDL-c levels were lower (1.19 ± 0.39 mmol/L vs. 1.33 ± 0.45 mmol/L, p = 0.017) compared to CKD 1 group. Among all the patients, a negative correlation was observed between IS and HDL-c levels (r = -0.244, p = 0.001). IS level was an independent risk factor for low HDL-c (<1.04 mmol/L) incidence even after controlling for potential confounders including concomitant disease, age, sex, blood pressure, BMI and laboratory biochemical test including eGFR (OR = 1.63, 95% CI: 1.11-2.39, p = 0.013). IS and HDL-c were both risk factors for predicting CKD stage 3. CONCLUSIONS: In early CKD stages, low HDL-c level is associated with increased IS levels, which may be an important contributor in the development of dyslipidemia in CKD patients.

Preß1-High-Density Lipoprotein in Cardiovascular Diseases.

Serum preß1-high-density lipoprotein (preß1-HDL) was defined by two-dimensional non-denaturing linear gel electrophoresis and apolipoprotein A-I immunoblotting. However, there are still debatable questions for its quantification and coronary artery disease (CAD) relevance. We have established a novel and simple method for human serum preß1-HDL quantification. We found that human lower preß1-HDL is an independent predictor for severer coronary artery stenosis. In this chapter, we will discuss all these.