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AimsAlanine aminotransferase (ALT) is positively related to diabetes risk in observational studies, whereas Mendelian randomization supports a linear causal association. In contrast, the relationship between ALT and diabetic nephropathy, and diabetic retinopathy is counter-intuitive in observational studies. Furthermore, no MR study has examined their causal association. The study aimed to investigate whether genetically determined ALT has a causal effect on diabetic nephropathy and diabetic retinopathy.MethodsGenetic instruments associated with ALT (P < 5×10-8) were obtained from a recent genome-wide association study (GWAS) that included 437,267 individuals of European ancestry. Summary data of diabetic microvascular complications were derived from the FinnGen study (3,283 cases and 181,704 controls for diabetic nephropathy, and 14,584 cases and 176,010 controls for diabetic retinopathy, both were of European ancestry). Effect estimation and pleiotropy testing were performed using inverse variance weighted (IVW), MR-Egger regression, weighted median, and mode-based estimator methods. We additionally performed sensitivity analysis excluding proxy single nucleotide polymorphisms (SNPs) or lowering the GWAS significance threshold (P < 5×10-7) to test the robustness of the results.ResultsBased on IVW, a 2-fold increase in genetically determined ALT level was positively associated with diabetic nephropathy (odd ratio, [95% confidence interval], 1.73 [1.26-2.37], P = 0.001) and diabetic retinopathy (1.29 [1.08-1.54], P = 0.005), but a null causal association in three pleiotropy robust methods, namely, MR-Egger, weighted median and mode-based estimator. We obtained similar results in the sensitivity analysis of excluding proxy SNPs or lowering the GWAS significance threshold.ConclusionsWith caution, we concluded that ALT plays no linear causal role in developing both diabetic nephropathy and diabetic retinopathy. Further investigations are required to test the hypothesis of a non-linear causal association.

The question of whether or not intermittent fasting diets improve the clinical indicators of glycolipid metabolism remains unclear. This study systematically reviewed the relevant clinical trials to evaluate the effects of intermittent fasting diet on glucose and lipid metabolism and insulin sensitivity in patients with metabolic syndrome. To evaluate the effect of intermittent fasting diet intervention on patients with disorders of glucose and lipid metabolism, random-effect or fixed-effect meta-analysis models were used to calculate the average difference before and after intermittent fasting diet intervention and the corresponding 95% confidence intervals (CIs). After intermittent fasting diet intervention, in terms of glucose metabolism, fasting blood glucose reduced by 0.15 mmol/L (95% CI: −0.23; −0.06), glycosylated hemoglobin reduced by 0.08 (95% CIs: −0.25; −0.10), insulin plasma levels reduced by 13.25 uUI (95% CIs: −16.69; −9.82), and HOMA-IR decreased by 0.31 on an average (95% CIs: −0.44; −0.19). In addition, BMI decreased by 0.8 kg/m2 (95% CIs: −1.32; −0.28), body weight reduced by 1.87 kg (95% CIs: −2.67; −1.07), and the waist circumference decreased by 2.08 cm (95% CIs: −3.06; −1.10). Analysis of lipid metabolism showed that intermittent fasting diet intervention effectively reduced the total cholesterol level by 0.32 mmol/L (95% CIs: −0.60; −0.05), low-density lipoprotein level by 0.22 mmol/L (95% CIs: −0.37; −0.07), and triglyceride level by 0.04 mmol/L (95% CIs: −0.15; −0.07). Intermittent fasting diets have certain therapeutic effects on blood glucose and lipids in patients with metabolic syndrome and significantly improve insulin resistance. It may be considered as an auxiliary treatment to prevent the occurrence and development of chronic diseases.

Background Lung adenocarcinoma (LUAD) has a poor prognosis. Circadian genes such as TIMELESS have been associated with several pathologies, including cancer. The expression of TIMELESS and the relationship between TIMELESS, infiltration of tumors and prognosis in LUAD requires further investigation. Methods In this study, we investigated the expression of TIMELESS and its association with survival across several types of human cancer using data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression Program. Noncoding RNAs (ncRNAs) regulating overexpression of TIMELESS in LUAD were explored with expression, correlation, and survival analyses. Immune cell infiltration and biomarkers were analyzed between different TIMELESS expression levels. The relationship between TIMELESS expression and immunophenoscores, which were used to predict response to immunotherapy, was evaluated. Results TIMELESS was identified as a potential oncogene in LUAD. NcRNA analysis showed MIR4435-2HG/hsa-miR-1-3p may interact with TIMELESS in a competitive endogenous RNA network in LUAD tumor tissues. Most immune cells were significantly decreased in TCGA LUAD tumor tissues with high TIMELESS expression except for CD4 + T cells and Th2 cells. TIMELESS expression in LUAD tumor tissues was significantly negatively correlated with neutrophil biomarkers, dendritic cell biomarkers (HLA-DPB1, HLA-DQB1, HLA-DRA, HLA-DPA1, CD1C) and an immunophenoscore that predicted outcomes associated with the use of immune checkpoint inhibitors. Conclusions These findings imply that ncRNAs-mediated TIMELESS overexpression in LUAD tumor tissues correlated with poor prognosis, reduced immune cell infiltration in the tumor microenvironment, and poor response to immune checkpoint inhibitors.

Background: Exosomes are involved in tumorigenesis, growth and metastasis. However, the prognostic value of exosome-related genes in lung adenocarcinoma (LUAD) remains unclear. Methods: Clinical and transcriptome data from The Cancer Genome Atlas LUAD cohort were used to construct a model based on exosome-related genes, which was validated with LUAD data from the Gene Expression Omnibus (GEO). Gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis were used to explore underlying mechanisms; the single-sample gene set enrichment analysis score was used to determine immune functions. Results: A 19-exosome-related gene signature for overall survival in LUAD was predictive in both The Cancer Genome Atlas and GEO LUAD cohorts. Immune-related and extracellular matrix-related pathways were enriched in differentially expressed genes. Immune states differed between high- and low-risk groups. Conclusion: The novel signature can be used to predict outcomes in LUAD.

Background: Coronavirus disease 2019 (COVID-19) and Influenza A are common disease caused by viral infection. The clinical symptoms and transmission routes of the two diseases are similar. However, there are no relevant studies on laboratory diagnostic models to discriminate COVID-19 and influenza A. This study aims at establishing a signature of laboratory findings to tell patients with COVID-19 apart from those with influenza A perfectly. Materials: In this study, 56 COVID-19 patients and 54 influenza A patients were included. Laboratory findings, epidemiological characteristics and demographic data were obtained from electronic medical record databases. Elastic network models, followed by a stepwise logistic regression model were implemented to identify indicators capable of discriminating COVID-19 and influenza A. A nomogram is diagramed to show the resulting discriminative model. Results: The majority of hematological and biochemical parameters in COVID-19 patients were significantly different from those in influenza A patients. In the final model, albumin/globulin (A/G), total bilirubin (TBIL) and erythrocyte specific volume (HCT) were selected as predictors. Using an external dataset, the model was validated to perform well. Conclusion: A diagnostic model of laboratory findings was established, in which A/G, TBIL and HCT were included as highly relevant indicators for the segmentation of COVID-19 and influenza A, providing a complimentary means for the precise diagnosis of these two diseases., 26 pages,3 figures

Background Psoriasis is an immune-mediated, inflammatory disorder of the skin with chronic inflammation and hyper-proliferation of the epidermis. Since psoriasis has genetic components and the diseased tissue of psoriasis is very easily accessible, it is natural to use high-throughput technologies to characterize psoriasis and thus seek targeted therapies. Transcriptional profiles change correspondingly after an intervention. Unlike cross-sectional gene expression data, longitudinal gene expression data can capture the dynamic changes and thus facilitate causal inference. Methods Using the iCluster method as a building block, an ensemble method was proposed and applied to a longitudinal gene expression dataset for psoriasis, with the objective of identifying key lncRNAs that can discriminate the responders from the non-responders to two immune treatments of psoriasis. Results Using support vector machine models, the leave-one-out predictive accuracy of the 20-lncRNA signature identified by this ensemble was estimated as 80%, which outperforms several competing methods. Furthermore, pathway enrichment analysis was performed on the target mRNAs of the identified lncRNAs. Of the enriched GO terms or KEGG pathways, proteasome, and protein deubiquitination is included. The ubiquitination-proteasome system is regarded as a key player in psoriasis, and a proteasome inhibitor to target ubiquitination pathway holds promises for treating psoriasis. Conclusions An integrative method such as iCluster for multiple data integration can be adopted directly to analyze longitudinal gene expression data, which offers more promising options for longitudinal big data analysis. A comprehensive evaluation and validation of the resulting 20-lncRNA signature is highly desirable.

Background Colon cancer (CC) is one of the most common malignant tumors, while Parkinson’s disease (PD) is the second most common neurodegenerative disorder. Recent accumulating evidence indicates that these two diseases are associated with each other. Also, from the perspective of long non-coding RNAs, some well-known genes such as H19 and PVT1 can link these two diseases together. Several studies have shown that patients with PD had a decreased risk of developing CC compared with patients without PD. However, controversies surround the relationship between PD and CC, and to date, no concordant conclusion has been drawn. Methods In this study, we aimed to assess the association between these two diseases based on lncRNA-to-lncRNA interactions. Motivated by the weighted gene co-expression network analysis method, a customized procedure was proposed and used to identify differentially correlated edges (DCEs) in the respective interaction networks for PD and CC and explore how these two diseases are linked. Results Of the two sets of DCEs for PD and CC, 16 pairs overlapped. Among them, 15 edges had opposite signs, with positive signs for CC indicating a gain of connectivity, whereas negative signs for PD indicating a loss of connectivity. Conclusions By using the lncRNA expression profiles, and a customized procedure, an answer to the question about how PD and CC are associated is provided.

Aims: To elucidate the association between ferroptosis-related genes and prognosis in patients with lung adenocarcinoma (LUAD). Materials & methods: A ferroptosis-related gene signature was made by lasso regression analysis through the LUAD datasets of the Cancer Genome Atlas. The prognostic value of the multigene signature was externally validated in the GSE72094 dataset from the Gene Expression Omnibus database. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis were used to explore underlying mechanisms. Results & conclusion: We established a novel ferroptosis-related gene signature for overall survival in LUAD that was predictive in both the training and validation cohorts. Immune-related pathways were significantly enriched, and immune status differed between the high- and low-risk groups. Targeting ferroptosis is a potential therapeutic option in LUAD. These results still need to be confirmed by more studies.

Background At present, the beneficial effect of the ketogenic diet (KD) on weight loss in obese patients is generally recognized. However, a systematic research on the role of KD in the improvement of glycemic and lipid metabolism of patients with diabetes is still found scarce. Methods This meta-study employed the meta-analysis model of random effects or of fixed effects to analyze the average difference before and after KD and the corresponding 95% CI, thereby evaluating the effect of KD on T2DM. Results After KD intervention, in terms of glycemic control, the level of fasting blood glucose decreased by 1.29 mmol/L (95% CI: −1.78 to −0.79) on average, and glycated hemoglobin A1c by 1.07 (95% CI: −1.37 to −0.78). As for lipid metabolism, triglyceride was decreased by 0.72 (95% CI: −1.01 to −0.43) on average, total cholesterol by 0.33 (95% CI: −0.66 to −0.01), and low-density lipoprotein by 0.05 (95% CI: −0.25 to −0.15); yet, high-density lipoprotein increased by 0.14 (95% CI: 0.03−0.25). In addition, patients’ weight decreased by 8.66 (95% CI: −11.40 to −5.92), waist circumference by 9.17 (95% CI: −10.67 to −7.66), and BMI by 3.13 (95% CI: −3.31 to −2.95). Conclusion KD not only has a therapeutic effect on glycemic and lipid control among patients with T2DM but also significantly contributes to their weight loss.

Studies have demonstrated that both squamous cell carcinomas (SCCs) and adenocarcinomas (ACs) possess some common molecular characteristics. Evidence has accumulated to support the theory that long non-coding RNAs (lncRNAs) serve as novel biomarkers and therapeutic targets in complex diseases such as cancer. In this study, we aimed to identify pan lncRNA signatures that are common to squamous cell carcinomas or adenocarcinomas with different tissues of origin. With the aid of elastic-net regularized regression models, a 35-lncRNA pan discriminative signature and an 11-lncRNA pan prognostic signature were identified for squamous cell carcinomas, whereas a 6-lncRNA pan discriminative signature and a 5-lncRNA pan prognostic signature were identified for adenocarcinomas. Among them, many well-known cancer relevant genes such as MALAT1 and PVT1 were included. The identified pan lncRNA lists can help experimental biologists generate research hypotheses and adopt existing treatments for less prevalent cancers. Therefore, these signatures warrant further investigation.

ObjectiveTo explore longitudinal change patterns of key laboratory tests in patients with COVID-19, and to identify independent prognostic factors by examining the associations between laboratory findings and outcomes of patients.MethodsThe multicenter study prospectively included 59 patients with COVID-19 treated at Jilin province from January 21, 2020 to May 5, 2020. Laboratory tests were included haematological, biochemical, and immunological tests.ResultsLaboratory findings, the characteristics of epidemiological and demographic data were extracted from electronic medical records. Eosinopenia was shown in 52.6% cases at onset, and the average value of eosinophil continued to significantly increase thereafter. Lymphopenia was found in 40.4% cases at onset, and the average value of lymphocyte was slowly elevated after day 5. Thrombocytopenia was shown in 12.3% cases at onset, and the average value of mean platelet volume was decreased sharply after day 7. The values of aspartate aminotransferase, lactate dehydrogenase, creatine kinase, creatinine kinase-muscle/brain activity, and cardiac troponin I, serum cardiac markers, were beyond the upper limit of RI from 6.1% to 30.6% at onset. The abnormity of liver function tests, kidney function tests, electrolytes was 2.0%∼59.2%, 2.0%∼4.1%, 6.0%∼30.0%, respectively. Eosinophil, platelet and carbondioxide combining power were selected as the prognostic factors.ConclusionsThe haematological, biochemical, and immunological tests were found significant abnormity at onset and longitudinal change patterns in the patients with COVID-19. Age, Eosinophil, PLT and CO2 may used to predict the recovery probability. Risk stratification and management could be improved for the patients with COVID-19 according to temporal trajectories of laboratory tests.Article SummaryThe longitudinal change patterns of the laboratory characteristics of affected patients were important to identify prognosis. Eosinophil, platelet and carbondioxide combining power may be independent predictors of recovery in patients with COVID-19.

Background Lung adenocarcinoma (LUAD) is one of the most common subtypes of lung cancer which is the leading cause of death in cancer patients. Circadian clock disruption has been listed as a likely carcinogen. However, whether the expression of circadian genes affects overall survival (OS) in LUAD patients remains unknown. In this article, we identified a circadian gene signature to predict overall survival in LUAD. Methods RNA sequencing (HTSeq-FPKM) data and clinical characteristics were obtained for a cohort of LUAD patients from The Cancer Genome Atlas (TCGA). A multigene signature based on differentially expressed circadian clock-related genes was generated for the prediction of OS using Least Absolute Shrinkage and Selection Operator (LASSO)-penalized Cox regression analysis, and externally validated using the GSE72094 dataset from the GEO database. Results Five differentially expressed genes (DEGs) were identified to be significantly associated with OS using univariate Cox proportional regression analysis (P < 0.05). Patients classified as high risk based on these five DEGs had significantly lower OS than those classified as low risk in both the TGCA cohort and GSE72094 dataset (P < 0.001). Multivariate Cox regression analysis revealed that the five-gene-signature based risk score was an independent predictor of OS (hazard ratio > 1, P < 0.001). Receiver operating characteristic (ROC) curves confirmed its prognostic value. Gene set enrichment analysis (GSEA) showed that Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways related to cell proliferation, gene damage repair, proteasomes, and immune and autoimmune diseases were significantly enriched. Conclusion A novel circadian gene signature for OS in LUAD was found to be predictive in both the derivation and validation cohorts. Targeting circadian genes is a potential therapeutic option in LUAD.

Lung adenocarcinoma (AC) and squamous cell lung carcinoma (SCC) are two major subtypes of non-small cell lung cancer (NSCLC). Previous studies have demonstrated that fundamental differences exist in the underlying mechanisms of tumor development, growth and invasion between these subtypes. The investigation of differentially-expressed genes (DEGs) between these two NSCLC subtypes is useful for determining and understanding such differences. The present study aimed to identify those DEGs using meta-analysis and the data from four microarray experiments, consisting of 164 AC and 161 SCC samples. Raw gene expression values were converted into the probability of expression (POE) representing the differentially-expressed probability of a gene and expression barcode values representing its expression status. The results indicated that when applying a meta-analysis using barcode values, heterogeneity in genes across studies was less severe than when applying a meta-analysis using POE values. DEGs in each meta-analysis method overlapped substantially (P=1.3×10−4), but the barcode method yielded a lower global false discovery rate. Based on this and several other performance statistics, it was concluded that the barcode approach outperformed the POE method. Finally, using those DEGs, ontology and pathway analyses were conducted. A number of genes and enriched pathways were found to be closely associated with NSCLC.

There is an "assessment gap" between the moment a patient's response to treatment is biologically determined and when a response can actually be determined clinically. Patients' biochemical profiles are a major determinant of clinical outcome for a given treatment. It is therefore feasible that molecular-level patient information could be used to decrease the assessment gap. Thanks to clinically accessible biopsy samples, high-quality molecular data for psoriasis patients are widely available. Psoriasis is therefore an excellent disease for testing the prospect of predicting treatment outcome from molecular data. Our study shows that gene-expression profiles of psoriasis skin lesions, taken in the first 4 weeks of treatment, can be used to accurately predict (>80% area under the receiver operating characteristic curve) the clinical endpoint at 12 weeks. This could decrease the psoriasis assessment gap by 2 months. We present two distinct prediction modes: a universal predictor, aimed at forecasting the efficacy of untested drugs, and specific predictors aimed at forecasting clinical response to treatment with four specific drugs: etanercept, ustekinumab, adalimumab, and methotrexate. We also develop two forms of prediction: one from detailed, platform-specific data and one from platform-independent, pathway-based data. We show that key biomarkers are associated with responses to drugs and doses and thus provide insight into the biology of pathogenesis reversion.

Feature selection in the framework of meta-analyses (meta feature selection), combines meta-analysis with a feature selection process and thus allows meta-analysis feature selection across multiple datasets. In the present study, a meta feature selection procedure that fitted a multiple Cox regression model to estimate the effect size of a gene in individual studies and to identify the overall effect of the gene using a meta-analysis model was proposed. The method was used to identify prognostic gene signatures for lung adenocarcinoma and lung squamous cell carcinoma. Furthermore, redundant gene elimination (RGE) is of crucial importance during feature selection, and is also essential for a meta feature selection process. The current study demonstrated that the proposed meta feature selection procedure with RGE outperforms that without RGE in terms of predictive ability, model parsimony and biological interpretation.

Background Monotonically expressed genes (MEGs) are genes whose expression values increase or decrease monotonically as a disease advances or time proceeds. Non-small cell lung cancer (NSCLC) is a multistage progression process resulting from genetic sequences mutations, the identification of MEGs for NSCLC is important. Results With the aid of a feature selection algorithm capable of identifying MEGs – the MFSelector method – two sets of potential MEGs were selected in this study: the MEGs across the different pathologic stages and the MEGs across the risk levels of death for the NSCLC patients at early stages. For the lung adenocarcinoma (AC) subtypes no statistically significant MEGs were identified across pathologic stages, however dozens of MEGs were identified across the risk levels of death. By contrast, for the squamous cell lung carcinoma (SCC) there were no statistically significant MEGs as either stage or risk level advanced. Conclusions The pathologic stage of non-small cell lung cancer patients at early stages has no prognostic value, making the identification of prognostic gene signatures for them more meaningful and highly desirable.

Background Feature selection and gene set analysis are of increasing interest in the field of bioinformatics. While these two approaches have been developed for different purposes, we describe how some gene set analysis methods can be utilized to conduct feature selection. Methods We adopted a gene set analysis method, the significance analysis of microarray gene set reduction (SAMGSR) algorithm, to carry out feature selection for longitudinal gene expression data. Results Using a real-world application and simulated data, it is demonstrated that the proposed SAMGSR extension outperforms other relevant methods. In this study, we illustrate that a gene’s expression profiles over time can be regarded as a gene set and then a suitable gene set analysis method can be utilized directly to select relevant genes associated with the phenotype of interest over time. Conclusions We believe this work will motivate more research to bridge feature selection and gene set analysis, with the development of novel algorithms capable of carrying out feature selection for longitudinal gene expression data. Electronic supplementary material The online version of this article (10.1186/s12911-018-0685-8) contains supplementary material, which is available to authorized users.

Background: We aimed to describe the laboratory characteristics of patients with laboratory confirmed coronavirus disease 2019 (COVID-19), and to compare the laboratory data between recovered and non-recovered patients. Methods: This is a multi-center study and 68 COVID-19 patients were recruited in Jilin Province, China, from January 21, 2020 to February 21, 2020. Laboratory tests were conducted at admission. Outcomes were followed up until February 21, 2020. Results: Of the 68 patients, 63 were diagnosed as mild and 5 as moderate or severe. After follow-up, there are 28 and 40 patients in recovered and non-recovered group, respectively. Lymphocytes, including immature leukocyte subpopulation, were significantly increased after day 10 in recovered patients. Platelets and thrombocytocrit were significantly increased, while mean platelet volume was reduced markedly from day 6 in recovered patients. High-sensitivity C-reactive protein was elevated at onset and continued to decline at day 7 in recovered patients. Cardiac troponin I is always higher from onset to recovery in recovered patients, yet it is sharply declined below the upper limit of reference interval after day 10. Cholinesterase and alanine aminotransferase were higher during the recovery process in recovered patients than in non-recovered patients. Both eosinophil and age were identified as independent predictors for recovery. Conclusions: Some markers had different change patterns between the recovered and non-recovered patients. Eosinophil may serve as an independent predictor for recovery in addition to age. The monitoring of the dynamic level of markers can give more effective clues for the judgment of the progress in COVID-19 patients. © 2021 AME Publishing Company. All rights reserved.

Aims Neuromyelitis optica spectrum disorders (NMOSD) is an inflammatory demyelinating autoimmune disorder in the central nervous system (CNS), which is mainly mediated by aquaporin 4 antibodies (AQP4-Ab). Interleukin (IL)-39 is a new pro-inflammatory cytokine which belongs to the IL-12 cytokine family. However, the role of IL-39 in patients with NMOSD is not completely understood. Therefore, the aim of this study is to explore the possible implication of IL-39 in the pathogenesis of NMOSD. Methods In this study, 50 patients with NMOSD, 20 patients with relapsing-remitting multiple sclerosis (RRMS), 30 patients with non-inflammatory neurological disorders (NND) and 78 healthy controls (HCs) were recruited. The levels of serum IL-39 were measured using the enzyme-linked immunosorbent assay (ELISA). Results Our study showed serum IL-39 levels in patients with NMOSD were significantly higher than that in RRMS patients, NND patients and HCs, and positively correlated with Expanded Disability Status Scale (EDSS) score. Conclusion These findings suggested that IL-39 may play a pro-inflammatory role in the pathogenesis of NMOSD and correlate with disease severity.

The origin of large genomes that underlies the long standing "C-value enigma" is only partially explained by selfish DNA. We investigated insertions and deletions (indels) of nucleotides and discussed their relevance in size evolution of random biological sequences (RBS) and genomes. By developing a probabilistic model of RBS based on size evolution of expandable sites in a thought perfect genome, it was found that insertion bias engenders exponential increase of average RBS sizes. When combined with existing large segments of genome that are not subject to selection pressure (e.g. selfish DNA), such insertion bias results in explosive expansion of genomes, and therefore helps explain the "C value enigma" besides selfish DNA. Such increase of RBS size is caused by the fundamental asymmetry of indels, with insertions result in more available sites and deletions result in less deletable nucleotides. In qualitative agreement with the size distribution of known genomes, tails of RBS size distributions exhibit exponential decay with probabilities of larger RBS segments being smaller. Unsurprisingly, a slight deletion bias (higher deletions probabilities) results in a slow decrease of average RBS size and may lead to their eventual vanishing. Contrary to intuition, strictly balanced insertion and deletion results in linearly increasing instead of completely fixed RBS size. Nonetheless, such slow linear increase of average RBS sizes with time are small in magnitude and are consequently not influential on genome size evolution, and certainly not a major contributor for the "C-value enigma". Our model suggested that insertion bias of nucleotides may provide complementary explanation for large genomes besides selfish DNA. The fundamental indel asymmetry is applicable for all forms of genomic insertions and deletions. Long-lasting exponential increase of genome size present energy and material requirement that is impossible to sustain. We therefore concluded that if there were explosively accelerating expansion caused by significant effective insertion bias for any survival species, it must have occurred sporadically. Our model also provided an explanation for the observed proportional evolution of genome size.

Lung cancer (LC) is a leading cause of cancer-associated mortalities worldwide. Adenocarcinoma (AC) and squamous cell carcinoma (SCC) account for ~70% of all cases of LC. Since AC and SCC are two distinct diseases, their corresponding prognostic genes associated with patient survival time are expected to be different. To date, only a few studies have distinguished patients with good prognosis from those with poor prognosis for each specific subtype. In the present study, the Cox filter model, a feature selection algorithm that identifies subtype-specific prognostic genes to incorporate pathway information and eliminate redundant genes, was adopted. By applying the proposed model to data on non-small cell lung cancer (NSCLC), it was demonstrated that both redundant gene elimination and search space restriction can improve the predictive capacity and the model stability of resulting prognostic gene signatures. To conclude, a pre-filtering procedure that incorporates pathway information for screening likely irrelevant genes prior to complex downstream analysis is recommended. Furthermore, a feature selection algorithm that considers redundant gene elimination may be preferable to one without such a consideration.

Background The aim of the present study was to compare correlation coefficients between anthropometric indices and blood glucose level, and to determine optimal cutoff points of obesity indices in a Chinese population. Methods 2419 males and 5140 females participated in this study in Changchun city. Weight, height, WC (waist circumference) and hip circumference were measured; and BMI (body mass index), WHtR (waist height ratio), WHR (waist hip ratio) and BAI (body adiposity index) were calculated by formulas. FPG (fasting plasma glucose), PPG (post-load plasma glucose), HbA1c (glycosylated hemoglobin) and FSI (fasting serum insulin) were measured. Results WHtR had the highest partial correlation coefficients with blood glucose and HbA1c in both males and females; however, BAI had the lowest coefficients. AUC (area under receiver operating characteristic curves) for WHtR in screening type 2 diabetes mellitus were higher than other indices. We confirmed that the optimal cutoff points of obesity for WHtR, WHR, WC, BMI and BAI were 0.55, 0.92, 88.1, 25.9 and 28.1 in males, and 0.52, 0.85, 81.6, 24.6 and 31.0 in females, respectively. Conclusions Central obesity correlates more closely to glucose metabolism in Chinese population than general obesity. WHtR is the best index to predict type 2 diabetes mellitus in Chinese adults.

Pathway-based feature selection algorithms, which utilize biological information contained in pathways to guide which features/genes should be selected, have evolved quickly and become widespread in the field of bioinformatics. Based on how the pathway information is incorporated, we classify pathway-based feature selection algorithms into three major categories-penalty, stepwise forward, and weighting. Compared to the first two categories, the weighting methods have been underutilized even though they are usually the simplest ones. In this article, we constructed three different genes' connectivity information-based weights for each gene and then conducted feature selection upon the resulting weighted gene expression profiles. Using both simulations and a real-world application, we have demonstrated that when the data-driven connectivity information constructed from the data of specific disease under study is considered, the resulting weighted gene expression profiles slightly outperform the original expression profiles. In summary, a big challenge faced by the weighting method is how to estimate pathway knowledge-based weights more accurately and precisely. Only until the issue is conquered successfully will wide utilization of the weighting methods be impossible.

Regularization methods that simultaneously select a small set of the most relevant features and build a classifier using the selected features have gained much attention recently in problems of classification of “omics” data. In many multi-class classification problems, which are of practical importance, the classes are naturally endowed with a hierarchical structure. However, such natural hierarchical structure is often ignored. Here, we use an existing regularization algorithm, Threshold Gradient Descent Regularization, in a hierarchical fashion, which takes advantage of natural biological structure to specifically tackle multi-class classification of microarray data. We apply this approach to one of the tasks presented by the sbv IMPROVER Diagnostic Signature Challenge: the Lung Cancer Sub-Challenge. Gene expression data from non-small cell lung carcinoma were used to classify tumors into adenocarcinoma and squamous cell carcinoma subtypes, and their clinical stages (I and II). Genetic and transcriptom...

R codes for the weighted-SAMGSR algorithm. (DOCX 76 kb)

Background Atopic dermatitis (AD) is a common inflammatory skin disease with limited treatment options. Several microarray experiments have been conducted on lesional/LS and non-lesional/NL AD skin to develop a genomic disease phenotype. Although these experiments have shed light on disease pathology, inter-study comparisons reveal large differences in resulting sets of differentially expressed genes (DEGs), limiting the utility of direct comparisons across studies. Methods We carried out a meta-analysis combining 4 published AD datasets to define a robust disease profile, termed meta-analysis derived AD (MADAD) transcriptome. Results This transcriptome enriches key AD pathways more than the individual studies, and associates AD with novel pathways, such as atherosclerosis signaling (IL-37, selectin E/SELE). We identified wide lipid abnormalities and, for the first time in vivo, correlated Th2 immune activation with downregulation of key epidermal lipids (FA2H, FAR2, ELOVL3), emphasizing the role of cytokines on the barrier disruption in AD. Key AD “classifier genes” discriminate lesional from nonlesional skin, and may evaluate therapeutic responses. Conclusions Our meta-analysis provides novel and powerful insights into AD disease pathology, and reinforces the concept of AD as a systemic disease. Electronic supplementary material The online version of this article (doi:10.1186/s12920-015-0133-x) contains supplementary material, which is available to authorized users.

Psoriasis is a complex inflammatory disease mediated by tumor necrosis factor (TNF)-α and cytokines secreted by specialized T-cell populations, e.g., IL-17, IL-22, and IFN-γ. The mechanisms by which innate and adaptive immune cytokines regulate inflammation in psoriasis are not completely understood. We sought to investigate the effects of TNF-α and IL-17 on keratinocyte (KC) gene profile, to identify genes that might be coregulated by these cytokines and determine how synergistically activated genes relate to the psoriasis transcriptome. Primary KCs were stimulated with IL-17 or TNF-α alone, or in combination. KC responses were assessed by gene array analysis, followed by reverse transcriptase-PCR confirmation for significant genes. We identified 160 genes that were synergistically upregulated by IL-17 and TNF-α, and 196 genes in which the two cytokines had at least an additive effect. Synergistically upregulated genes included some of the highest expressed genes in psoriatic skin with an impressive correlation between IL-17/TNF-α-induced genes and the psoriasis gene signature. KCs may be key drivers of pathogenic inflammation in psoriasis through integrating responses to TNF-α and IL-17. Our data predict that psoriasis therapy with either TNF or IL-17 antagonists will produce greater modulation of the synergistic/additive gene set, which consists of the most highly expressed genes in psoriasis skin lesions.

Aims/Introduction The aims of the present study were to evaluate the diagnostic value of fasting plasma glucose, 2-h postload plasma glucose and glycosylated hemoglobin (HbA1c) measurements in the screening of diabetes and prediabetes, and to determine the cut-off point of HbA1c in the diagnosis of diabetes and prediabetes in a Chinese population. Materials and Methods A total of 7,611 individuals aged 40 years or older, who did not have a prior history of diabetes, were randomly selected in the Changchun area. For each participant, a questionnaire was completed, and a physical examination and an oral glucose tolerance test were carried out. The values of fasting plasma glucose, 2-h postload plasma glucose and HbA1c were compared by area under the receiver operating characteristic curves. The Youden index was used to identify the optimal cut-off point of HbA1c in the diagnosis of diabetes and prediabetes. Results The prevalence of newly diagnosed diabetes and prediabetes was 12.71% and 29.39%, respectively. In participants with newly diagnosed diabetes, the area under the receiver operating characteristic curve was 0.8368 for fasting plasma glucose, 0.9330 for 2-h postload plasma glucose and 0.8064 for HbA1c; whereas for prediabetes, these values were 0.8022, 0.9288 and 0.6895, respectively. In addition, an HbA1c threshold of 6.3% showed the highest Youden index (0.4799) for detecting diabetes; furthermore, an HbA1c threshold of 5.8% showed the highest Youden index (0.2866) for detecting prediabetes. Conclusions HbA1c ≥6.3% (45 mmol/mol) and between 5.8% and 6.2% (40–44 mmol/mol) were the optimal cut-off values for the diagnosis of diabetes and prediabetes, respectively, in a Chinese population.

The existence of fundamental differences between lung adenocarcinoma (AC) and squamous cell carcinoma (SCC) in their underlying mechanisms motivated us to postulate that specific genes might exist relevant to prognosis of each histology subtype. To test on this research hypothesis, we previously proposed a simple Cox-regression model based feature selection algorithm and identified successfully some subtype-specific prognostic genes when applying this method to real-world data. In this article, we continue our effort on identification of subtype-specific prognostic genes for AC and SCC, and propose a novel embedded feature selection method by extending Threshold Gradient Descent Regularization (TGDR) algorithm and minimizing on a corresponding negative partial likelihood function. Using real-world datasets and simulated ones, we show these two proposed methods have comparable performance whereas the new proposal is superior in terms of model parsimony. Our analysis provides some evidence on the existence of such subtype-specific prognostic genes, more investigation is warranted.

Background Non-small cell lung cancer (NSCLC) is the predominant histological type of lung cancer, accounting for up to 85% of cases. Disease stage is commonly used to determine adjuvant treatment eligibility of NSCLC patients, however, it is an imprecise predictor of the prognosis of an individual patient. Currently, many researchers resort to microarray technology for identifying relevant genetic prognostic markers, with particular attention on trimming or extending a Cox regression model. Adenocarcinoma (AC) and squamous cell carcinoma (SCC) are two major histology subtypes of NSCLC. It has been demonstrated that fundamental differences exist in their underlying mechanisms, which motivated us to postulate the existence of specific genes related to the prognosis of each histology subtype. Results In this article, we propose a simple filter feature selection algorithm with a Cox regression model as the base. Applying this method to real-world microarray data identifies a histology-specific prognostic gene signature. Furthermore, the resulting 32-gene (32/12 for AC/SCC) prognostic signature for early-stage AC and SCC samples has superior predictive ability relative to two relevant prognostic signatures, and has comparable performance with signatures obtained by applying two state-of-the art algorithms separately to AC and SCC samples. Conclusions Our proposal is conceptually simple, and straightforward to implement. Furthermore, it can be easily adapted and applied to a range of other research settings. Reviewers This article was reviewed by Leonid Hanin (nominated by Dr. Lev Klebanov), Limsoon Wong and Jun Yu. Electronic supplementary material The online version of this article (doi:10.1186/s13062-015-0051-z) contains supplementary material, which is available to authorized users.

QQ plot. Comparison of parameters. (PDF 1005Â kb)

All datasets intially considered before applying inclusion/exclusion criteria. (DOCX 65Â kb)

logFCHs correlations of MADAD and treatments A) Dupilumab (300mg), B) Cyclosporin (W12), and C) UVB. (PDF 42 kb)

A) Prisma. B) MADAD Datasets. C) Meta-Analysis Workflow. (PDF 608Â kb)

Supplementary materials and methods. (DOCX 111Â kb)

A) Inflammatory Skin Disease Gene Sets. B) MADAD IDD-DEGs IPA Canonical Pathways. (PDF 85Â kb)

The aim of the present study was to compare correlation coefficients between anthropometric indices and blood glucose level, and to determine optimal cutoff points of obesity indices in a Chinese population.2419 males and 5140 females participated in this study in Changchun city. Weight, height, WC (waist circumference) and hip circumference were measured; and BMI (body mass index), WHtR (waist height ratio), WHR (waist hip ratio) and BAI (body adiposity index) were calculated by formulas. FPG (fasting plasma glucose), PPG (post-load plasma glucose), HbA1c (glycosylated hemoglobin) and FSI (fasting serum insulin) were measured.WHtR had the highest partial correlation coefficients with blood glucose and HbA1c in both males and females; however, BAI had the lowest coefficients. AUC (area under receiver operating characteristic curves) for WHtR in screening type 2 diabetes mellitus were higher than other indices. We confirmed that the optimal cutoff points of obesity for WHtR, WHR, WC, BMI and BAI were 0.55, 0.92, 88.1, 25.9 and 28.1 in males, and 0.52, 0.85, 81.6, 24.6 and 31.0 in females, respectively.Central obesity correlates more closely to glucose metabolism in Chinese population than general obesity. WHtR is the best index to predict type 2 diabetes mellitus in Chinese adults.

Background As microarray technology has become mature and popular, the selection and use of a small number of relevant genes for accurate classification of samples has arisen as a hot topic in the circles of biostatistics and bioinformatics. However, most of the developed algorithms lack the ability to handle multiple classes, arguably a common application. Here, we propose an extension to an existing regularization algorithm, called Threshold Gradient Descent Regularization (TGDR), to specifically tackle multi-class classification of microarray data. When there are several microarray experiments addressing the same/similar objectives, one option is to use a meta-analysis version of TGDR (Meta-TGDR), which considers the classification task as a combination of classifiers with the same structure/model while allowing the parameters to vary across studies. However, the original Meta-TGDR extension did not offer a solution to the prediction on independent samples. Here, we propose an explicit method to estimate the overall coefficients of the biomarkers selected by Meta-TGDR. This extension permits broader applicability and allows a comparison between the predictive performance of Meta-TGDR and TGDR using an independent testing set. Results Using real-world applications, we demonstrated the proposed multi-TGDR framework works well and the number of selected genes is less than the sum of all individualized binary TGDRs. Additionally, Meta-TGDR and TGDR on the batch-effect adjusted pooled data approximately provided same results. By adding Bagging procedure in each application, the stability and good predictive performance are warranted. Conclusions Compared with Meta-TGDR, TGDR is less computing time intensive, and requires no samples of all classes in each study. On the adjusted data, it has approximate same predictive performance with Meta-TGDR. Thus, it is highly recommended.

BACKGROUND Tumor treatment is the mainstay of therapy for paraneoplastic neurologic disorders (PNDs), but it is only effective in some cases and other treatment options are limited. OBJECTIVE To evaluate the short-term use of a combination of prednisone and tacrolimus for acute neurologic worsening in PND in which intracellular antigens are targeted. DESIGN Retrospective single-center case series of patients with PND treated with tacrolimus. SETTING The Rockefeller University Hospital, a research hospital in New York, New York. PATIENTS Twenty-six patients with PND with high titer (≥1:1000) anti-HuD, anti-Yo, or anti-CRMP5 autoantibodies were enrolled. Patients were referred from Memorial Sloan Kettering Cancer Center or self-referred. Two patients discontinued intervention owing to adverse events. INTERVENTIONS Patients were treated with tacrolimus, 0.15-0.30 mg/kg per day, in 2 divided oral doses with 60 mg per day of oral prednisone, tapered off during 1 to 4 weeks. MAIN OUTCOME MEASURES The primary outcome measure was median survival. Neurologic examinations before and after treatment as well as adverse events are described. RESULTS Median survival time was 52 months from time of diagnosis. Some patients experienced neurologic improvement that was functionally meaningful. The incidence of adverse events was similar to that generally reported with tacrolimus. CONCLUSIONS A short course of prednisone and tacrolimus to target central nervous system T cells in patients with PND with acute neurologic decline in which intracellular antigens are targeted was well tolerated and warrants further study. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00378326.

FK506 (Tacrolimus) is a potent inhibitor of calcineurin that blocks IL2 production and is widely used to prevent transplant rejection and treat autoimmunity. FK506 treatment of dendritic cells (FKDC) limits their capacity to stimulate T cell responses. FK506 does not prevent DC survival, maturation, or costimulatory molecule expression, suggesting that the limited capacity of FKDC to stimulate T cells may be due to inhibition of calcineurin signaling in the DC. Instead, we demonstrate that DC inhibit T cells by sequestering FK506 and continuously releasing the drug over several days. T cells encountering FKDC proliferate but fail to upregulate the survival factor bcl-xl and die, and IL2 restores both bcl-xl and survival. In mice, FKDC act in an antigen-specific manner to inhibit T-cell mediated autoimmune arthritis. This establishes that DCs can act as a cellular drug delivery system to target antigen specific T cells. DOI: http://dx.doi.org/10.7554/eLife.00105.001, eLife digest Although our health depends on our immune system's ability to recognize and attack foreign material, this same response can cause the body to reject an organ transplant or even to spontaneously attack itself (this is called autoimmune disease). To help prevent rejection, patients who receive donated organs are given immunosuppressant drugs, with a compound called FK506, or Tacrolimus, the most commonly used. However, FK506 can have a number of serious side effects, including high blood pressure, kidney damage and diabetes. The job of starting an immune response falls in large part to a type of white blood cell called the dendritic cell, which patrols the body in search of cells in trouble—such as those infected with viruses. Dendritic cells are efficient at engulfing dying cells, which they break down and display fragments of on their cell surface. These fragments—which are known as antigens—are presented directly to T cells, which trigger a cascade of additional immune responses leading ultimately to the destruction of infected cells. In some cases of autoimmune disease, however, T cells begin to mistake the body's own cells for infected cells and to launch attacks against healthy tissue. Evidence suggests that immunosuppressive drugs such as FK506 can help to tone down these inappropriate immune responses. However, the use of FK506 to treat autoimmune disease has been limited by its side effects. Now, Orange et al. have shown that dendritic cells can be exploited to deliver drugs such as FK506 in a targeted and controlled manner. When the researchers loaded dendritic cells with FK506, they found that the cells sequestered the drug and then released it slowly in quantities that were sufficient to inhibit T-cell responses for at least 72 hr. Using a mouse model of rheumatoid arthritis—an autoimmune disease characterized by inflammation and destruction of joint tissue—Orange and co-workers demonstrated that their novel drug delivery system could be therapeutically useful. They loaded dendritic cells displaying the antigen that triggers the mouse immune system to attack joint tissue, with FK506, and used the resulting cells to treat arthritic mice. Mice that received these cells showed less severe arthritis than control animals treated with dendritic cells that had not been loaded with FK506. Moreover, the total dose of FK506 that the mice were exposed to was very low, with the result that they showed no evidence of the side effects typically seen with this drug. This proof-of-concept study suggests that dendritic cells could be used for the gradual and controlled delivery of drugs to specific target cells within the immune system. By precisely targeting relevant immune cells, it should be possible to use much lower drug doses, and thereby reduce side effects. Follow-up studies are now required to determine whether dendritic cells can be used as vehicles for the delivery of other drugs to treat a range of diseases. DOI: http://dx.doi.org/10.7554/eLife.00105.002

Background The interaction between Src homology 2 domain-containing protein tyrosine phosphatase (SHP-2) of gastric epithelial cells and cagA from H. pylori plays a crucial role in developments of gastric atrophy and gastric cancer. This study aimed to investigate the association of haplotype tagging SNPs (htSNPs) in the PTPN11 gene encoding SHP-2 with gastric atrophy and gastric cancer in Chinese population. Methods The subjects comprised 414 patients with gastric cancer, 109 individuals with gastric atrophy and 923 healthy controls. Blood was collected from October 2008 to October 2010. Five htSNPs rs2301756, rs12423190, rs12229892, rs7958372 and rs4767860 from the PTPN11 gene were selected and genotyped by Taqman assay. Serum Ig G antibodies to H. pylori were detected by ELISA. Gastric atrophy was screened by the levels of serum pepsinogenIandII, and confirmed by endoscopy and histopatholgical examinations. Odds ratio (ORs) and 95% confidence intervals (CIs) were calculated by a multivariate logistic regression. Results Among H. pylori seropositive subjects, age and gender-adjusted OR of gastric atrophy was 2.47 (95%CI 1.13-4.55, P = 0.02) for CC genotype compared with CT/TT genotypes, suggesting a recessive model of genetic risk for rs12423190. The prevalence of H. pylori seropositivity were significantly higher in groups of gastric cancer and gastric atrophy compared to the control group (70.3% vs. 75.2% vs. 49.7%, P Conclusions Our study provides the first evidence that rs12423190 polymorphism of the PTPN11 gene is significantly associated with an increased risk of gastric atrophy in H. pylori infected Chinese Han population, suggesting that rs12423190 polymorphism could be used as a useful marker of genetic susceptibility to gastric atrophy among H. pylori infected subjects. The biological roles of this polymorphism require a further investigation.

The zinc finger antiviral protein (ZAP) is a host factor that mediates inhibition of viruses in the Filoviridae, Retroviridae and Togaviridae families. We previously demonstrated that ZAP blocks replication of Sindbis virus (SINV), the prototype Alphavirus in the Togaviridae family at an early step prior to translation of the incoming genome and that synergy between ZAP and one or more interferon stimulated genes (ISGs) resulted in maximal inhibitory activity. The present study aimed to identify those ISGs that synergize with ZAP to mediate Alphavirus inhibition. Using a library of lentiviruses individually expressing more than 350 ISGs, we screened for inhibitory activity in interferon defective cells with or without ZAP overexpression. Confirmatory tests of the 23 ISGs demonstrating the largest infection reduction in combination with ZAP revealed that 16 were synergistic. Confirmatory tests of all potentially synergistic ISGs revealed 15 additional ISGs with a statistically significant synergistic effect in combination with ZAP. These 31 ISGs are candidates for further mechanistic studies. The number and diversity of the identified ZAP-synergistic ISGs lead us to speculate that ZAP may play an important role in priming the cell for optimal ISG function.

Background Many studies have been published on the association between single nucleotide polymorphisms (SNP) near the IL28B gene and response to the combined treatments of pegylated-interferon (PegIFN) and ribavirin (RBV) in chronic HCV-infected patients, but without identical conclusions. The aim of this study was to assess impact of the IL28B polymorphisms on the effect of HCV standard treatment using meta-analysis based method. Methods Association studies between polymorphisms of rs12979860 or rs8099917 and response to PegIFN/RBV treatment in chronic HCV patients were retrieved from PubMed. Data of qualified studies on sustained virological response (SVR) in different genotypes were extracted and analyzed using meta-analysis method in Stata 10 software. Results Thirty-four papers, containing 46 independent studies, were included in the analysis. In the HCV G1/4 patients without treatment history, individuals carrying rs12979860 CC genotype were more likely to achieve SVR (OR 3.97, 95%CI 3.29–4.80) compared to those carrying CT/TT genotypes. Similar results were observed in the HCV G1/4 patients with unsuccessful or unknown treatment history (OR 3.76, 95%CI 2.67–5.28) or in the patients co-infected with human immunodeficiency virus (OR 5.20, 95%CI 3.04–8.90). However, associations could not be observed in HCV G2/3 patients. For rs8099917, similar results were obtained for genotype TT compared to genotypes TG/GG, indicating that TT genotype was significantly associated with better treatment response in patients infected with genotype 1 or 4 HCV, but not genotype 2 or 3 HCV. Conclusion Polymorphisms of rs12979860 and rs8099917 near IL28B only associate with the treatment response to PegIFN/RBV in patients infected with HCV genotype 1 or 4 but not with genotype 2 or 3, irrespective of the previous treatment history or HIV co-infected status. Therefore, identification of IL28B genotypes is necessary only in patients infected with relatively difficult-to-treat genotype 1 or 4 HCV.