Accurate SNP and mutation detection by targeted custom microarray-based genomic enrichment of short-fragment sequencing libraries

Microarray-based enrichment of selected genomic loci is a powerful method for genome complexity reduction for next-generation sequencing. Since the vast majority of exons in vertebrate genomes are smaller than 150 nt, we explored the use of short fragment libraries (85–110 bp) to achieve higher enrichment specificity by reducing carryover and adverse effects of flanking intronic sequences. High enrichment specificity (60–75%) was obtained with a relative even base coverage. Up to 98% of the target-sequence was covered more than 20× at an average coverage depth of about 200×. To verify the accuracy of SNP/mutation detection, we evaluated 384 known non-reference SNPs in the targeted regions. At ∼200× average sequence coverage, we were able to survey 96.4% of 1.69 Mb of genomic sequence with only 4.2% false negative calls, mostly due to low coverage. Using the same settings, a total of 1197 novel candidate variants were detected. Verification experiments revealed only eight false positive calls, indicating an overall false positive rate of less than 1 per ∼200 000 bp. Taken together, short fragment libraries provide highly efficient and flexible enrichment of exonic targets and yield relatively even base coverage, which facilitates accurate SNP and mutation detection. Raw sequencing data, alignment files and called SNPs have been submitted into GEO database http://www.ncbi.nlm.nih.gov/geo/ with accession number {"type":"entrez-geo","attrs":{"text":"GSE18542","term_id":"18542"}}GSE18542.     

X-box binding protein 1 (XBP1): a potential role in chemotherapy response,clinical pathologic features,non-inflamed tumour microenvironment for breast cancer

X-box binding protein 1 (XBP1) is mainly expressed in breast cancer (BC) in human cancers. Its tumorigenesis and favourable prognosis are contradictory, and its essential role in chemotherapeutic response and immunosuppression is unknown in BC. The study firstly identified XBP1 who received neoadjuvant chemotherapy (NAC) from {"type":"entrez-geo","attrs":{"text":"GSE25055","term_id":"25055"}}GSE25055 and {"type":"entrez-geo","attrs":{"text":"GSE24460","term_id":"24460"}}GSE24460. Associations between XBP1 expression and clinicopathological characteristics was investigated using Oncomine, TCGA, UALCAN and bc-GenExMiner. The prognostic value of XBP1 was assessed using the Kaplan–Meier Plotter, bc-GenExMiner, {"type":"entrez-geo","attrs":{"text":"GSE25055","term_id":"25055"}}GSE25055, and {"type":"entrez-geo","attrs":{"text":"GSE25056","term_id":"25056"}}GSE25056. Furthermore, we systematically correlated XBP1 and immunological characteristics in the BC tumour microenvironment (TME) using TISIDB, TIMER, {"type":"entrez-geo","attrs":{"text":"GSE25055","term_id":"25055"}}GSE25055, {"type":"entrez-geo","attrs":{"text":"GSE25056","term_id":"25056"}}GSE25056 and TCGA dataset. Finally, an essential role of XBP1 in chemotherapy response was evaluated based on {"type":"entrez-geo","attrs":{"text":"GSE25055","term_id":"25055"}}GSE25055, {"type":"entrez-geo","attrs":{"text":"GSE25065","term_id":"25065"}}GSE25065, {"type":"entrez-geo","attrs":{"text":"GSE24460","term_id":"24460"}}GSE24460, {"type":"entrez-geo","attrs":{"text":"GSE5846","term_id":"5846"}}GSE5846, ROC Plotter and CELL databases. Furthermore, XBP1 mRNA expression levels were obviously highest in BC among human cancers and were significantly related to a good prognosis. In addition, XBP1 mRNA and protein levels were higher in the luminal subtype than in normal tissues and basal-like subtype, which might be attributed to membrane transport-related processes. Apart from BC, negative immunological correlations of XBP1 were not observed in other malignancies. XBP1 might shape the non-inflamed TME in BC. Finally, XBP1 expression was higher in chemo-resistive than chemo-sensitive cases, it had a predictive value and could independently predict chemotherapy response in BC patients receiving NAC. Our study suggests that the essential role of XBP1 in clinical pathologic features, non-inflamed TME, chemotherapy response in BC.     

Expression of the Genetic Suppressor Element 24.2 (GSE24.2) Decreases DNA Damage and Oxidative Stress in X-Linked Dyskeratosis Congenita Cells

The predominant X-linked form of Dyskeratosis congenita results from mutations in DKC1, which encodes dyskerin, a protein required for ribosomal RNA modification that is also a component of the telomerase complex. We have previously found that expression of an internal fragment of dyskerin ({"type":"entrez-geo","attrs":{"text":"GSE24","term_id":"24"}}GSE24.2) rescues telomerase activity in X-linked dyskeratosis congenita (X-DC) patient cells. Here we have found that an increased basal and induced DNA damage response occurred in X-DC cells in comparison with normal cells. DNA damage that is also localized in telomeres results in increased heterochromatin formation and senescence. Expression of a cDNA coding for {"type":"entrez-geo","attrs":{"text":"GSE24","term_id":"24"}}GSE24.2 rescues both global and telomeric DNA damage. Furthermore, transfection of bacterial purified or a chemically synthesized {"type":"entrez-geo","attrs":{"text":"GSE24","term_id":"24"}}GSE24.2 peptide is able to rescue basal DNA damage in X-DC cells. We have also observed an increase in oxidative stress in X-DC cells and expression of {"type":"entrez-geo","attrs":{"text":"GSE24","term_id":"24"}}GSE24.2 was able to diminish it. Altogether our data indicated that supplying {"type":"entrez-geo","attrs":{"text":"GSE24","term_id":"24"}}GSE24.2, either from a cDNA vector or as a peptide reduces the pathogenic effects of Dkc1 mutations and suggests a novel therapeutic approach.     

Exploring the Novel Computational Drug Target and Associated Key Pathways of Oral Cancer

Oral cancer (OC) is a serious health concern that has a high fatality rate. The oral cavity has seven kinds of OC, including the lip, tongue, and floor of the mouth, as well as the buccal, hard palate, alveolar, retromolar trigone, and soft palate. The goal of this study is to look into new biomarkers and important pathways that might be used as diagnostic biomarkers and therapeutic candidates in OC. The publicly available repository the Gene Expression Omnibus (GEO) was to the source for the collection of OC-related datasets. {"type":"entrez-geo","attrs":{"text":"GSE74530","term_id":"74530"}}GSE74530, {"type":"entrez-geo","attrs":{"text":"GSE23558","term_id":"23558"}}GSE23558, and {"type":"entrez-geo","attrs":{"text":"GSE3524","term_id":"3524"}}GSE3524 microarray datasets were collected for analysis. Minimum cut-off criteria of |log fold-change (FC)| > 1 and adjusted p < 0.05 were applied to calculate the upregulated and downregulated differential expression genes (DEGs) from the three datasets. After that only common DEGs in all three datasets were collected to apply further analysis. Gene ontology (GO) and pathway analysis were implemented to explore the functional behaviors of DEGs. Then protein–protein interaction (PPI) networks were built to identify the most active genes, and a clustering algorithm was also implemented to identify complex parts of PPI. TF-miRNA networks were also constructed to study OC-associated DEGs in-depth. Finally, top gene performers from PPI networks were used to apply drug signature analysis. After applying filtration and cut-off criteria, 2508, 3377, and 670 DEGs were found for {"type":"entrez-geo","attrs":{"text":"GSE74530","term_id":"74530"}}GSE74530, {"type":"entrez-geo","attrs":{"text":"GSE23558","term_id":"23558"}}GSE23558, and {"type":"entrez-geo","attrs":{"text":"GSE3524","term_id":"3524"}}GSE3524 respectively, and 166 common DEGs were found in every dataset. The GO annotation remarks that most of the DEGs were associated with the terms of type I interferon signaling pathway. The pathways of KEGG reported that the common DEGs are related to the cell cycle and influenza A. The PPI network holds 88 nodes and 492 edges, and CDC6 had the highest number of connections. Four clusters were identified from the PPI. Drug signatures doxorubicin and resveratrol showed high significance according to the hub genes. We anticipate that our bioinformatics research will aid in the definition of OC pathophysiology and the development of new therapies for OC.     

Immune implication of an autophagy-related prognostic signature in uveal melanoma

Uveal Melanoma (UM) is a rare cancer deriving from melanocytes within the uvea. It has a high rate of metastasis, especially to the liver, and a poor prognosis thereafter. Autophagy, an intracellular programmed digestive process, has been associated with the development and progression of cancers, with controversial pro- and anti-tumour roles. Although previous studies have been conducted on autophagy-related genes (ARGs) in various cancer types, its role in UM requires a deeper understanding for improved diagnosis and development of novel therapeutics. In the present study, Zheng et al. used univariate Cox regression followed by least absolute shrinkage and selection operator (Lasso) regression to identify a robust 9-ARG signature prognostic of survival in a total of 230 patients with UM. The authors used the Cancer Genome Atlas (TCGA) UM cohort as a training cohort (n=80) to identify the signature and validated it in another four independent cohorts of 150 UM patients from the Gene Expression Omnibus (GEO) repository ({"type":"entrez-geo","attrs":{"text":"GSE22138","term_id":"22138"}}GSE22138, {"type":"entrez-geo","attrs":{"text":"GSE27831","term_id":"27831"}}GSE27831, {"type":"entrez-geo","attrs":{"text":"GSE44295","term_id":"44295"}}GSE44295 and {"type":"entrez-geo","attrs":{"text":"GSE84976","term_id":"84976"}}GSE84976). This 9-ARG signature was also significantly associated with the enrichment of cancer hallmarks, including angiogenesis, IL6-KJAK-STAT3 signalling, reactive oxygen species pathway and oxidative phosphorylation. More importantly, this signature is associated with immune-related functional pathways and immune cell infiltration. Thus, this 9-ARG signature predicts prognosis and provides deeper insights into the immune mechanisms in UM, with potential implications for future immunotherapy.     

A ferroptosis-related gene signature for overall survival prediction and immune infiltration in lung squamous cell carcinoma

Background: Ferroptosis is associated with cancer initiation and progression. However, the molecular mechanism and prognostic value of ferroptosis-related genes in lung squamous cell carcinoma (LUSC) are poorly understood.Methods: The mRNA expression profiles, methylation data, and clinical information of patients with LUSC were downloaded from TCGA and GEO database. Ferroptosis-related differentially expressed genes (DEGs) were identified between cancerous and non-cancerous tissues, and their prognostic value was systemically investigated by bioinformatic analyses.Results: A ferroptosis-related gene signature (ALOX5, TFRC, PHKG2, FADS2, NOX1) was constructed using multivariate Cox regression analysis and represented as a risk score. Overall survival (OS) probability was significantly lower in the high-risk group than in the low-risk group (P<0.001), and receiver operating characteristic curve showed a good predictive capacity (AUC = 0.739). The risk score was an independent prognostic factor for LUSC. A nomogram was constructed to predict the OS probabilities at 1, 3, and 5 years. High-risk score was associated with increased immune infiltration, lower methylation levels, higher immune checkpoint genes expression levels, and better chemotherapy response. Cell adhesion molecules, focal adhesion, and extracellular matrix receptor interaction were the main pathways in the high-risk group. The signature was validated using the TCGA test cohort, entire TCGA cohort, {"type":"entrez-geo","attrs":{"text":"GSE30219","term_id":"30219"}}GSE30219, {"type":"entrez-geo","attrs":{"text":"GSE157010","term_id":"157010"}}GSE157010, {"type":"entrez-geo","attrs":{"text":"GSE73403","term_id":"73403"}}GSE73403, and {"type":"entrez-geo","attrs":{"text":"GSE4573","term_id":"4573"}}GSE4573 datasets. The gene disorders in patients with LUSC were validated using real-time PCR and single-cell RNA sequencing analysis.Conclusions: A ferroptosis-related gene signature was constructed to predict OS probability in LUSC. This could facilitate novel therapeutic methods and guide individualized therapy.     

Identification of potential biomarkers in dengue via integrated bioinformatic analysis

Dengue fever virus (DENV) is a global health threat that is becoming increasingly critical. However, the pathogenesis of dengue has not yet been fully elucidated. In this study, we employed bioinformatics analysis to identify potential biomarkers related to dengue fever and clarify their underlying mechanisms. The results showed that there were 668, 1901, and 8283 differentially expressed genes between the dengue-infected samples and normal samples in the {"type":"entrez-geo","attrs":{"text":"GSE28405","term_id":"28405"}}GSE28405, {"type":"entrez-geo","attrs":{"text":"GSE38246","term_id":"38246"}}GSE38246, and {"type":"entrez-geo","attrs":{"text":"GSE51808","term_id":"51808"}}GSE51808 datasets, respectively. Through overlapping, a total of 69 differentially expressed genes (DEGs) were identified, of which 51 were upregulated and 18 were downregulated. We identified twelve hub genes, including MX1, IFI44L, IFI44, IFI27, ISG15, STAT1, IFI35, OAS3, OAS2, OAS1, IFI6, and USP18. Except for IFI44 and STAT1, the others were statistically significant after validation. We predicted the related microRNAs (miRNAs) of these 12 target genes through the database miRTarBase, and finally obtained one important miRNA: has-mir-146a-5p. In addition, gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were carried out, and a protein–protein interaction (PPI) network was constructed to gain insight into the actions of DEGs. In conclusion, our study displayed the effectiveness of bioinformatics analysis methods in screening potential pathogenic genes in dengue fever and their underlying mechanisms. Further, we successfully predicted IFI44L and IFI6, as potential biomarkers with DENV infection, providing promising targets for the treatment of dengue fever to a certain extent.     

Classifying Integrated Signature Molecules in Macrophages of Rheumatoid Arthritis,Osteoarthritis, and Periodontal Disease: An Omics-Based Study

Rheumatoid arthritis (RA), osteoarthritis (OA), and periodontal disease (PD) are chronic inflammatory diseases that are globally prevalent, and pose a public health concern. The search for a potential mechanism linking PD to RA and OA continues, as it could play a significant role in disease prevention and treatment. Recent studies have linked RA, OA, and PD to Porphyromonas gingivalis (PG), a periodontal bacterium, through a similar dysregulation in an inflammatory mechanism. This study aimed to identify potential gene signatures that could assist in early diagnosis as well as gain insight into the molecular mechanisms of these diseases. The expression data sets with the series IDs {"type":"entrez-geo","attrs":{"text":"GSE97779","term_id":"97779"}}GSE97779, {"type":"entrez-geo","attrs":{"text":"GSE123492","term_id":"123492"}}GSE123492, and {"type":"entrez-geo","attrs":{"text":"GSE24897","term_id":"24897"}}GSE24897 for macrophages of RA, OA synovium, and PG stimulated macrophages (PG-SM), respectively, were retrieved and screened for differentially expressed genes (DEGs). The 72 common DEGs among RA, OA, and PG-SM were further subjected to gene–gene correlation analysis. A GeneMANIA interaction network of the 47 highly correlated DEGs comprises 53 nodes and 271 edges. Network centrality analysis identified 15 hub genes, 6 of which are DEGs (API5, ATE1, CCNG1, EHD1, RIN2, and STK39). Additionally, two significantly up-regulated non-hub genes (IER3 and RGS16) showed interactions with hub genes. Functional enrichment analysis of the genes showed that “apoptotic regulation” and “inflammasomes” were among the major pathways. These eight genes can serve as important signatures/targets, and provide new insights into the molecular mechanism of PG-induced RA, OA, and PD.     

Circulating lncRNA UCA1 and lncRNA PGM5-AS1 act as potential diagnostic biomarkers for early-stage colorectal cancer

Background: Colorectal cancer (CRC) is one of the most common and significant malignant diseases worldwide. In the present study, we evaluated two long non-coding RNAs (lncRNAs) in CRC patients as diagnostic markers for early-stage CRC.Methods: Using Gene Expression Omnibus (GEO) datasets {"type":"entrez-geo","attrs":{"text":"GSE102340","term_id":"102340"}}GSE102340, {"type":"entrez-geo","attrs":{"text":"GSE126092","term_id":"126092"}}GSE126092, {"type":"entrez-geo","attrs":{"text":"GSE109454","term_id":"109454"}}GSE109454 and {"type":"entrez-geo","attrs":{"text":"GSE115856","term_id":"115856"}}GSE115856, 14 differentially expressed lncRNAs were identified between cancer and adjacent tissues, among which, the two most differentially expressed were confirmed using quantitative real-time polymerase chain reaction (qRT-PCR) in 200 healthy controls and 188 CRC patients. A receiver operating characteristic (ROC) analysis was employed to evaluate the diagnostic accuracy for CRC.Results: From four GEO datasets, three up-regulated and eleven down-regulated lncRNAs were identified in CRC tissues, among which, lncRNA urothelial carcinoma-associated 1 (UCA1) and lncRNA phosphoglucomutase 5-antisense RNA 1 (PGM5-AS1) were the most significantly up- and down-regulated lncRNAs in CRC patient plasma, respectively. The area under the ROC curve was calculated to be 0.766, 0.754 and 0.798 for UCA1, PGM5-AS1 and the combination of these two lncRNAs, respectively. Moreover, the diagnostic potential of these two lncRNAs was even higher for the early stages of CRC. The combination of UCA1 and PGM5-AS1 enhanced the AUC to 0.832, and when the lncRNAs were used with carcinoembryonic antigen (CEA), the AUC was further improved to 0.874.Conclusion: In the present study, we identified two lncRNAs, UCA1 and PGM5-AS1, in CRC patients’ plasma, which have the potential to be used as diagnostic biomarkers of CRC.     

Role of PCK2 in the proliferation of vascular smooth muscle cells in neointimal hyperplasia

Vascular smooth muscle cell (VSMC) proliferation is a hallmark of neointimal hyperplasia (NIH) in atherosclerosis and restenosis post-balloon angioplasty and stent insertion. Although numerous cytotoxic and cytostatic therapeutics have been developed to reduce NIH, it is improbable that a multifactorial disease can be successfully treated by focusing on a preconceived hypothesis. We, therefore, aimed to identify key molecules involved in NIH via a hypothesis-free approach. We analyzed four datasets ({"type":"entrez-geo","attrs":{"text":"GSE28829","term_id":"28829"}}GSE28829, {"type":"entrez-geo","attrs":{"text":"GSE43292","term_id":"43292"}}GSE43292, {"type":"entrez-geo","attrs":{"text":"GSE100927","term_id":"100927"}}GSE100927, and {"type":"entrez-geo","attrs":{"text":"GSE120521","term_id":"120521"}}GSE120521), evaluated differentially expressed genes (DEGs) in wire-injured femoral arteries of mice, and determined their association with VSMC proliferation in vitro. Moreover, we performed RNA sequencing on platelet-derived growth factor (PDGF)-stimulated human VSMCs (hVSMCs) post-phosphoenolpyruvate carboxykinase 2 (PCK2) knockdown and investigated pathways associated with PCK2. Finally, we assessed NIH formation in Pck2 knockout (KO) mice by wire injury and identified PCK2 expression in human femoral artery atheroma. Among six DEGs, only PCK2 and RGS1 showed identical expression patterns between wire-injured femoral arteries of mice and gene expression datasets. PDGF-induced VSMC proliferation was attenuated when hVSMCs were transfected with PCK2 siRNA. RNA sequencing of PCK2 siRNA-treated hVSMCs revealed the involvement of the Akt-FoxO-PCK2 pathway in VSMC proliferation via Akt2, Akt3, FoxO1, and FoxO3. Additionally, NIH was attenuated in the wire-injured femoral artery of Pck2-KO mice and PCK2 was expressed in human femoral atheroma. PCK2 regulates VSMC proliferation in response to vascular injury via the Akt-FoxO-PCK2 pathway. Targeting PCK2, a downstream signaling mediator of VSMC proliferation, may be a novel therapeutic approach to modulate VSMC proliferation in atherosclerosis.     

Structural Variation-Associated Expression Changes Are Paralleled by Chromatin Architecture Modifications

Copy number variants (CNVs) influence the expression of genes that map not only within the rearrangement, but also to its flanks. To assess the possible mechanism(s) underlying this “neighboring effect”, we compared intrachromosomal interactions and histone modifications in cell lines of patients affected by genomic disorders and control individuals. Using chromosome conformation capture (4C-seq), we observed that a set of genes flanking the Williams-Beuren Syndrome critical region (WBSCR) were often looping together. The newly identified interacting genes include AUTS2, mutations of which are associated with autism and intellectual disabilities. Deletion of the WBSCR disrupts the expression of this group of flanking genes, as well as long-range interactions between them and the rearranged interval. We also pinpointed concomitant changes in histone modifications between samples.We conclude that large genomic rearrangements can lead to chromatin conformation changes that extend far away from the structural variant, thereby possibly modulating expression globally and modifying the phenotype.GEO Series accession number: {"type":"entrez-geo","attrs":{"text":"GSE33784","term_id":"33784"}}GSE33784, {"type":"entrez-geo","attrs":{"text":"GSE33867","term_id":"33867"}}GSE33867.     

The effect of interaction between EtOH dosage and exposure time on gene expression in DPSC

Alcohol (EtOH) dosage and exposure time can affect gene expression. However, whether there exists synergistic effect is unknown. Here, we analyzed the hDPSC gene microarray dataset GSE57255 downloaded from Gene Expression Omnibus and found that the interaction between EtOH dosage and exposure time on gene expression are statistically significant for two probes: 201917_s_at near gene SLC25A36 and 217649_at near gene ZFAND5. GeneMania showed that SLC25A36 and ZFAND5 were related to 20 genes, three of which had alcohol-related functions. WebGestalt revealed that the 22 genes were enriched in 10 KEGG pathways, four of which are related to alcoholic diseases. We explored the possible nonlinear interaction effect and got 172 gene probes with significant p-values. However, no significantly enriched pathways based on the 172 probes were detected. Our analyses indicated a possible molecular mechanism that could help explain why alcohol consumption has both deleterious and beneficial effects on human health.     

Age-related DNA methylation in normal breast tissue and its relationship with invasive breast tumor methylation

Age is a key risk factor for breast cancer and epigenetic alterations may contribute to age-related increases in breast cancer risk, though the relation of age-related methylation in normal breast tissues with altered methylation in breast tumors is unclear. We investigated the relation of age with DNA methylation in normal breast tissues genome-wide using two data sets from the Gene Expression Omnibus (GEO) database ({"type":"entrez-geo","attrs":{"text":"GSE32393","term_id":"32393"}}GSE32393 and {"type":"entrez-geo","attrs":{"text":"GSE31979","term_id":"31979"}}GSE31979). We validated our observations in an independent set of normal breast tissues, examined age-related methylation in normal breast for enrichment of genomic features, and compared age-related methylation in normal tissue with methylation alterations in breast tumors. Between the two array-based methylation data sets, there were 204 CpG loci with significant (P < 0.05) and consistent age-related methylation, 97% of which were increases in methylation. Our validation sets confirmed the direction of age-related DNA methylation changes in all measured regions. Among the 204 age-related CpG loci, we observed a significant enrichment for CpG islands (P = 8.7E-6) and polycomb group protein target genes (P = 0.03). In addition, 24 of the 204 CpGs with age-related methylation in normal breast were significantly differentially methylated between normal and breast tumor tissues. We identified consistent age-related methylation changes in normal breast tissue that are further altered in breast tumors and may represent early events contributing to breast carcinogenesis. This work identifies age-related methylation in normal breast tissue and begins to deconstruct the contribution of aging to epigenetic alterations present in breast tumors.     

Up‐regulated SAMD9L modulated by TLR2 and HIF‐1α as a promising biomarker in tuberculosis

The aim of this study was to identify potential biomarkers of TB in blood and determine their function in Mtb‐infected macrophages. First of all, WGCNA was used to analyse 9451 genes with significant changes in TB patients’ whole blood. The 220 interferon‐γ‐related genes were identified, and then 30 key genes were screened using Cytoscape. Then, the AUC values of key genes were calculated to further narrow the gene range. Finally, we identified 9 genes from {"type":"entrez-geo","attrs":{"text":"GSE19444","term_id":"19444"}}GSE19444. ROC analysis showed that SAMD9L, among 9 genes, had a high diagnostic value (AUC = 0.925) and a differential diagnostic value (AUC>0.865). To further narrow down the range of DEGs, the top 10 hub‐connecting genes were screened from monocytes ({"type":"entrez-geo","attrs":{"text":"GSE19443","term_id":"19443"}}GSE19443). Finally, we obtained 4 genes (SAMD9L, GBP1, GBP5 and STAT1) by intersections of genes from monocytes and whole blood. Among them, it was found that the function of SAMD9L was unknown after data review, so this paper studied this gene. Our results showed that SAMD9L is up‐regulated and suppresses cell necrosis, and might be regulated by TLR2 and HIF‐1α during Mtb infection. In addition, miR‐181b‐5p is significantly up‐regulated in the peripheral blood plasma of tuberculosis patients, which has a high diagnostic value (AUC = 0.969).     

Gene-expression signature predicts postoperative recurrence in stage I non-small cell lung cancer patients

About 30% stage I non-small cell lung cancer (NSCLC) patients undergoing resection will recur. Robust prognostic markers are required to better manage therapy options. The purpose of this study is to develop and validate a novel gene-expression signature that can predict tumor recurrence of stage I NSCLC patients. Cox proportional hazards regression analysis was performed to identify recurrence-related genes and a partial Cox regression model was used to generate a gene signature of recurrence in the training dataset −142 stage I lung adenocarcinomas without adjunctive therapy from the Director''s Challenge Consortium. Four independent validation datasets, including {"type":"entrez-geo","attrs":{"text":"GSE5843","term_id":"5843"}}GSE5843, {"type":"entrez-geo","attrs":{"text":"GSE8894","term_id":"8894"}}GSE8894, and two other datasets provided by Mayo Clinic and Washington University, were used to assess the prediction accuracy by calculating the correlation between risk score estimated from gene expression and real recurrence-free survival time and AUC of time-dependent ROC analysis. Pathway-based survival analyses were also performed. 104 probesets correlated with recurrence in the training dataset. They are enriched in cell adhesion, apoptosis and regulation of cell proliferation. A 51-gene expression signature was identified to distinguish patients likely to develop tumor recurrence (Dxy = −0.83, P<1e-16) and this signature was validated in four independent datasets with AUC >85%. Multiple pathways including leukocyte transendothelial migration and cell adhesion were highly correlated with recurrence-free survival. The gene signature is highly predictive of recurrence in stage I NSCLC patients, which has important prognostic and therapeutic implications for the future management of these patients.