Association between Triglyceride-Glucose Index and 1-year Recurrent Stroke after Acute Ischemic Stroke: Results from the Xi'an Stroke Registry Study of China.

INTRODUCTION: The triglyceride-glucose (TyG) index is reported to be related to poor functional outcomes and all-cause mortality post-stroke. However, the association between TyG index and recurrent stroke after acute ischemic stroke (AIS) has not been well described. We aimed to identify whether the TyG index was associated with 1-year recurrent stroke after AIS. METHODS: Baseline patient information was collected at admission, and the TyG index was calculated. Recurrent stroke events were followed up at 1, 3, 6, and 12 months after diagnosis. We then examined the association between the TyG index and risk of 1-year recurrent stroke using multivariable Cox regression models and restricted cubic spline analyses. RESULTS: Among 2,288 participants, the mean TyG index was 8.8  0.7. Those in the fourth quartile (Q4) demonstrated higher recurrent stroke risk than those in Q1 (adjusted hazard ratio [HR] = 1.63; 95% confidence interval [CI], 0.98-2.72; p = 0.059). Subgroup analysis revealed a sex-specific association between TyG index and recurrent stroke (p for interaction = 0.022). Additionally, restricted cubic splines analyses showed a non-linear association between the TyG index and 1-year recurrent stroke. In females, patients in the Q4 had a 2.95-fold increased recurrent stroke risk than did patients in the Q1 (adjusted HR =2.95; 95% CI, 1.09-7.94; p = 0.032); the risk increased when the TyG index was > 8.73. However, no significant correlation was observed in males. CONCLUSION: A non-linear association was found between the TyG index and 1-year recurrent stroke risk. Subsequently, a high TyG index could predict an increased 1-year recurrent stroke risk in female AIS patients.

INTAC endonuclease and phosphatase modules differentially regulate transcription by RNA polymerase II.

Gene expression in metazoans is controlled by promoter-proximal pausing of RNA polymerase II, which can undergo productive elongation or promoter-proximal termination. Integrator-PP2A (INTAC) plays a crucial role in determining the fate of paused polymerases, but the underlying mechanisms remain unclear. Here, we establish a rapid degradation system to dissect the functions of INTAC RNA endonuclease and phosphatase modules. We find that both catalytic modules function at most if not all active promoters and enhancers, yet differentially affect polymerase fate. The endonuclease module induces promoter-proximal termination, with its disruption leading to accumulation of elongation-incompetent polymerases and downregulation of highly expressed genes, while elongation-competent polymerases accumulate at lowly expressed genes and non-coding elements, leading to their upregulation. The phosphatase module primarily prevents the release of paused polymerases and limits transcriptional activation, especially for highly paused genes. Thus, both INTAC catalytic modules have unexpectedly general yet distinct roles in dynamic transcriptional control.

Coordinated regulation of RNA polymerase II pausing and elongation progression by PAF1.

Pleiotropic transcription regulator RNA polymerase II (Pol II)-associated factor 1 (PAF1) governs multiple transcriptional steps and the deposition of several epigenetic marks. However, it remains unclear how ultimate transcriptional outcome is determined by PAF1 and whether it relates to PAF1-controlled epigenetic marks. We use rapid degradation systems and reveal direct PAF1 functions in governing pausing partially by recruiting Integrator-PP2A (INTAC), in addition to ensuring elongation. Following acute PAF1 degradation, most destabilized polymerase undergoes effective release, which presumably relies on skewed balance between INTAC and P-TEFb, resulting in hyperphosphorylated substrates including SPT5. Impaired Pol II progression during elongation, along with altered pause release frequency, determines the final transcriptional outputs. Moreover, PAF1 degradation causes a cumulative decline in histone modifications. These epigenetic alterations in chromatin likely further influence the production of transcripts from PAF1 target genes.

Genetic Polymorphisms of Very Important Pharmacogene Variants in the Blang Population from Yunnan Province in China.

BACKGROUND: We aimed to enrich the pharmacogenomic information of a Blang population (BP) from Yunnan Province in China. METHODS: We genotyped 55 very important pharmacogene (VIP) variants from the PharmGKB database and compared their genotype distribution (GD) in a BP with that of 26 populations by the χ 2 test. The minor allele frequency (MAF) distribution of seven significantly different single-nucleotide polymorphisms (SNPs) was conducted to compare the difference between the BP and 26 other populations. RESULTS: Compared with the GD of 55 loci in the BP, among 26 studied populations, GWD, YRI, GIH, ESN, MSL, TSI, PJL, ACB, FIN and IBS were the top-10 populations, which showed a significantly different GD >35 loci. CHB, JPT, CDX, CHS, and KHV populations had a significantly different GD <20 loci. A GD difference of 27-34 loci was found between the BP and 11 populations (LWK, CEU, ITU, STU, PUR, CLM, GBR, ASW, BEB, MXL and PEL). The GD of five loci (rs750155 (SULT1A1), rs4291 (ACE), rs1051298 (SLC19A1), rs1131596 (SLC19A1) and rs1051296 (SLC19A1)) were the most significantly different in the BP as compared with that of the other 26 populations. The genotype frequency of rs1800764 (ACE) and rs1065852 (CYP2D6) was different in all populations except for PEL and LWK, respectively. MAFs of rs1065852 (CYP2D6) and rs750155 (SULT1A1) showed the largest fluctuation between the BP and SAS, EUR, AFR and AMR populations. CONCLUSION: Our data can provide theoretical guidance for safe and efficacious personalized drug use in the Blang population.

Genetic analysis of pharmacogenomic VIP variants in the Wa population from Yunnan Province of China.

BACKGROUND: The variation of drug responses and target does among individuals is mostly determined by genes. With the development of pharmacogenetics and pharmacogenomics, the differences in drug response between different races seem to be mainly caused by the genetic diversity of pharmacodynamics and pharmacokinetics genes. Very important pharmacogenetic (VIP) variants mean that genes or variants play important and vital roles in drug response, which have been listed in pharmacogenomics databases, such as Pharmacogenomics Knowledge Base (PharmGKB). The information of Chinese ethnic minorities such as the Wa ethnic group is scarce. This study aimed to uncover the significantly different loci in the Wa population in Yunnan Province of China from the perspective of pharmacogenomics, to provide a theoretical basis for the future medication guidance, and to ultimately achieve the best treatment in the future. RESULTS: In this study, we recruited 200 unrelated healthy Wa adults from the Yunnan province of China, selected 52 VIP variants from the PharmGKB for genotyping. We also compared the genotype frequency and allele distribution of VIP variants between Wa population and the other 26 populations from the 1000 Genomes Project ( http://www.1000Genomes.org/ ). Next, χ2 test was used to determine the significant points between these populations. The study results showed that compared with the other 26 population groups, five variants rs776746 (CYP3A5), rs4291 (ACE), rs3093105 (CYP4F2), rs1051298 (SLC19A1), and rs1065852 (CYP2D6) had higher frequencies in the Wa population. The genotype frequencies rs4291-TA, rs3093105-CA, rs1051298-AG and rs1065852-GA were higher than those of the other populations, and the allele distributions of rs4291-T and rs3093105-C were significantly different. Additionally, the difference between the Wa ethnic group and East Asian populations, such as CDX, CHB, and CHS, was the smallest. CONCLUSIONS: Our research results show that there is a significant difference in the distribution of VIP variants between the Wa ethnic group and the other 26 populations. The study results will have an effect on supplementing the pharmacogenomics information for the Wa population and providing a theoretical basis for individualised medication for the Wa population.

Analysis of CYP2J2 mutations in the Chinese Uyghur population.

Genetic characteristics of CYP2J2 in different populations may be helpful to explore interethnic variability in drug response and disease susceptibility. There is no information about the genetic profile of CYP2J2 in the Chinese Uyghur population. We used PCR and first-generation sequencing technology to investigate CYP2J2 mutations in 100 unrelated healthy Chinese Uyghurs. The chi-square test was used to compare genotyping data of CYP2J2 in the Chinese Uyghur population with other ethnic groups. The SIFT and PolyPhen-2 online tools were used to predict the protein function of the novel nonsynonymous mutations in CYP2J2. CADD software was used to predict pathogenicity of the mutations. We found twenty-eight mutations in CYP2J2, five new mutations, three alleles (*1, *7 and *8), and three genotypes (*1/*1, *1/*7 and *1/*8) in the Chinese Uyghur population. The allele frequencies of CYP2J2 *1, *7 and *8 were 96%, 3.45%, and 0.5%, respectively. Interethnic comparison found that subgenotype *1 in Uyghur was significantly higher than in Taiwanese and African Americans, and *7 frequency in Uyghur was slightly lower than that in Taiwanese and African Americans (P<0.05); *8 was only found in Chinese Uyghur and Korean populations, with frequencies of 0.5% and 0.8%, respectively. Furthermore, the protein prediction results revealed that the five nonsynonymous mutations could influence protein structure and function. The observations of this study give rise to useful information on CYP2J2 mutations in Chinese Uyghurs, which may support future important clinical implications for the use of medications metabolized by CYP2J2.

Fc receptor-like 1, 3, and 6 variants are associated with rheumatoid arthritis risk in the Chinese Han population.

BACKGROUND: Rheumatoid arthritis (RA) is the most common autoimmune system diseases in our world. More studies in recent years have shown that FCRL gene polymorphisms is closely related to autoimmune diseases. It is suggested that genetic factors play a crucial role in the pathogenesis of this disease. In this study, we aimed to investigate the relationship between FCRL1 rs2050568, FCRL3 rs2317230 and FCRL6 rs58240276 polymorphisms and RA risk in the Chinese Han population. 506 with RA patients and 509 healthy controls were recruited in this study, and the single nucleotide polymorphisms (SNPs) was successfully genotyped using the Agena MassARRAY platform. Odds ratios (ORs) and 95% confidence intervals (95% CIs) after adjusting for age and gender were conducted to assess these SNPs polymorphisms and RA risk. The multifactor dimensionality reduction (MDR) method was conducted to analyze SNP-SNP interaction. RESULTS: Our results revealed that there no significant association was observed between the allele and genotype frequencies among these SNPs and RA risk (all p > 0.05). Straified analysis by age and gender, the results confirmed that FCRL1 rs2050568 T/T genotype enhanced the risk of RA in females (p = 0.014). The G/T - T/T genotype of FCRL3 rs2317230 was correlated with a decreased RA risk in males (p = 0.021). We also observed that the C/T-T/T genotype of FCRL6 rs58240276 was increased the risk of RA in the group at age >  54 years (p = 0.016). In addition, FCRL1 rs2050568-TT, FCRL6 rs58240276-TT and FCRL1 rs2050568-TT, FCRL3 rs2317230-TT, FCRL6 rs58240276-TT are the best models for multi-site MDR analysis (p < 0.05), and the two best models mentioned above and classes RA have the most significant correlation. CONCLUSIONS: Our study demonstrated that FCRL1 rs2050568, FCRL3 rs2317230, and FCRL6 rs58240276 polymorphisms were correlated with RA susceptibility in the Chinese Han population.

Dissecting esophageal squamous-cell carcinoma ecosystem by single-cell transcriptomic analysis.

Esophageal squamous-cell carcinoma (ESCC), one of the most prevalent and lethal malignant disease, has a complex but unknown tumor ecosystem. Here, we investigate the composition of ESCC tumors based on 208,659 single-cell transcriptomes derived from 60 individuals. We identify 8 common expression programs from malignant epithelial cells and discover 42 cell types, including 26 immune cell and 16 nonimmune stromal cell subtypes in the tumor microenvironment (TME), and analyse the interactions between cancer cells and other cells and the interactions among different cell types in the TME. Moreover, we link the cancer cell transcriptomes to the somatic mutations and identify several markers significantly associated with patients' survival, which may be relevant to precision care of ESCC patients. These results reveal the immunosuppressive status in the ESCC TME and further our understanding of ESCC.

SPT5 stabilizes RNA polymerase II, orchestrates transcription cycles, and maintains the enhancer landscape.

Transcription progression is governed by multitasking regulators including SPT5, an evolutionarily conserved factor implicated in virtually all transcriptional steps from enhancer activation to termination. Here we utilize a rapid degradation system and reveal crucial functions of SPT5 in maintaining cellular and chromatin RNA polymerase II (Pol II) levels. Rapid SPT5 depletion causes a pronounced reduction of paused Pol II at promoters and enhancers, distinct from negative elongation factor (NELF) degradation resulting in short-distance paused Pol II redistribution. Most genes exhibit downregulation, but not upregulation, accompanied by greatly impaired transcription activation, altered chromatin landscape at enhancers, and severe Pol II processivity defects at gene bodies. Phosphorylation of an SPT5 linker at serine 666 potentiates pause release and is antagonized by Integrator-PP2A (INTAC) targeting SPT5 and Pol II, while phosphorylation of the SPT5 C-terminal region links to 3' end termination. Our findings position SPT5 as an essential positive regulator of global transcription.

Impacts of LOC105371267 Variants on Breast Cancer Susceptibility in Northern Chinese Han Females: A Population-Based Case-Control Study.

BACKGROUND: LOC105371267, also known as PR-lncRNA1, was reported to be a p53-regulated long noncoding RNA (lncRNA), which played an essential role in the pathogenesis of breast cancer (BC). We aimed to observe the potential association between LOC105371267 polymorphisms and BC risk in Northern Chinese Han females. METHODS: Totally, 555 healthy individuals and 561 patients with BC were recruited. Five candidate SNPs (rs6499221, rs3931698, rs8044565, rs3852740, and rs111577197) of LOC105371267 were genotyped with the Agena MassARRAY system. Odds ratio (OR) and 95% confidence intervals (CIs) were applied to evaluate the relationship of LOC105371267 genetic polymorphisms with BC susceptibility. Additionally, stratification analysis based on clinical features and haplotype analysis were also conducted. Finally, multifactor dimensionality reduction (MDR) analysis was performed to assess the SNP-SNP interaction among LOC105371267 variants, and false-positive report probability (FPRP) analysis was used to validate the result of this study. RESULTS: In this study, rs3931698 was a protective factor of BC in total (GG homozygote: OR = 0.30, 95% CI: 0.11-0.82, p=0.018; recessive model: OR = 0.30, 95% CI: 0.11-0.84, p=0.021). In stratification analysis based on the average age of 52 years and clinical characteristics (PR status, III-IV TNM stage), rs3931698 was also demonstrated to be associated with BC susceptibility. In addition, rs6499221 and rs3852740 were also associated with BC susceptibility among patients at age <52 years and patients with BC in a positive status. Thus, the haplotype analysis had a negative result for the incidence of BC (p > 0.05), and haplotype consisting of rs8044565 and rs111577197 was nonsignificantly associated with the BC risk. Finally, MDR and FPRP analyses also validated the result of this study. CONCLUSION: Polymorphisms rs3931698, rs6499221, and rs3852740 of LOC105371267 were found to be associated with the risk of BC in total, and stratification analysis in the Northern Chinese Han females suggested that LOC105371267 variants might be helpful to predict BC progression.

Population Genetic Difference of Pharmacogenomic VIP Variants in the Tibetan Population.

BACKGROUND: Genetic variation influences drug reaction or adverse prognosis. The purpose of this research was to genotype very important pharmacogenetic (VIP) variants in the Tibetan population. METHODS AND MATERIALS: Blood samples from 200 Tibetans were randomly collected and 59 VIP variants were genotyped, and then compared our data to 26 other populations in the 1000 project to further analyze and identify significant difference. RESULTS: The results showed that on comparing with most of the 26 populations from the 1000 project, rs4291 (ACE), rs1051296 (SLC19A1) and rs1065852 (CYP2D6) significantly differed in the Tibetan population. Furthermore, three significant loci were related to drug response. In addition, the allele frequency of Tibetans least differed from that of East Asian populations, and most differed from that of Americans. CONCLUSION: Three significant loci of variation ACE rs4291, SLC19A1 rs1051296 and CYP2D6 rs1065852 were associated with drug response. This result will contribute to improving the information of the Tibetan in the pharmacogenomics database, and providing a theoretical basis for clinical individualised drug use in Tibetans.

The Impacts of IL1R1 and IL1R2 Genetic Variants on Rheumatoid Arthritis Risk in the Chinese Han Population: A Case-Control Study.

BACKGROUND: Rheumatoid arthritis (RA), an autoimmune systemic inflammatory disease, largely resulted from genetic factor. Our purpose was to explore the association for IL1R1 and IL1R2 genetic variants with RA susceptibility in the Chinese Han population. PATIENTS AND METHODS: A total of 508 RA patients and 494 controls were involved in this case-control study; single-nucleotide polymorphisms (SNPs) genotyping was identified by the Agena MassARRAY platform. The relationship between polymorphisms and RA susceptibility was calculated using the Pearson's Chi-square test with odds ratios and 95% confidence intervals (CIs) in multiple genetic models. The Pearson's Chi-square test and Student's t-test were used for sample basic characteristic analysis. And linkage disequilibrium (LD) analysis and haplotype analysis were performed by logistic regression analysis. RESULTS: The result from this study showed that rs2072472 (IL1R2) was an increased risk factor of RA (adjusted OR = 1.41, p = 0.011). Stratified analysis indicated SNPs rs10490571, rs956730, rs3917318 of IL1R1, and SNPs rs4851527, rs719250, rs3218896, rs3218977, rs2072472 of IL1R2 had impacts on RA risk after stratification based on gender and average age (54 years). Finally, haplotype analysis revealed that Ars3218977Ars2072472 haplotype in IL1R2 was related to a decreased RA risk (adjusted OR = 0.79; 95% CI = 0.65-0.94; p = 0.010). Yet, rs3917225(IL1R1) and rs11674595(IL1R2) were not significant in RA association analysis. CONCLUSION: We determined SNPs (rs3917318, rs956730, rs1049057) of IL1R1 and SNPs (rs3218977, rs719250, rs4851527, rs3218896, rs2072472) of IL1R2 were correlated with the RA susceptibility in the Chinese Han population.

Impact of ESR1 Polymorphisms on Risk of Breast Cancer in the Chinese Han Population.

BACKGROUND: The estrogen receptor-1 (ESR1) gene encodes estrogen receptor-α, which is a major biomarker in the development of breast cancer. This study aimed to investigate the effect of ESR1 polymorphisms on breast cancer in Chinese Han women. MATERIALS AND METHODS: We genotyped 4 candidate single nucleotide polymorphisms (SNPs) in ESR1 among 503 patients with breast cancer and 503 healthy people using the Agena MassARRAY platform. The association between ESR1 polymorphisms and breast cancer risk was evaluated using odds ratios (ORs) and 95% confidence intervals (95% CIs) under 4 genetic models. The HaploReg v4.1 and GEPIA database were used for SNP functional annotation and ESR1 expression analysis, respectively. RESULTS: The T allele of rs9383938 in ESR1 was significantly associated with an increased breast cancer risk (OR, 1.26; 95% CI, 1.05-1.50; P = .013). In genetic models, rs9383938 increased breast cancer risk in the codominant model (OR, 1.54; 95% CI, 1.07-2.22; P = .021), the dominant model (OR, 1.31; 95% CI, 1.01-1.68; P = .040), and the additive model (OR, 1.24; 95% CI, 1.04-1.48; P = .017). Stratification analysis showed that rs9383938 and rs2228480 raised the breast cancer susceptibility in individuals aged younger than 52 years old. Rs1801132 of ESR1 was significantly associated with the status of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 in the allele model and genetic models (P < .05). CONCLUSIONS: This study demonstrated that ESR1 polymorphisms might influence breast cancer susceptibility in the Chinese Han population. Further mechanism studies are needed to confirm the contribution of ESR1.

Single-cell transcriptomic analysis in a mouse model deciphers cell transition states in the multistep development of esophageal cancer.

Esophageal squamous cell carcinoma (ESCC) is prevalent in some geographical regions of the world. ESCC development presents a multistep pathogenic process from inflammation to invasive cancer; however, what is critical in these processes and how they evolve is largely unknown, obstructing early diagnosis and effective treatment. Here, we create a mouse model mimicking human ESCC development and construct a single-cell ESCC developmental atlas. We identify a set of key transitional signatures associated with oncogenic evolution of epithelial cells and depict the landmark dynamic tumorigenic trajectories. An early downregulation of CD8+ response against the initial tissue damage accompanied by the transition of immune response from type 1 to type 3 results in accumulation and activation of macrophages and neutrophils, which may create a chronic inflammatory environment that promotes carcinogen-transformed epithelial cell survival and proliferation. These findings shed light on how ESCC is initiated and developed.

Metabolic remodeling by TIGAR overexpression is a therapeutic target in esophageal squamous-cell carcinoma.

Rationale: Whole-genome sequencing has identified many amplified genes in esophageal squamous-cell carcinoma (ESCC). This study investigated the role and clinical relevance of these genes in ESCC. Methods: We collected ESCC and non-tumor esophageal tissues from 225 individuals who underwent surgery. Clinical data were collected and survival time was measured from the date of diagnosis to the date of last follow-up or death. Patient survival was compared with immunohistochemical staining score using Kaplan-Meier methods and hazard ratios were calculated by Cox models. Cells with gene overexpression and knockout were analyzed in proliferation, migration and invasion assays. Cells were also analyzed for levels of intracellular lactate, NADPH, ATP and mRNA and protein expression patterns. Protein levels in cell line and tissue samples were measured by immunoblotting or immunohistochemistry. ESCC cell were grown as xenograft tumors in nude mice. Primary ESCC in genetically engineered mice and patient-derived xenograft mouse models were established for test of therapeutic effects. Results: We show that TP53-induced glycolysis and apoptosis regulator (TIGAR) is a major player in ESCC progression and chemoresistance. TIGAR reprograms glucose metabolism from glycolysis to the glutamine pathway through AMP-activated kinase, and its overexpression is correlated with poor disease outcomes. Tigar knockout mice have reduced ESCC tumor burden and growth rates. Treatment of TIGAR-overexpressing ESCC cell xenografts and patient-derived tumor xenografts in mice with combination of glutaminase inhibitor and chemotherapeutic agents achieves significant more efficacy than chemotherapy alone. Conclusion: These findings shed light on an important role of TIGAR in ESCC and might provide evidence for targeted treatment of TIGAR-overexpressing ESCC.

Novel hyaluronic acid-modified temperature-sensitive nanoparticles for synergistic chemo-photothermal therapy.

This study has developed a versatile nano-system with the combined advantages of photothermal effect, active tumor-targeting, temperature-sensitive drug release, and photoacoustic imaging. The nano-system consists of the core of the phase change material (PCM), the outer polypyrrole (PPY) shell and the hyaluronic acid (HA) modified in the PPY shell. The obtained composite nanoparticles (denoted as DTX/PPN@PPY@HA) were spherical with a mean diameter of about 232.7 nm. In vivo and in vitro photoacoustic imaging experiments show that DTX/PPN@PPY@HA is an effective photoacoustic contrast agent, which can be used for accurate localization of tumor region and real-time guidance of photothermal chemotherapy. DTX/PPN@PPY@HA shows good photothermal effects and temperature-sensitive drug release. In addition, cellular experiments showed that DTX/PPN@PPY@HA could be efficiently internalized into tumor cells and produce significant cytotoxicity with the help of near-infrared (NIR) laser. Furthermore, the remarkable inhibition of DTX/PPN@PPY@HA against tumor growth was achieved in 4T1 tumor-bearing mice model.

CCGD-ESCC: A Comprehensive Database for Genetic Variants Associated with Esophageal Squamous Cell Carcinoma in Chinese Population.

Esophageal squamous-cell carcinoma (ESCC) is one of the most lethal malignancies in the world and occurs at particularly higher frequency in China. While several genome-wide association studies (GWAS) of germline variants and whole-genome or whole-exome sequencing studies of somatic mutations in ESCC have been published, there is no comprehensive database publically available for this cancer. Here, we developed the Chinese Cancer Genomic Database-Esophageal Squamous Cell Carcinoma (CCGD-ESCC) database, which contains the associations of 69,593 single nucleotide polymorphisms (SNPs) with ESCC risk in 2022 cases and 2039 controls, survival time of 1006 ESCC patients (survival GWAS) and gene expression (expression quantitative trait loci, eQTL) in 94 ESCC patients. Moreover, this database also provides the associations between 8833 somatic mutations and survival time in 675 ESCC patients. Our user-friendly database is a resource useful for biologists and oncologists not only in identifying the associations of genetic variants or somatic mutations with the development and progression of ESCC but also in studying the underlying mechanisms for tumorigenesis of the cancer. CCGD-ESCC is freely accessible at http://db.cbi.pku.edu.cn/ccgd/ESCCdb.

Integrative analysis of gene expression profiles reveals specific signaling pathways associated with pancreatic duct adenocarcinoma.

BACKGROUND: Pancreatic duct adenocarcinoma (PDAC) remains a major health problem because conventional cancer treatments are relatively ineffective against it. Microarray studies have linked many genes to pancreatic cancer, but the available data have not been extensively mined for potential insights into PDAC. This study attempted to identify PDAC-associated genes and signaling pathways based on six microarray-based profiles of gene expression in pancreatic cancer deposited in the gene expression omnibus database. METHODS: Pathway network methods were used to analyze core pathways in six publicly available pancreatic cancer gene (GSE71989, GSE15471, GSE16515, GSE32676, GSE41368 and GSE28735) expression profiles. Genes potentially linked to PDAC were assessed for potential impact on survival time based on data in The Cancer Genome Atlas and International Cancer Genome Consortium databases, and the expression of one candidate gene (CKS2) and its association with survival was examined in 102 patients with PDAC from our hospital. Effects of CKS2 knockdown were explored in the PDAC cell lines BxPC-3 and CFPAC-1. RESULTS: The KEGG signaling pathway called "pathway in cancer" may play an important role in pancreatic cancer development and progression. Five genes (BIRC5, CKS2, ITGA3, ITGA6 and RALA) in this pathway were significantly associated with survival time in patients with PDAC. CKS2 was overexpressed in PDAC samples from our hospital, and higher CKS2 expression in these patients was associated with shorter survival time. CKS2 knockdown substantially inhibited PDAC cell proliferation in vitro. CONCLUSIONS: Analysis integrating existing microarray datasets allowed identification of the "pathway in cancer" as an important signaling pathway in PDAC. This integrative approach may be powerful for identifying genes and pathways involved in cancer.