SOWAHB polymorphisms affect thyroid cancer risk in the Chinese Han population.

OBJECTIVES: This study aimed to detect the correlation between SOWAHB polymorphisms and Thyroid cancer (TC) risk in the Chinese Han population. METHODS: We genotyped SOWAHB variants in 510 TC patients and 509 controls using Agena MassARRAY. We assessed the association between SOWAHB polymorphisms and TC susceptibility, with the significant results evaluated through FPRP analysis. We predicted TC risk by the SNP-SNP interaction, analyzed by MDR. RESULTS: Carriers with rs2703129 CC had a lower probability of TC (codominant, recessive: p = 0.002), while subjects with rs1874564 AG had an increased risk of developing TC (codominant, recessive: p = 0.000, log-additive: p = 0.028). In subjects aged > 45 years, rs2703129 may reduce TC predisposition (codominant: p = 0.011, recessive: p = 0.007), but there was an increased association between rs1874564 and TC risk (codominant: p = 0.030, dominant: p = 0.047). Also, rs2703129 was associated with a lower risk of TC among males (codominant: p = 0.018, recessive: p = 0.013). Conversely, rs1874564 was associated with an increased risk of TC in females (codominant: p = 0.001, dominant: p = 0.003). CONCLUSION: SOWAHB SNPs were related to the occurrence of TC, and rs2703129 may be a protective site for TC.

SKP2 Contributes to AKT Activation by Ubiquitination Degradation of PHLPP1, Impedes Autophagy, and Facilitates the Survival of Thyroid Carcinoma.

Papillary thyroid carcinoma (PTC) is the most common subtype of thyroid carcinoma. Despite a good prognosis, approximately a quarter of PTC patients are likely to relapse. Previous reports suggest an association between S-phase kinase-associated protein 2 (SKP2) and the prognosis of thyroid cancer. SKP1 is related to apoptosis of PTC cells; however, its role in PTC remains largely elusive. This study aimed to understand the expression and molecular mechanism of SKP2 in PTC. SKP2 expression was upregulated in PTC tissues and closely associated with clinical diagnosis. In vitro and in vivo knockdown of SKP2 expression in PTC cells suppressed cell growth and proliferation and induced apoptosis. SKP2 depletion promoted cell autophagy under glucose deprivation. SKP2 interacted with PH domain leucine-rich repeat protein phosphatase-1 (PHLPP1), triggering its degradation by ubiquitination. Furthermore, SKP2 activates the AKT-related pathways via PHLPP1, which leads to the cytoplasmic translocation of SKP2, indicating a reciprocal regulation between SKP2 and AKT. In conclusion, the upregulation of SKP2 leads to PTC proliferation and survival, and the regulatory network among SKP2, PHLPP1, and AKT provides novel insight into the molecular basis of SKP2 in tumor progression.

Stochastic simulation of seawater intrusion in the Longkou area of China based on the Monte Carlo method.

Seawater intrusion is a common groundwater pollution problem, which has a great impact on ecological environment and economic development. In this paper, a numerical simulation model of variable density groundwater was constructed to simulate and predict the future seawater intrusion in Longkou city, Shandong Province of China. The influence of the sensitive parameter uncertainty of the model on the simulation results was evaluated by using the Monte Carlo method. In order to reduce the computational load from repeatedly calling the simulation model, the surrogate model was established by using the support vector regression (SVR) method. After training, the correlation coefficient R2 of the input-output relationship between the SVR surrogate model and the seawater intrusion simulation model reached 0.9957, with an average relative error of 0.2%, indicating that the surrogate model has a high fitting accuracy. Stochastic simulations of seawater intrusion showed that the seawater intrusion in the Longkou area will gradually aggravate at a slow rate, and the increase of seawater intrusion in the study area after 30 years was expected to range from - 6.03% to 7.37% at the 80% confidence level.

Clinical validation of a 90-gene expression test for tumor tissue of origin diagnosis: a large-scale multicenter study of 1417 patients.

BACKGROUND: Once malignancy tumors were diagnosed, the determination of tissue origin and tumor type is critical for clinical management. Although the significant advance in imaging techniques and histopathological approaches, the diagnosis remains challenging in patients with metastatic and poorly differentiated or undifferentiated tumors. Gene expression profiling has been demonstrated the ability to classify multiple tumor types. The present study aims to assess the performance of a 90-gene expression test for tumor classification (i.e. the determination of tumor tissue of origin) in real clinical settings. METHODS: Formalin-fixed paraffin-embedded samples and associated clinicopathologic information were collected from three cancer centers between January 2016 and January 2021. A total of 1417 specimens that met quality control criteria (RNA quality, tumor cell content ≥ 60% and so on) were analyzed by the 90-gene expression test to identify the tumor tissue of origin. The performance was evaluated by comparing the test results with histopathological diagnosis. RESULTS: The 1417 samples represent 21 main tumor types classified by common tissue origins and anatomic sites. Overall, the 90-gene expression test reached an accuracy of 94.4% (1338/1417, 95% CI: 0.93 to 0.96). Among different tumor types, sensitivities were ranged from 74.2% (head&neck tumor) to 100% (adrenal carcinoma, mesothelioma, and prostate cancer). Sensitivities for the most prevalent cancers of lung, breast, colorectum, and gastroesophagus are 95.0%, 98.4%, 93.9%, and 90.6%, respectively. Moreover, specificities for all 21 tumor types are greater than 99%. CONCLUSIONS: These findings showed robust performance of the 90-gene expression test for identifying the tumor tissue of origin and support the use of molecular testing as an adjunct to tumor classification, especially to those poorly differentiated or undifferentiated tumors in clinical practice.

Long non-coding RNA AGAP2-AS1 promotes cell proliferation and invasion through regulating miR-193a-3p/LOXL4 axis in laryngeal squamous cell carcinoma.

Laryngeal squamous cell carcinoma (LSCC) is an aggressive malignancy with highly mortality rate. Long non-coding RNA (lncRNA) AGAP2-AS1 is an identified oncogene in several types of cancers. However, the role of AGAP2-AS1 in LSCC remains unclear. The expression levels of AGAP2-AS1 in LSCC tissues and cell lines were measured using qRT-PCR. AGAP2-AS1 was knocked down in LSCC cells through transfection with siRNA-AGAP2-AS1. Cell proliferation and invasion were detected using MTT and transwell assays. Dual-luciferase reporter gene assay was performed to confirm the interaction with AGAP2-AS1 and downstream genes. Our results showed that AGAP2-AS1 expression was remarkably increased in human LSCC tissues and cell lines. Knockdown of AGAP2-AS1 significantly inhibited the proliferation and invasion of LSCC cells. In addition, AGAP2-AS1 sponged miR-193a-3p and regulated its expression in LSCC cells. Inhibition of miR-193a-3p reversed the effects of AGAP2-AS1 knockdown on LSCC cells. Furthermore, Lysyl oxidase-like 4 (LOXL4) was a target gene of miR-193a-3p and the role of miR-193a-3p was mediated by LOXL4. In conclusion, these findings suggest that knockdown of AGAP2-AS1 inhibited the proliferation and invasion of LSCC cells through regulating the miR-193a-3p/LOXL4 axis.

The effect of VAV3 polymorphisms on thyroid cancer.

BACKGROUND: The incidence of thyroid cancer is rising rapidly in China, but there are few studies on the risk factors of thyroid cancer in the Chinese Han population. METHODS: We performed this case-control study of 510 patients and 509 controls to for determine the linkage of VAV3 variants (rs17019602, rs7521681, rs4915076, and rs1777451) with thyroid cancer susceptibility by computing the odds ratio (OR) and 95% confidence intervals (CI). Multi-factor dimension reduction (MDR) analysis was conducted to assess interaction of VAV3 genetic variants. RESULTS: We found that rs7521681 was remarkably related to a higher risk of thyroid cancer (OR = 1.74, p = 0.012), whereas rs4915076 (OR = 0.66, p = 0.001) significantly decreased thyroid cancer susceptibility. Stratified analyses showed that rs4915076 had a protective role in thyroid cancer in both ages >45 years (OR = 0.70, p = 0.017) and age ≤45 years (OR = 0.63, p = 0.007). Rs17019602 could increase the susceptibility of thyroid cancer in men (OR = 4.76, p = 0.049). Rs7521681 was related to an increased risk of thyroid cancer in women (OR = 1.97, p = 0.012). Rs4915076 could protect individuals from thyroid cancer both in men (OR = 0.60, p = 0.031) and women (OR = 0.68, p = 0.010). Moreover, rs4915076 was the best single-locus model to predict thyroid cancer. Interestingly, the interaction model of rs17019602, rs7521681, rs4915076, rs1777451, and age was a candidate gene-environment model. CONCLUSION: Our results indicated VAV3 variants were associated with thyroid cancer, which provides a new sight into etiology of thyroid cancer.

Gene Expression Profiling for Differential Diagnosis of Liver Metastases: A Multicenter, Retrospective Cohort Study.

BACKGROUND: Liver metastases (LM) are the most common tumors encountered in the liver and continue to be a significant cause of morbidity and mortality. Identification of the primary tumor of any LM is crucial for the implementation of effective and tailored treatment approaches, which still represents a difficult problem in clinical practice. METHODS: The resection or biopsy specimens and associated clinicopathologic data were archived from seven independent centers between January 2017 and December 2020. The primary tumor sites of liver tumors were verified through evaluation of available medical records, pathological and imaging information. The performance of a 90-gene expression assay for the determination of the site of tumor origin was assessed. RESULT: A total of 130 LM covering 15 tumor types and 16 primary liver tumor specimens that met all quality control criteria were analyzed by the 90-gene expression assay. Among 130 LM cases, tumors were most frequently located in the colorectum, ovary and breast. Overall, the analysis of the 90-gene signature showed 93.1% and 100% agreement rates with the reference diagnosis in LM and primary liver tumor, respectively. For the common primary tumor types, the concordance rate was 100%, 95.7%, 100%, 93.8%, 87.5% for classifying the LM from the ovary, colorectum, breast, neuroendocrine, and pancreas, respectively. CONCLUSION: The overall accuracy of 93.8% demonstrates encouraging performance of the 90-gene expression assay in identifying the primary sites of liver tumors. Future incorporation of the 90-gene expression assay in clinical diagnosis will aid oncologists in applying precise treatments, leading to improved care and outcomes for LM patients.

UriBLAD: A Urine-Based Gene Expression Assay for Noninvasive Detection of Bladder Cancer.

Bladder cancer is the most common urinary system neoplasm, with approximately 550,000 new cases per year worldwide. Current methods for diagnosis and monitoring of bladder cancer are often invasive and/or lack sensitivity and specificity. In this study, the authors aimed to develop an accurate, noninvasive urine-based gene expression assay for the detection of bladder cancer. Urine specimens were collected at five Chinese hospitals from patients with bladder cancer, and from healthy and other control subjects. The expression levels of 70 genes were characterized by quantitative RT-PCR in a training cohort of 211 samples. Machine learning approaches were used to identify a 32-gene signature to classify cancer status. The performance of this gene signature was further validated in a multicenter, prospective cohort of 317 samples. In the blind validation set, the 32-gene signature achieved encouraging performance of 90% accuracy, 83% sensitivity, and 95% specificity. The area under the receiver operating characteristic curve reached 0.93. Importantly, the 32-gene signature performed well in the detection of non-muscle invasive tumor and low-grade tumor with sensitivities of 81.6% and 81%, respectively. In conclusion, we present a novel gene expression assay using urine samples that can accurately discriminate patients with bladder cancer from controls. The results might prompt further development of this gene expression assay into an in vitro diagnostic test amenable to routine clinical practice.

The Genetic Polymorphisms in the MIR17HG Gene Are Associated with the Risk of Head and Neck Squamous Cell Carcinoma in the Chinese Han Population.

PURPOSE: Head and neck squamous cell carcinoma (HNSCC) is the most common malignant tumors in the world. Genetic variants have an important role in HNSCC progression. Our study is aimed at exploring the relationship between MIR17HG polymorphisms and HNSCC risk in the Chinese Han population. METHODS: We recruited 537 HNSCC cases and 533 healthy subjects to detect the correlation of six polymorphisms in MIR17HG with HNSCC susceptibility. The associations were evaluated by computing odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression analysis. RESULTS: Our study revealed that rs7336610 (OR 1.77, 95%CI = 1.09-2.86, and p = 0.021) and rs1428 (OR 1.73, 95%CI = 1.07-2.81, and p = 0.025) are strongly associated with increased susceptibility to HNSCC in men. Besides, rs17735387 played a crucial protective role in stage III/IV HNSCC patients (OR 0.34, 95%CI = 0.12-0.95, and p = 0.040) compared with stage I/II. CONCLUSION: Our study firstly indicated that MIR17HG polymorphisms are significantly associated with HNSCC susceptibility, which suggests that MIR17HG has a potential role in the occurrence of HNSCC.

IL-1RN gene polymorphisms reduces thyroid cancer risk in Chinese Han population.

The purpose of this study was to investigate the effect of IL-1RN polymorphisms on thyroid cancer (TC) risk in Han population. Genotypes of four single nucleotide polymorphisms (SNPs) (rs17042888, rs928940, rs3181052, and rs452204) were analyzed by Agena MassARRAY. Meanwhile, we used the logistic regression to calculate the odds ratios (ORs) and 95% confidence intervals (CIs), and significant differences were evaluated by t test and χ2 test. Findings found that allele "G" of rs452204 and rs3181052 in interleukin-1 receptor antagonist (IL-1RN) reduced the risk of TC. (OR = 0.72, 95% CI = 0.55-0.94, p = .017; OR = 0.73, 95% CI = 0.56-0.94, p = .017, respectively). Hierarchical analysis indicated that three SNPs (rs17042888, rs3181052, and rs452204) significantly reduced the risk of TC among females or individuals older than 48 years (p < .05). Our findings indicate that IL-1RN polymorphisms may contribute to a protective role against TC risk.

Development and Clinical Validation of a 90-Gene Expression Assay for Identifying Tumor Tissue Origin.

The accurate identification of tissue origin in patients with metastatic cancer is critical for effective treatment selection but remains a challenge. The aim of this study is to develop a gene expression assay for tumor molecular classification and integrate it with clinicopathologic evaluations to identify the tissue origin for cancer of uncertain primary (CUP). A 90-gene expression signature, covering 21 tumor types, was identified and validated with an overall accuracy of 89.8% (95% CI, 0.87-0.92) in 609 tumor samples. More specifically, the classification accuracy reached 90.4% (95% CI, 0.87-0.93) for 323 primary tumors and 89.2% (95% CI, 0.85-0.92) for 286 metastatic tumors, with no statistically significant difference (P = 0.71). Furthermore, in a real-life cohort of 141 CUP patients, predictions by the 90-gene expression signature were consistent or compatible with the clinicopathologic features in 71.6% of patients (101/141). Findings suggest that this novel gene expression assay could efficiently predict the primary origin for a broad spectrum of tumor types and support its diagnostic utility of molecular classification in difficult-to-diagnose metastatic cancer. Additional studies are ongoing to further evaluate the clinical utility of this novel gene expression assay in predicting primary site and directing therapy for CUP patients.

IL-1B rs2853550 polymorphism contributes to esophageal cancer susceptibility in Chinese Han population of Northwest China.

BACKGROUND: Esophageal cancer (EC) is one of the most common human cancers, with a particularly aggressive behavior and increased incidence worldwide. The aim of this study was to assess the associations of single-nucleotide polymorphisms (SNPs) in IL-1B with the risk of EC in a northwest Chinese Han population. METHODS: In order to evaluate the correlations between IL-1B polymorphisms and EC risk, an Agena MassARRAY platform was used to determine the genotype of the candidate SNPs among 384 EC patients and 499 controls. The associations between IL-1B variants and EC risk were examined using logistic regression analysis with adjustment for gender and age. Haplotype construction and analysis were performed to detect the potential associations between haplotypes within IL-1B and EC susceptibility. Additionally, bioinformatics databases were used for gene expression analysis and SNP functional prediction. RESULTS: A significant relationship was found between IL-1B rs2853550 and an increased risk of EC in the allele model [odds ratio (OR) = 1.38, 95% confidence interval (95% CI): 1.01-1.89, p = 0.041), the codominant model (A/G, OR = 1.63, 95% CI: 1.10-2.42, p = 0.011), and the dominant model (OR = 1.49, 95% CI: 1.02-2.18, p = 0.041). Functional analysis revealed the potential effects of rs2853550, which further reinforced its influence on EC susceptibility. However, there were no statistically significant differences for other SNPs or haplotypes between EC cases and healthy controls. Expression analysis conducted with dataset indicated that the expression level of IL-1B was higher in EC cases than that in normal samples. CONCLUSIONS: This study demonstrated that rs2853550 in IL-1B might increase EC susceptibility in the Chinese Han population of Northwest China.

Genetic variations of CARMN affect risk of esophageal cancer in northwest China.

BACKGROUND: As one of the common malignant tumors, esophageal cancer has significant heterogeneity in morbidity and mortality between gender, geographic distribution, race and histology. We used single nucleotide polymorphism (SNP) to identify disease-related alleles, and to explore the relationship between gene variations and esophageal cancer susceptibility in northwest China. METHODS: Six candidate SNPs (rs13177623, rs12654195, rs11168100, rs353303, rs353300, rs353299) selected from cancer related gene Cardiac mesoderm enhancer-associated non-coding RNA (CARMN) were genotyped by Agena MassARRAY platform. SPSS 18.0 software was used for logistic regression analysis of genotyping results, and Haploview 4.2 software was utilized for linage disequilibrium (LD) analysis. RESULTS: We observed a significant association between genotype TT of rs353299 and the decreasing esophageal cancer risk (OR = 0.42, 95% CI = 0.18-0.97, p = 0.042). The stratified analysis revealed that the influence of three CARMN polymorphisms (rs11168100, rs353300 and rs353299) on esophageal cancer risk is age-, gender-, smoking-, drinking- and lymph node metastasis status- dependent (p < 0.05). Haplotype analysis results indicated that Trs11168100Ars353303Trs353300Crs353299 acts as a protective factor of esophageal cancer with OR of 0.71 (95% CI = 0.52-0.98, p = 0.038), while Ars11168100Grs353303Crs353300 and Ars11168100Ars353303 have 1.49-fold (OR = 1.49, 95% CI = 1.02-2.19, p = 0.041) and 1.57-fold (OR = 1.57, 95% CI = 1.05-2.35, p = 0.027) increased risk of esophageal cancer, respectively. CONCLUSION: The results of our study suggested that CARMN variations may affect the risk of esophageal cancer.

Influence of hydraulic gradient and temperature on the migration of E. coli in saturated porous media during bank filtration: a case study at the Second Songhua River, Songyuan, Northeastern China.

River bank filtration can effectively reduce the number of pathogenic microorganisms infiltrating into groundwater from surface water. Groundwater seepage velocity and temperature are considered to be important factors affecting the process, but the magnitude and mechanism of their impacts have not been clear for a long time. Based on the actual monitoring data of the Escherichia coli concentrations and soil samples of Second Songhua riverside source area, the migration of E. coli in saturated porous media under different velocities and different temperatures was studied using saturated soil column transport experiments. Concurrently, the migration characteristics of E. coli in the riverside source area were replicated by mathematical simulation. According to the field monitoring results, the concentration of E. coli decreased in the riverbank infiltration zone, and the removal rate was greater than 96%. The column experimental results showed that the lower the flow velocity was and the higher the temperature was, the greater the removal rate of E. coli was. And the flow velocity was the main factor affecting the removal of E. Coli. The mathematical simulation results showed that under the conditions of the largest hydraulic gradient (20%) and the highest concentration of E. coli (2500 MPN/100 mL) in river water, the safe exploitation distance of groundwater that did not cause a risk of E. coli pollution was more than 7 m away from the river bank. These findings are expected to provide a scientific basis for the design of water intake schemes and the optimization of mining technology.

Precision medicine for hepatocellular carcinoma: driver mutations and targeted therapy.

Hepatocellular carcinoma (HCC) is the third most frequent cause of tumor-related mortality and there are an estimated approximately 850,000 new cases annually. Most HCC patients are diagnosed at middle or advanced stage, losing the opportunity of surgery. The development of HCC is promoted by accumulated diverse genetic mutations, which confer selective growth advantages to tumor cells and are called "driver mutations". The discovery of driver mutations provides a novel precision medicine strategy for late stage HCC, called targeted therapy. In this review, we summarized currently discovered driver mutations and corresponding signaling pathways, made an overview of identification methods of driver mutations and genes, and classified targeted drugs for HCC. The knowledge of mutational landscape deepen our understanding of carcinogenesis and promise future precision medicine for HCC patients.

DIRC3 and near NABP1 genetic polymorphisms are associated laryngeal squamous cell carcinoma patient survival.

Laryngeal squamous cell carcinoma (LSCC) is one of the most common and aggressive malignancies of the upper digestive tract. The present study is a retrospective analysis of data from a prospective longitudinal study. A total of 170 male LSCC patients (average age, 60.75±10.082) at the First Affiliated Hospital of Xi'an Jiaotong University School of Medicine were recruited between January 2002 and April 2013 for this study. We assessed correlations between patient characteristics and survival, and sequenced genomic DNA from patient peripheral blood samples. We found that the single nucleotide polymorphisms (SNPs), rs11903757, with closest proximity to NABP1 and SDPR, and rs966423 in DIRC3, were associated with survival in LSCC patients. Median follow-up was 38 months (range 3-122) and median survival time was 48 months. LSCC patients with total laryngectomy, poor differentiation, T3-T4 stage, N1-N2 stage or III-IV TNM stage had reduced survival. This is the first study to demonstrate that the rs11903757 GT (HR=2.036; 95% CI, 1.071-3.872; p=0.030) and rs966423 TT (HR=11.677; 95% CI, 3.901-34.950; p=0.000) genotypes predict poor patient outcome. These polymorphisms may serve as useful clinical markers to predict patient survival, and to guide individual patient therapeutic decisions.

Effects of live yeast supplementation on lipopolysaccharide-induced inflammatory responses in broilers.

The effects of supplemental live yeast (LY) on inflammatory responses in broilers challenged with lipopolysaccharide (LPS) were investigated. One-day-old broilers were randomly divided into two treatment groups with two subgroups of each (8 replicate pens; 10 birds/pen) and were fed a basal diet without or with 0.5 g/kg of LY (Saccharomyces cerevisiae NCYC 47Hr+, 1.0 × 1010 CFU/g). Birds from each subgroup of the two treatment groups were intra-abdominally injected with LPS (1.5 mg/kg of BW) or saline at 21, 23, 25, and 27 d of age. Samples were obtained after 8 h of the first injection (d 21) and the last injection (d 27), respectively. Results showed that no treatment differences (P > 0.05) were detected in the relative spleen and bursa weights, as well as serum lysozyme activity and ceruloplasmin content regardless of the immunological status. LY addition tended to alleviate (P = 0.097) LPS-induced increase in serum α-acid glycoprotein content on d 27. LPS induced increased (P < 0.05) serum nitric oxide content and myeloperoxidase activity on d 21 and 27, however, there was a tendency towards reduced (P < 0.10) serum nitric oxide content and myeloperoxidase activity on d 21 in response to LY inclusion. Besides, LY-fed birds had lower (P < 0.05) serum nitric oxide content on d 27 relative to the control counterparts. LPS resulted in increased (P < 0.05) relative mRNA expression of splenic interleukin-1ß on d 21 and 27, but which was lower (P < 0.05) in LY-treated birds compared with that in control. In conclusion, dietary supplementation of LY had potential to alleviate LPS-induced inflammation in broilers.