Evaluation of hepatic functional reserve of hepatocellular carcinoma (≤ 5 cm) by liver shear wave velocity combined with multiple parameters.

Background: Normal hepatic functional reserve is the key to avoiding liver failure after liver surgery. This study investigated the assessment of hepatic functional reserve using liver shear wave velocity (LSWV) combined with biochemical indicators, tumor volume, and portal vein diameter. Methods: In this single-center prospective study, a total of 123 patients with hepatocellular carcinoma (HCC) were divided into a test group (n=92) and a validation group (n=31). All patients were Child-Pugh grade A. The indocyanine green retention rate at 15 min (ICG-R15), liver shear wave velocity (LSWV), portal vein diameter (Dpv), alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), γ-glutamyl transpeptidase (γ-GGT), albumin (ALB), prothrombin time (PT), and also liver tumor volume (maximum diameter ≤5 cm) were measured. In the test group, multiple parameters were used to evaluate hepatic functional reserve, and the multiparametric model was established. Receiver operating characteristic (ROC) curve analysis was conducted to assess the diagnostic performance of the multiparametric model. In the validation group, the predictive effectiveness of the multiparametric model was analyzed using consistency tests. Results: It was revealed that LSWV, ALB, and PT were statistically significant in evaluation of the hepatic functional reserve (P<0.05). The multiparametric model was formulated as follows: Y= -18.954 + 9.726*LSWV-0.397*ALB+2.063*PT. The value of the area under the curve (AUC) for the multiparametric model was 0.913 (95% confidence interval (CI): 0.835-0.962, P< 0.01), with a cutoff value of 16.656 (sensitivity, 0.763; specificity, 0.926). The Kappa value of consistency testing was 0.655 (P<0.01). Conclusion: LSWV combined with ALB and PT exhibited a high predictive effectiveness for the assessment of hepatic functional reserve, assisting the clinical diagnosis and management of liver diseases.

Health-Related quality of life and DNA Methylation-Based aging biomarkers among survivors of childhood cancer.

BACKGROUND: Childhood cancer survivors are at high risk for morbidity and mortality and poor patient-reported outcomes, typically health-related-quality-of-life (HRQOL). However, associations between DNA methylation (DNAm)-based aging biomarkers and HRQOL have not been evaluated. METHODS: DNAm was generated with Infinium EPIC BeadChip on blood-derived DNA (median[range] for age at blood draw = 34.5[18.5-66.6] years) and HRQOL was assessed with age at survey (32.3[18.4-64.5] years) from 2,206 survivors in the St Jude Lifetime Cohort. DNAm-based aging biomarkers, including epigenetic age using multiple clocks (eg, GrimAge) and others (eg, DNAmB2M beta-2-microglobulin; DNAmADM: adrenomedullin), were derived from the DNAm Age Calculator (https://dnamage.genetics.ucla.edu). HRQOL was assessed using the Medical Outcomes Study 36-Item Short-Form Health Survey to capture eight domains, and physical and mental component summaries (PCS and MCS). General linear models evaluated associations between HRQOL and epigenetic age acceleration (EAA, eg, EAA_GrimAge) or other age-adjusted DNAm-based biomarkers (eg, ageadj_DNAmB2M) after adjusting for age at blood draw, sex, cancer treatments, and DNAm-based surrogate for smoking pack-years. All P values were 2-sided. RESULTS: Worse HRQOL was associated with greater EAA_GrimAge (PCS ß[95%CI]=-0.18[-0.251,-0.11] years, P = 1.85 × 10-5; and four individual HRQOL domains), followed by ageadj_DNAmB2M (PCS: -0.08[-0.124,-0.037], P = .003; and three individual HRQOL domains), and ageadj_DNAmADM (PCS: -0.082[-0.125,-0.039], P = .002; and two HRQOL domains). EAA_Hannum (Hannum clock) was not associated with any HRQOL. CONCLUSIONS: Overall and domain-specific measures of HRQOL are associated with DNAm measures of biological aging. Future longitudinal studies should test biological aging as a potential mechanism underlying the association between poor HRQOL and increased risk of clinically assessed adverse health outcomes.

Deciphering essential druggable genes reveals potential immune-inflammatory axis in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a malignant tumor with a high mortality rate and poor prognosis in patients. Its pathogenesis is a complex process of multi-factors and multi-steps. However, the etiology and exact molecular mechanism are not completely clear. METHODS: Here, we constructed a specific-expressed network based on RNA sequencing data. Gene and miRNA expression profiles and clinical evidence were integrated to detect hepatocellular carcinoma survival modules. Finally, we attempted to identify potential key biomarkers and drug targets by integrating drug sensitivity analysis and immune infiltration analysis. RESULTS: A total of 42 prognostic modules for hepatocellular carcinoma were detected. The prognostic modules were significantly enriched with known cancer-related molecules and 12.93 % molecules of prognostic modules had been found were the targets of small molecule drug. In addition, we found that 38 of 42 (90.48 %) essential genes were associated with the proportions of at least one of the 7 immune cell types. CONCLUSION: We integrated clinical prognosis information, RNA sequencing data, and drug activity data to explore risk modules of hepatocellular carcinoma. Through drug sensitivity analysis and immune infiltration analysis, we assessed the value of hub genes in the modules as potential biomarkers and drug targets for hepatocellular carcinoma. The protocol provides new insight into parsing the molecular mechanism and theoretical basis of hepatocellular carcinoma.

Metronomic dosing of ovarian cancer cells with the ATR inhibitor AZD6738 leads to loss of CDC25A expression and resistance to ATRi treatment.

OBJECTIVE: ATR kinase inhibitors promote cell killing by inducing replication stress and through potentiation of genotoxic agents in gynecologic cancer cells. To explore mechanisms of acquired resistance to ATRi in ovarian cancer, we characterized ATRi-resistant ovarian cancer cells generated by metronomic dosing with the clinical ATR inhibitor AZD6738. METHODS: ATRi-resistant ovarian cancer cells (OVCAR3 and OV90) were generated by dosing with AZD6738 and assessed for sensitivity to Chk1i (LY2603618), PARPi (Olaparib) and combination with cisplatin or a CDK4/6 inhibitor (Palbociclib). Models were characterized by diverse methods including silencing CDC25A in OV90 cells and assessing impact on ATRi response. Serum proteomic analysis of ATRi-resistant OV90 xenografts was performed to identify circulating biomarker candidates of ATRi-resistance. RESULTS: AZD6738-resistant cell lines are refractory to LY2603618, but not to Olaparib or combinations with cisplatin. Cell cycle analyses showed ATRi-resistant cells exhibit G1/S arrest following AZD6738 treatment. Accordingly, combination with Palbociclib confers resistance to AZD6738. AZD6738-resistant cells exhibit altered abundances of G1/S phase regulatory proteins, including loss of CDC25A in AZD6738-resistant OV90 cells. Silencing of CDC25A in OV90 cells confers resistance to AZD6738. Serum proteomics from AZD6738-resistant OV90 xenografts identified Vitamin D-Binding Protein (GC), Apolipoprotein E (APOE) and A1 (APOA1) as significantly elevated in AZD6738-resistant backgrounds. CONCLUSIONS: We show that metronomic dosing of ovarian cancer cells with AZD6738 results in resistance to ATR/ Chk1 inhibitors, that loss of CDC25A expression represents a mechanism of resistance to ATRi treatment in ovarian cancer cells and identify several circulating biomarker candidates of CDC25A low, AZD6738-resistant ovarian cancer cells.

Serial Transthoracic Ultrasonography Studies in Hematopoietic Cell Transplant Patients: A Tool for Early Lung Pathology Detection.

Early detection of pulmonary complications can improve outcomes for patients with hematological malignancy (HM). For detecting lung injuries, lung ultrasound (LUS) images have been found to be of greater sensitivity than radiographic images. Our group performed a pilot study of LUS imaging to enhance early detection of pulmonary complications in HM patients. This prospective single-center feasibility study evaluated LUS for detecting pulmonary complications in 18 HM patients enrolled while hospitalized for a hematopoietic cell transplant (HCT) (concurrent-HCT group) or re-hospitalized for complications (post-HCT group). Serial LUS exams were performed and assigned a score from 0 to 5 based on pleural line, B-line, consolidation and pleural effusion features. Correlations between patients' clinical characteristics and LUS features were analyzed. Comparisons between the LUS and radiographic images were evaluated. In the concurrent-HCT patients (79 LUS exams), non-significant fluctuating findings were commonly identified, but one-third of the patients presented pathologic findings (LUS scores ≥ 3). In the post-HCT patients (29 LUS exams), LUS images revealed severe pathologic findings (LUS score = 5) in every patient and, compared with radiographic images, were more sensitive for detecting pleural effusions (p < 0.05). LUS can be routinely performed on hospitalized HM patients, allowing point-of-care early detection of pulmonary complications.

Proteogenomic analysis of lung adenocarcinoma reveals tumor heterogeneity, survival determinants, and therapeutically relevant pathways.

We present a deep proteogenomic profiling study of 87 lung adenocarcinoma (LUAD) tumors from the United States, integrating whole-genome sequencing, transcriptome sequencing, proteomics and phosphoproteomics by mass spectrometry, and reverse-phase protein arrays. We identify three subtypes from somatic genome signature analysis, including a transition-high subtype enriched with never smokers, a transversion-high subtype enriched with current smokers, and a structurally altered subtype enriched with former smokers, TP53 alterations, and genome-wide structural alterations. We show that within-tumor correlations of RNA and protein expression associate with tumor purity and immune cell profiles. We detect and independently validate expression signatures of RNA and protein that predict patient survival. Additionally, among co-measured genes, we found that protein expression is more often associated with patient survival than RNA. Finally, integrative analysis characterizes three expression subtypes with divergent mutations, proteomic regulatory networks, and therapeutic vulnerabilities. This proteogenomic characterization provides a foundation for molecularly informed medicine in LUAD.

Germline mutation landscape of DNA damage repair genes in African Americans with prostate cancer highlights potentially targetable RAD genes.

In prostate cancer, emerging data highlight the role of DNA damage repair genes (DDRGs) in aggressive forms of the disease. However, DDRG mutations in African American men are not yet fully defined. Here, we profile germline mutations in all known DDRGs (N = 276) using whole genome sequences from blood DNA of a matched cohort of patients with primary prostate cancer comprising of 300 African American and 300 European Ancestry prostate cancer patients, to determine whether the mutation status can enhance patient stratification for specific targeted therapies. Here, we show that only 13 of the 46 DDRGs identified with pathogenic/likely pathogenic mutations are present in both African American and European ancestry patients. Importantly, RAD family genes (RAD51, RAD54L, RAD54B), which are potentially targetable, as well as PMS2 and BRCA1, are among the most frequently mutated DDRGs in African American, but not in European Ancestry patients.

Omarigliptin Prevents TNF-α-Induced Cellular Senescence in Rat Aorta Vascular Smooth Muscle Cells.

Cellular senescence is one of the most significant factors involved in aging and age-related diseases. Senescence of vascular smooth muscle cells (VSMCs) adversely affects the function of the cardiovascular system and contributes to the development of atherosclerosis, hypertension, and other cardiovascular diseases. Glucagon-like peptide-1 (GLP-1) is an important incretin hormone involved in insulin release and vascular tone. GLP-1 is quickly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4). Omarigliptin is a new DPP-4 inhibitor that has demonstrated anti-inflammatory and antioxidative stress properties. In the present study, we investigated the effects of the selective DPP-4 inhibitor omarigliptin (OMG) on VSMCs exposed to insult from tumor necrosis factor-α (TNF-α), one of the main inflammatory signaling molecules involved in cellular senescence. We found that OMG could suppress TNF-α-induced expression of pro-inflammatory cytokines (interleukin-1ß (IL-1ß), IL-6, and IL-8) and inhibit oxidative stress by reducing the production of H2O2 and protein carbonyl. OMG ameliorated the increase in senescence-associated ß-galactosidase (SA-ß-gal) and telomerase activity induced by TNF-α. The plasminogen activator inhibitor-1 (PAI-1)/p53/p21 pathway is a key inducer of cellular senescence. OMG ameliorated the acetylation of p53 at lysine 382 (K382) and subsequent activation of p21 via inhibition of PAI-1. Importantly, our experiments revealed that blockage of silent information-regulator 1 (SIRT1) abolished the inhibitory effects of OMG on p53 acetylation, SA-ß-gal activity, and telomerase activity in VSMCs. These results suggest that OMG may have the potential to delay or prevent the progression of age-related cardiovascular diseases by modulating the activity of SIRT1.

Tensin 1 (TNS1) is a modifier gene for low body mass index (BMI) in homozygous [F508del]CFTR patients.

Cystic fibrosis (CF) is a life-limiting autosomal recessive genetic disease caused by variants in the CFTR gene, most commonly by the [F508del] variant. Although CF is a classical Mendelian disease, genetic variants in several modifier genes have been associated with variation of the clinical phenotype for pulmonary and gastrointestinal function and urogenital development. We hypothesized that whole genome sequencing of a well-phenotyped CF populations might identify novel variants in known, or hitherto unknown, modifier genes. Whole genome sequencing was performed on the Illumina HiSeq X platform for 98 clinically diagnosed cystic fibrosis patient samples from the Adult CF Clinic at the University of California San Diego (UCSD). We compared protein-coding, non-silent variants genome wide between CFTR [F508del] homozygotes vs CFTR compound heterozygotes. Based on a single variant score test, we found 3 SNPs in common variants (MAF >5%) that occurred at significantly different rates between homozygous [F508del]CFTR and compound heterozygous [F508del]CFTR patients. The 3 SNPs were all located in one gene on chromosome 2: Tensin 1 (TNS1: rs3796028; rs2571445: and rs918949). We observed significantly lower BMIs in homozygous [F508del]CFTR patients who were also homozygous for Tensin 1 rs918949 (T/T) (p = 0.023) or rs2571445 (G/G) (p = 0.02) variants. The Tensin 1 gene is thus a potential modifier gene for low BMI in CF patients homozygous for the [F508del]CFTR variant.

Significance of circulating tumor cells in the portal vein regarding metastases and vascular invasion in hepatocellular carcinoma patients.

BACKGROUND: Vascular invasion is an important risk factor of poor prognosis in hepatocellular carcinoma (HCC) patients. The detection of circulating tumor cells (CTCs) in the blood is direct evidence of tumor presence. There are few reports on CTCs and metastasis and vascular invasion of HCC. The purpose of this study was to analyze the significance of CTCs in the portal vein regarding metastases and vascular invasion in HCC patients. METHODS: A total of 104 HCC patients diagnosed and treated in Zhengzhou University People's Hospital were enrolled. Surgery was performed in 60 individuals. Portal vein blood samples were collected before treatment for CTCs detection. We used the isolation by size of epithelial tumor cells (ISET) and fluorescence in situ hybridization (FISH) to enrich and classify CTCs from blood samples. The patients were divided into metastasis and nonmetastasis groups according to the metastasis status before treatment. Differences in clinical indicators such as alpha-fetoprotein (AFP) levels, tumor size, CTCs count, and macrovascular tumor thrombus between the two groups were analyzed as well as the associations of CTCs count with the above indicators. For individuals with postoperative pathology, the relationship between CTCs counts and microvascular invasion (MVI) was analyzed. RESULTS: The amounts of portal vein CTCs were higher in patients with metastases compared with the nonmetastases group (20 vs. 7; z=3.795; P<0.001). Multivariate logistic regression analysis showed that the CTC count was a risk factor for HCC metastasis [odds ratio (OR) =1.044; 95% CI: 1.011-1.079]. The sensitivity and specificity of CTC count in predicting HCC metastasis were 82.93% and 52.38%, respectively. CTC count was significantly correlated with tumor size (rs=0.308; P=0.001), vascular invasion (z=4.211; P<0.001), and MVI (z=12.763; P=0.002). A threshold CTC count of seven showed the most significant power for predicting metastasis. CONCLUSIONS: Vascular invasion positivity was closely related to HCC metastasis. Portal vein CTC count before treatment was correlated with vascular invasion and could be considered one of the factors affecting HCC metastasis. However, the ability of CTC count was limited in predicting HCC metastasis due to insufficient specificity.

Identifying four DNA methylation gene sites signature for predicting prognosis of osteosarcoma.

BACKGROUND: Osteosarcoma (OS) is a common malignant bone tumor in children and adolescents. DNA methylation plays a crucial role in the prognosis prediction of cancer. Identification of novel DNA methylation sites biomarkers could be beneficial for the prognosis of OS patients. In this study, we aim to find an efficient methylated site model for predicting survival in OS. METHODS: DNA methylation data were downloaded from the Cancer Genome Atlas database (TCGA) and the GEO database. Cox proportional hazard regression and random survival forest algorithm (RSFVH) were applied to identify DNA methylated site signature in the samples randomly assigned to the training subset and the other samples as the test subset. By randomizing 71 clinical samples into two individual groups and a series of statistical analyses between the two groups, a DNA methylation signature is verified. RESULTS: This signature comprises four methylation sites (cg04533248, cg12401425, cg13997435, and cg15075357) associated with the patient training group from the univariate Cox proportional hazards regression analysis, RSFVH, and multivariate Cox regression analysis. Kaplan-Meier survival curves showed the OS patients in the high-risk group have a poor 5-year overall survival compared with the low-risk group, and this finding was identified in the test data set. A ROC analysis was performed in the current research. The results revealed that this signature was an independent predictor of patient survival by investigating the AUC of the four methylation sites signature in the training data set (AUC =0.861) and test data set, respectively (AUC =0.920). The nomogram described in the current study placed a great guiding value for predicting 1-, 2-, 3-year survival of the OS by combining age, gender, grade, and TNM stage as covariates with the RS of patients' methylation related signatures. CONCLUSIONS: Our study proved that this signature might be a powerful prognostic tool for survival rate evaluation and guide tailored therapy for OS patients.

Digitoxin Inhibits Epithelial-to-Mesenchymal-Transition in Hereditary Castration Resistant Prostate Cancer.

Castration Resistant Prostate Cancer (CRPC) is thought to be driven by a collaborative mechanism between TNFα/NFκB and TGFß signaling, leading to inflammation, Epithelial-to-Mesenchymal-Transition (EMT), and metastasis. Initially, TGFß is a tumor suppressor, but in advanced metastatic disease it switches to being a tumor promoter. TGFBR2 may play a critical role in this collaboration, as its expression is driven by NFκB and it is the primary receptor for TGFß. We have previously reported that the cardenolide drug digitoxin blocks TNFα/NFκB-driven proinflammatory signaling. We therefore hypothesized that digitoxin might break the collaborative process between NFκB and TGFß by also inhibiting expression of TGFBR2. We therefore tested whether TGFß-driven EMT and resulting metastases would be suppressed. Here we show, in vitro, that digitoxin inhibits NFκB-driven TGFBR2 expression, as well as Vimentin, while elevating E-cadherin expression. Digitoxin also significantly reduces HSPB1 mRNA and the HSPB1/RBFOX2 mRNA ratio in PC3 cells. In vivo, in a syngeneic, immune competent rat model of metastatic CRPC, we show that digitoxin also suppresses Tgfbr2 expression, as well as expression of other genes classically driven by NFκB, and of multiple EMT genes associated with metastasis. Concurrently, digitoxin suppresses tumor growth and metastasis in these animals, and prolongs survival. Gross tumor recurrence following tumor resection also appears prevented in ca 30% of cases. While the existence of a collaboration between NFκB and TGFß to drive EMT and metastasis has previously been appreciated, we show here, for the first time, that chronic, low concentrations of digitoxin are able to block CRPC tumor progression, EMT and the ensuing metastatic disease.

Angelica polysaccharide alleviates oxidative response damage in HaCaT cells through up-regulation of miR-126.

BACKGROUND: Pressure ulcers (PUs) prevalence has been considered as an index for patient safety and cure quality of hospital and community. Skin cellular oxidative response damage is existed in the development of PUs. Angelica polysaccharide (AP) has the anti-oxidation function. Therefore, our goal was to investigate the mechanism of AP in relieving cellular oxidative damage. METHODS: Transfected HaCaT cells with miR-126 inhibitor, pre-treated by AP, and then treated by H2O2. CCK-8 assay and flow cytometry detection were set to test viability and apoptosis of cells respectively. qRT-PCR and western blot tested levels of miR-126 and oxidative damage relative factors. ROS assay tested the production of ROS in cells. RESULTS: Cellular oxidative response damage was induced by H2O2 at concentration of 300 µM. We found that AP could attenuate cellular oxidative response damage caused by H2O2 that it elevated cell viability, attenuated cell apoptosis and production of ROS and promoted activation of PI3K/AKT and mTOR signal pathways. Further, miR-126 was up-regulated by AP. The up-regulation of miR-126 could activate the PI3K/AKT and mTOR signal pathways. CONCLUSION: Our study demonstrated that AP attenuated cellular oxidative response damage in HaCaT cells by positively regulated miR-126.

Analysis of expression levels of IL-17 and IL-34 and influencing factors for prognosis in patients with lupus nephritis.

Expression levels of interleukin-17 (IL-17) and IL-34 was investigated to analyze the influencing factors for prognosis in patients with lupus nephritis (LN). Clinical data of 45 patients (LN group) treated and diagnosed with LN via renal biopsy in Yanan University Affiliated Hospital from October 2010 to October 2012 and 50 healthy subjects (control group) were analyzed retrospectively. Levels of serum IL-17 and IL-34 were detected via enzyme-linked immunosorbent assay. Correlations of serum IL-17 and IL-34 with urinary protein in LN patients were analyzed via Pearson correlation analysis. Univariate survival analysis was performed using the Kaplan-Meier method, and multivariate analysis was performed for LN prognosis using the Cox proportional hazards model. Levels of serum IL-34 and IL-17 in patients in LN group were significantly higher than those in control group (P<0.001). Serum IL-17 and IL-34 in LN patients were positively correlated with urinary protein (r= 0.436 and 0.714, P<0.05). Adverse factors affecting the prognosis of 45 LN patients including age, hemoglobin, platelet, blood uric acid, urinary protein, IL-17 and IL-34, showing statistically significant differences (P<0.05). Age, hemoglobin, blood uric acid, urinary protein, IL-17 and IL-34 were independent risk factors for poor prognosis of LN (P<0.05). The inflammatory factors IL-17 and IL-34 are highly expressed in the serum of LN patients. Levels of serum IL-17 and IL-34 in LN patients have positive correlations with urinary protein. Results of univariate and multivariate Cox regression analyses reveal that age, hemoglobin, blood uric acid, urinary protein, IL-17 and IL-34 are independent risk factors for poor prognosis of LN. IL-17 and IL-34 can therefore serve as effective indexes for clinical diagnosis, treatment and prognosis of LN.

Three-Dimensional Echocardiography-derived strain values acquired by a novel analysis program.

OBJECTIVE: This in vitro study calculated longitudinal strain (LS) from different ultrasound systems (GE Vivid E9 and Philips IE 33) before and after myocardial infarct (MI) using a vendor-independent analysis software package (TomTec's 4D LV Analysis) to validate the variation of two ultrasound systems. METHODS: Ten freshly harvested porcine hearts were passively driven by a pulsatile pump apparatus at stroke volumes (SV) 30-70 mL. Full-volume three-dimensional echocardiography (3DE) data were acquired before and after MI using two different ultrasound systems. LS was derived from TomTec and validated against sonomicrometry data. RESULTS: Linear regression analyses showed excellent correlations between TomTec-calculated LS values and sonomicrometry data for both normal and simulated MI groups (GE: R2  = 0.72/0.68, Philip: R2  = 0.71/0.66). Bland-Altman analyses demonstrated overestimation of echo-derived strain values for all groups. Both ultrasound system-derived strain values demonstrated decreased LS after MI, and the average change in strain after infarct was roughly 30% in GE images and 25% in Philips images. CONCLUSIONS: Both GE and Philips echocardiographic systems can be analyzed with TomTec's program, and these images correlated well with sonomicrometry with acceptable variations.

Characterising cis-regulatory variation in the transcriptome of histologically normal and tumour-derived pancreatic tissues.

OBJECTIVE: To elucidate the genetic architecture of gene expression in pancreatic tissues. DESIGN: We performed expression quantitative trait locus (eQTL) analysis in histologically normal pancreatic tissue samples (n=95) using RNA sequencing and the corresponding 1000 genomes imputed germline genotypes. Data from pancreatic tumour-derived tissue samples (n=115) from The Cancer Genome Atlas were included for comparison. RESULTS: We identified 38 615 cis-eQTLs (in 484 genes) in histologically normal tissues and 39 713 cis-eQTL (in 237 genes) in tumour-derived tissues (false discovery rate <0.1), with the strongest effects seen near transcriptional start sites. Approximately 23% and 42% of genes with significant cis-eQTLs appeared to be specific for tumour-derived and normal-derived tissues, respectively. Significant enrichment of cis-eQTL variants was noted in non-coding regulatory regions, in particular for pancreatic tissues (1.53-fold to 3.12-fold, p≤0.0001), indicating tissue-specific functional relevance. A common pancreatic cancer risk locus on 9q34.2 (rs687289) was associated with ABO expression in histologically normal (p=5.8×10-8) and tumour-derived (p=8.3×10-5) tissues. The high linkage disequilibrium between this variant and the O blood group generating deletion variant in ABO (exon 6) suggested that nonsense-mediated decay (NMD) of the 'O' mRNA might explain this finding. However, knockdown of crucial NMD regulators did not influence decay of the ABO 'O' mRNA, indicating that a gene regulatory element influenced by pancreatic cancer risk alleles may underlie the eQTL. CONCLUSIONS: We have identified cis-eQTLs representing potential functional regulatory variants in the pancreas and generated a rich data set for further studies on gene expression and its regulation in pancreatic tissues.

Fisetin inhibits laryngeal carcinoma through regulation of AKT/NF-κB/mTOR and ERK1/2 signaling pathways.

Targeting cancer cells is crucial for improving the efficiency of laryngeal cancer treatment. However, the signaling pathway and therapeutic strategy, related to the tumor, still need further research. Dietary flavonoid fisetin (3,3',4',7-tetrahydroxyflavone) found in many fruits and vegetables has been shown in preclinical studies to inhibit cancer growth through regulating cell cycle, apoptosis, angiogenesis, invasion and metastasis without causing any toxicity to normal cells. PI3K/AKT and ERK1/2 have been known as essential signaling pathways to modulate cell proliferation, apoptosis as well as autophagy via mTOR, Caspase-3 and NF-κB signals. In our study, flow cytometry and western blot assays suggested that apoptosis was induced by fisetin administration, promoting Caspase-3 expressions by regulating PI3K/AKT/NF-κB. Additionally, fisetin suppressed TU212 cells proliferation, which was linked with ERK1/2 inactivation. Further, the activation of PI3K/AKT-regulated mTOR was inhibited by fisetin, leading to transcription suppression and proliferation inhibition of TU212 cells. In vivo studies also showed that the tumor volume and weight of nude mice were reduced for fisetin use with KI-67 decrease and LC3II increase in tumor tissue samples. Together, our data indicated that fisetin had a potential role in controlling human laryngeal cancer through inhibiting tumor cell proliferation, inducing apoptosis and autophagy regulated by ERK1/2 and AKT/NF-κB/mTOR signaling pathways, which might provide a therapeutic strategy for laryngeal cancer inhibition in future.

Rare Germline Copy Number Variations and Disease Susceptibility in Familial Melanoma.

Mounting evidence suggests that copy number variations (CNVs) can contribute to cancer susceptibility. The main goal of this study was to evaluate the role of germline CNVs in melanoma predisposition in high-risk melanoma families. We used genome-wide tiling comparative genomic hybridization and single nucleotide polymorphism arrays to characterize CNVs in 335 individuals (240 melanoma cases) from American melanoma-prone families (22 with germline CDKN2A or CDK4 mutations). We found that the global burden of overall CNVs (or deletions or duplications separately) was not significantly associated with case-control or CDKN2A/CDK4 mutation status after accounting for the familial dependence. However, we identified several rare CNVs that either involved known melanoma genes (e.g., PARP1, CDKN2A) or cosegregated with melanoma (duplication on 10q23.23, 3p12.2 and deletions on 8q424.3, 2q22.1) in families without mutations in known melanoma high-risk genes. Some of these CNVs were correlated with expression changes in disrupted genes based on RNASeq data from a subset of melanoma cases included in the CNV study. These results suggest that rare cosegregating CNVs may influence melanoma susceptibility in some melanoma-prone families and genes found in our study warrant further evaluation in future genetic analyses of melanoma.

Evaluation of left and right ventricular myocardial function after lung resection using speckle tracking echocardiography.

The impact of major lung resections on myocardial function has not been well-investigated. We aimed to identify this impact through the use of speckle tracking echocardiography (STE) to evaluate the right and left ventricular myocardial function in patients who underwent lung resections.Thirty patients who had lung resections were recruited for this study. Ten patients who underwent pneumonectomies were matched by age and sex, with 20 patients who underwent lobectomies. STE was performed on both right and left ventricle (RV and LV). Strain values of pre and postlung resections were compared in both the pneumonectomy group and the lobectomy group. Comparison between the pneumonectomy group and the lobectomy group was also studied.Left ventricular ejection fraction remained normal (>55%), but significantly decreased after lung resection in both the pneumonectomy group and the lobectomy group. An accelerated heart rate was observed in both groups after lung resection, with the pneumonectomy group demonstrating extra rapid heart rate (P < 0.05). Strain values in the RV and LV decreased in both groups after lung resection, with the pneumonectomy group exhibiting a further decrease in longitudinal strain in LV and RV when compared with the lobectomy group (P < 0.05).Right and left ventricular dysfunction can occur after lung resection regardless of pneumonectomy or lobectomy, and lobectomy may have a less significant impact on myocardial functions. This study demonstrated that STE is able to detect acute cardiac dysfunction after lung resection.

Whole exome sequencing in families at high risk for Hodgkin lymphoma: identification of a predisposing mutation in the KDR gene.

Hodgkin lymphoma shows strong familial aggregation but no major susceptibility genes have been identified to date. The goal of this study was to identify high-penetrance variants using whole exome sequencing in 17 Hodgkin lymphoma prone families with three or more affected cases or obligate carriers (69 individuals), followed by targeted sequencing in an additional 48 smaller HL families (80 individuals). Alignment and variant calling were performed using standard methods. Dominantly segregating, rare, coding or potentially functional variants were further prioritized based on predicted deleteriousness, conservation, and potential importance in lymphoid malignancy pathways. We selected 23 genes for targeted sequencing. Only the p.A1065T variant in KDR (kinase insert domain receptor) also known as VEGFR2 (vascular endothelial growth factor receptor 2) was replicated in two independent Hodgkin lymphoma families. KDR is a type III receptor tyrosine kinase, the main mediator of vascular endothelial growth factor induced proliferation, survival, and migration. Its activity is associated with several diseases including lymphoma. Functional experiments have shown that p.A1065T, located in the activation loop, can promote constitutive autophosphorylation on tyrosine in the absence of vascular endothelial growth factor and that the kinase activity was abrogated after exposure to kinase inhibitors. A few other promising mutations were identified but appear to be "private". In conclusion, in the largest sequenced cohort of Hodgkin lymphoma families to date, we identified a causal mutation in the KDR gene. While independent validation is needed, this mutation may increase downstream tumor cell proliferation activity and might be a candidate for targeted therapy.