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Background: Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level. Methods: We conducted a gene–environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer genome-wide association study (GWAS) datasets (Pancreatic Cancer Cohort Consortium I–III and Pancreatic Cancer Case Control Consortium). Obesity (body mass index ≥30 kg/m2) and diabetes (duration ≥3 years) were the environmental variables of interest. Approximately 870,000 SNPs (minor allele frequency ≥0.005, genotyped in at least one dataset) were analyzed. Case–control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site, and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual GWAS summary statistics. Results: No genome-wide significant interactions (departures from a log-additive odds model) with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions, but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the FAM63A (family with sequence similarity 63 member A) gene (significance threshold P < 1.25 × 10−6) was observed in the meta-analysis (PGxE = 1.2 ×10−6, PJoint = 4.2 ×10−7). Conclusions: This analysis did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans. Impact: This study may contribute to discovering the mechanism of diabetes-associated pancreatic cancer.

BACKGROUND: Previous studies have found that meat-derived mutagens increase, and vitamin C or E decrease, the risk of pancreatic cancer. OBJECTIVE: The aim of this study was to determine whether intake of vitamin C or E modulates the association between meat-derived mutagen exposure and risk of pancreatic cancer. DESIGN: We conducted a case-control study in 1321 patients with pathologically confirmed pancreatic ductal adenocarcinoma (PDAC) and 1061 healthy controls (aged 28–88 y). Cases and controls were frequency-matched by age, sex, and race/ethnicity. Mutagen intake was assessed using a meat preparation questionnaire. Intakes of vitamin C, E, and other dietary components were assessed via a food-frequency questionnaire in a subset of 811 cases and 818 controls. ORs and 95% CIs were estimated in multivariable-adjusted logistic regression models. RESULTS: The risk of PDAC was not associated with meat intake but was associated with consumption of well-done grilled or barbecued chicken (OR: 1.57; 95% CI: 1.18, 2.09; P = 0.001). Intake of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline was associated with increased PDAC risk (P(trend )= 0.047). Participants in the highest, as compared with the lowest, quintile of 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (PhIP) intake experienced a 38% increased risk of PDAC (95% CI: 1.00, 1.90; P = 0.048). Intakes of total vitamin C or E from food and supplements or from supplements alone were each inversely associated with PDAC risk. Stratified analyses showed differential associations for PhIP intake and PDAC risk, such that risk increased among individuals with lower intake of vitamin C or E and decreased among those with higher vitamin intake. Significant interactions of dietary vitamin C, dietary vitamin E, and total vitamin E with PhIP intake were detected (P(interaction )= 0.023

Purpose Oral mucositis is one of the most prevalent side effects in patients undergoing radiation therapy for head and neck cancers. Current therapeutic agents such as palifermin recombinant human keratinocyte growth factor and amifostine do not efficiently or fully prevent mucositis. Dimethyl sulfoxide (DMSO), a free-radical scavenger, has shown therapeutic benefits in many preclinical and clinical studies. This study aimed to investigate the efficacy of DMSO in a clinically relevant mouse model of acute, radiation-induced oral mucositis. Methods and Materials Oral mucositis was induced by a high single and fractioned irradiation of the head and neck area in C57BL/6J mice, and the effects of DMSO (by intraperitoneal injection) were assessed by macroscopic and histopathological examination. Epithelial stem and progenitor cells were analyzed by immunohistochemical staining of p63 and Ki-67, and DNA double-strand breaks (DSBs) were visualized by immunofluorescence detection of γ-H2AX. Tumor xenograft was obtained using CAL-27 cells. Results Pretreatment with DMSO protected the oral mucosa from severe acute radiation injury, reduced the extent of radiation-induced weight loss, and had no significant effects on tumor weight in irradiated or nonirradiated xenograft mice. Furthermore, the efficacy of DMSO was superior to that of recombinant human keratinocyte growth factor and amifostine. DMSO treatment prevented the loss of proliferative lingual epithelial stem and progenitor cells upon irradiation. More interestingly, the average levels of γ-H2AX foci were significantly decreased in p63-positive epithelial stem cells at 6 hours, but not at 2 hours, after irradiation, indicating that DMSO facilitated DNA DSB repair rather than suppressing the indirect action of irradiation. Conclusions DMSO prevents the loss of proliferative lingual epithelial stem and progenitor cells upon irradiation by facilitating DNA DSB repair, thereby protecting against radiation-induced mucositis without tumor protection. Given its high efficacy and low toxicity, DMSO could be a potential treatment option to prevent radiation-induced oral mucositis.

It is of great scientific interest to identify interactions between genetic variants and environmental exposures that may modify the risk of complex diseases. However, larger sample sizes are usually required to detect gene-by-environment interaction (G × E) than required to detect genetic main association effects. To boost the statistical power and improve the understanding of the underlying molecular mechanisms, we incorporate functional genomics information, specifically, expression quantitative trait loci (eQTLs), into a data-adaptive G × E test, called aGEw. This test adaptively chooses the best eQTL weights from multiple tissues and provides an extra layer of weighting at the genetic variant level. Extensive simulations show that the aGEw test can control the Type 1 error rate, and the power is resilient to the inclusion of neutral variants and noninformative external weights. We applied the proposed aGEw test to the Pancreatic Cancer Case-Control Consortium (discovery cohort of 3,585 cases and 3,482 controls) and the PanScan II genome-wide association study data (replication cohort of 2,021 cases and 2,105 controls) with smoking as the exposure of interest. Two novel putative smoking-related pancreatic cancer susceptibility genes, TRIP10 and KDM3A, were identified. The aGEw test is implemented in an R package aGE.

Previous findings on the association of genetic factors and pancreatic cancer survival are limited and inconsistent. In a two-stage study, we analyzed the existing genome-wide association study dataset of 868 pancreatic cancer patients from MD Anderson Cancer Center in relation to overall survival using Cox regression. Top hits were selected for replication in another 820 patients from the same institution using the Taqman genotyping method. Functional annotation, pathway analysis, and gene expression analysis were conducted using existing software and databases. We discovered genome-wide significant associations of patient survival with three imputed SNPs which, in complete LD (r2=1), were intronic SNPs of the PAIP2B (rs113988120) and DYSF genes (rs112493246 and rs138529893) located on chromosome 2. The variant alleles were associated with a 3.06-fold higher risk of death (95% confidence interval [CI]=2.10-4.47, P = 6.4 × 10-9) after adjusting for clinical factors. Eleven SNPs were tested in the replication study and the association of rs113988120 with survival was confirmed (HR: 1.57, 95% CI: 1.13-2.20,P = 0.008). In silico analysis found rs1139988120 might lead to altered motif. This locus is in LD (D'=0.77) with 3 eQTL SNPs near or belong to the NAGK and MCEE genes. According to The Cancer Genome Atlas data and our previous RNA-sequencing data, the mRNA expression level of PAIP2B but not NAGK, MCEE or DYSF was significantly lower in pancreatic tumors than in normal adjacent tissues. Additional validation efforts and functional studies are warranted to demonstrate whether PAIP2B is a novel tumor suppressor gene and a potential therapeutic target for pancreatic cancer. This article is protected by copyright. All rights reserved.

As whole-exome/genome sequencing data become increasingly available in genetic epidemiology research consortia, there is emerging interest in testing the interactions between rare genetic variants and environmental exposures that modify the risk of complex diseases. However, testing rare-variant-based gene-by-environment interactions (GxE) is more challenging than testing the genetic main effects due to the difficulty in correctly estimating the latter under the null hypothesis of no GxE effects and the presence of neutral variants. In response, we have developed a family of powerful and data-adaptive GxE tests, called "aGE" tests, in the framework of the adaptive powered score test, originally proposed for testing the genetic main effects. Using extensive simulations, we show that aGE tests can control the type I error rate in the presence of a large number of neutral variants or a nonlinear environmental main effect, and the power is more resilient to the inclusion of neutral variants than that of existing methods. We demonstrate the performance of the proposed aGE tests using Pancreatic Cancer Case-Control Consortium Exome Chip data. An R package "aGE" is available at http://github.com/ytzhong/projects/.

Objective To compare the protective effect of rhKGF, CBLB502 and WR2721 on radiation-induced oral mucositis (ROM). Methods Fifty male 6-8-week-old C57BL/6J mice were randomly divided into normal group, irradiation control group, rhKGF group, CBLB502 group, and WR2721 group (n=10 each). The 30-day survival rate and change in body weight of mice that had received 17Gy irradiation of head and neck area were recorded. In another group of 20 mice, 1% toluidine blue staining and HE staining were used to observe oral ulcers and pathological changes in the tongue tissue. The proliferation of keratinocyte cells was assessed by Ki-67 immunohistochemistry. Results Compared with the irradiation control group, administration of rhKGF and WR2721 could significantly improve the 30-day survival rate, accelerate the recovery of body weight, and promote the proliferation of keratinized epithelial cells of mice after irradiation, without inducing obvious oral mucositis. However, There was no significant difference between CBLB502 group and irradiation control group in survival rate, body weight and pathological changes in tongue tissues of mice. Conclusion rhKGF and WR2721 could alleviate ROM and improve the survival of mice, while CBLB502 has no such effect. DOI: 10.11855/j.issn.0577-7402.2015.05.19

BACKGROUND Salivary gland carcinomas (SGCs) are a rare malignancy with unknown etiology. The objective of the current study was to identify genetic variants modifying the risk of SGC and its major subtypes: adenoid cystic carcinoma and mucoepidermoid carcinoma. METHODS The authors conducted a genome-wide association study in 309 well-defined SGC cases and 535 cancer-free controls. A single-nucleotide polymorphism (SNP)-level discovery study was performed in non-Hispanic white individuals followed by a replication study in Hispanic individuals. A logistic regression analysis was applied to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). A meta-analysis of the results was conducted. RESULTS A genome-wide significant association with SGC in non-Hispanic white individuals was detected at coding SNPs in CHRNA2 (cholinergic receptor, nicotinic, alpha 2 [neuronal]) (OR, 8.55; 95% CI, 4.53-16.13 [P = 3.6 × 10−11]), OR4F15 (olfactory receptor, family 4, subfamily F, member 15) (OR, 5.26; 95% CI, 3.13-8.83 [P = 3.5 × 10−10]), ZNF343 (zinc finger protein 343) (OR, 3.28; 95% CI, 2.12-5.07 [P = 9.1 × 10−8]), and PARP4 (poly(ADP-ribose) polymerase family, member 4) (OR, 2.00; 95% CI, 1.54-2.59 [P = 1.7 × 10−7]). Meta-analysis of the non-Hispanic white and Hispanic cohorts identified another genome-wide significant SNP in ELL2 (meta-OR, 1.86; 95% CI, 1.48-2.34 [P = 1.3 × 10−7]). Risk alleles were largely enriched in mucoepidermoid carcinoma, in which the SNPs in CHRNA2, OR4F15, and ZNF343 had ORs of 15.71 (95% CI, 6.59-37.47 [P = 5.2 × 10−10]), 15.60 (95% CI, 6.50-37.41 [P = 7.5 × 10−10]), and 6.49 (95% CI, 3.36-12.52 [P = 2.5 × 10−8]), respectively. None of these SNPs retained a significant association with adenoid cystic carcinoma. CONCLUSIONS To the best of the authors' knowledge, the current study is the first to identify a panel of SNPs associated with the risk of SGC. Confirmation of these findings along with functional analysis of identified SNPs are needed. Cancer 2015;121:2367–2374. © 2015 American Cancer Society.

A windowed DFT method is proposed for power system frequency measurement involving amplitude modulation. First, an error analysis of conventional DFT based method considering amplitude modulation is given. Second, a noval a window DFT function is proposed method to eliminate these errors is given based on the relation among three consecutive DFT values. Due to its high precision and low required processing effort, the proposed algorithm is a good candidate for online frequency measurement.

Objective To reproduce and evaluate a rat model of inhalation lung injury caused by black gunpowder smog. Methods The smog composition was analyzed and a rat model of inhalation lung injury was reproduced. Forty two healthy male Wistar rats were randomly divided into normal control (NC) group and 1h, 2h, 6h, 24h, 48h and 96h after inhalation group (n=6). The arterial blood gas, wet to dry weight ratio (W/D) of lung, leukocyte count, and protein concentration in broncho-alveolar lavage fluid (BALF) were determined. Macroscopic and microscopic changes in lung tissue were observed. Results The composition of black gunpowder smog was composed mainly of CO2 and CO, and their concentrations remained stable within 12 minutes. Smog inhalation caused a significant hypoxemia, the concentration of blood COHb reached a peak value 1h, and the W/D of lung reached peak value 2h after inhalation (P

To adapt to the requirements of the charging and discharging of the lithium battery, the paper presents a three-level based bidirectional energy storage converter topology.It has strong adaptability and can manage the charge and discharge of multi-series and parallel battery module. The mathematical model of the converter is analyzed, and the two operation modes of the converter control strategy are studied; Analysis the feed-forward decoupling control of three-level rectifier, and the variable scale factor is used to control midpoint potential. The simulation results demonstrate the feasibility of the design.

This paper presents an architecture for 32-bit datapath Advanced Encryption Standard(AES) IP core based on FPGA. It uses finite state machine, and supports encryption, decryption and key expansion. The round-key is calculated before the beginning of encryption and decryption. It consumes less hardware resources. It is implemented on Cyclone II FPGA EP2C35F672C6, which consumes less than 55% logic elements of the resources. The IP core can operate at a maximum clock frequency of 100 MHz. Compared with 128-bit datapath AES, it can interface with CPU easily.

Event detection is one of the major applications of wireless sensor networks (WSNs). Most of existing medium access control (MAC) protocols are mainly optimized for the situation under which an event only generates one packet on a single sensor node. When an event generates multiple packets on a single node, the performance of these MAC protocols degrades rapidly. In this paper, we present a new synchronous duty-cycle MAC protocol called SR-MAC for the event detection applications in which multiple packets are generated on a single node. SR-MAC introduces a new scheduling mechanism that reserves few time slots during the SLEEP period for the nodes to transmit multiple packets. By this approach, SR-MAC can schedule multiple packets generated by an event on a single node to be forwarded over multiple hops in one operational cycle without collision. We use event delivery latency (EDL) and event delivery ratio (EDR) to measure the event detection capability of the SR-MAC protocol. Through detailed ns-2 simulation, the results show that SR-MAC can achieve lower EDL, higher EDR and higher network throughput with guaranteed energy efficiency compared with R-MAC, DW-MAC and PR-MAC.

Many energy efficiency asynchronous duty-cycle MAC (media access control) protocols have been proposed in recent years. However, in these protocols, wireless sensor nodes almost choose their wakeup time randomly during the operational cycle, which results in the packet delivery latency increased significantly on the multiple hops path. To reduce the packet delivery latency on multi-hop path and energy waste of the sender’s idle listening, a new low latency routing-enhanced asynchronous duty-cycle MAC protocol was presented, called REA-MAC. In REA-MAC, each sensor node decided when it waked up to send the beacon based on cross-layer routing information. Furthermore, the sender adaptively waked up based on the relationship between the transmission request time and the wakeup time of its next hop node. The simulation results show that REA-MAC reduces delivery latency by 60% compared to RI-MAC and reduces 8.77% power consumption on average. Under heavy traffic, REA-MAC’s throughput is 1.48 times of RI-MAC’s.

In recent years,most existing engineering structures which have approached their normal life span, such as concrete plate, concrete beam etc., Almost all of these architecture structures are subjected to damage due to external loads, initial design defect etc. Structural damage detection and assessment has been becoming a focus of increasing interest in civil engineering field. However,At present, the study on structural damage detection is still at initial stage and the adopted main approaches are theoretical analysis and numerical simulation, but physical models are scarce. This leads to the yielded theories and methods are not sufficiently applicable for practical engineering application. Aiming at this, this paper focuses on developing effective methods of using wavelet and neural networks to detect the damage of elastic thin plate due to their extensive applications in civil engineering.

Two-dimensional elastic thin plates are widely used in civil engineering structures. The plates deteriorate gradually under service conditions, which influence the safety of engineering structures. How to identify the damage of the plate is one of the hot issues in the civil engineering fields. The relevant theoretical analysis and numerical simulation are stressed, but the physical model experiments are few. There are some problems among the theory, methods and practical engineering applications. A method is presented for determining damage location and degree of civil engineering structures based on model testing of two-dimensional steel plates.

Reinforced concrete (RC) structures taking full advantages of concrete and reinforcing steel bars are widely applied in civil engineering. Concrete bridges are subjected to alternate loads as well as static loads, much importance should be attached to their fatigue. Reinforced concrete beams are the elementary members of concrete bridges. Fatigue failure mode and fatigue life prediction of normal or high-strength RC beams were the research focus at home. The fatigue behavior of low-strength RC beams was studied through four-point bending fatigue test in the paper. The test results indicated that all beams fractured for concrete shear failure, which made the fatigue life of low-strength concrete beams drop greatly compared to that of normal or high-strength concrete beams, because the fatigue failure of normal or high-strength concrete beams were caused by the fracture of one or more reinforcing steel bars; the mid-span deflection development of low-strength RC beams had three phases, and the middle phase occupied about 90% of whole fatigue life, also in the second phase the mid-span deflection developed linearly with the increasing of cycle numbers. This research work provides necessary basis for the fatigue life deterioration of low-strength RC beams.

Reinforced concrete (RC) structures are widely used in civil engineering for their merits. A good-quality concrete provides a highly alkaline environment that forms a passive film on reinforcement surface, preventing steel bars from corroding. Due to chloride attack or concrete carbonization, corrosion of embedded reinforcement in concrete members is common for RC structures. Much importance should be attached to the fatigue of corroded concrete bridges because they bear not only static loads but also alternate loads. Followed along with the aging of bridge structures, the increase of traffic volumes, the augment of vehicle loads as well as the deterioration of service environment, many corroded concrete bridges are urgently needed security appraisal and residual fatigue life forecast. Fatigue of corroded RC beams is a key problem for the existing corrosion-damaged concrete bridges. But the interrelated research was little. Based on the most new study information, the production on fatigue of corroded concrete beams was listed and analyzed, and the problems on fatigue of corroded concrete beams were indicated.

Long-term type 2 diabetes is a known risk factor for pancreatic cancer (PC). We hypothesized that genetic variants in glucose metabolism modify individual susceptibility to PC, especially those associated with diabetes. We retrospectively genotyped 26 single-nucleotide polymorphisms of 5 glucose metabolism genes: glucokinase (GCK), glutamine-fructose-6-phosphate transaminase 1 (GFPT1), glucose phosphate isomerase (GPI), hexokinase 2 (HK2), and O-linked N-acetylglucosamine transferase (OGT) in a case–control study of PC conducted at MD Anderson during 2004 to 2010. Initial genotyping was conducted in 706 patients with PC and 706 cancer-free controls by using the Sequenom method. A HK2 genotype (R844K) with low frequency of homozygous variant was further examined in additional 948 patients and 476 controls. In the combined set of 1,654 cases and 1,182 controls, we showed a significant association of the HK2 R844K GA/AA genotype with reduced PC risk (OR = 0.78; 95% CI, 0.64–0.94; P = 0.009) and a significant interaction with diabetes (Pinteraction < 0.001). The HK2 R844K GA/AA genotype was associated with a reduced risk of PC among nondiabetic individuals (OR = 0.68; 95% CI, 0.56–0.83) but with increased risk among diabetic patients (OR = 3.69; 95% CI, 2.34–5.82). These risk associations remained statistically significant when the analysis was restricted to whites or after exclusion of recent onset diabetes. No significant main effect of other genes or significant interaction of genotype with other risk factors was observed. The findings show a potential role of HK2 gene, alone or in interaction with diabetes, in modifying the risk of PC. Cancer Prev Res; 4(5); 758–66. ©2011 AACR.

Background: The genetic factors predisposing individuals with obesity or diabetes to pancreatic cancer have not been identified. Aims: To investigate the hypothesis that obesity- and diabetes-related genes modify the risk of pancreatic cancer. Methods: We genotyped 15 single nucleotide polymorphisms of fat mass and obesity-associated (FTO), peroxisome proliferators-activated receptor gamma (PPARγ), nuclear receptor family 5 member 2 (NR5A2), AMPK, and ADIPOQ genes in 1,070 patients with pancreatic cancer and 1,175 cancer-free controls. Information on risk factors was collected by personal interview. Adjusted ORs (AOR) and 95% CIs were calculated using unconditional logistic regression. Results: The PPARγ P12A GG genotype was inversely associated with risk of pancreatic cancer (AOR, 0.21; 95% CI, 0.07–0.62). Three NR5A2 variants that were previously identified in a genome-wide association study were significantly associated with reduced risk of pancreatic cancer, AORs ranging from 0.57 to 0.79. Two FTO gene variants and one ADIPOQ variant were differentially associated with pancreatic cancer according to levels of body mass index (BMI; Pinteraction = 0.0001, 0.0015, and 0.03). For example, the AOR (95% CI) for FTO IVS1-2777AC/AA genotype was 0.72 (0.55–0.96) and 1.54 (1.14–2.09) in participants with a BMI of less than 25 or 25 kg/m2 or more, respectively. We observed no significant association between AMPK genotype and pancreatic cancer and no genotype interactions with diabetes or smoking. Conclusion: Our findings suggest the PPARγ P12A GG genotype and NR5A2 variants may reduce the risk for pancreatic cancer. A positive association of FTO and ADIPOQ gene variants with pancreatic cancer may be limited to persons who are overweight. Impact: The discovery of genetic factors modifying the risk of pancreatic cancer may help to identify high-risk individuals for prevention efforts. Cancer Epidemiol Biomarkers Prev; 20(5); 779–92. ©2011 AACR.

Altered glucose metabolism is the most common metabolic hallmark of malignancies. The authors tested the hypothesis that glucose metabolism gene variations affect clinical outcome in pancreatic cancer.The authors retrospectively genotyped 26 single nucleotide polymorphisms from 5 glucose metabolism genes in 154 patients with localized disease and validated the findings in 552 patients with different stages of pancreatic adenocarcinoma. Association between genotypes and overall survival (OS) was evaluated using multivariate Cox proportional hazard regression models with adjustment for clinical predictors.Glucokinase (GCK) IVS1 + 9652CT and hexokinase 2 (HK2) N692N homozygous variants were significantly associated with reduced OS in the training set of 154 patients (P.001). These associations were confirmed in the validation set of 552 patients and in the combined dataset of all 706 patients (P ≤ .001). In addition, HK2 R844K variant K allele was associated with a better survival in the validation set and the combined dataset (P ≤ .001). When data were further analyzed by disease stage, glutamine-fructose-6-phosphate transaminase (GFPT1) IVS14-3094TC, HK2 N692N and R844K in patients with localized disease and GCK IVS1 + 9652CT in patients with advanced disease were significant independent predictors for OS (P ≤ .001). Haplotype CGG of GPI and GCTATGG of HK2 were associated with better OS, respectively, with P values of .004 and .007.The authors demonstrated that glucose metabolism gene polymorphisms affect clinical outcome in pancreatic cancer. These observations support a role of abnormal glucose metabolism in pancreatic carcinogenesis.

To test the hypothesis that polymorphic variants of antioxidant genes modify the risk of pancreatic cancer, we examined seven single-nucleotide polymorphisms (SNPs) of genes coding for superoxide dismutase (SOD) 2, glutathione S-transferase alpha 4 (GSTA4), catalase and glutathione peroxidase in 575 patients with pancreatic adenocarcinoma and 648 healthy controls in a case-control study. Information on risk factors was collected by personal interview and dietary information was collected by a self-administered food frequency questionnaire. Genotypes were determined using the Taqman method. Adjusted odds ratio (AOR) and 95% confidence interval (CI) were estimated by unconditional logistic regression. No significant main effect of genotype was observed. A borderline significant interaction between diabetes and SOD2 Ex2+24T>C CT/TT genotype was observed (P interaction = 0.051); the AORs (95% CI) were 0.98 (0.73-1.32) for non-diabetics carrying the CT/TT genotype, 1.73 (0.94-3.18) for diabetics carrying the CC genotype and 3.49 (2.22-5.49) for diabetics carrying the CT/TT genotype compared with non-diabetics carrying the CC genotype. Moreover, the SOD2 -1221G>A AA genotype carriers had a significantly increased risk for pancreatic cancer among those with a low dietary vitamin E intake but decreased risk among those with a high vitamin E intake (P interaction = 0.002). There was a non-significant interaction between diabetes and GSTA4 Ex5-64G>A genotypes (P interaction = 0.078). No significant interaction between genotype with cigarette smoking or vitamin C intake was observed. These data suggest that genetic variations in antioxidant defenses modify the risk of pancreatic cancer in diabetics or individuals with a low dietary vitamin E intake.

The velocity of an over-burst coal seam is about 1/3 compared to a normal coal seam based on laboratory test results. This can be considered as a basis to confirm the area of coal and gas burst by seismic exploration technique. Similarly, the simulation result of the theoretical seismic model shows that there is obvious distinction between over-burst coal and normal coal based on the coal reflection’s travel-time, energy and frequency. The results from the actual seismic data acquired in the coal and gas over-burst cases is consistent with that of the laboratory and seismic modeling; that is, in the coal and gas burst region, seismic reflection travel time is delayed, seismic amplitude is weakened and seismic frequency is reduced. Therefore, it can be concluded that seismic exploration technique is promising for use in distinguishing coal and gas over-burst regions based on the variation of seismic reflection travel time, amplitude and frequency.

Concurrent diabetes has been linked with an increased risk of death in many cancers, but findings in pancreatic cancer have been inconsistent. We performed a systematic review and meta-analysis to assess the effect of diabetes on survival in patients with pancreatic cancer. Of 4, 463 original articles, 41 were included in the review; 29 studies with 33 risk estimates were included in the meta-analysis. In the overall comparison of patients with pancreatic cancer and diabetes with their nondiabetic counterparts, the former had significantly higher all-cause mortality (pooled HR: 1.13; 95% CI: 1.04–1.22). Subgroup analyses showed that diabetes was associated with poor survival in patients with resectable disease (HR: 1.37; 95% CI: 1.15–1.63) but not in those with unresectable disease (HR: 1.07; 95% CI: 0.89–1.29). The HR (95% CI) was 1.52 (1.20–1.93) for patients with new-onset diabetes (≤2 years of diabetes duration) and 1.22 (0.83–1.80) for those with longstanding diabetes (>2 years). Diabetes was associated with higher mortality overall in patients with pancreatic cancer. The effect of diabetes on overall survival was associated with the stages of tumor and the duration of diabetes.

The aim was to investigate the effects of theGABABreceptor antagonist, CGP46381, on form-deprivation myopia (FDM) in guinea pigs. Twenty-four guinea pigs had monocular visual deprivation induced using a diffuser for 11 days (day 14 to 25). The deprived eyes were treated with daily subconjunctival injections (100 μl) of either 2% CGP46381, 0.2% CGP46381, or saline or received no injection. The fellow eyes were left untreated. Another six animals received no treatment. At the start and end of the treatment period, ocular refractions were measured using retinoscopy and vitreous chamber depth (VCD) and axial length (AL) using A-scan ultrasound. All of the deprived eyes developed relative myopia (treated versus untreated eyes,P<0.05). The amount of myopia was significantly affected by the drug treatment (one-way ANOVA,P<0.0001). The highest dose tested, 2% CGP46381, significantly inhibited myopia development compared to saline (2% CGP46381: −1.08 ± 0.40 D, saline: −4.33 ± 0.67 D,P<0.01). The majority of these effects were due to less AL (2% CGP46381: 0.03 ± 0.01 mm, saline: 0.13 ± 0.02 mm,P<0.01) and VCD (2% CGP46381: 0.02 ± 0.01 mm, saline: 0.08 ± 0.01 mm,P<0.01) elongation. The lower dose tested, 0.2% CGP46381, did not significantly inhibit FDM (P>0.05). Subconjunctival injections of CGP46381 inhibit FDM development in guinea pigs in a dose-dependent manner.

Three corrosion degrees of reinforcement are chosen in this paper, which are considered to simulate minor, medium and severe degrees of corrosion in this field. A reinforcement mass loss about 5% is used to define a minor degree of corrosion, whereas mass losses about 10% and 20% are used to define medium and severe degree of corrosion, respectively. Fifteen specimens of the three corrosion degrees and seven uncorroded specimens are tested under fatigue. According to the results of the fatigue tests, using stress range as fatigue parameter and 50% as guaranteed probability, the fatigue S-N curves of the four different corrosion degrees of deformed reinforcement adaptable for fatigue reliability evaluation are put forward. These curves provide necessary principle for predicting the residual fatigue lives of aged existing reinforced concrete bridges.

Background: Chronic inflammation is implicated in pancreatic cancer carcinogenesis. Advanced glycation end-products (AGEs), which are rich in cooked red meat and cigarette smoke, can perpetuate inflammation by binding to the receptor for advanced glycation end products (AGER, also known as RAGE). We hypothesized that genetic variation of the AGEs/AGER pathway affects pancreatic cancer risk by modulating chronic inflammation. Methods: We conducted a two-stage case-control study to examine the association between 96 single nucleotide polymorphisms (SNPs) in 21 genes (GLO1, MSR1, PINK1, KIF17, AGPAT1, AKR1B1, DDOST, CD36, SCARB1, AGER, APP, HMGB1, S100A8, S100B, S100P, S100A12, MMP9, ADAM10, PPARG, NOTCH4, and PDGF) of the AGEs/AGER pathway and risk of pancreatic cancer. The discovery study was conducted in 672 pancreatic cancer cases and 1361 controls ascertained from the Women’s Health Initiative (WHI) Study matched on age, race/ethnicity and study arm. The validation study was conducted in a PANC4 pooled hospital-based case-control study of 1,034 women cases and 989 women controls. A pooled analysis of 1706 cases and 2350 controls was also performed. SNP data were obtained or imputed from the previously performed GWASs. Pancreatic cancer risk was calculated as odds ratios (ORs) and 95% confidence intervals (Cis) using logistic regression models adjusting for age, race/ethnicity, body mass index (BMI), type 2 diabetes, and smoking using an additive genetic model. The potential interaction between individual SNP and red meat intake and cigarette smoking was examined. A false discovery rate (FDR) adjusted q value < 0.20 was considered statistically significant in the pooled analyses. We also conducted logistic-Kernel machine (LKM) test to examine the association between sets of SNP and risk of pancreatic cancer in the pooled dataset. Results: We identified 11 SNPs with raw P values < 0.10 in the discovery stage in the WHI study. However, none of the SNPs was validated in the validation and pooled dataset. The LKM test showed that sets of SNPs in CD36 (P = 9.3E-10), GLO1(P =2.0E-7), and DDOST (P = 2.5E-4) were significantly associated with pancreatic cancer risk. We found an interaction effect between the GLO1 SNP rs6932648 and smoking status (never versus ever) in the WHI study (P for interaction = 0.01) and the pooled dataset (P for interaction = 0.049). In the pooled dataset, the variant T allele of rs6932648 (MAF = 0.12) was associated with increased risk of pancreatic cancer among ever smokers (additive OR = 1.26, 95% CI: 1.02-1.55), but not among never smokers (additive OR = 0.94, 95% CI: 0.78-1.14), compared with the C allele. Summary and Conclusion: We did not observe significant association between any of 96 single SNP and pancreatic cancer risk. However, we found combined set of SNPs in the GLO1, DDOST, and CD36 genes were associated with risk of pancreatic cancer. GLO SNP rs6932648 may modify the association between smoking and risk of pancreatic cancer. GLO1, DDOST, and CD36 are involved in detoxification or clearance of AGEs compounds. Further investigation of AGEs and receptors systems in pancreatic cancer is warranted. Citation Format: Guochong Jia, Kathryn Royse, Hongwei Tang, Donghui Li, Liang Chen, Lesley Tinker, Gloria Petersen, Alison Klein, Peter Richardson, Donna White, Haleh Sangi-Haghapeykar, Hashem B. El-Serag, Li Jiao. Genetic variations in the AGEs/AGER pathway and risk of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-160. doi:10.1158/1538-7445.AM2017-LB-160

Introduction: Obesity and diabetes are two major modifiable risk factors for pancreatic cancer. Genetic variation affecting the risk of obesity- and diabetes-related pancreatic cancer have yet to be comprehensively investigated at the genome-wide level. Aims: To identify novel gene-environment interactions (GxE) of obesity/diabetes on pancreatic cancer risk. Methods: We conducted a multi-stage genome-wide gene-diabetes and gene-obesity interaction study using GWAS data of 7095 cases and 10710 controls from Pancreatic Cancer Consortium (PanScan I, PanScan II and PanScan III) and Pancreatic Cancer Case Control Consortium (PanC4). About 870,000 SNPs, having MAF ≥ 0.005 and having been genotyped in at least one study, were analyzed. Missing genotypes were imputed using IMPUTE2 and the Haplotype Reference Consortium (HRC) reference panel. Case-control (CC) and case-only (CO) methods were used for SNP-level GxE analysis. Fixed-, random- and joint-effect models built in “rareGE” R package were used for gene-based GxE analysis. About 20,000 genes that have at least one SNP genotyped were included in the analysis. Age, gender and principal components accounting for subpopulation structure were adjusted in both SNP-level and gene-level analyses. Obesity was defined as body mass index ≥30 mg/m2. Diabetics with Results: No genome-wide significant (P Conclusions: In the largest genome-wide GxE analysis for pancreatic cancer to date, we identified a significant diabetes interacting gene in pancreatic cancer, which was consistently replicated in 4 individual GWAS studies. This observation identifies FAM63A as a candidate for future functional studies to understand its role in pancreatic cancer etiology. Further increasing the sample size may unveil additional genetic loci that contribute to the susceptibility to pancreatic cancer via G x E. Citation Format: Hongwei Tang, Lai Jiang, Laufey T. Amundadottir, Harvey A. Risch, Rachael S. Stolzenberg-Solomon, Alison P. Klein, Brian M. Wolpin, Gloria Petersen, Nilanjan Chatterjee, Donghui Li, Peter Kraft, Peng Wei. Genomewide gene-diabetes and gene-obesity interaction scan in 7095 cases and 10710 controls from Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case Control Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1295. doi:10.1158/1538-7445.AM2017-1295

To study the antiproliferation effect on HepG2 cells and its underlying mechanism of the active chemical composition of the Viburnum Odoratissimum.3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) reduction assay and trypan blue dye exclusion assay were used to assess the effect of vibsane-type diterpenoids on the proliferation of various tumor cells. Alterations in cell cycle and apoptosis were determined by flowcytometry. The enzymatic activity of caspase-3/7 was measured by Apo-ONE homogeneous Caspase-3/7 Assay kit.Compound 1 #, a vibsane-type diterpenoid, was found to significantly inhibit the growth of HepG2 cells by anticancer proliferation activity screening. It was demonstrated that the modified groups on side chain coupled to C11 site affected the cell growth-inhibition activity of compounds by structure-activity analysis. In addition, HepG2 cell line was most sensitive to compound 1 #, which induced growth arrest of HepG2 cells in a dose- and time-dependent manner. Study on the mechanisms underlying these effects indicated that compound 1 # induced significant G0/G1 phase arrest of HepG2 cells in a time- and concentration-dependent manner. Meanwhile, It was found that higher concentrations of compound (5-10 micromol/L) caused evident increase in the unmber of apoptotic cells and dose-dependent activation of caspase-3/7.Vibsane-type diterpenoids could significantly inhibit the growth of HCC HepG2 cells. Induction of cell cycle arrest and apoptosis may play important roles in their anticancer effects.

Most complex human diseases are likely the consequence of the joint actions of genetic and environmental factors. Identification of gene-environment (G × E) interactions not only contributes to a better understanding of the disease mechanisms, but also improves disease risk prediction and targeted intervention. In contrast to the large number of genetic susceptibility loci discovered by genome-wide association studies, there have been very few successes in identifying G × E interactions, which may be partly due to limited statistical power and inaccurately measured exposures. Although existing statistical methods only consider interactions between genes and static environmental exposures, many environmental/lifestyle factors, such as air pollution and diet, change over time, and cannot be accurately captured at one measurement time point or by simply categorizing into static exposure categories. There is a dearth of statistical methods for detecting gene by time-varying environmental exposure interactions. Here, we propose a powerful functional logistic regression (FLR) approach to model the time-varying effect of longitudinal environmental exposure and its interaction with genetic factors on disease risk. Capitalizing on the powerful functional data analysis framework, our proposed FLR model is capable of accommodating longitudinal exposures measured at irregular time points and contaminated by measurement errors, commonly encountered in observational studies. We use extensive simulations to show that the proposed method can control the Type I error and is more powerful than alternative ad hoc methods. We demonstrate the utility of this new method using data from a case-control study of pancreatic cancer to identify the windows of vulnerability of lifetime body mass index on the risk of pancreatic cancer as well as genes that may modify this association.

To develop an indirect immunofluorescence assay (IFA) kit for detecting anti-Toxoplasma gondii IgG.Based on the established IFA method, we established an IFA kit for the detection of human T. gondii infection. The optimal working concentrations of T. gondii IgG-positive human serum and FITC-labeled goat anti-human IgG antibody were determined. Sensitivity, specificity, reproducibility, and storage period of this kit were studied, and compared with an imported kit.The optimal working concentration of T. gondii IgG-positive human serum and FITC-labeled goat anti-human IgG antibody was 1:40 and 1:100, respectively. The maximum dilution of T. gondii IgG-positive human serum that the kit can detect was 1:640. No cross reaction was observed with sera from patients with vivax malaria, falciparum malaria, schistosomiasis, echinococcosis, or cysticercosis. Cross reaction was observed to the rheumatoid factor positive sera. The sensitivity, specificity, positive predictive value, negative predictive value, concordance, Youden index of this kit was 90.9%, 100%, 100%, 96.2%, 97.2%, and 0.91, respectively; and that of the imported kit was 100%, 98%, 95.7%, 100%, 98.6%, and 0.98, respectively. There was no significant difference in sensitivity and specificity between the two kits (P0.05).The IFA kit shows adequate sensitivity and specificity for detection of anti-T. gondii IgG.

Cigarette smoking is the best established modifiable risk factor for pancreatic cancer. Genetic factors that underlie smoking-related pancreatic cancer have previously not been examined at the genome-wide level. Taking advantage of the existing Genome-wide association study (GWAS) genotype and risk factor data from the Pancreatic Cancer Case Control Consortium, we conducted a discovery study in 2028 cases and 2109 controls to examine gene-smoking interactions at pathway/gene/single nucleotide polymorphism (SNP) level. Using the likelihood ratio test nested in logistic regression models and ingenuity pathway analysis (IPA), we examined 172 KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, 3 manually curated gene sets, 3 nicotine dependency gene ontology pathways, 17 912 genes and 468 114 SNPs. None of the individual pathway/gene/SNP showed significant interaction with smoking after adjusting for multiple comparisons. Six KEGG pathways showed nominal interactions (P < 0.05) with smoking, and the top two are the pancreatic secretion and salivary secretion pathways (major contributing genes: RAB8A, PLCB and CTRB1). Nine genes, i.e. ZBED2, EXO1, PSG2, SLC36A1, CLSTN1, MTHFSD, FAT2, IL10RB and ATXN2 had P interaction < 0.0005. Five intergenic region SNPs and two SNPs of the EVC and KCNIP4 genes had P interaction < 0.00003. In IPA analysis of genes with nominal interactions with smoking, axonal guidance signaling $$\left(P=2.12\times 1{0}^{-7}\right)$$ and α-adrenergic signaling $$\left(P=2.52\times 1{0}^{-5}\right)$$ genes were significantly overrepresented canonical pathways. Genes contributing to the axon guidance signaling pathway included the SLIT/ROBO signaling genes that were frequently altered in pancreatic cancer. These observations need to be confirmed in additional data set. Once confirmed, it will open a new avenue to unveiling the etiology of smoking-associated pancreatic cancer.

Background: Obesity and diabetes are potentially alterable risk factors for pancreatic cancer. Genetic factors that modify the associations of obesity and diabetes with pancreatic cancer have previously not been examined at the genome-wide level. Methods: Using genome-wide association studies (GWAS) genotype and risk factor data from the Pancreatic Cancer Case Control Consortium, we conducted a discovery study of 2,028 cases and 2,109 controls to examine gene–obesity and gene–diabetes interactions in relation to pancreatic cancer risk by using the likelihood-ratio test nested in logistic regression models and Ingenuity Pathway Analysis (IPA). Results: After adjusting for multiple comparisons, a significant interaction of the chemokine signaling pathway with obesity (P = 3.29 × 10−6) and a near significant interaction of calcium signaling pathway with diabetes (P = 1.57 × 10−4) in modifying the risk of pancreatic cancer were observed. These findings were supported by results from IPA analysis of the top genes with nominal interactions. The major contributing genes to the two top pathways include GNGT2, RELA, TIAM1, and GNAS. None of the individual genes or single-nucleotide polymorphism (SNP) except one SNP remained significant after adjusting for multiple testing. Notably, SNP rs10818684 of the PTGS1 gene showed an interaction with diabetes (P = 7.91 × 10−7) at a false discovery rate of 6%. Conclusions: Genetic variations in inflammatory response and insulin resistance may affect the risk of obesity- and diabetes-related pancreatic cancer. These observations should be replicated in additional large datasets. Impact: A gene–environment interaction analysis may provide new insights into the genetic susceptibility and molecular mechanisms of obesity- and diabetes-related pancreatic cancer. Cancer Epidemiol Biomarkers Prev; 23(1); 98–106. ©2013 AACR.

Background: Genetic factors that are associated with pancreatic cancer survival have previously been examined in Genome-Wide Association Studies (GWAS), but the results are inconsistent due to limited sample size. Method: We performed a two-stage study on pancreatic cancer survival. The discovery phase took advantage of the existing GWAS data of 868 patients with European descendent from a case-control study conducted at MD Anderson. The validation study on ten top hits was conducted in another 820 white patients with Taqman. The missing genotypes were imputed using IMPUTE2 based on 1000 Genomes Project. Cox regression model was fitted to calculate allele-specific hazard ratios (HR) and 95% confidence intervals (95% CI) with adjustment for demographics, tumor stage, resection, and chemotherapy. Results: After imputation, 7,738,399 SNPs with a Quality Score >0.03, minor allele frequency >0.01, and Hardy-Weinberg equilibrium were obtained for analysis. Three loci in complete LD at chromosome 2 were associated with overall survival (OS) at genome-wide significance (P = 1 ×): rs113988120 in PAIP2B (poly(A) binding protein interacting protein 2B), rs112493246 and rs138529893 in DYSF (dysferlin). The variant allele was associated with 3.02 fold higher risk of dying (95% CI: 2.07-4.40). SNP rs113988120 and nine others were examined in the validation study and rs113988120 remained nominally significant (P = 2.85 ×; HR: 1.45, 95% CI: 1.04-2.03). In the combined datasets of 1688 patients, this SNP was significantly associated with OS (P = 1.46 × and HR = 1.80 (95% CI: 1.42-2.30). Conclusion: These observations support our hypothesis that genetic variations to a certain degree influence patient survival in pancreatic cancer. Key words: Pancreatic cancer, GWAS, Survival Citation Format: Hongwei Tang. Genome-wide scan for genetic markers modifying survival of pancreatic cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3132.

Background Pancreatic cancer is the fourth leading cause of cancer death in the U.S. and the etiology of this highly lethal disease has not been well defined. To identify genetic susceptibility factors for pancreatic cancer, we conducted pathway analysis of genome-wide association study (GWAS) data in 3,141 pancreatic cancer patients and 3,367 controls with European ancestry. Methods Using the gene set ridge regression in association studies (GRASS) method, we analyzed 197 pathways identified from the Kyoto Encyclopedia of Genes and Genomes database. We used the logistic kernel machine (LKM) test to identify major contributing genes to each pathway. We conducted functional enrichment analysis of the most significant genes (P

To observe the changes of alveolar macrophage (AM) phagocytosis and the levels of TNF-alpha and IL-6 in AM supernatants and bronchoalveolar lavage fluid (BALF) of rats with Pneumocystis pneumonia (PCP).Wistar rats were injected with dexamethasone intramuscularly and continually to establish the model of PCP, the AM phagocytosis and levels of TNF-alpha and IL-6 in AM supernatants and BALF of rats with PCP were detected, meanwhile, the normal controls were set.The phagocyting percentage [(20.61 +/- 2.04)%] and phagocyting index (0.25 +/- 0.21) of the PCP group were significantly lower than those [(25.45 +/- 3.1)% and (0.31 +/- 0.16)] of the control group (P0.05), TNF-alpha (16.84 +/- 0.86) pg/ml and IL-6 (1.05 +/- 0.19) pg/ml in BALF of the PCP group were significantly higher than those [(12.48 +/- 0.84) pg/ml and (0.86 +/- 0.11) pg/ml] of the control group (P0.05), but there were no significant differences for the levels of TNF-alpha and IL-6 in AM supernatants between the two groups (P0.05).AM phagocytosis reduces evidently of PCP rats, but the levels of TNF-alpha and IL-6 in BALF rise evidently.

Indirect Rotor-Field-Oriented Control (IRFOC) techniques brought on a renaissance in modern high-performance control of PWM inverter fed SPIM. In this paper, an IRFOC system is proposed for SPIMs including a relatively simple and effective decoupling scheme. This is achieved by introducing two new decoupling signals to the system. However, model asymmetry in SPIMs causes extra coupling between two stator windings. To use the field orientation control, the asymmetry must be eliminated by using an appropriate variable changing. A computer simulation of the IRFOC for Single-Phase Induction Motor drive is carried out to test the validity of the proposed method at nominal and zero speed. The design, analysis, and implementation for a 800W Single-Phase Induction Motor are completely carried out using a dSPACE DS1103 digital signal processor (DSP) based real-time data acquisition control (DAC) system, and MATLAB/Simulink environment. Digital simulation and experimental results are presented to show the improvement in performance of the proposed algorithm.

Objective : Insulin-like growth factor (IGF)-axis genes plays a critical role in cancer development and progression via their impact on the RAS/MAPK/ERK and PI3K/AKT/mTOR signaling pathways. We hypothesized that IGF-axis genetic variants modify individual susceptibility to pancreatic cancer. Methods : We retrospectively genotyped 41 single-nucleotide polymorphisms of 10 IGF-axis genes ( IGF1 , IGF2 , IGF1R , IGF2R , IGFBP1 , IGFBP3 , IGFBP5 , IRS1 , IRS2 , and IRS4 ) in 706 pancreatic cancer patients and 706 cancer-free controls using Sequenom and TaqMan technology. The association between genotype and pancreatic cancer risk was evaluated using multivariate logistic regression. A P value ≤.007 at a false discovery rate of 10% was set as the significance level. Results : We observed that the IGF1 *10212C>A and Ex4+2776G>A and IGF1R IVS2−70184A>G and IVS2+46329T>C variant genotypes were significantly associated with decreased pancreatic cancer risk (odds ratio [OR] range, 0.60–0.75) and that IGFBP1 Ex4+111A>G (I253M) was significantly associated with increased pancreatic cancer risk (OR=1.46) after adjusted for other risk factors and multiple comparisons ( P ≤.007). IGF2R and IGFBP3 variant haplotypes were associated with increased and decreased pancreatic cancer risk, respectively ( P IGF1R IVS2+46329T>C and IGF2R Ex45+11C>T (L2222L) genotypes with diabetes ( P interaction =.05) and interaction of IGF2R and IRS1 genotypes with alcohol consumption ( P interaction =.03 and .019, respectively) on increased pancreatic cancer risk. Conclusion : These findings support our hypothesis that polymorphic variants of IGF-axis genes act alone or jointly with other risk factors to affect susceptibility to pancreatic cancer.