Demographics, clinical, laboratory and histology, auto-antibodies, derived clinical scores and therapy are reported. Results: Results: 13 Females and 2 Males. Mean age 33.3 yrs, range 14-68 years. 50% of cohort had significant disease, initial mean MELD 14.8 (6-26). Comorbid diseases 2 Type I diabetes, single cases of Hyperthyroidism, Interstitial Lung Disease, Non-Hodgkins Lymphoma and Ulcerative Colitis with Primary Sclerosing Colangitis. Initial Bilirubin mean 92.38 improving to 16.35 after treatment. ALT improved mean of

345.23 to 45.85. 8 Liver Biopsies 6 typical. ANA positive in 10 cases. ASMA positive selleck chemical in a single case. No ALKM positive samples. Treatment improved Child-Pugh Score to a mean of 6.2 range of 5-10. Initial treatment with prednisone at 30 mg/day followed by azathioprine. Currently 10 still on Low dose Prednisone. Conclusion: Conclusions: AIH at CHBAH has a female predominance affecting mainly young adults. 50% are clinically ill at presentation. The ANA was a good indicator of disease but ASMA and ALKM were not. pANCA may be a better option. Liver biopsies have proved to be typical. Immunosuppressive therapy

gave a good response in the majority of cases. The HLA class type and T Cell response for our population has yet to be described and is currently being investigated Key Word(s): 1. AutoImmune Hepatitis; Dabrafenib supplier 2. South Africa; Presenting Author: PRABHA SAWANT Additional Authors: PATHIK PARIKH, JATIN PATEL Corresponding Author: PRABHA SAWANT

Affiliations: Professor and Head, Department of Gastroenterology; Resident, Department of Gastroenterology Objective: There is a paucity of literature evaluating Fibroscan in Chronic liver disease and correlation with its severity.The aim of this study was to evaluate the role of Fibroscan® (Echosens, Paris) in chronic liver disease and to see correlation of Liver stiffness with Child Pugh and MELD scoring. Methods: In this single centre case control study, all patients suspected of chronic liver disease (CLD) referred to us were advised ultrasound to detect liver disease.Complete blood count, liver function tests, antinuclear antibody, Anti smooth muscle antibody, Anti LKM1, Serum ceruloplasmin, HBsAg 上海皓元 and Anti HCV were carried out along with a GI endoscopy in all patients to classify the chronic liver disease.Patients with dyspepsia and normal upper GI scopy and ultrasound were taken as controls. Fibroscan was carried out by an experienced examiner in all patients. Fibroscan findings with success rate >60% and IQR/Median <30% were only included in the study. The statistical difference between the groups were calculated by ANOVA. Results: 363 patients were evaluated, however successful Fibroscan was possible in 247 patients (68%); 93 CLD (Alcoholic liver disease: 48, Hepatitis B related CLD: 16, Hepatitis C related CLD: 4, other causes of CLD: 25), 87 fatty liver and 67 controls.

We hypothesized that PBEF might play a role selleck chemical in acute and chronic liver damage. We show that PBEF is strongly up-regulated in human chronic liver diseases and acute experimental hepatitis. Mice overexpressing hepatic

PBEF at baseline are more susceptible to liver damage during ConA- or D-galactosamine/lipopolysaccharide (LPS)–mediated hepatitis, whereas FK866 protected mice from acute hepatic injury induced by either ConA or D-galactosamine/LPS. ALT, alanine aminotransferase; AST, aspartate aminotransferase; ConA, concanavalin A; CTP, Child-Turcotte-Pugh; ELISA, enzyme-linked immunosorbent assay; IFNγ, interferon-γ; IL, interleukin; LPS, lipopolysaccharide; LTA, lipoteichoic acid; mRNA, messenger RNA; NAD, nicotinamide adenine dinucleotide; Nampt, nicotinamide phosphoribosyltransferase; PARP, poly (adenosine diphosphate-ribose) polymerase; PBEF, pre–B cell colony–enhancing factor; PCR, polymerase chain reaction; RT-PCR, reverse-transcription polymerase chain reaction; shRNA, short hairpin RNA; SIRT, sirtuin; TNFα, tumor necrosis factor α; TUNEL, terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate

nick-end labeling. Serum samples were obtained from 83 randomly selected, consecutive patients with clinically, biochemically, radiologically, and histologically confirmed diagnosis of chronic liver disease. Chronic liver disease was staged according to Child-Turcotte-Pugh (CTP) criteria.20 Thirty-nine age- and sex-matched healthy subjects served as a control group. Baseline characteristics of chronic liver disease patients are reported in Table 1. Informed consent was obtained, and the study was approved by the local CP-690550 solubility dmso ethics committee of the Innsbruck Medical University. Nine milliliters of blood were collected in Sarstedt Monovette tubes. Blood was centrifuged at 1,200g for 15 minutes and 1-mL aliquots were stored at −80°C until assayed. Each sample was assigned an encoding number, and all assays were performed in duplicate in a blinded manner. Six- to eight-week old MCE公司 female C57BL/6 mice were obtained from Charles River (Sulzfeld, Germany). Mice were housed in accordance with institutional animal care with open access

to standard chow and water. Animal experiments were approved by the Austrian Federal Ministry of Science and Research (license number: 66011/34-II/10b/2009). Unless stated otherwise, mice were injected intravenously through the lateral tail vein with 15 mg/kg ConA from Canavalia ensiformis (Sigma-Aldrich, St. Louis, MO) in endotoxin-free phosphate-buffered saline. Mice received an intraperitoneal injection of 700 mg/kg D-galactosamine (Carl Roth, Karlsruhe, Germany) and 1 μg/kg lipopolysaccharide (InvivoGen, San Diego, CA). Mice were euthanized at the indicated time after injection. FK866 was purchased from Axon Medchem (Groningen, Netherlands) and dissolved in dimethyl sulfoxide; 25-mg/mL aliquots were stored at −80°C until further use.

34 Several strains check details that developed the most pronounced liver injury, C57BL/10J and NZW/LacJ, also exhibited increased levels of Grp78 and Chop and an increase in Chop transcript. Notably, these ER stress markers were not induced consistently in other strains with high liver injury, which suggests that ER stress may not be a requisite event in alcoholic liver disease. Alternatively, it is also likely that selective persistence of ER chaperone and CHOP expression is evidence of failure to adapt to chronic unfolded protein response,42 thus serving as a prodeath factor that exacerbates liver injury caused by alcohol.

ER stress has also been implicated as one of the regulatory mechanisms in hepatocyte lipid metabolism.28 A key interconnectedness between hepatic steatosis and ER stress, including the physiological role of the ER stress protein find more sensors in lipid homeostasis, has been demonstrated in several recent publications.43 In this study we observed an unexpected down-regulation of Srebf1 and lack of induction of Cebpa in strains with high liver injury and liver steatosis. In prior work, up-regulation of SREBP1 and lipogenesis

has been observed, albeit in a mouse strain not studied here. The difference may be related to the severity of ER stress or other unknown factors. A down-regulation of transcription factors involved in lipid synthesis has also been suggested as a sign of failure to adapt to chronic ER stress. For example, steatosis develops in the liver of tunicamycin-treated mice and is associated with unresolved ER stress, prolonged up-regulation of Chop, and inhibition of metabolic master regulators.28 In addition, silencing of SREBP1 in vitro has led to dramatic loss of cell viability by way of induction of apoptosis.44 Most recent studies demonstrated that the decreased SAM/SAH ratio as a consequence of hyperhomocysteinemia appears to have a key role, as it can affect the ratio of phosphatidylcholine to phosphatidylethanolamine in ER membrane that could either lead to increased processing of SREBP145 or ER stress response.46 In Caenorhabditis elegans, decreased

SAM/SAH leads to decreased phosphatidylcholine/phosphatidylethanolamine ratio in ER, resulting in transcription-independent activation of SREBP1 and induction MCE of lipogenesis and one-carbon metabolism.45 However, the latter compensatory attempt to correct SAM/SAH may be impaired by the effects of alcohol. Although the precise mechanism of alcohol-induced effects on one-carbon metabolism remain to be determined and additional studies are needed to further investigate the differences in the role of ER stress in apoptosis and steatohepatitis among susceptible and resistant strains, our data clearly point to the genetic factors that may control adaptation to ER stress as one of the key events in the predisposition to alcoholic liver disease.

Up-regulation of ERBB3 was strongly associated with microscopic vascular invasion of HCC (P = 0.034; Table 1) and early recurrence (P = 003; Fig. 2C). We next asked whether up-regulation of ERBB3 is associated with I-BET-762 in vivo constitutive activation of ERBB3. We assayed the coexpression of other ERBB members and NRGs, the ligands of ERBB3. EGFR and HER2 were expressed

in most of the HCC cells, whereas ERBB3 and NRG1 were expressed in all of the HCC cells (Fig. 3A). ERBB4 was not detected in any of the HCC cells (Fig. 3A). In addition, both NRG1 and pERBB3 were also detected in all of the tested HCC tissues (Fig. 3B), and this suggested constitutive activation of ERBB3 in HCC, very likely via an NRG1/ERBB3 autocrine mechanism. To confirm the involvement of an NRG1/ERBB3 autocrine loop in ERBB3 activation in HCC, we determined whether HCC cells secrete bioactive NRG1 to activate ERBB3 of HCC cells. Phosphorylation of ERBB3 of starved Huh7 and HepG2 cells was induced (presumably activated) R788 ic50 by treatment with the recombinant NRG1 (Fig. 4A) or the conditioned media of most of the HCC cells (Fig. 4B). To verify the presence of bioactive

NRG1 in the conditioned media, we used antibodies against NRG1 to block its interaction with ERBB3. As shown in Fig. 4C, phosphorylation of ERBB3 was abolished because the conditioned media had been treated with antibodies against NRG1 before its administration to HCC cells.

Pretreatment of the conditioned media with antibodies against the extracellular domain of ERBB3 was used as the positive control (Fig. 4C). In parallel, MCE HeLa cells, which did not express ERBB3, were treated with the conditioned media of HCC cells to rule out the possibility of contaminants of pERBB3 in the conditioned media due to lysis of the donor HCC cells (Fig. 4D). Treatment of HeLa cells with recombinant NRG1 was used as the control. If ERBB3 of the HCC cells was activated via an autocrine loop, we expected that silencing of the expression of endogenous NRG1 would suppress phosphorylation of their own ERBB3 and abolish the bioactivity of the conditioned media to phosphorylate ERBB3 of the target cells. As shown in Fig. 4E, silencing of the expression of endogenous NRG1 by RNA interference in HCC cells suppressed their own ERBB3 phosphorylation (Fig. 4E) and eliminated the activity of their conditioned media to phosphorylate ERBB3 of the target cells (Fig. 4F). Altogether, we conclude that the constitutive activation of ERBB3 in HCC cells was achieved via an autocrine mechanism by the synthesis/secretion of bioactive NRG1 from HCC cells to activate their own ERBB3. To identify the partners for the dimerization and activation of ERBB3 upon NRG1 binding, we investigated whether EGFR or HER2 was required for ERBB3 activation in SK-Hep1, Huh7, and HepG2 cells.

As the benefits of a top-down approach are countered by the cost and risks of adverse events, more emphasis is placed on identifying predictors of aggressive disease or using a rapid step-up strategy. Patient age under 40, stricturing disease, weight loss, corticosteroid requirement at presentation and perianal disease have all been suggested as indicators of severe disease.47,48 Loss of response.  While the anticipated duration of therapy with biological agents is often Palbociclib undefined, loss of response occurs in approximately 13%

of patients per year of treatment.49 Drug trough levels have been proposed as a predictor of continued response, or to explain the cause of loss of response.50 Neutralizing antibodies to anti-TNF agents can result in reduction in trough levels, and subsequent non-response. Anti-drug antibodies may also be associated with injection site and infusion reactions. The rheumatological literature reports a progression from decreasing trough levels to detection of anti-drug antibodies and finally a loss of response.51 Anti-drug

antibodies are seen in 9–28% of those treated with infliximab,5 and 3–17% of those treated with adalimumab.25,50,52 They occur more frequently with intermittent anti-TNF therapy.53 Co-administration with BGB324 a second immunosuppressive agent reduces the risk of antibody development.54 Strategies to prevent their development include scheduled maintenance therapy and co-administration of corticosteroids or other immunomodulators (see below). With decrease in response, dose intensification,

decreased dosing interval, re-induction or drug switching can be performed.20,27,55–57 Only the latter two approaches are government subsidized in Australia.58 Evidence relating to anti-drug antibodies to trough levels and a loss of response is at times unclear.50 It is unknown which (if any) strategies to maintain trough levels will 上海皓元 result in prolonged clinical effect. Anti-TNF agent trough level, and anti-drug antibody measurement is not widely available at present. Treatment failure.  Treatment failure comprises primary non-response, adverse drug reactions and loss of response. It occurs in up to 50% of those on scheduled maintenance therapy.48 Enrollment in trials of new therapeutic agents such as ustekinumab and vedolizumab, and surgery remain options for failure of existing biological agents. Switching.  Changing anti-TNF agents secondary to treatment failure or loss of response is an accepted therapeutic maneuver. The efficacy of adalimumab59–63 and certolizumab pegol64 in those with loss of response or treatment failure prior to biological therapy has been shown in open label studies, while the success of adalimumab in this setting has been demonstrated in a placebo-controlled trial.56 Switching to a third anti-TNF agent following failure of the two other anti-TNF agents is safe and effective.

Diagnostic age, LE and EYLL of the different pathologic types, genders and tumor locations were compared. Results: Gastric cancers have a male and non-cardiac predominant prevalence, and near 88.6% as adenocarcinoma in pathology. There were shorter LE and larger EYLL in gastric cancers with cardia location and adenocarcinoma than those with non-cardia location and other histological types (P < 0.05). The female with gastric adenocarcinoma had a younger diagnostic age, longer LE, but a larger EYLL than males (P < 0.05). The estimated life-years saved per case if gastric cancer diagnosed early was higher in female

than in male this website (P < 0.05). Conclusion: The adenocarcinoma histological type, male gender, and cardiac location determine with a shorter LE and larger EYLL in gastric cancer. Early detection of gastric cancer can prominently save the person-years of life, especially

more evident for females with adenocarcinoma. Key Word(s): 1. sex gender; 2. pathologic types; 3. life expectancy (LE); 4. years of life lost; Presenting Author: WENTING XU Additional Authors: NONGHUA LU Corresponding Author: NONGHUA LU Affiliations: the First Affiliated Hospital buy PLX4032 of Nanchang University Objective: Recent studies have implied that ectopic activation of the Wnt pathway occurs in many human cancers. However, glycogen synthase kinase-3beta (GSK-3β) that acts 上海皓元 as a multifunctional serine/threonine kinase plays a crucial regulatory role in the Wnt signal transduction pathway. The change of GSK-3β and phosphorylation of GSK-3β (the inactive state of GSK-3β) in gastric cancer tissues and their association with the first class carcinogenic factor-helicobacter pylori (H.pylori) remain unknown. Methods: We examined expression of GSK-3β and phosphorylation of GSK-3β by immunohistochemical procedure from 165 patients with or without H.pylori infection who underwent endoscopy at our hospital.

Among these, there were 39 cases of chronic gastritis, 40 cases of intestinal metaplasia, 39 cases of dysplasia and 47 cases of gastric cancer; 79 cases of the H.pylori positive and 86 cases of the H.pylori negative overall. Results: There is a statistically significant difference on the expression of GSK-3β (P < 0.001) and phosphorylated GSK-3β (P < 0.05) in various stages of gastric mucosal lesion, with the lower expression of GSK-3β and higher expression of phosphorylated GSK-3β in gastric carcinoma group. In the 79 cases of H.pylori positive group, the result was also obvious. By further observing the different expression of GSK-3β and phosphorylated GSK-3β with and without H.pylori infection in each stage of gastric mucosal lesion, we found that the expressiones of them were independent of H.pylori infection in chronic gastritis, intestinal metaplasia and atypical hyperplasia group (P > 0.

Pseudocontinuous ASL was collected using 30 pairs of tag and control acquisition using a 3-dimensional gradient-echo spin-echo (GRASE) acquisition. All images were registered to a high-resolution anatomical atlas. Average CBF measurements

within regions of contrast-enhancement and T2 hyperintensity were evaluated between the two modalities. Additionally, voxel-wise correlation between CBF measurements obtained with DSC and ASL were assessed. Results demonstrated a positive linear correlation between DSC and ASL measurements of CBF when regional average values were compared; however, click here a statistically significant voxel-wise correlation was only observed in around 30-40% of patients. These results suggest DSC and ASL may provide regionally similar, but spatially different measurements of

CBF. Magnetic resonance imaging (MRI) is the mainstay of brain tumor imaging, both in diagnosis and treatment. Traditionally, clinicians rely on contrast enhancement to characterize the relative degree of malignancy in suptratentorial see more tumors. However, with increasing evidence for the critical role of angiogenesis in determination of tumor malignancy and growth potential, imaging modalities capable of quantifying cerebral blood flow (CBF) have become attractive alternatives. Several studies have shown that higher grade brain tumors have significantly higher perfusion measurements than low-grade tumors,[1-3] suggesting that CBF measurements may be a better method

for characterizing brain tumor angiogenesis and monitor treatment response. As antiangiogenic therapy is now the standard of care for recurrent malignant gliomas, there is a significant need for monitoring changes in cerebral blood flow within medchemexpress areas of suspected tumor independent of contrast enhancement. The gold standard for perfusion MR imaging is dynamic susceptibility contrast (DSC) MRI, which uses a bolus injection of paramagnetic contrast agent, usually gadolinium, as a nondiffusible tracer for CBF. Calculations of CBF, CBV (cerebral blood volume; the fraction of tissue volume occupied by blood), and mean transit time (MTT = CBF/CBV, the time it takes for blood to pass through the vasculature within the tissue of interest) can be made simultaneously. However, this requires deconvolving the arterial input function (AIF) from the time series data. As a result, few studies have been done on the reproducibility of DSC measurements of CBF. Arterial spin labeling (ASL) is a continually evolving noninvasive technique for quantifying CBF. ASL uses magnetically tagged blood water as an endogenous, diffusible tracer for blood flow. Specifically, blood in a feeding artery is subjected to an inversion pulse, and the magnetization can be followed as it is transferred to brain tissue by capillary exchange at a rate dependent on perfusion of the tissue.

Conclusion: Specific modifications of the disulfide bond within the lipoic-acid-conjugated PDC-E2 moiety, i.e., by an electrophilic agent renders PDC-E2 immunogenic in a genetically susceptible host. (HEPATOLOGY 2013) Antimitochondrial autoantibodies (AMAs) to the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2) are the serological hallmark of primary biliary cirrhosis (PBC).1-4 Previous analysis of the antibody specificity of anti-PDC-E2 revealed a number of subpopulations of anti-PDC-E2 antibodies that recognized either the PDC peptide, PDC peptide conjugated with lipoic acid,

or lipoic acid itself.5-7 Interestingly, PDC-E2-specific antibodies are present long before the onset of clinical symptoms and may represent a relic of initiating immunological events.8 Recent studies by quantitative structure-activity relationship (QSAR) analysis demonstrated that AMA-positive buy Pifithrin-�� PBC

sera, but not controls, reacted to a number Regorafenib in vivo of xenobiotic modified PDC-E2 structures,9-11 with a particularly striking level of reactivity against 6,8-bis(acetylthio) octanoic acid (SAc)-PDC-E2.12 This observation is critical because SAc is a modified form of lipoic acid in which both sulfur atoms of the disulfide bond of the lipoyl ring are modified by acetyl groups (Fig. 1), thereby maintaining PDC-E2 in a reduced state by preventing disulfide bond formation; this reduced state facilitates xenobiotic modification of PDC-E2.13 We hypothesized that the presence of antibodies directed against the SAc-PDC-E2 conjugate in sera from PBC patients suggests that this structure is involved in loss of tolerance. Such data would also support the thesis that chemical modification of self-proteins plays an important role in autoimmunity,7, 14-16 exemplified by minocycline-induced autoimmunity, whereby minocycline binding to self macromolecules produces immunogenic self antigens that become the target MCE公司 of disease-generating, crossreactive autoantibodies.17, 18 Thus, to address our hypothesis

and define the antibody reactivity to the SAc moiety, we studied the serological reactivity of 241 AMA-positive PBC patients, 34 AMA-negative PBC patients, 86 patients with primary sclerosing cholangitis (PSC), 95 patients with autoimmune hepatitis (AIH), and 60 healthy controls against SAc-conjugated bovine serum albumin (BSA), 2-octynoic acid (2OA)-conjugated BSA, recombinant PDC-E2 (rPDC-E2), and BSA itself. Importantly, we mapped specific reactivities of a nested subset of 24 AMA-positive SAc-BSA-positive PBC sera, including use of various affinity-purified antisera and inhibition studies. Interestingly, our data suggest that immunoglobulin M (IgM) reactivity to SAc reflects the footprints of xenobiotic modification of PDC-E2. Finally, we report herein that the IgM reactivity to SAc persists from early- to late-stage PBC with only minimal IgG reactivity.

Furthermore, moderately elevated level of alkaline phosphatase (ALP) and high γ-glutamyl transferase (GGT) values are good discriminator of ALD. Thus, the purpose of this study was to evaluate whether serum liver enzyme ratio including GGT: ALP can be used this website as a sensitive and specific biomarker for differential diagnosis of ALD. Methods: Clinically diagnosed 627 ALD patients and 432 age & gender matched non-alcoholic healthy individual as control were enrolled for the study. Liver function test panel

including GGT were analyzed by Vitalab flexor junior auto analyzer at Department of Clinical Biochemistry, Dhulikhel Hospital-Kathmandu University Hospital, Dhulikhel, Nepal. The best cut-off value for serum enzyme ratios including GGT: ALP that predicts ALD was determined

by ROC curve using SPSS package 11.5 version. Results: The GGT to ALP ratio ≥3.0 was found to be 73.4 % sensitive and 100% specific for the diagnosis of ALD while de ritis ratio was 27.8% sensitive and 100% specific. Conclusion: The GGT to ALP ratio was found to be sensitive and specific non-invasive biomarker for diagnosis of ALD in comparison to existing biomarker. Also, this ratio was based on common parameters of liver function panel which can be investigated in any routine clinical chemistry laboratory. Key Word(s): 1. ALD; 2. biomarker; 3. GGT/ALPratio; 4. deritis ratio; Presenting Author: XIAOLI PAN Additional Authors: JINZUO LUO, PEI WANG, ZHIJUN WANG, YUHU SONG, JIN YE Corresponding Author: JIN YE Affiliations: Union Hospital Objective: Nonalcoholic Vemurafenib purchase fatty liver disease (NAFLD) is characterized by steatosis associated with liver inflammation. As NAFLD processing, the content of triglyceride is increased in the hepatocytes, which makes them have typical vacuoles just like adipocytes. Whether the morphological changes of the hepatocytes indicate potential functional changes is not clear. Methods: C57BL/6J mice were fed high fat (HF) diets containing 42% fat calories for 12, 16, 20, or 24 weeks and compared to

the regular MCE公司 chow. The markers for adipocyte in the liver were detected by RT-PCR and western blot analysis. Double immunofluorescence labeling for confocal laser scanning microscopy was used to identify the phenotypic changes of the steatotic hepatocytes. Results: After 12 Weeks, the adipocyte markers aP2 and peroxisome proliferator-activated receptor γ increased at both mRNA and protein level. FITC-labeled adipocyte marker aP2 and rhodamine-labeled hepatocyte marker albumin were both dyed in the cytoplasm of hepatocyte in NAFLD by confocal laser scanning microscopy. The expression of cell membrane-bound E-Cadherin and albumin were reduced in the steatotic hepatocytes comparing to the controls. The steatotic hepatocytes could release proinflammatory cytokines to activate kupper cells. Conclusion: There are not only the morphological changes of the hepatocytes in the process of NAFLD, but also the functional and phenotypic changes.

Additionally, we also

found some evidence of multiplicative interaction between XRCC4 and GSTM1 (ORinteraction = 2.13 [95% CI: 1.87-2.42]; Pinteraction buy BAY 80-6946 = 1.56 × 10−30; data not shown). To assess possible interactive effects of matching factors and rs28383151 polymorphism on HCC risk, we performed a series of bivariate stratified analyses by matching factors, such as HBV and HCV infection, age, race, and sex, on this polymorphism and did not find that these factors modulated the effect of this polymorphism on HCC risk (Pinteraction > 0.05; Supporting Table 8). This implied that these matching factors should be effectually manipulated and should not modify the association Smoothened Agonist concentration between rs28383151 polymorphism and HCC related to AFB1 exposure. To study the correlation between rs28383151 polymorphism and AFB1 exposure years in the risk for HCC, we analyzed the joint effects of AFB1 exposure years and XRCC4 genotypes on HCC risk (Table 2). In this analysis, we used as a reference the lowest risk group: those who had rs28383151-GG and short-term AFB1-exposure years. We observed that increasing the number of exposure years consistently increased HCC risk; moreover, this risk was more pronounced among subjects with the risk

genotypes of XRCC4 (OR, >1). We found some evidence of multiplicatively interactive effects of genotypes and exposure years on HCC risk (19.61 > 5.28 × 1.98) according to the previously published formula (OReg > OReg’ × ORe’g).15 Additionally, a similar increased-risk trend was also found in the sequential joint-effects analysis of this polymorphism MCE and AFB1 exposure levels for HCC risk (11.26 > 5.76 × 1.35; Table 2). To investigate the potential effects of rs28383151 polymorphism on XRCC4

expression, we analyzed the association between this polymorphism and XRCC4 protein using immunohistochemistry (IHC) in the cancerous tissues of 1,499 HCC cases. The data showed that the genotypes with rs28383151 A alleles were significantly related to decreased XRCC4 expression in hepatocellular tumor tissues, compared with rs28383151-GG (Fig. 1A; P < 0.01). To further analyze this correlation, subjects were divided into three groups based on XRCC4 expression scores in the tumors, representing low (immunoreactive score [IRS]: 1-3), medium (IRS, 4-6), and high (IRS, >6) expression of XRCC4. Spearman’s r test exhibited this polymorphism negatively related to the levels of XRCC4 protein (r = −0.242; Supporting Table 9). Representative photographs exhibit the aforementioned correlation between genotypes and expression levels (Fig.