https://nova.newcastle.edu.au/vital/access/ /manager/Index en-au 5 https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:34307 -8) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6-2.5; P = 9.7 × 10^-9). The association with A*33:01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A*33:01 was significant genome wide for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 was associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the lipopolysaccharide-responsive vesicle trafficking, beach and anchor containing gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6-2.7; P = 4.8 × 10^-9). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR, 5.4; 95% CI, 3.0-9.5; P = 7.1 × 10^-9). We validated the association between A*33:01 terbinafine- and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224. Conclusions In a GWAS of persons of European descent with DILI, we associated HLA-A*33:01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non-drug-specific risk factors.]]> Wed 27 Feb 2019 09:54:18 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:42216 Wed 22 Mar 2023 15:44:59 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:40083 Helicobacter pylori induces strong inflammatory responses that are directed at clearing the infection, but if not controlled, these responses can be harmful to the host. We investigated the immune-regulatory effects of the innate immune molecule, nucleotide-binding oligomerization domain-like receptors (NLR) family CARD domain-containing 5 (NLRC5), in patients and mice with Helicobacter infection. Methods: We obtained gastric biopsies from 30 patients in Australia. We performed studies with mice that lack NLRC5 in the myeloid linage (Nlrc5^møKO) and mice without Nlrc5 gene disruption (controls). Some mice were gavaged with H pylori SS1 or Helicobacter felis; 3 months later, stomachs, spleens, and sera were collected, along with macrophages derived from bone marrow. Human and mouse gastric tissues and mouse macrophages were analyzed by histology, immunohistochemistry, immunoblots, and quantitative polymerase chain reaction. THP-1 cells (human macrophages, controls) and NLRC5^-/- THP-1 cells (generated by CRISPR-Cas9 gene editing) were incubated with Helicobacter and gene expression and production of cytokines were analyzed. Results: Levels of NLRC5 messenger RNA were significantly increased in gastric tissues from patients with H pylori infection, compared with patients without infection (P <.01), and correlated with gastritis severity (P <.05). H pylori bacteria induced significantly higher levels of chemokine and cytokine production by NLRC5^-/- THP-1 macrophages than by control THP-1 cells (P <.05). After 3 months of infection with H felis, Nlrc5^mø-KO mice developed gastric hyperplasia (P <.0001), splenomegaly (P <.0001), and increased serum antibody titers (P <.01), whereas control mice did not. Nlrc5^mø-KO mice with chronic H felis infection had increased numbers of gastric B-cell follicles expressing CD19 (P <.0001); these follicles had features of mucosa-associated lymphoid tissue lymphoma. We identified B-cell-activating factor as a protein that promoted B-cell hyperproliferation in Nlrc5^mø-KO mice. Conclusions: NLRC5 is a negative regulator of gastric inflammation and mucosal lymphoid formation in response to Helicobacter infection. Aberrant NLRC5 signaling in macrophages can promote B-cell lymphomagenesis during chronic Helicobacter infection.]]> Thu 14 Jul 2022 12:19:41 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:34276 MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer.]]> Thu 13 Jan 2022 10:31:35 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:2202 Sat 24 Mar 2018 08:30:10 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:12780 Sat 24 Mar 2018 08:18:20 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:20807 V1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We investigated whether patients with IBS have SCN5A variants that affect the function of Na_V1.5. Methods: We performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without IBS (controls). Mutant forms of SCN5A were expressed in human embryonic kidney-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls. Results: Missense mutations were found in SCN5A in 13 of 584 patients (2.2%, probands). Diarrhea-predominant IBS was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (31%) than diarrhea-predominant IBS (10%; P <.05). Electrophysiologic analysis showed that 10 of 13 detected mutations disrupted Na_V1.5 function (9 loss-of-function and 1 gain-of-function function). The p. A997T-Na_V1.5 had the greatest effect in reducing Na_V1.5 function. Incubation of cells that expressed this variant with mexiletine restored their sodium current and administration of mexiletine to 1 carrier of this mutation (who had constipation-predominant IBS) normalized their bowel habits. In the genome-wide association study and 4 replicated studies, the SCN5A locus was strongly associated with IBS. Conclusions: About 2% of patients with IBS carry mutations in SCN5A. Most of these are loss-of-function mutations that disrupt Na_V1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options.]]> Sat 24 Mar 2018 08:05:59 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:18543 Sat 24 Mar 2018 07:50:17 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:18546 Sat 24 Mar 2018 07:50:13 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:4946 Sat 24 Mar 2018 07:48:06 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:286 Sat 24 Mar 2018 07:42:49 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:27609 3-fold more likely to report adequate relief than those given placebo (odds ratio = 3.1; 95% confidence interval: 1.1-9.0). Neither amitriptyline nor escitalopram appeared to affect GE or meal-induced satiety after the 10-week period in any group. Subjects with delayed GE were less likely to report adequate relief than subjects with normal GE (odds ratio = 0.4; 95% confidence interval: 0.2-0.8). Both antidepressants improved overall quality of life. Conclusions Amitriptyline, but not escitalopram, appears to benefit some patients with FD, particularly those with ulcer-like (painful) FD. Patients with delayed GE do not respond to these drugs.]]> Sat 24 Mar 2018 07:39:41 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:27399 Sat 24 Mar 2018 07:34:09 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:24867 Sat 24 Mar 2018 07:11:21 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:53764 Mon 15 Jan 2024 09:56:13 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:46206 Mon 14 Nov 2022 11:29:50 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:52808 Fri 27 Oct 2023 14:20:34 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:44100 –9 and replicated the finding in the validation set (OR 1.48; 95% CI 1.09–1.99; P = .01). The minor allele frequency showed the same effect size (OR > 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR 1.62; 95% CI 1.32–1.98; P = 4.0 × 10^–6; allele frequency = 13.3%), but the polymorphism was associated with DILI of other causes (OR 1.37; 95% CI 1.21–1.56; P = 1.5 × 10^–6; allele frequency = 11.5%). Among amoxicillin- and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A*02:01 and DRB1*15:01. Conclusions: In a genome-wide association study, we identified rs2476601 in PTPN22 as a non-HLA variant that associates with risk of liver injury caused by multiple drugs and validated our finding in a separate cohort. This variant has been associated with increased risk of autoimmune diseases, providing support for the concept that alterations in immune regulation contribute to idiosyncratic DILI.]]> Fri 07 Oct 2022 14:21:42 AEDT ]]>