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Papers by John Wilson

Human Molecular Genetics, 2012

Cancer research, 2000

Profound alterations in host metabolism in lung cancer patients with weight loss have been report... more Profound alterations in host metabolism in lung cancer patients with weight loss have been reported, including elevated phosphomonoesters (PMEs) as detected by 31P magnetic resonance spectroscopy (MRS). In healthy subjects, infusion of L-alanine induced significant increases in hepatic PMEs and phosphodiesters (PDEs) due to rising concentrations of 3-phosphoglycerate and phosphoenolpyruvate, respectively. The aim of the present study was to monitor these changes in the tumor-free liver of lung cancer patients during L-alanine infusion by means of simultaneous 31P MRS and turnover measurements. Twenty-one lung cancer patients without liver metastases with (CaWL) or without weight loss (CaWS), and 12 healthy control subjects were studied during an i.v. L-alanine challenge of 1.4-2.8 mmol/kg followed by 2.8 mmol/kg/h for 90 min. Plasma L-alanine concentrations increased during alanine infusion, from 0.35-0.37 mM at baseline to 5.37 +/- 0.14 mM in the CaWL patients, 6.67 +/- 0.51 mM in ...

The American Journal of Gastroenterology, 2003

OBJECTIVES: Single nucleotide variations in the CARD15 gene have recently been shown to be associ... more OBJECTIVES: Single nucleotide variations in the CARD15 gene have recently been shown to be associated with Crohn's disease (CD). Of special interest is a cytosine insertion at position 3020 of exon 11 (3020insC), which leads to a stop codon, truncation of the CARD15 protein, and an altered function of CARD15. The aim of the study was to evaluate this frameshift mutation in Dutch, multiple-affected families with inflammatory bowel disease (IBD). METHODS: Ninety-three Caucasian, multiple-affected families with IBD were recruited by interviewing patients attending our department. Sixty-one probands had CD, and 32 probands ulcerative colitis (UC). The diagnosis of probands and affected family members was verified according to standard criteria. In addition, 81 healthy, unrelated controls were included. Genomic DNA was isolated from venous blood of all participants to determine the CARD15 3020insC mutation by using an allele-specific polymerase chain reaction, followed by agarose gel electrophoresis and DNA sequencing. RESULTS: Association with CARD15 3020insC was statistically significant for CD, but not for UC. In one of the multiple-affected families, middle-aged and elderly homozygous carriers were identified without CD. CONCLUSIONS: Although CARD15 3020insC appears to be etiologically important in CD, homozygous carriage does not always lead to IBD.

European Journal of Gastroenterology & Hepatology, 2007

Objectives The single nucleotide variations R702W, G908R and L1007fs in the CARD15 gene have been... more Objectives The single nucleotide variations R702W, G908R and L1007fs in the CARD15 gene have been found to be independently associated with Crohn's disease. The aim of this study was to evaluate the prevalence of these gene variations in Dutch multiple inflammatory bowel disease-affected families, in sporadic inflammatory bowel disease patients and in healthy controls. Methods Dutch Caucasians from multiple inflammatory bowel disease-affected families were recruited, including 78 probands with Crohn's disease, 34 probands with ulcerative colitis and 71 inflammatory bowel diseaseaffected and 100 non-affected family members. In addition, 45 sporadic inflammatory bowel disease patients (36 Crohn's disease and nine ulcerative colitis), and 77 unrelated healthy controls were included. Genomic DNA was isolated to determine CARD15 R702W, G908R and L1007fs. For these mutations, we evaluated disease susceptibility and correlation with inflammatory bowel disease phenotypes. Results In all included unrelated inflammatory bowel disease-affected probands, the R702W, G908R and L1007fs allele frequencies were 8.8, 6.1 and 11.0%, respectively, for Crohn's disease, and 4.7, 0 and 2.3% for ulcerative colitis. In controls, the allele frequencies were 5.9, 0.7 and 1.9%, respectively. G908R and L1007fs were associated with Crohn's disease (P = 0.006 and 0.001, respectively). Compound heterozygotes for any of the three mutations were 11 (9.2%) in Crohn's disease patients, but none in ulcerative colitis patients nor controls. Carriage of CARD15 mutations was not associated with familial disease (P Z 0.38). Inflammatory bowel disease-affected family members of Crohn's disease probands carrying L1007fs, however, were carriers significantly more often than expected (P < 0.001). In Crohn's disease patients, a significant trend was found between carriage of at least one CARD15 mutation and between carriage of L1007fs and behaviour of disease, including more carriers with stricturing and even more with penetrating disease (P = 0.006 and 0.017, respectively). Conclusion In the Dutch population, CARD15 G908R and L1007fs are associated with Crohn's disease. Although no difference was found between sporadic and familial cases, in L1007fs-positive multiple affected families the inflammatory bowel disease-affected relatives are more likely than expected to carry this mutation. In Crohn's disease, carriage of at least one CARD15 mutation is associated with a more complicated disease behaviour.

Digestive and Liver Disease, 2005

Background and aims. Interleukin-10 is an anti-inflammatory and immunomodulatory cytokine. Interl... more Background and aims. Interleukin-10 is an anti-inflammatory and immunomodulatory cytokine. Interleukin-10 deficient mice are prone to develop chronic colitis. Administration of recombinant human interleukin-10 has been proposed to have a beneficial effect in a subgroup of patients with Crohn's disease. Recently, we found an interleukin-10 Gly15Arg mutation in a family with Crohn's disease which is associated with reduced interleukin-10 secretion by in vitro stimulated monocytes and lymphocytes. We hypothesised that this interleukin-10 mutation plays a role in maintaining the inflammatory process in Crohn's disease in some families. Patients and methods. We evaluated interleukin-10 Gly15Arg in 379 patients with Crohn's disease, and 75 unrelated healthy controls. Also, first degree family members of interleukin-10 Gly15Arg carriers were evaluated. Additionally, mutation carriers and their relatives were evaluated for CARD15 R702W, G908R, and 1007fs. Results. Two patients with Crohn's disease were heterozygous for the interleukin-10 Gly15Arg mutation. No homozygotes were found. The Gly15Arg mutation was not observed in the controls. In first degree family members of the Crohn's disease-affected interleukin-10 Gly15Arg carriers, the mutation was found in Crohn's disease-affected as well as in their apparently healthy individuals. All family members carried one or two CARD15 mutation(s). Conclusion. The interleukin-10 Gly15Arg mutation is rare in patients with Crohn's disease, and is not associated with the disease in the Netherlands.

Journal of Clinical Pathology, 2006

Genetics in Medicine, 2019

World Journal of Gastroenterology, 2019

Author contributions: Wensink D drafted the manuscript; Langendonk JG, Wagenmakers MAEM and Wilso... more Author contributions: Wensink D drafted the manuscript; Langendonk JG, Wagenmakers MAEM and Wilson JH edited and revised the manuscript. Wensink D approved the final version of the manuscript.

Hepatology, 2019

On top of weekly heme, we initiated weekly blood transfusions and hydroxycarbamide 1,000 mg once ... more On top of weekly heme, we initiated weekly blood transfusions and hydroxycarbamide 1,000 mg once daily, to reduce erythroid heme synthesis. Within 2 weeks, symptoms improved and blood pressure returned to normal. Three months later he was still improving. He has no abdominal pain or weaknesses. Plasma ALA dropped from 10,270 to 3,298 nmol/L.

Digestive Diseases and Sciences, 1990

Plasma thromboxane concentrations were found to be significantly elevated in acute necrotizing pa... more Plasma thromboxane concentrations were found to be significantly elevated in acute necrotizing pancreatitis in rats, whereas prostaglandin 12 levels were not. The significance of these alterations was investigated. Pancreatitis was induced by injecting 5% sodium taurocholate into the pancreatic duct. Iloprost (ZK 36374, a stable analog of prostaglandin I 2, 25 ng/kg body weight) decreased the mortality rate from 100% to 50%. When treatment with iloprost was combined with simultaneous administration of either Sibelium (flunarizine R 14 950, 0.2 mg/kg body weight) or dazmegrel (UK 38 485, 50 mg/kg body weight) an additional decrease in the mortality rate was recorded. Dazmegrel is a selective thromboxane A 2 synthetase inhibitor and flunar&ine (a calcium entry blocker) also inhibits the effects of elevated thromboxane A 2 levels. With flunarizine and iloprost the mortality rate was 40% (P < 0.05); with dazmegrel and iloprost it was 10% (P < 0.01). The results of the present study suggest that thromboxane A 2 and prostaglandin 12 play a role in the course of acute necrotizing pancreatitis.

Digestive Diseases and Sciences, 1992

The effects of a long-acting somatostatin analog (SMS 201-995) were studied in an established mod... more The effects of a long-acting somatostatin analog (SMS 201-995) were studied in an established model of acute necrotizing pancreatitis in rats. SMS 201-995, when given prior to induction of pancreatitis, decreased the mortality rate from 100% to 40% (P = 0.0001). When treatment was given after induction of pancreatitis, the mortality rate was 75% (P = 0.2). Administration of SMS 201-995 did not influence the serum concentrations of amylase markedly, but the lipase levels were significantly lowered (P < 0.05). The low levels of serum insulin and the glucose level in whole blood were not influenced. The volume of ascitic fluid was reduced (P < 0.01). Moreover, less peritoneal fat necrosis was seen, suggesting a reduction in toxic factors in the ascitic fluid. Treatment with SMS 201-995 prior to induction of pancreatitis caused a significant increase in the levels of circulating 6-keto-PGFt~, the stable metabolite of prostaglandin 12 (P < 0.01). The levels of thromboxane B 2 and prostaglandin E2 did not change significantly. The present data support the hypothesis that SMS 201-995 is an activator of prostaglandin 12, thereby modifying the course of the disease.

European Journal of Internal Medicine, 2002

Background: Elevated mortality due to cardiovascular disease has been reported for patients with ... more Background: Elevated mortality due to cardiovascular disease has been reported for patients with Barrett's esophagus (BE). We compared the prevalence of risk factors for cardiovascular disease in patients with BE, reflux esophagitis (RE), and non-ulcer dyspepsia (NUD) with that of the general population. Methods: Patients with upper gastrointestinal complaints and BE, RE, or NUD were compared with a matched cohort from the general population using a questionnaire and blood pressure and cholesterol measurements. Results: Hypertension occurred more frequently in patients with BE (odds ratio 5.1, P,0.0001) and RE (odds ratio 3.8, P,0.001), but not in those with NUD. Serum total cholesterol was higher in BE (P50.02) and borderline in RE (P50.06) but not in NUD. Mean HDL cholesterol levels, body mass index, and smoking did not differ. Conclusions: This study suggests that BE and RE found at diagnostic endoscopy are associated with an increased prevalence of hypertension and a higher total cholesterol level than in the general population. If so, this would explain the increased mortality during the follow-up of BE patients, and it should be taken into account when designing or evaluating follow-up studies of BE.

Drug Development Research, 2003

Preliminary clinical data suggest that adenosine 5'-triphosphate (ATP) may inhibit lung tumor gro... more Preliminary clinical data suggest that adenosine 5'-triphosphate (ATP) may inhibit lung tumor growth. Because studies of ATP on lung cancer cells are lacking, the aim of the present study was to explore effects of extracellular ATP on the growth and morphology of human lung tumor cells. Five human lung tumor cell lines derived from tumors with different cellular characteristics, i.e., a small cell carcinoma (GLC4), a large cell carcinoma (H460), a squamous cell carcinoma (H520), a mesothelioma (MERO82), and a papillary adenocarcinoma (H441), were exposed to 0, 0.5, 1, 2, and 3 mM ATP. Total cell numbers and dead or damaged cells were measured on days 1, 2, and 3. ATP induced a significant, dose-dependent growth inhibition in GLC4, H460, H520, and MERO82 cells. In contrast, H441 cells showed already maximal inhibition at 0.5 mM. Compared to untreated control cell lines, a significant growth inhibition (mean 7 SEM) of 65 7 5% (GLC4), 59 7 5% (H460), 45 7 5% (H520), 3872% (MERO82), and 55 7 8% (H441) was shown after 3 days incubation with 3 mM ATP. ATP also induced changes in morphology and attachment to the substratum. Although not demonstrated by the Trypan Blue exclusion test, on photographs it seems that ATP induces death of GLC4 and H460 cells at higher concentrations. In conclusion, in four out of five explored lung tumor cell lines, ATP induces a dose-dependent growth inhibition. Lung adenocarcinoma cells show already maximal inhibition at the lowest tested ATP dose. There is a relationship between growth inhibition and morphology changes.

Clinical Science, 2000

Stable-isotope tracers were used to assess whether levels of phosphomonoesters (PME) and phosphod... more Stable-isotope tracers were used to assess whether levels of phosphomonoesters (PME) and phosphodiesters (PDE) in the livers of lung cancer patients, as observed by 31 P magnetic resonance (MR) spectroscopy, reflect elevated whole-body glucose turnover and gluconeogenesis from alanine. Patients with advanced non-small-cell lung cancer without liver metastases (n l 24 ; weight loss 0-24 %) and healthy control subjects (n l 13) were studied after an overnight fast. 31 P MR spectra of the liver in vivo were obtained, and glucose turnover and gluconeogenesis from alanine were determined simultaneously using primed-constant infusions of [6,6-2 H 2 ]glucose and [3-13 C]alanine. Liver PME concentrations were 6 % higher in lung cancer patients compared with controls (not significant) ; PME levels in patients with 5 % weight loss were significantly higher than in patients with 5 % weight loss (P 0.01). PDE levels did not differ between the groups. In lung cancer patients, whole-body glucose production was 19 % higher (not significant) and gluconeogenesis from alanine was 42 % higher (P 0.05) compared with healthy subjects ; turnover rates in lung cancer patients with 5 % weight loss were significantly elevated compared with both patients with 5 % weight loss and healthy subjects (P 0.05). PME levels were significantly correlated with glucose turnover and gluconeogenesis from alanine in lung cancer patients (r l 0.48 and r l 0.48 respectively ; P 0.05). In conclusion, elevated PME levels in lung cancer patients appear to reflect increased glucose flux and gluconeogenesis from alanine. These results are consistent with the hypothesis that elevated PME levels are due to contributions from gluconeogenic intermediates.

Anti-Cancer Drugs, 2003

We recently reported that regular infusions of adenosine 5 0-triphosphate (ATP) inhibited loss of... more We recently reported that regular infusions of adenosine 5 0-triphosphate (ATP) inhibited loss of body weight and quality of life in patients with non-small cell lung cancer (NSCLC). In the present paper we investigated whether ATP affects tumor growth and survival in the same group of patients. Fifty-eight NSCLC patients (stage IIIB or IV) were randomly assigned to receive either 10 i.v. 30-h ATP infusions every 2-4 weeks over a 24-week period (n = 28) or no ATP (control patients, n = 30). ATP was given for a median of 6.5 infusions. Differences in time to progression and survival between patients in both groups were tested by means of the log-rank test and Cox regression analysis. Forty-nine patients were evaluable for tumor response. None of the evaluable patients showed a complete or partial response. Median time to progression was 3.9 months [95% confidence interval (CI) = 2.3-5.5] in the ATP group compared to 3.0 months (95% CI = 2.4-3.7) in the control group (p = 0.71). Median survival was 5.6 months (95% CI = 1.1-10.1) for the ATP group and 4.7 months (95% CI = 2.6-6.8) for the control group (p = 0.68). ATP treatment was associated with a significant increase in survival in the subgroup of weight-losing patients with stage IIIB NSCLC: in this subgroup, median survival was 9.3 months (95% CI = 2.1-16.5) for ATP-treated patients versus 3.5 months (95% CI = 2.3-4.7) for control patients (between-group difference: p = 0.009). No significant effect of ATP was observed for weight-losing patients with stage IV NSCLC or for weight-stable NSCLC patients. Although ATP as a single therapy does not lead to tumor regression or increased survival in patients with advanced lung cancer, it may prolong survival in weight-losing patients with stage IIIB lung cancer. The latter finding is intriguing, but requires confirmation in larger clinical trials. Anti-Cancer Drugs 14:639-644 c 2003 Lippincott Williams & Wilkins.

Aim: To investigate whether mutations in the STK11/LKB1 gene and genes implicated in the colorect... more Aim: To investigate whether mutations in the STK11/LKB1 gene and genes implicated in the colorectal adenoma-carcinoma sequence are involved in Peutz-Jeghers syndrome (PJS) related tumorigenesis. Methods: We analysed 39 polyps and 5 carcinomas of 17 PJS patients from 13 families for loss of heterozygosity (LOH) at 19pl3.3 (STK11/LKB1 gene locus), 5q21 (APC gene locus), 18q21-22 (Smad4 and Smad2 gene locus) and 17pl3 (p53 gene locus) and evaluated immunohistochemical staining for p53. Also, mutational analysis of K-ras codon 12, APC and p53 and immunohistochemistry for Smad4 expression was performed on all carcinomas. Results: LOH at 19p was observed in 38% (15/39) of the polyps and in all carcinomas (n=5). Interestingly, 86% (6/7) of polyps from patients with cancer had LOH, versus 29% (9/31) of polyps from the remaining patients (p=0.01). In 1 polyp from a patient without a germline STK11/LKB1 mutation, no LOH at 19p, or at three alternative PJS candidate loci (19q, 6p and 6q) was found. No LOH at 5q was observed. However, mutational analysis revealed an APC mutation in 4 out of 5 carcinomas. LOH at 17p was not observed in polyps and carcinomas; immunohistochemistry showed expression of p53 in 1 carcinoma and focal expression in 3 polyps. At subsequent sequence analysis, no p53 mutation was found. One carcinoma had an activating K-ras codon 12 mutation and another carcinoma showed 18q LOH, however, no loss of Smad4 expression was seen. Conclusions: These results provide further evidence that STK11/LKB1 acts as a tumorsuppressor gene, and may be involved in early stages of PJS-tumorigenesis. Further research is needed to investigate whether LOH in PJS-polyps can serve as a biomarker to predict cancer. Differences in molecular genetic alterations noted between the adenoma-carcinoma sequence and PJS-related tumors suggest the presence of a distinct pathway of carcinogenesis.

Journal of Inherited Metabolic Disease, 2018

Introduction A small proportion of patients with acute intermittent porphyria (AIP) suffer from r... more Introduction A small proportion of patients with acute intermittent porphyria (AIP) suffer from recurrent porphyric attacks, with a severely diminished quality of life. In this retrospective case-control study, the burden of disease is quantified and compared among three AIP patient subgroups: cases with recurrent attacks, cases with one or occasional attacks and asymptomatic carriers. Methods Data from patient records and questionnaires were collected in patients between 1960 and 2016 at the Erasmus Medical Center, Rotterdam, the Netherlands. We collected symptoms related to porphyria, porphyria related complications, attack frequency, hospitalisation frequency, hospitalisation days related to acute porphyric attacks, frequency of heme infusions and medical healthcare costs based on hospitalisations and heme therapy. Results In total 11 recurrent AIP cases, 24 symptomatic AIP cases and 53 AIP carriers as controls were included. All recurrent patients reported porphyria related symptoms, such as pain, neurological and/or psychiatric disorders, and nearly all developed complications, such as hypertension and chronic kidney disease. In the recurrent cases group, the median lifelong number of hospitalisation days related to porphyric attacks was 82 days per patient (range 10-374), and they spent a median of 346 days (range 34-945) at a day-care facility for prophylactic heme therapy; total follow-up time was 243 person-years (PYRS). In the symptomatic non-recurrent group the median lifelong number of hospitalisation days related to porphyric attacks was 7 days per patient (range 1-78), total follow-up time was 528 PYRS. The calculated total medical healthcare cost for recurrent cases group was €5.8 million versus €0.3 million for the symptomatic cases group.

Clinical cancer research : an official journal of the American Association for Cancer Research, 2003

Peutz-Jeghers syndrome (PJS) is a hamartomatous polyposis disorder with a high cancer risk. Debat... more Peutz-Jeghers syndrome (PJS) is a hamartomatous polyposis disorder with a high cancer risk. Debate exists about the premalignant potential of hamartomas. Also, treatment options other than surveillance are not available. Therefore, molecular alterations in hamartomas and PJS carcinomas were studied. The objective was (a) to evaluate expression of cyclooxygenase (COX)-2 as target for chemopreventive treatment and (b) to define the neoplastic potential of hamartomas at the molecular level. Paraffin-embedded samples of 24 PJS hamartomas, including 2 hamartomas with dysplastic changes, and 11 PJS carcinomas were available. Slides were stained with antibodies against COX-2, beta-catenin, cyclin D1, p21(waf1/cip1), Ki-67, and p53. DNA was studied for loss of heterozygosity (LOH) at 19p (STK11), 5q (APC), and 17p (TP53); mutations in beta-catenin, APC, and K-RAS; and microsatellite instability. Moderate or strong epithelial COX-2 was present in 25% of hamartomas, including two hamartomas w...

Journal of inherited metabolic disease, 2015