Publications by authors named "Alkwin Wanders"

33 Publications

Collagenous Gastritis in Children: Incidence, Disease Course, and Associations With Autoimmunity and Inflammatory Markers.

Clin Transl Gastroenterol 2020 08;11(8):e00219

Department of Pediatric Gastroenterology, Hepatology and Nutrition, Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Göteborg, Sweden.

Introduction: Collagenous gastritis (CG), a rare disorder of unknown etiology, has been postulated to have immune-mediated mechanisms. We investigated (i) the incidence and prevalence of CG in a pediatric population; (ii) the clinical, endoscopic, and histologic characteristics of childhood-onset CG; and (iii) the evidence for autoimmunity and/or inflammatory activity in these patients.

Methods: Clinical, endoscopic, and histologic data were reviewed longitudinally in a population-based Swedish cohort of 15 patients with childhood-onset CG diagnosed in the period 2008-2019. A set of 11 autoantibodies, 4 blood inflammatory biomarkers, and the human leukocyte antigen DQ2/DQ8 genotype was analyzed cross-sectionally.

Results: The incidence rate of childhood-onset CG was 0.25/100,000 person-years, with an incidence rate ratio of girls to boys of 4.2 (95% confidence interval, 1.2-15). The prevalence of CG was 2.1/100,000 in children aged younger than 18 years. The endoscopic and histologic findings remained pathologic in all the examined patients during a median follow-up of 4.4 years. Many patients had heredity for autoimmune disorders (47%) and/or tested positive for autoantibodies (40%) or human leukocyte antigen DQ2/DQ8 (53%). No associated autoimmune comorbidities were observed. The serum levels of calprotectin and amyloid A were increased in 10/15 (67%) and 5/15 (33%) of the patients, respectively, whereas plasma C-reactive protein levels were normal in all, but 1 patient.

Discussion: The results indicate that childhood-onset CG is rare and has a chronic disease course. Although signs of autoimmune predisposition are frequent, early development of autoimmune comorbidities seems seldom. Serum calprotectin and amyloid A represent novel candidate biomarkers of inflammatory activity in CG (see Visual Abstract, Supplementary Digital Content 4, http://links.lww.com/CTG/A349).
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http://dx.doi.org/10.14309/ctg.0000000000000219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431242PMC
August 2020

Prevention of Rat Intestinal Injury with a Drug Combination of Melatonin and Misoprostol.

Int J Mol Sci 2020 Sep 15;21(18). Epub 2020 Sep 15.

Department of Pharmaceutical Biosciences, Uppsala University, 752 37 Uppsala, Sweden.

A healthy intestinal barrier prevents uptake of allergens and toxins, whereas intestinal permeability increases following chemotherapy and in many gastrointestinal and systemic diseases and disorders. Currently, there are no approved drugs that target and repair the intestinal epithelial barrier while there is a medical need for such treatment in gastrointestinal and related conditions. The objective of this single-pass intestinal perfusion study in rats was to investigate the preventive cytoprotective effect of three mucosal protective drugs-melatonin, misoprostol, and teduglutide-with different mechanisms of action on an acute jejunal injury induced by exposing the intestine for 15 min to the anionic surfactant, sodium dodecyl sulfate (SDS). The effect was evaluated by monitoring intestinal clearance of Cr-labeled ethylenediaminetetraacetate and intestinal histology before, during, and after luminal exposure to SDS. Our results showed that separate pharmacological pretreatments with luminal misoprostol and melatonin reduced acute SDS-induced intestinal injury by 47% and 58%, respectively, while their use in combination abolished this injury. This data supports further development of drug combinations for oral treatments of conditions and disorders related to a dysregulated or compromised mucosal epithelial barrier.
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http://dx.doi.org/10.3390/ijms21186771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555796PMC
September 2020

Vagotomy and subsequent risk of inflammatory bowel disease: a nationwide register-based matched cohort study.

Aliment Pharmacol Ther 2020 06 22;51(11):1022-1030. Epub 2020 Apr 22.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Background: The vagus nerve provides essential parasympathetic innervation to the gastrointestinal system and is known to have anti-inflammatory properties.

Aims: To explore the relationship between vagotomy and the risk of inflammatory bowel disease (IBD) and its major categories: Crohn's disease (CD) and ulcerative colitis (UC).

Methods: A matched cohort comprising 15 637 patients undergoing vagotomy was identified through the Swedish Patient Register from 1964 to 2010. Each vagotomised patient was matched for birth year and gender with 40 nonvagotomised individuals on the date of vagotomy. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for IBD using flexible parametric models adjusted for matching variables, year of vagotomy, birth country, chronic obstructive pulmonary disease and comorbidity index.

Results: We observed 119 (0.8%) patients with vagotomy developed IBD compared to 3377 (0.5%) IBD cases in nonvagotomised individuals. The crude incidence of IBD (per 1000 person-years) was 0.38 for vagotomised patients and 0.25 for nonvagotomised individuals. We observed a time-dependent elevated risk of IBD associated with vagotomy, for instance, the HR (95% CI) was 1.80 (1.40-2.31) at year 5 and 1.49 (1.14-1.96) at year 10 post-vagotomy. The association appeared to be stronger for truncal than selective vagotomy and limited to CD (HR was 3.63 [1.94-6.80] for truncal and 2.06 [1.49-2.84] for selective vagotomy) but not UC (1.36 [0.71-2.62] for truncal and 1.25 [0.95-1.63] for selective vagotomy).

Conclusions: We found a positive association between vagotomy and later IBD, particularly for CD. The finding indirectly underlines the beneficial role of the vagal tone in IBD.
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http://dx.doi.org/10.1111/apt.15715DOI Listing
June 2020

Tissue factor in ulcerative colitis, with and without concomitant primary sclerosing cholangitis.

Ups J Med Sci 2019 Nov 27;124(4):238-245. Epub 2019 Nov 27.

Department of Medical Sciences, Gastroenterology Research Group, Uppsala University, Uppsala, Sweden.

Ulcerative colitis (UC) in patients with the severe disease primary sclerosing cholangitis (PSC) constitutes a distinct clinical phenotype (PSC-UC) with a high incidence of colorectal cancer. Today, PSC-UC diagnosis is built on clinical observations only. Tissue factor (TF) has a potential use in UC diagnostics, and also in colorectal cancer prognostication. Here we evaluate TF expression in an inflammatory bowel disease (IBD) cohort, with special focus on differences between UC and PSC-UC patients. Colonic biopsies from UC ( = 23), PSC ( = 24), and healthy controls ( = 11) were stained for TF by immunohistochemistry. Mononuclear cell contribution to TF expression was verified using flow cytometry. TF was distributed at three distinct colonic locations: in subepithelial pericryptal sheath cells, in mononuclear cells, and in the intestinal stroma. In contrast to UC-where inflammation was accompanied with TF up-regulation-PSC-UC activity remained low during inflammation. Stromal TF positivity was found exclusively in ongoing inflammation. Our study provides additional support for a divergent pathogenesis in PSC-UC, with an inflammatory environment that differs from classical UC. Stromal TF emerges as a new marker of colonic inflammation.
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http://dx.doi.org/10.1080/03009734.2019.1689209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6968534PMC
November 2019

Diminished DEFA6 Expression in Paneth Cells Is Associated with Necrotizing Enterocolitis.

Gastroenterol Res Pract 2018 21;2018:7345426. Epub 2018 Oct 21.

Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.

Background: Necrotizing enterocolitis (NEC) is the most common gastrointestinal disorder in premature infants with a high morbidity and mortality. Paneth cell dysfunction has been suggested to be involved in the pathogenesis of NEC. Defensin alpha-6 (DEFA6) is a specific marker for Paneth cells acting as part of the innate immunity in the human intestines. The aim of this study was to investigate the expression of DEFA6 in infants with NEC.

Materials And Methods: Infants who underwent bowel resection for NEC at level III NICU in Sweden between August 2004 and September 2013 were eligible for the study. Macroscopically vital tissues were selected for histopathological evaluation. All infants in the control group underwent laparotomy and had ileostomy due to dysmotility, and samples were taken from the site of the stoma. DEFA6 expression was studied by immunohistochemistry. Digital image analysis was used for an objective and precise description of the samples.

Results: A total of 12 infants were included in the study, eight with NEC and four controls. The tissue samples were taken from the colon ( = 1), jejunum ( = 1), and ileum ( = 10). Both the NEC and control groups consisted of extremely premature and term infants (control group: 25-40 gestational weeks, NEC group: 23-39 gestational weeks). The postnatal age at the time of surgery varied in both groups (control group: 4-47 days, NEC group: 4-50 days). DEFA6 expression in the NEC group was significantly lower than that in the control group and did not correlate with gestational age.

Conclusion: The diminished DEFA6 expression in Paneth cells associated with NEC in this study supports the hypothesis that alpha-defensins are involved in the pathophysiology of NEC. Future studies are needed to elucidate the role of alpha-defensins in NEC aiming at finding preventive and therapeutic strategies against NEC.
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http://dx.doi.org/10.1155/2018/7345426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215571PMC
October 2018

High Serum sCD40 and a Distinct Colonic T Cell Profile in Ulcerative Colitis Associated With Primary Sclerosing Cholangitis.

J Crohns Colitis 2019 Mar;13(3):341-350

Department of Medical Sciences, Gastroenterology Research Group, University Hospital, Uppsala, Sweden.

Background And Aims: There is a strong association between primary sclerosing cholangitis [PSC] and ulcerative colitis [UC], but the immunological link between the two diseases is obscure. We compared serum cytokine profiles of patients with PSC-UC and UC, and investigated a number of selected cytokines in colonic biopsy samples. We also assessed the presence and activation of T cells in peripheral blood and colonic mucosa.

Methods: Serum samples from 22 patients with PSC-UC, 28 patients with UC, and 19 controls were analysed by a proximity extension assay including 92 inflammatory cytokines. Biopsies from caecum, sigmoid colon, and rectum were collected from the same patients. Quantitative analysis for IFN-γ, IL-2, IL-4, IL-5, IL-13, IL-17A/ E/F, IL-21, IL-22, IL-23, and IL-27 was carried out on tissue homogenates. T cell phenotype was evaluated by flow cytometry.

Results: By multivariate analysis we identified a cluster of serum cytokines with higher levels in PSC-UC, and sCD40 in particular was strongly associated with this patient group. In contrast, colonic cytokines were only modestly increased in PSC-UC, whereas several Th1-, Th2-, and Th17-associated cytokines were increased in UC. Patients with PSC-UC had increased colonic levels of CXCR3-positive CD8+ T cells but fewer CD25-positive CD4+ T cells. An increased CRTH2/CXCR3-quote indicated a predominance of Th-2 type CD4+ T cells in UC patients.

Conclusions: Our study reveals different cytokine profiles and T cell profiles in PSC-UC and UC, with higher systemic levels of cytokines in PSC-UC, and a more pronounced colonic inflammation in UC. Serum sCD40 could potentially be investigated as a marker for PSC in UC.
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http://dx.doi.org/10.1093/ecco-jcc/jjy170DOI Listing
March 2019

Downregulated eosinophil activity in ulcerative colitis with concomitant primary sclerosing cholangitis.

J Leukoc Biol 2018 07 30;104(1):173-183. Epub 2018 Mar 30.

Department of Medical Sciences, Gastroenterology Research Group, University Hospital, Uppsala, Sweden.

Primary sclerosing cholangitis (PSC) is a chronic bile duct inflammation strongly connected to ulcerative colitis (UC). PSC is associated with an increased risk of colon cancer, but the link between the intestinal and the bile duct inflammation is still unknown. Also, the involvement of intestinal immune cells in the pathogenesis of PSC remains to be determined. The eosinophil granulocyte is one of the immune cells implicated in the inflammatory process of ulcerative colitis. This study was performed to determine how the accumulation and activation of intestinal eosinophils may differ between UC with and without concomitant PSC, and how this may be influenced by the cytokine/chemokine profile of the intestinal compartment. Eosinophils from peripheral blood and multiple parts of the colon were analyzed by flow cytometry. The intestinal level of inflammatory mediators was assessed using a multiplex proximity extension assay and a quantitative immunoassay. We found that colonic eosinophils were more abundant in both UC and PSC-UC compared with controls, but that their expression of activation markers was significantly increased in UC only. The colonic level of pro-inflammatory cytokines was increased in active UC but not in PSC-UC. In conclusion, we show for the first time that eosinophil activation phenotype discriminates between UC and PSC-UC, and that this may depend on the local cytokine profile of the colonic mucosa.
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http://dx.doi.org/10.1002/JLB.3MA0517-175RDOI Listing
July 2018

Enhanced protection of the renal vascular endothelium improves early outcome in kidney transplantation: Preclinical investigations in pig and mouse.

Sci Rep 2018 03 26;8(1):5220. Epub 2018 Mar 26.

Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.

Ischemia reperfusion injury is one of the major complications responsible for delayed graft function in kidney transplantation. Applications to reduce reperfusion injury are essential due to the widespread use of kidneys from deceased organ donors where the risk for delayed graft function is especially prominent. We have recently shown that coating of inflamed or damaged endothelial cells with a unique heparin conjugate reduces thrombosis and leukocyte recruitment. In this study we evaluated the binding capacity of the heparin conjugate to cultured human endothelial cells, to kidneys from brain-dead porcine donors, and to murine kidneys during static cold storage. The heparin conjugate was able to stably bind cultured endothelial cells with high avidity, and to the renal vasculature of explanted kidneys from pigs and mice. Treatment of murine kidneys prior to transplantation reduced platelet deposition and leukocyte infiltration 24 hours post-transplantation, and significantly improved graft function. The present study thus shows the benefits of enhanced protection of the renal vasculature during cold storage, whereby increasing the antithrombotic and anti-adhesive properties of the vascular endothelium yields improved renal function early after transplantation.
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http://dx.doi.org/10.1038/s41598-018-21463-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979943PMC
March 2018

Active cytomegalovirus infection diagnosed by real-time PCR in patients with inflammatory bowel disease: a prospective, controlled observational study (.).

Scand J Gastroenterol 2016 Sep 4;51(9):1075-80. Epub 2016 May 4.

d Department of Medical Sciences, Clinical Microbiology and Infectious Medicine , Uppsala University , Uppsala , Sweden.

Objective: It is assumed that cytomegaloviral (CMV) infection in inflammatory bowel disease (IBD) is caused by reactivation due to the immunosuppressive therapy, but the role of CMV as a pathophysiological factor and prognostic marker in IBD is unclear. The aim of this study was to investigate CMV infection in IBD, with real-time polymerase chain reaction (PCR) and immunohistochemistry, with emphasis on newly diagnosed disease.

Materials And Methods: In this prospective, controlled study, 67 patients with IBD and 34 control patients with irritable bowel syndrome (IBS) or rectal bleeding were included. Serology for CMV was analysed along with CMV DNA in plasma, mucosal biopsies, and faeces. Mucosal biopsies were further analysed with histopathology and CMV immunohistochemistry.

Results: Detection of CMV IgM was more common in patients with IBD, compared to controls, 21% versus 3%. CMV DNA was found in 16% of patients with newly diagnosed, untreated IBD and in 38% of steroid-treated patients. Four of the five patients that needed urgent surgery were CMV-DNA positive in at least one of three sample types. None of the controls had detectable CMV DNA.

Conclusions: Active CMV infection was found in high proportions of newly diagnosed untreated patients with IBD, in patients on immunosuppression and in patients in the need of surgery. Low CMV-DNA levels in non-immunosuppressed patients were not a risk factor for the development of more severe IBD, while the detection of CMV DNA in patients on immunosuppressive therapy may foresee disease progression.
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http://dx.doi.org/10.3109/00365521.2016.1156154DOI Listing
September 2016

Importance of Absent Neoplastic Epithelium in Patients Treated With Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

Ann Surg Oncol 2016 Apr 17;23(4):1149-56. Epub 2015 Nov 17.

Department of Surgical Sciences, Colorectal Surgery, Uppsala University, Uppsala, Sweden.

Background: The importance of absent neoplastic epithelium in specimens from cytoreductive surgery (CRS) is unknown. This study aimed to investigate the prevalence and prognostic value of histopathology without neoplastic epithelium in patients treated with CRS and hyperthermic intraperitoneal chemotherapy (HIPEC).

Methods: Data were extracted from medical records and histopathology reports for patients treated with initial CRS and HIPEC at Uppsala University Hospital, Sweden, between 2004 and 2012. Patients with inoperable disease and patients undergoing palliative non-CRS surgery were excluded from the study. Patients lacking neoplastic epithelium in surgical specimens from CRS, with or without mucin, were classified as "neoplastic epithelium absent" (NEA), and patients with neoplastic epithelium were classified as "neoplastic epithelium present" (NEP).

Results: The study observed NEA in 78 of 353 patients (22 %). Mucin was found in 28 of the patients with NEA. For low-grade appendiceal mucinous neoplasms and adenomas, the 5-year overall survival rate was 100 % for NEA and 84 % for NEP, and the 5-year recurrence-free survival rate was 100 % for NEA and 59 % for NEP. For appendiceal/colorectal adenocarcinomas (including tumors of the small intestine), the 5-year overall survival rate was 61 % for NEA and 38 % for NEP, and the 5-year recurrence-free survival rate was 60 % for NEA and 14 % for NEP. Carcinoembryonic antigen level, peritoneal cancer index, and completeness of the cytoreduction score were lower in patients with NEA.

Conclusions: A substantial proportion of patients undergoing CRS and HIPEC have NEA. These patients have a favorable prognosis and a decreased risk of recurrence. Differences in patient selection can affect the proportion of NEA and hence explain differences in survival rates between reported series.
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http://dx.doi.org/10.1245/s10434-015-4989-yDOI Listing
April 2016

Celiac disease, collagenous sprue and microscopic colitis in IBD. Observations from a population-based cohort of IBD (ICURE).

Scand J Gastroenterol 2015 28;50(10):1234-40. Epub 2015 Apr 28.

Department of Medical Sciences, Uppsala University , Uppsala , Sweden.

Objective: Inflammatory bowel disease (IBD), microscopic colitis and celiac disease are all diseases with worldwide distribution and increased incidence has been reported from many areas. There is a shortage of studies investigating the occurrence of these diseases in the same individual and whether those affected demonstrate any particular phenotype. The aim of the study was to describe the concomitant incidence of microscopic colitis and celiac disease in a population-based IBD cohort.

Methods: All 790 individuals in a prospective population-based cohort included 2005-09 from Uppsala region, Sweden, were reviewed regarding the appearance of microscopic or celiac disease before or after IBD diagnosis.

Results: Fifty percent (396/790) of the patients had been examined for the possibility of celiac disease. Seventeen patients with celiac disease were found, representing 2.2% of the cohort. Patients with celiac disease were younger compared to the non-celiac patients and those with colitis had more often an extensive inflammation of the colon. Seventy-one percent (12/17) were women. The majority of the patients were diagnosed with celiac disease before IBD. Five patients with IBD had an earlier diagnosis of microscopic colitis or developed it after the IBD diagnosis. One teenager developed collagenous sprue, misinterpreted as a severe relapse of ulcerative colitis (UC) resulting in colectomy.

Conclusions: The risk for celiac disease seems not to be increased in IBD, but those affected by both diseases seem to be predominantly women with extensive UC. There is a potential association between microscopic colitis and IBD.
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http://dx.doi.org/10.3109/00365521.2015.1041152DOI Listing
May 2016

Phenotypic expansion of visceral myopathy associated with ACTG2 tandem base substitution.

Eur J Hum Genet 2015 Dec 18;23(12):1679-83. Epub 2015 Mar 18.

Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Biomedical Centre, Uppsala University, Uppsala, Sweden.

Familial visceral myopathy (FVM) is a rare heritable and heterogeneous condition due to impaired smooth muscle function. We identified a family segregating 11 individuals with a spectrum of visceral symptoms involving the small intestine, colon, biliary tract, urinary tract and uterus. Whole-exome sequencing revealed a novel heterozygous tandem base substitution c.806_807delinsAA (p.(Gly269Glu)) in ACTG2, encoding smooth muscle actin γ-2, in affected family members. Variants in ACTG2 were recently identified in FVM with intestinal pseudo-obstruction as well as with the congenital megacystics-microcolon-intestinal hypoperistalsis syndrome. In our family, eight affected members presented with severe complications from the biliary and/or the urinary tracts in addition to gastrointestinal pseudo-obstructions. Furthermore, all affected mothers had a history of assisted deliveries owing to poor progress during labor and weak uterine contractions. The variable involvement of multiple smooth muscle-dependent organs in our family, including the biliary tract and the uterus, add to the phenotypic spectrum associated with ACTG2 missense variants.
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http://dx.doi.org/10.1038/ejhg.2015.49DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795199PMC
December 2015

Monitoring dominant strictures in primary sclerosing cholangitis with brush cytology and FDG-PET.

J Hepatol 2014 Dec 9;61(6):1352-7. Epub 2014 Aug 9.

Gastroenterology Research Group, Department of Medical Sciences, Uppsala University Hospital, Sweden. Electronic address:

Background & Aims: Despite a high risk of cholangiocellular adenocarcinoma (CCA) it is unclear how surveillance of patients with primary sclerosing cholangitis (PSC) should be performed.

Methods: We evaluated a follow-up algorithm of brush cytology and positron emission tomography/computed tomography with [(18)F] fluorodeoxyglucose ([(18)F]FDG-PET/CT), measured as maximum standardized uptake values, normalized to the liver background (SUVmax/liver) at 180 min, in PSC patients with dominant bile duct strictures.

Results: Brush cytology with high grade dysplasia (HGD) was detected in 12/70 patients (17%), yielding a diagnostic sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 56%, 89%, 75%, and 88%, respectively. Preemptive liver transplantations due to repeated HGD before manifest CCA were performed in six patients. Receiver operating characteristic (ROC) analysis of [(18)F]FDG uptake showed that a SUVmax/liver quotient of 3.3 was able to discriminate between CCA and non-malignant disease with a sensitivity, specificity, PPV and NPV for CCA of 89%, 92%, 62%, 98%, respectively. A SUVmax/liver >3.3 detected CCA in 8/9 patients whereas a quotient <2.4 excluded CCA. Combining brush cytology and quantitative [(18)F]FDG-PET/CT yielded a sensitivity for HGD and/or CCA of 100% and a specificity of 88%.

Conclusion: Early detection of HGD before manifest CCA is feasible with repeated brush cytology and may allow for preemptive liver transplantation. [(18)F]FDG-PET/CT has a high sensitivity for manifest CCA and a negative scan indicates a non-malignant state of the disease. Brush cytology and [(18)F]FDG-PET/CT are complementary in monitoring and managing PSC patients with dominant strictures.
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http://dx.doi.org/10.1016/j.jhep.2014.07.032DOI Listing
December 2014

The human gastrointestinal tract-specific transcriptome and proteome as defined by RNA sequencing and antibody-based profiling.

J Gastroenterol 2015 Jan 1;50(1):46-57. Epub 2014 May 1.

Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjölds Väg 20, 751 85, Uppsala, Sweden,

Background: The gastrointestinal tract (GIT) is subdivided into different anatomical organs with many shared functions and characteristics, but also distinct differences. We have combined a genome-wide transcriptomics analysis with immunohistochemistry-based protein profiling to describe the gene and protein expression patterns that define the human GIT.

Methods: RNA sequencing data derived from stomach, duodenum, jejunum/ileum and colon specimens were compared to gene expression levels in 23 other normal human tissues analysed with the same method. Protein profiling based on immunohistochemistry and tissue microarrays was used to sub-localize the corresponding proteins with GIT-specific expression into sub-cellular compartments and cell types.

Results: Approximately 75% of all human protein-coding genes were expressed in at least one of the GIT tissues. Only 51 genes showed enriched expression in either one of the GIT tissues and an additional 83 genes were enriched in two or more GIT tissues. The list of GIT-enriched genes with validated protein expression patterns included various well-known but also previously uncharacterised or poorly studied genes. For instance, the colon-enriched expression of NXPE family member 1 (NXPE1) was established, while NLR family, pyrin domain-containing 6 (NLRP6) expression was primarily found in the human small intestine.

Conclusions: We have applied a genome-wide analysis based on transcriptomics and antibody-based protein profiling to identify genes that are expressed in a specific manner within the human GIT. These genes and proteins constitute important starting points for an improved understanding of the normal function and the different states of disease associated with the GIT.
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http://dx.doi.org/10.1007/s00535-014-0958-7DOI Listing
January 2015

Vanishing bile duct-like syndrome in a patient with Hodgkin lymphoma - pathological development and restitution.

Acta Oncol 2014 Sep 3;53(9):1271-5. Epub 2014 Apr 3.

Department of Oncology, Central Hospital , Karlstad , Sweden.

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http://dx.doi.org/10.3109/0284186X.2014.897001DOI Listing
September 2014

Genes regulating tight junctions and cell adhesion are altered in early experimental necrotizing enterocolitis.

J Pediatr Surg 2013 Nov;48(11):2308-12

Department of Women's and Children's Health, Division of Pediatric Surgery, Uppsala University, Sweden. Electronic address:

Background/purpose: Necrotizing enterocolitis (NEC) represents one of the gravest complications in preterm infants and carries significant morbidity and mortality. Increased intestinal permeability may play an important role in the pathogenesis of NEC. In this study we investigated the genes regulating structural proteins such as tight junctions (TJ) and cell adhesion in a neonatal rat model of early NEC.

Methods: The studies were performed on Sprague-Dawley rat pups. Experimental NEC was induced using hypoxia/re-oxygenation treatment on day 1 after birth. Intestinal specimens from the ileum were obtained, mRNA was purified, and the transcriptome was analyzed using microarray.

Results: We found several TJ genes such as claudins 1, 8, 14, 15, and gap junction protein to be affected. Alterations in genes involved in the inflammatory response was confirmed, along with several genes regulating proteins used as biomarkers for NEC.

Conclusion: This study indicates that tight junctions and cell adhesion may play a critical role in the pathogenesis of early experimental NEC. Better understanding of the pathogenesis of NEC may lead to novel strategies for the prevention and treatment of NEC.
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http://dx.doi.org/10.1016/j.jpedsurg.2013.06.027DOI Listing
November 2013

An infection-enhanced oncolytic adenovirus secreting H. pylori neutrophil-activating protein with therapeutic effects on neuroendocrine tumors.

Mol Ther 2013 Nov 2;21(11):2008-18. Epub 2013 Jul 2.

Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.

Helicobacter pylori neutrophil-activating protein (HP-NAP) is a major virulence factor involved in H. pylori infection. HP-NAP can mediate antitumor effects by recruiting neutrophils and inducing Th1-type differentiation in the tumor microenvironment. It therefore holds strong potential as a therapeutic gene. Here, we armed a replication-selective, infection-enhanced adenovirus with secretory HP-NAP, Ad5PTDf35-[Δ24-sNAP], and evaluated its therapeutic efficacy against neuroendocrine tumors. We observed that it could specifically infect and eradicate a wide range of tumor cells lines from different origin in vitro. Insertion of secretory HP-NAP did not affect the stability or replicative capacity of the virus and infected tumor cells could efficiently secrete HP-NAP. Intratumoral administration of the virus in nude mice xenografted with neuroendocrine tumors improved median survival. Evidence of biological HP-NAP activity was observed 24 hours after treatment with neutrophil infiltration in tumors and an increase of proinflammatory cytokines such as tumor necrosis factor (TNF)-α and MIP2-α in the systemic circulation. Furthermore, evidence of Th1-type immune polarization was observed as a result of increase in IL-12/23 p40 cytokine concentrations 72 hours postvirus administration. Our observations suggest that HP-NAP can serve as a potent immunomodulator in promoting antitumor immune response in the tumor microenvironment and enhance the therapeutic effect of oncolytic adenovirus.
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http://dx.doi.org/10.1038/mt.2013.153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3831034PMC
November 2013

Human enterovirus species B in ileocecal Crohn's disease.

Clin Transl Gastroenterol 2013 Jun 27;4:e38. Epub 2013 Jun 27.

Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.

Objectives: Advanced ileocecal Crohn's disease (ICD) is characterized by strictures, inflammation in the enteric nervous system (myenteric plexitis), and a high frequency of NOD2 mutations. Recent findings implicate a role of NOD2 and another CD susceptibility gene, ATG16L1, in the host response against single-stranded RNA (ssRNA) viruses. However, the role of viruses in CD is unknown. We hypothesized that human enterovirus species B (HEV-B), which are ssRNA viruses with dual tropism both for the intestinal epithelium and the nervous system, could play a role in ICD.

Methods: We used immunohistochemistry and in situ hybridization to study the general presence of HEV-B and the presence of the two HEV-B subspecies, Coxsackie B virus (CBV) and Echovirus, in ileocecal resections from 9 children with advanced, stricturing ICD and 6 patients with volvulus, and in intestinal biopsies from 15 CD patients at the time of diagnosis.

Results: All patients with ICD had disease-associated polymorphisms in NOD2 or ATG16L1. Positive staining for HEV-B was detected both in the mucosa and in myenteric nerve ganglia in all ICD patients, but in none of the volvulus patients. Expression of the cellular receptor for CBV, CAR, was detected in nerve cell ganglia.

Conclusions: The common presence of HEV-B in the mucosa and enteric nervous system of ICD patients in this small cohort is a novel finding that warrants further investigation to analyze whether HEV-B has a role in disease onset or progress. The presence of CAR in myenteric nerve cell ganglia provides a possible route of entry for CBV into the enteric nervous system.
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http://dx.doi.org/10.1038/ctg.2013.7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3696939PMC
June 2013

Microscopic colitis in Uppsala health region, a population-based prospective study 2005-2009.

Scand J Gastroenterol 2013 Jul 31;48(7):825-30. Epub 2013 May 31.

Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

Objective: The aim of this study is to report on the incidence of microscopic colitis (MC), any possible relation with inflammatory bowel disease (IBD), concomitant drug consumption, related diseases and the clinical course of the diseases.

Methods: Both new cases of IBD and MC were registered at the same time in the same geographical area. The study started in the county of Uppsala 2005-2006, and other parts of the surrounding health region were included 2007-2009. Established morphological criteria were used, i.e. a layer of subepithelial collagen band ≥ 10 μm in collagenous colitis (CC) with concomitant inflammation and at least 20 lymphocytes per 100 epithelial cells in lymphocytic colitis (LC).

Results: The authors found 272 new cases of MC, 154 with CC and 118 with LC. The mean age-adjusted incidence was 7.0/1,000,000 for CC and 4.8/100,000 for LC. The clinical course was dominated by single episodes with diarrhea or intermittent symptoms, but 14% suffered from chronic diarrhea. In 10% of the cases, diagnosis was made in individuals without chronic watery diarrhea. Although not systematically tested, concomitant celiac disease was found in approximately 5% of the patients.

Conclusions: The incidence of MC in Uppsala health region is similar to other studied areas. The majority of patients had a self-limiting or easily treated condition, but 14% need a more or less continuous medication. Ten percent of the patients demonstrate other symptoms than chronic watery diarrhea. The possibility of concomitant celiac disease should be considered in new cases of MC.
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http://dx.doi.org/10.3109/00365521.2013.800993DOI Listing
July 2013

Magnetic resonance imaging flowmetry demonstrates portal vein dilatation subsequent to oxaliplatin therapy in patients with colorectal liver metastasis.

HPB (Oxford) 2013 Apr 20;15(4):265-72. Epub 2012 Aug 20.

Department of Surgery, Uppsala University, 75185 Uppsala, Sweden.

Objectives: Sinusoidal injury (SI) after oxaliplatin-based therapies for colorectal liver metastasis (CRLM) can increase postoperative morbidity. Preoperative methods to estimate SI are lacking. The aim of this study was to identify SI by evaluating portal vein haemodynamics.

Methods: Magnetic resonance imaging flowmetry (MRIF) was used to estimate portal vein haemodynamics in 29 patients with CRLM before liver surgery. Sinusoidal injury was evaluated from resected non-tumorous liver parenchyma according to the combined vascular injury (CVI) score of ≥3.

Results: All patients with SI (six of 29) received oxaliplatin; however, a significant association could not be proven (P= 0.148). Oxaliplatin-treated patients showed portal vein dilatation in both the SI and non-SI groups compared with patients who had not received oxaliplatin (Bonferroni corrected P= 0.003 and P= 0.039, respectively). Mean portal velocity tended to be lower in patients with SI compared with oxaliplatin-treated patients without SI (Bonferroni corrected P= 0.087). A mean portal velocity of ≤14.35 cm/s together with a cross-section area of ≥1.55 cm(2) was found to predict SI with sensitivity of 100% and specificity of 78%.

Conclusions: Oxaliplatin treatment was associated with portal vein dilatation. Patients with SI showed a tendency towards decreased mean portal flow velocity. This may indicate that SI is associated with an increased resistance to blood flow in the liver parenchyma. Portal vein haemodynamic variables estimated by MRIF can identify patients without SI non-invasively.
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http://dx.doi.org/10.1111/j.1477-2574.2012.00540.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3608980PMC
April 2013

In vitro autoradiography of carcinoembryonic antigen in tissue from patients with colorectal cancer using multifunctional antibody TF2 and (67/68Ga)-labeled haptens by pretargeting.

Am J Nucl Med Mol Imaging 2012 28;2(2):141-50. Epub 2012 Mar 28.

Department of Medicinal Chemistry, Preclinical PET Platform, Uppsala University Uppsala, Sweden.

The carcinoembryonic antigen (CEA) was visualized in vitro in tissue from patients with colorectal cancer with trivalent bispecific antibody TF2 and two hapten molecules, [(67/68)Ga]Ga-IMP461 and [(67/68)Ga]Ga-IMP485 by means of pretargeting. Colorectal cancer tissue samples obtained from surgery at Uppsala University Hospital, were frozen fresh and cryosectioned. The two hapten molecules comprising 1,4,7-triazacyclononanetriacetic acid chelate moiety (NOTA) were labeled with (67)Ga or (68)Ga. The autoradiography was conducted by incubating the tissue samples with the bispecific antibody TF2, followed by washing and incubation with one of the radiolabeled hapten molecules. After washing, drying and exposure to phosphor imager plates, the autoradiograms were analyzed and compared to standard histochemistry (hematoxylin-eosin). Pronounced binding was found in the tissue from colorectal cancer using the bispecific antibody TF2 and either of the haptens [(67/68)Ga]Ga-IMP461 and [(67/68)Ga]Ga-IMP485. Distinct binding was also detected in the epithelium of most samples of neighboring tissue, taken at a minimum of 10 cm from the site of the tumor. It is concluded that pretargeting CEA with the bispecific antibody TF2 followed by the addition of (67/68)Ga-labeled hapten is extremely sensitive for visualizing this marker for colorectal cancer. This methodology is therefore a very specific complement to other histochemical techniques in the diagnosis of biopsies or in samples taken from surgery. Use of the pretargeting technique in vivo may also be an advance in diagnosing patients with colorectal cancer, either using (67)Ga and SPECT or (68)Ga and PET.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3477725PMC
November 2012

αB-Crystallin regulates expansion of CD11b⁺Gr-1⁺ immature myeloid cells during tumor progression.

FASEB J 2013 Jan 2;27(1):151-62. Epub 2012 Oct 2.

Department of Immunology, Genetics, and Pathology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

The molecular chaperone αB-crystallin has emerged as a target for cancer therapy due to its expression in human tumors and its role in regulating tumor angiogenesis. αB-crystallin also reduces neuroinflammation, but its role in other inflammatory conditions has not been investigated. Here, we examined whether αB-crystallin regulates inflammation associated with tumors and ischemia. We found that CD45(+) leukocyte infiltration is 3-fold increased in tumors and ischemic myocardium in αB-crystallin-deficient mice. Notably, αB-crystallin is prominently expressed in CD11b(+) Gr-1(+) immature myeloid cells (IMCs), known as regulators of angiogenesis and immune responses, while lymphocytes and mature granulocytes show low αB-crystallin expression. αB-Crystallin deficiency results in a 3-fold higher accumulation of CD11b(+) Gr-1(+) IMCs in tumors and a significant rise in CD11b(+) Gr-1(+) IMCs in spleen and bone marrow. Similarly, we noted a 2-fold increase in CD11b(+) Gr-1(+) IMCs in chronically inflamed livers in αB-crystallin-deficient mice. The effect of αB-crystallin on IMC accumulation is limited to pathological conditions, as CD11b(+) Gr-1(+) IMCs are not elevated in naive mice. Through ex vivo differentiation of CD11b(+) Gr-1(+) cells, we provide evidence that αB-crystallin regulates systemic expansion of IMCs through a cell-intrinsic mechanism. Our study suggests a key role of αB-crystallin in limiting expansion of CD11b(+) Gr-1(+) IMCs in diverse pathological conditions.
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http://dx.doi.org/10.1096/fj.12-213017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528311PMC
January 2013

Histopathological classification of pseudomyxoma peritonei and the prognostic importance of PINCH protein.

Anticancer Res 2012 Apr;32(4):1443-8

Department of Surgical Sciences, Section of Surgery, Uppsala University, Uppsala, Sweden.

Aim: The aims of this study were i) to assess a new and more detailed histopathological classification and to analyze concordance between pathologists in the histopathological classification of pseudomyxoma peritonei (PMP); ii) to analyze the expression in the stroma of the particularly interesting new cysteine-histidine (PINCH) protein and its prognostic importance in PMP.

Materials And Methods: Surgical specimens from 81 patients, classified according to the Ronnett et al histopathological classification were compared to a new system with four groups ranging from indolent to aggressive growth patterns. PINCH protein expression was analyzed and was related to clinical variables.

Results: The new four-group classification provided better prognostic information than the classification according to Ronnett et al. (p=0.04). Expression of the PINCH protein in the stroma was found in 83% of the cases and was associated with high tumor burden (p=0.002) and a poor prognosis (p=0.04).

Conclusion: The proposed new PMP classification system may provide additional prognostic information. PINCH protein is expressed in PMP and has prognostic information.
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April 2012

The value of pre-operative magnetic resonance spectroscopy in the assessment of steatohepatitis in patients with colorectal liver metastasis.

J Hepatol 2012 Mar 23;56(3):640-6. Epub 2011 Oct 23.

Department of Surgery, Uppsala University, Uppsala, Sweden.

Background & Aims: Neoadjuvant chemotherapy prior to liver surgery for colorectal metastases can cause marked steatosis (≥ 33%) and steatohepatitis defined by non-alcoholic fatty liver disease activity score (NAS) as adverse effects on liver parenchyma. The aim of this study was to evaluate the steatosis level prior to liver resection using proton magnetic resonance spectroscopy ((1)H MRS) and to compare it with digital quantification of steatosis (DQS) and "classical" histopathology.

Methods: (1)H MRS at 3T evaluated steatosis in 35 patients with colorectal liver metastasis, planned for liver resection. Non-tumorous liver parenchyma samples were obtained after surgery for classical histopathology and DQS utilising automated software for quantification of histopathological slides using image processing.

Results: Classical histopathology defined marked steatosis in nine patients. Histopathology was less reliable than DQS (interclass correlation coefficient - ICC 0.771) or (1)H MRS (ICC 0.722) in steatosis estimation. (1)H MRS showed very similar steatosis levels and high reliability compared to DQS (ICC 0.955). Steatohepatitis was observed in seven patients (NAS ≥ 4) and (1)H MRS was able to predict it with 100% sensitivity and 89% specificity at threshold 10.9%, without knowing lobular inflammation or hepatocyte ballooning. BMI was significantly higher in the groups with marked steatosis and steatohepatitis. Standard blood tests or chemotherapy had no predictive value.

Conclusions: (1)H MRS is a reliable non-invasive tool for steatosis assessment, and interestingly, it was able to predict steatohepatitis defined by NAS ≥ 4 in patients planned for liver resection of colorectal metastases after neoadjuvant chemotherapy.
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http://dx.doi.org/10.1016/j.jhep.2011.10.006DOI Listing
March 2012

Cancer associated epigenetic transitions identified by genome-wide histone methylation binding profiles in human colorectal cancer samples and paired normal mucosa.

BMC Cancer 2011 Oct 19;11:450. Epub 2011 Oct 19.

The Linnaeus Centre for Bioinformatics, Department of Cell and Molecular Biology, Science for Life Laboratory, Uppsala University, Sweden.

Background: Despite their well-established functional roles, histone modifications have received less attention than DNA methylation in the cancer field. In order to evaluate their importance in colorectal cancer (CRC), we generated the first genome-wide histone modification profiles in paired normal colon mucosa and tumor samples.

Methods: Chromatin immunoprecipitation and microarray hybridization (ChIP-chip) was used to identify promoters enriched for histone H3 trimethylated on lysine 4 (H3K4me3) and lysine 27 (H3K27me3) in paired normal colon mucosa and tumor samples from two CRC patients and for the CRC cell line HT29.

Results: By comparing histone modification patterns in normal mucosa and tumors, we found that alterations predicted to have major functional consequences were quite rare. Furthermore, when normal or tumor tissue samples were compared to HT29, high similarities were observed for H3K4me3. However, the differences found for H3K27me3, which is important in determining cellular identity, indicates that cell lines do not represent optimal tissue models. Finally, using public expression data, we uncovered previously unknown changes in CRC expression patterns. Genes positive for H3K4me3 in normal and/or tumor samples, which are typically already active in normal mucosa, became hyperactivated in tumors, while genes with H3K27me3 in normal and/or tumor samples and which are expressed at low levels in normal mucosa, became hypersilenced in tumors.

Conclusions: Genome wide histone modification profiles can be used to find epigenetic aberrations in genes associated with cancer. This strategy gives further insights into the epigenetic contribution to the oncogenic process and may identify new biomarkers.
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http://dx.doi.org/10.1186/1471-2407-11-450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3216894PMC
October 2011

Prompt reversal of a severe complement activation by eculizumab in a patient undergoing intentional ABO-incompatible pancreas and kidney transplantation.

Transpl Int 2011 Aug 22;24(8):e61-6. Epub 2011 Jun 22.

Section of Transplantation Surgery, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.

We describe the presumably first intentional ABO-incompatible deceased-donor kidney and pancreas transplantation with a severe antibody-mediated rejection during a rebound of isoagglutinins. Rejection was successfully treated with eculizumab, which inhibits the terminal pathway of complement. Complement analysis (C3, C3d,g, and a modified assay of classical complement-related hemolytic function) documented complement activation and confirmed that eculizumab completely blocked complement function. At 6 months, the patient had normal kidney and pancreas function, and histological evaluations revealed no evidence of sustained graft damage. This successful transplantation suggests that ABO barriers can safely be overcome without extensive preconditioning, when the complement inhibitor eculizumab is included.
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http://dx.doi.org/10.1111/j.1432-2277.2011.01290.xDOI Listing
August 2011

AdCD40L immunogene therapy for bladder carcinoma--the first phase I/IIa trial.

Clin Cancer Res 2010 Jun 4;16(12):3279-87. Epub 2010 May 4.

Division of Urology, Uppsala University, Uppsala, Sweden.

Purpose: Immunotherapy with Bacillus Calmette-Guerin (BCG) instillation is recommended for high-risk, non-muscle invasive bladder cancer. Bacillus Calmette-Guerin is not effective in advanced tumors, and better alternatives are warranted. Immunostimulating gene therapy with adenoviral vectors expressing CD40 ligand (AdCD40L) has shown efficacy in tumor models. CD40 ligand stimulates systemic immunity and may be effective in local and invasive human disease.

Experimental Design: Patients with invasive bladder cancer scheduled for cystectomy or patients with T(a) tumors were enrolled in a phase I/IIa trial. Patients were treated with three cycles of intrabladder Clorpactin WCS-90 prewash, followed by AdCD40L instillation 1 week apart. Safety, gene transfer, immune effects, and antitumor responses were monitored.

Results: All eight recruited patients were treated as scheduled, and therapy was well tolerated. The main adverse effect was transient local pain during prewash. Postoperatively, urinary tract infections and one case of late septicemia with elevated potassium were reported. No adverse events were ascribed to vector therapy. Gene transfer was detected in biopsies, and bladders were heavily infiltrated with T cells. The effector marker IFN-gamma increased in biopsies, whereas levels of circulating T regulatory cells were reduced. Histologic evaluation indicated that AdCD40L therapy reduced the load of malignant cells.

Conclusions: To our knowledge, this is the first report on immunogene therapy in bladder cancer and the first using AdCD40L in vivo. Local AdCD40L gene therapy was safe, boosted immune activation, and should be further evaluated as a single or an adjuvant therapy for urothelial malignancies.
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http://dx.doi.org/10.1158/1078-0432.CCR-10-0385DOI Listing
June 2010

Histone H3 lysine 27 trimethylation in adult differentiated colon associated to cancer DNA hypermethylation.

Epigenetics 2009 Feb 1;4(2):107-13. Epub 2009 Mar 1.

Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

DNA hypermethylation of gene promoters is a common epigenetic alteration occurring in cancer cells. However, little is known about the mechanisms instructing these cancer-specific DNA hypermethylation events. Recent reports have suggested that genes bound by polycomb/Histone H3 lysine 27 trimethylation (H3K27me3) in embryonic stem (ES) cells are frequent targets for cancer-specific DNA hypermethylation. This polycomb-premarking is assumed to be restrained to ES cells, even though almost no polycomb/H3K27me3 binding profiles are available for differentiated tissues. We generated H3K27me3 profiles in human normal colon and they significantly overlapped with those of ES cells and genes hypermethylated in colorectal cancer (CRC). Moreover, colon H3K27me3 was more restricted to genes hypermethylated in CRC, while ES H3K27me3 was also common in genes hypermethylated in other tumors. Therefore, the suggested polycomb pre-marking of genes for cancer DNA hypermethylation is not necessarily limited to ES or early precursor cells but can occur later in differentiated tissues.
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http://dx.doi.org/10.4161/epi.4.2.8038DOI Listing
February 2009

TP53 mutations predict for poor survival in de novo diffuse large B-cell lymphoma of germinal center subtype.

Leuk Res 2009 Jan 15;33(1):60-6. Epub 2008 Aug 15.

Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Uppsala, Sweden.

Presence of TP53 mutations has been associated with poor prognosis in diffuse large B-cell lymphoma (DLBCL), although this has remained controversial. The TP53 codon 72 polymorphism has shown negative impact on cancer survival, but this has not been analyzed in DLBCL. Furthermore, the MDM2 SNP309 has been associated with earlier age of onset in DLBCL. Here, we investigated the clinical impact of TP53 mutations, MDM2 SNP309 and TP53 codon 72 polymorphisms on survival in DLBCL of germinal center (GC) and non-GC subtypes. Thirteen of the 102 (12.7%) patients displayed TP53 mutations. Overall, TP53 mutations had a significant effect on lymphoma-specific survival (LSS, P=0.009) and progression-free survival (PFS, P=0.028). In particular, inferior survival was observed in TP53-mutated DLBCLs of GC subtype (LSS, P=0.002 and PFS, P=0.006). Neither MDM2 SNP309 nor the TP53 codon 72 polymorphism had an impact on age of onset or survival. Altogether, our data suggests that TP53 mutations are associated with poor outcome in GC-DLBCL patients.
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http://dx.doi.org/10.1016/j.leukres.2008.06.022DOI Listing
January 2009