Asymmetric crypt fission in colectomy specimens in patients with ulcerative colitis

2020 ◽  
pp. jclinpath-2020-206694
Author(s):  
Carlos A Rubio ◽  
Peter T Schmidt
Keyword(s):  
Ulcerative Colitis ◽  
Normal Colon ◽  
Homeostatic Mechanism ◽  
Colon Crypt ◽  
Crypt Fission ◽  
Colonic Crypts ◽  
Symmetric Fission ◽  
Mucosal Dysplasia ◽  
Asymmetric Fission ◽  
Histological Parameter

AimsWe previously found colonic crypts with asymmetric fission bordering regenerating ulcers in ulcerative colitis (UC). The present objective was to assess the frequency of asymmetric crypt-fission in colectomy specimens from patients with long-lasting UC.MethodsH&E-stained sections from seven colectomies from patients with UC without dysplasia or carcinoma were investigated. Symmetric fission was characterised by branched colon crypts showing ≥2 identical crypts, whereas asymmetric fission exhibited branched colon crypt portraying ≥2 dissimilar crypts, differing in diameter, length and/or shape.ResultsThe number of crypts in fission in the 89 sections was 3586; of those, 2930 (81.7%) were asymmetric and the remaining 656 (18.3%), symmetric. Out of 927 vertically-cut crypts (in well-oriented sections), 912 (98.4%) were asymmetric, and the remaining 14 (1.6%), symmetric, and out 2660, cross-cut (transected) crypts in fission, 2018 (75.9%) were asymmetric and the remaining 642 (24.1%), symmetric.ConclusionCrypt fission is rarely found in the normal colon in adults. Symmetric crypt fission found in UC is possibly triggered by a compensatory homeostatic mechanism of crypt production in mucosal areas replaced by chronic inflammation. But asymmetric crypt fission is a pathological aberration that affects crypts in patients with a particular predisposition to develop mucosal dysplasia. It is suggested that this previously unattended histological parameter be included in the pathological descriptions of colectomy specimens from patients with UC.

Asymmetric crypt fission in sessile serrated lesions

2020 ◽  
pp. jclinpath-2020-207008 ◽  
Author(s):  
Carlos A Rubio ◽  
Peter T Schmidt
Keyword(s):  
Somatic Mutations ◽  
Colon Mucosa ◽  
Normal Colon ◽  
Normal Colon Mucosa ◽  
Crypt Fission ◽  
Tumour Suppressor Protein ◽  
Serrated Lesions ◽  
Symmetric Fission ◽  
Proliferating Cell ◽  
Asymmetric Fission

ObjectiveSessile serrated lesions without dysplasia (SSL-ND) are epitomised by dilated crypts with epithelial serrations and architectural distortions portraying boot-shapes, L-shapes or inverted-T shapes. Recently, crypts in asymmetric fission were detected in SSL-ND. The purpose was to assess the frequency of crypts in asymmetric fission in a cohort of SSL-ND.MethodsThe frequency of crypts in fission was assessed in 60 SSL-ND, the distribution of cell proliferation in 48 SSL-ND and the expression of maspin, a tumour-suppressor protein, in 29 SSL-ND.ResultsOut of the 60 SSL-ND, 40 (66.7%) showed crypts in fission: 39 (65%) SSL-ND had crypts in asymmetric fission and one SSL-ND (1.7%), in symmetric fission (p<0.05). Of 1495 crypts recorded in the 60 SSL-ND, 73 (4.9%) were in asymmetric fission but only one (0.06%), in symmetric fission (p<0.05). Out of the 48 Ki67-immunostained SSL-ND,15 (31%) showed randomly distributed proliferating cell-domains. All 29 SSL-ND revealed maspin-upregulation (including crypts in asymmetric and symmetric fission). In contrast, the normal colon mucosa showed occasional single crypts in symmetric fission, proliferating cell-domains limited to the lower thirds of the crypts, absence of crypts in asymmetric fission and remained maspin negative.ConclusionsSSL-ND thrive with crypts in asymmetric fission displaying randomly distributed proliferating cell-domains and maspin-upregulation. These histo-biological aberrations disclose pathological cryptogenesis and suggest possibly unfolding somatic mutations in SSL-ND. The present findings may open new vistas on the parameters pertinent to the susceptibility of SSL-ND to develop dysplasia and carcinoma.

DNA content and mucosal dysplasia in ulcerative colitis

1989 ◽  
Vol 32 (12) ◽  
pp. 1055-1059 ◽  
Author(s):  
Jörgen Rutegård ◽  
Lars Åhsgren ◽  
Roger Stenling ◽  
Göran Roos
Keyword(s):  
Ulcerative Colitis ◽  
Dna Content ◽  
Mucosal Dysplasia

Enterocytes are the primary source of the chemokine ENA-78 in normal colon and ulcerative colitis

1997 ◽  
Vol 273 (1) ◽  
pp. G75-G82 ◽  
Author(s):  
S. Keates ◽  
A. C. Keates ◽  
E. Mizoguchi ◽  
A. Bhan ◽  
C. P. Kelly
Keyword(s):  
Ulcerative Colitis ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Primary Source ◽  
Fold Increase ◽  
Human Colon ◽  
Neutrophil Recruitment ◽  
Normal Colon ◽  
Necrosis Factor Alpha ◽  
Cytokine Stimulation

Epithelial cell-derived neutrophil-activating protein-78 (ENA-78) is a neutrophil-directed C-X-C chemokine. We report that Caco-2 and T84 human intestinal epithelial cells produce ENA-78 after stimulation by interleukin (IL)-1 beta or tumor necrosis factor-alpha. Caco-2 cells show increased IL-8 production at 4-12 h and increased ENA-78 production at 8-24 h after cytokine stimulation. Immunohistochemical studies in normal human colon and in ulcerative colitis demonstrate ENA-78 immunoreactivity principally associated with crypt epithelial cells. Furthermore, human colonic tissues from patients with ulcerative colitis show elevated levels of ENA-78 mRNA (24-fold increase, P < 0.01) and protein (4-fold increase, P < 0.05) compared with normal controls. Thus ENA-78 is produced in normal colon and in ulcerative colitis and is predominantly of enterocyte origin. The kinetics of ENA-78 induction in human colon epithelial cell lines are delayed and prolonged compared with IL-8. We propose that ENA-78 and IL-8 serve complementary and sequential roles in neutrophil recruitment in ulcerative colitis. ENA-78 as an enterocyte-derived, neutrophil-activating chemokine may be especially important in neutrophil recruitment from the lamina propria into the epithelial layer.

scholarly journals Somatic evolution in non-neoplastic IBD-affected colon

2019 ◽  
Author(s):  
Sigurgeir Olafsson ◽  
Rebecca E. McIntyre ◽  
Tim Coorens ◽  
Timothy Butler ◽  
Hyunchul Jung ◽  
...  
Keyword(s):  
Chronic Inflammatory Disease ◽  
Interleukin 17 ◽  
Normal Colon ◽  
Synonymous Mutations ◽  
Somatic Evolution ◽  
Colonic Crypts ◽  
Increased Risk ◽  
Inflammatory Bowel ◽  
Selection Mechanisms ◽  
Mutational Processes

Summary paragraphInflammatory bowel disease (IBD) is a chronic inflammatory disease associated with increased risk of gastrointestinal cancers. Here, we whole-genome sequenced 447 colonic crypts from 46 IBD patients, and compared these to 412 crypts from 41 non-IBD controls. The average mutation rate of affected colonic epithelial cells is 2.4-fold that of healthy colon and this increase is mostly driven by acceleration of mutational processes ubiquitously observed in normal colon. In contrast to the normal colon, where clonal expansions outside the confines of the crypt are rare, we observed widespread millimeter-scale clonal expansions. We discovered non-synonymous mutations in ARID1A, FBXW7, PIGR and ZC3H12A, and genes in the interleukin 17 and Toll-like receptor pathways, under positive selection in IBD. These results suggest distinct selection mechanisms in the colitis-affected colon and that somatic mutations potentially play a causal role in IBD pathogenesis.

scholarly journals Is histological remission of ulcerative colitis achievable?

2021 ◽  
Vol 93 (8) ◽  
pp. 975-981
Author(s):  
Oleg V. Knyazev ◽  
Anna V. Kagramanova ◽  
Sergei G. Khomeriki ◽  
Asfold I. Parfenov
Keyword(s):  
Ulcerative Colitis ◽  
Clinical Remission ◽  
Therapeutic Efficacy ◽  
Disease Recurrence ◽  
Mucosal Healing ◽  
Colon Mucosa ◽  
Normal Colon ◽  
Laboratory Markers ◽  
Important Challenge ◽  
Histological Remission

Current conception of deep remission in patients with ulcerative colitis (UC) consists of clinical remission, endoscopic mucosal healing and normalization of laboratory markers. Histological remission should not be used as a primary end point for therapeutic efficacy, but instead should be considered as a marker of deep remission. The main goal of UC treatment should be focused on endoscopic healing of colon mucosa, decrease of inflammation activity, prolonged remission, absence of disease recurrence, and also histologic remission. Nevertheless, the term histologic remission has not yet been fully validated and no histologic indexes have been standardized. We need single unified definition for remission, based on multicentral studies analysis. One of important challenge is restoration of normal colon mucosal and results of multiple studies showed contradictory tests for assessing histologic remission, thus remaining an issue for further discussion.

scholarly journals DOP50 The landscape of somatic mutations in non-neoplastic IBD-affected colon

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S088-S089
Author(s):  
S Olafsson ◽  
R E McIntyre ◽  
T Coorens ◽  
T Butler ◽  
P Robinson ◽  
...  
Keyword(s):  
Positive Selection ◽  
Somatic Mutations ◽  
Intestinal Inflammation ◽  
Base Substitution ◽  
Interleukin 17 ◽  
Clonal Structure ◽  
Normal Colon ◽  
Colonic Crypts ◽  
Mutation Burden ◽  
Chronic Intestinal Inflammation

Abstract Background Under normal physiological conditions, colonic crypts accrue ~40 somatic mutations for every year of life. That somatic mutations contribute to the development of cancer is well established, but their patterns, burden and functional consequences in diseases other than cancer have not been extensively studied and our understanding of the effects of chronic inflammation on the mutational profile and clonal structure of the colon is limited. Here, we investigated how the recurrent cycles of inflammation, ulceration and regeneration seen in IBD impact the mutational and clonal structure of intestinal epithelia. Methods We isolated and whole-genome sequenced ~400 individual colonic crypts from 46 IBD patients and compared these to ~400 crypts from 41 non-IBD controls. We compared the mutation burden, mutational signature exposure, clonal structure and cancer driver mutation landscape in crypts from actively and previously inflamed regions with crypts dissected from controls. Results We estimated the base substitution rate of affected colonic epithelial cells to be doubled after IBD onset. This change was primarily driven by acceleration of mutational processes ubiquitously observed in normal colon (Figure 1), and we did not detect an IBD-specific mutational process. In contrast to the normal colon, where clonal expansions outside the confines of the crypt are rare, we observed widespread millimetre-scale clonal expansions, even in the absence of mutations in KRAS, TP53 and APC (Figure 2). We discovered that mutations in ARID1A, PIGR and ZC3H12A, and genes in the interleukin 17 and Toll-like receptor pathways, were under positive selection in colonic crypts from IBD patients (Figure 3). With the exception of ARID1A, these genes and pathways have not been previously associated with cancer risk. A previously published mouse model of ZC3H12A suggests that LoF mutations in this gene may facilitate healing of affected mucosa without promoting tumorigenesis. This could make the encoded protein an attractive drug target. The observed enrichment of mutations in PIGR and IL17 and TLR pathways suggests that somatic mutations may initiate, maintain or perpetuate IBD pathogenesis through disruption of microbe-epithelial homeostasis. Conclusion Our results provide new insights into the consequences of chronic intestinal inflammation on the mutational profile and clonal structure of colonic epithelia. We identify the mutagens driving the increase in mutation burden and mutations which are under positive selection in the context of inflammation. Our results suggest that studying somatic mutations in the colon can reveal putative drug targets and pathogenic mechanisms for IBD.

T-antigen expression by peanut agglutinin staining relates to mucosal dysplasia in ulcerative colitis

1985 ◽  
Vol 28 (1) ◽  
pp. 11-17 ◽  
Author(s):  
Eric Pihl ◽  
Anita Peura ◽  
William R. Johnson ◽  
Francis T. McDermott ◽  
Edward S. R. Hughes
Keyword(s):  
Ulcerative Colitis ◽  
Antigen Expression ◽  
T Antigen ◽  
Peanut Agglutinin ◽  
Mucosal Dysplasia

Characterizing heterogeneity in KRAS mutant colorectal cancers (CRC) using cellular, mutation, and immune profiles.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 657-657
Author(s):  
Anguraj Sadanandam ◽  
Pawan Poudel ◽  
Elisa Fontana ◽  
Chanthirika Ragulan
Keyword(s):  
Interferon Gamma ◽  
Kras Mutation ◽  
Individual Cell ◽  
Pik3ca Mutation ◽  
Cell Types ◽  
Hypergeometric Test ◽  
Normal Colon ◽  
Pik3ca Mutations ◽  
Downstream Signaling ◽  
Colon Crypt

657 Background: Approximately 30%-50% of CRC patients have KRAS mutation, and they are associated with lack of treatment response to anti-EGFR therapy. KRAS mutant CRCs are heterogeneous that not all mutant tumors are dependent on its downstream signaling. At this era of the search for therapeutic targets related to mutant KRAS, it is essential to understand the underlying heterogeneity in KRAS mutant metastatic CRCs with a goal of identifying personalized therapeutic vulnerabilities. To understand KRAS mutation further, in this study we classified KRAS mutant CRCs based on individual cell types in the normal colon crypt and associated them with PIK3CA mutations and interferon-gamma responsive signature. Methods: Publicly available RNAseq gene expression data from KRAS mutant samples were used. Classification of CRC samples into CRCassigner subtypes, KRAS mutation dependents/independent groups, and interferon gamma-responsive status was performed using published signatures. Results: CRC samples (n>200) with KRAS mutant and wild-type statuses were classified into all the five CRCAssigner subtypes (goblet-like, enterocyte, transit-amplifying, stem-like and inflammatory) that represent individual cell types in the normal colon crypt. Interestingly, goblet-like subtype was found to be enriched for KRAS mutation. Among those KRAS mutant CRCs from all the subtypes (n=61), goblet-like samples showed significant enrichment (false discovery rate <0.05; hypergeometric test) for KRAS dependent signature, whereas stem-like subtype showed KRAS independent signature. KRAS independent stem-like CRCs showed increased PIK3CA mutation and expression of interferon-gamma responsive genes compared to dependent CRCs. Conclusions: Overall, KRAS mutant CRCs are heterogeneous with differentiated subtype highly dependent on the mutation and its signalling pathway, whereas less differentiated/stem-like subtype CRCs are independent of the mutation. Also, the enrichment of PIK3CA mutation and interferon-gamma responsive genes mainly in KRAS independent CRC subtype present a potential opportunity to target them using combination immunotherapeutics.

On the nuclear mass parameter in asymmetric fission

1977 ◽  
Vol 55 (22) ◽  
pp. 1972-1975 ◽  
Author(s):  
C. T. Trinh ◽  
R. C. Sharma
Keyword(s):  
Mass Parameter ◽  
Nuclear Fission ◽  
Nuclear Mass ◽  
Schrödinger’S Equation ◽  
Symmetric Fission ◽  
Schrödinger's Equation ◽  
Asymmetric Fission

The nuclear fission mass parameter is derived by solving Schrödinger's equation under adiabatic assumption for a pear-shaped asymmetric potential. It is also concluded that asymmetric fission proceeds faster than symmetric fission.

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