Development Of Metaplasia Research Articles

R-spondin/YAP axis promotes gastric oxyntic gland regeneration and Helicobacter pylori-associated metaplasia in mice.

The stomach corpus epithelium is organized into anatomical units that consist of glands and pits. Mechanisms that control the cellular organization of corpus glands and enable their recovery upon injury are not well understood. R-spondin 3 (RSPO3) is a WNT-signaling enhancer that regulates stem cell behavior in different organs. Here, we investigated the function of RSPO3 in the corpus during homeostasis, upon chief and/or parietal cell loss, and during chronic Helicobacter pylori infection. Using organoid culture and conditional mouse models, we demonstrate that RSPO3 is a critical driver of secretory cell differentiation in the corpus gland toward parietal and chief cells, while its absence promoted pit cell differentiation. Acute loss of chief and parietal cells induced by high dose tamoxifen - or merely the depletion of LGR5+ chief cells - caused an upregulation of RSPO3 expression, which was required for the initiation of a coordinated regenerative response via the activation of yes-associated protein (YAP) signaling. This response enabled a rapid recovery of the injured secretory gland cells. However, in the context of chronic H. pylori infection, the R-spondin-driven regeneration was maintained long term, promoting severe glandular hyperproliferation and the development of premalignant metaplasia.

Primary Adenocarcinoma at Ileostomy—A Rare Late Complication: Three Cases and Literature Review

Introduction Primary adenocarcinoma at the ileostomy site is a rare complication, with only 57 cases reported in the literature. The primary diagnosis is usually ulcerative colitis (UC) or familial adenomatous polyposis (FAP). Cases We present 3 cases of adenocarcinoma at the ileostomy site. Two of our 3 cases have a previous diagnosis of cancer, with no previous diagnosis of UC or FAP. Discussion Adenocarcinoma at ileostomy is a rare late complication of permanent ileostomy. Possible etiologies are chronic irritation and changes in bacterial flora that lead to metaplasia and cancer development. Conclusion Adenocarcinoma at the ileostomy site is a rare complication with good prognosis if detected early. Diagnosis is by biopsy, and treatment is surgical. A biopsy should be considered in any abnormal growth around the ileostomy.

Gastroduodenal injury and repair: novel targets for therapeutic intervention.

Although the mucosal barrier serves as a primary interface between the environment and host, little is understood about the repair of acute, superficial lesions or deeper, persistent lesions that if not healed, can be the site of increased permeability to luminal antigens, inflammation and/or neoplasia development. Recent studies have focused on focal adhesion kinase, which regulates controlled matrix adhesion during restitution after superficial injury. Actin polymerization regulates cell migration and the importance of actin-related proteins was also highlighted. Work on SARS-CoV-2 infection lent important new insights on gastroduodenal mucosal injury in patients with Covid-19 infection and work done with organoids and intestine-on-a-chip contributed new understanding about how coronaviruses infect gastrointestinal tissues and its resulting barrier dysfunction. A novel risk stratification paradigm was proposed to assist with decision making about repeat endoscopy for patients with gastric or duodenal ulcers and new therapeutic options were studied for ulcer disease. Lastly, work to support the mechanism of metaplasia development after deep injury and parietal cell loss was provided using novel transgenic mouse models. Recent studies highlight novel molecular targets to promote mucosal healing after injury of the gastroduodenal mucosa.

Gastric intestinal metaplasia development in African American predominant United States population.

BACKGROUNDGastric cancer significantly contributes to cancer mortality globally. Gastric intestinal metaplasia (GIM) is a stage in the Correa cascade and a premalignant lesion of gastric cancer. The natural history of GIM formation and progression over time is not fully understood. Currently, there are no clear guidelines on GIM surveillance or management in the United States.AIMTo investigate factors associated with GIM development over time in African American-predominant study population.METHODSThis is a retrospective longitudinal study in a single tertiary hospital in Washington DC. We retrieved upper esophagogastroduodenoscopies (EGDs) with gastric biopsies from the pathology department database from January 2015 to December 2020. Patients included in the study had undergone two or more EGDs with gastric biopsy. Patients with no GIM at baseline were followed up until they developed GIM or until the last available EGD. Exclusion criteria consisted of patients age < 18, pregnancy, previous diagnosis of gastric cancer, and missing data including pathology results or endoscopy reports. The study population was divided into two groups based on GIM status. Univariate and multivariate Cox regression was used to estimate the hazard induced by patient demographics, EGD findings, and Helicobacter pylori (H. pylori) status on the GIM status. RESULTSOf 2375 patients who had at least 1 EGD with gastric biopsy, 579 patients were included in the study. 138 patients developed GIM during the study follow-up period of 1087 d on average, compared to 857 d in patients without GIM (P = 0.247). The average age of GIM group was 64 years compared to 56 years in the non-GIM group (P < 0.001). In the GIM group, adding one year to the age increases the risk for GIM formation by 4% (P < 0.001). Over time, African Americans, Hispanic, and other ethnicities/races had an increased risk of GIM compared to Caucasians with a hazard ratio (HR) of 2.12 (1.16, 3.87), 2.79 (1.09, 7.13), and 3.19 (1.5, 6.76) respectively. No gender difference was observed between the study populations. Gastritis was associated with an increased risk for GIM development with an HR of 1.62 (1.07, 2.44). On the other hand, H. pylori infection did not increase the risk for GIM.CONCLUSIONAn increase in age and non-Caucasian race/ethnicity are associated with an increased risk of GIM formation. The effect of H. pylori on GIM is limited in low prevalence areas.

COPD: Perspectives of Immune Peptide Therapy and Lung Cancer Prevention

Background: Chronic obstructive pulmonary disease (COPD) occurs due to chronic inflammation, which leads to thickening of the airway walls, increased mucus production and, ultimately, permanent changes in lung structure. Meta-analysis indicates an increased risk of lung cancer in patients with COPD, so timely and comprehensive cancer prevention is extremely important. Objective: Determine the mechanisms of interaction between immune peptides and immunocompetent cells, which lead to the elimination of pathogens and prevent the development of metaplasia on the background of chronic inflammation. Methods: Selection and analysis of open access scientific publications. Results: Restoring the ability of secretory cells to synthesize IgA and maintaining this synthesis at the appropriate level can provide the necessary protection of the respiratory system from infection. Strengthening immune surveillance over the mucous membrane promotes not only the elimination of pathogens, but also to the destruction and removal of disabled and infected cells and cells that have undergone metaplasia - this is how the immunity program is implemented to counteract infection and prevent cancer. Conclusion: The use of exogenous anti-infective peptides for the treatment and prevention of exacerbations of COPD in the context of antibiotic resistance, to stimulate airway immune function and to prevent cancer is currently considered a promising area in clinical pulmonology.

Macrophage-intrinsic DUOX1 contributes to type 2 inflammation and mucus metaplasia during allergic airway disease.

The NADPH oxidase DUOX1 contributes to epithelial production of alarmins, including interleukin (IL)-33, in response to injurious triggers such as airborne protease allergens, and mediates development of mucus metaplasia and airway remodeling in chronic allergic airways diseases. DUOX1 is also expressed in non-epithelial lung cell types, including macrophages that play an important role in airway remodeling during chronic lung disease. We therefore conditionally deleted DUOX1 in either lung epithelial or monocyte/macrophage lineages to address its cell-specific actions in innate airway responses to acute airway challenge with house dust mite (HDM) allergen, and in chronic HDM-driven allergic airway inflammation. As expected, acute responses to airway challenge with HDM, as well as type 2 inflammation and related features of airway remodeling during chronic HDM-induced allergic inflammation, were largely driven by DUOX1 with the respiratory epithelium. However, in the context of chronic HDM-driven inflammation, DUOX1 deletion in macrophages also significantly impaired type 2 cytokine production and indices of mucus metaplasia. Further studies revealed a contribution of macrophage-intrinsic DUOX1 in macrophage recruitment upon chronic HDM challenge, as well as features of macrophage activation that impact on type 2 inflammation and remodeling.

SLC26A9 deficiency causes gastric intraepithelial neoplasia in mice and aggressive gastric cancer in humans

BackgroundSolute carrier family 26 member (SLC26A9) is a Cl− uniporter with very high expression levels in the gastric mucosa. Here, we describe morphological and molecular alterations in gastric mucosa of slc26a9−/− mice and in selective parietal cell-deleted slc26a9fl/fl/Atp4b-Cre mice and correlate SLC26A9 expression levels with morphological and clinical parameters in a cohort of gastric cancer (GC) patients.MethodsThe expression patterns of genes related to transport and enzymatic function, proliferation, apoptosis, inflammation, barrier integrity, metaplasia and neoplasia development were studied by immunohistochemistry (IHC), quantitative RT-PCR, in situ hybridization and RNA microarray analysis. SLC26A9 expression and cellular/clinical phenotypes were studied in primary human GC tissues and GC cell lines.ResultsWe found that both complete and parietal cell-selective Slc26a9 deletion in mice caused spontaneous development of gastric premalignant and malignant lesions. Dysregulated differentiation of gastric stem cells in an inflammatory environment, activated Wnt signaling, cellular hyperproliferation, apoptosis inhibition and metaplasia were observed. Analysis of human gastric precancerous and cancerous tissues revealed that SLC26A9 expression progressively decreased from atrophic gastritis to GC, and that downregulation of SLC26A9 was correlated with patient survival. Exogenous expression of SLC26A9 in GC cells induced upregulation of the Cl−/HCO3− exchanger AE2, G2/M cell cycle arrest and apoptosis and suppressed their proliferation, migration and invasion.ConclusionsOur data indicate that SLC26A9 deletion in parietal cells is sufficient to trigger gastric metaplasia and the development of neoplastic lesions. In addition, we found that SLC26A9 expression decreases during human gastric carcinogenesis, and that exogenous SLC26A9 expression in GC cells reduces their malignant behavior.Graphical abstract

Insight into preventive effects of anti-oxidative carbon monoxide (CO) against the chronic inflammation-induced esophageal metaplasia development and progression

Insight into preventive effects of anti-oxidative carbon monoxide (CO) against the chronic inflammation-induced esophageal metaplasia development and progression

IL13 Acts Directly on Gastric Epithelial Cells to Promote Metaplasia Development During Chronic Gastritis.

Background & AimsIt is well established that chronic inflammation promotes gastric cancer–associated metaplasia, but little is known regarding the mechanisms by which immune cells and cytokines regulate metaplastic cellular changes. The goals of this study were to identify interleukin 13 (IL13)-producing immune cells, determine the gastric epithelial cell response(s) to IL13, and establish the role(s) of IL13 in metaplasia development.MethodsExperiments used an established mouse model of autoimmune gastritis (TxA23), TxA23×Il4ra-/- mice, which develop gastritis but do not express the IL4/IL13-receptor subunit IL4Rα, and TxA23×Il13-Yfp mice, which express yellow fluorescent protein in IL13-producing cells. Flow cytometry was used to measure IL13 secretion and identify IL13-producing immune cells. Mouse and human gastric organoids were cultured with IL13 to determine epithelial cell response(s) to IL13. Single-cell RNA sequencing was performed on gastric epithelial cells from healthy and inflamed mouse stomachs. Mice with gastritis were administered IL13-neutralizing antibodies and stomachs were analyzed by histopathology and immunofluorescence.ResultsWe identified 6 unique subsets of IL13-producing immune cells in the inflamed stomach. Organoid cultures showed that IL13 acts directly on gastric epithelium to induce a metaplastic phenotype. IL4Rα-deficient mice did not progress to metaplasia. Single-cell RNA sequencing determined that gastric epithelial cells from IL4Rα-deficient mice up-regulated inflammatory genes but failed to up-regulate metaplasia-associated transcripts. Neutralization of IL13 significantly reduced and reversed metaplasia development in mice with gastritis.ConclusionsIL13 is made by a variety of immune cell subsets during chronic gastritis and promotes gastric cancer–associated metaplastic epithelial cell changes. Neutralization of IL13 reduces metaplasia severity during chronic gastritis.

Chief cell plasticity is the origin of metaplasia following acute injury in the stomach mucosa

ObjectiveMetaplasia arises from differentiated cell types in response to injury and is considered a precursor in many cancers. Heterogeneous cell lineages are present in the reparative metaplastic mucosa with response...

Multi-omics of the esophageal microenvironment identifies signatures associated with progression of Barrett\u2019s esophagus

BackgroundThe enrichment of Gram-negative bacteria of oral origin in the esophageal microbiome has been associated with the development of metaplasia. However, to date, no study has comprehensively assessed the relationships between the esophageal microbiome and the host.MethodsHere, we examine the esophageal microenvironment in gastro-esophageal reflux disease and metaplasia using multi-omics strategies targeting the microbiome and host transcriptome, followed by targeted culture, comparative genomics, and host-microbial interaction studies of bacterial signatures of interest.ResultsProfiling of the host transcriptome from esophageal mucosal biopsies revealed profound changes during metaplasia. Importantly, five biomarkers showed consistent longitudinal changes with disease progression from reflux disease to metaplasia. We showed for the first time that the esophageal microbiome is distinct from the salivary microbiome and the enrichment of Campylobacter species as a consistent signature in disease across two independent cohorts. Shape fitting and matrix correlation identified associations between the microbiome and host transcriptome profiles, with a novel co-exclusion relationship found between Campylobacter and napsin B aspartic peptidase. Targeted culture of Campylobacter species from the same cohort revealed a subset of isolates to have a higher capacity to survive within primary human macrophages. Comparative genomic analyses showed these isolates could be differentiated by specific genomic features, one of which was validated to be associated with intracellular fitness. Screening for these Campylobacter strain-specific signatures in shotgun metagenomics data from another cohort showed an increase in prevalence with disease progression. Comparative transcriptomic analyses of primary esophageal epithelial cells exposed to the Campylobacter isolates revealed expression changes within those infected with strains with high intracellular fitness that could explain the increased likelihood of disease progression.ConclusionsWe provide a comprehensive assessment of the esophageal microenvironment, identifying bacterial strain-specific signatures with high relevance to progression of metaplasia.

IL-4 and IL-13 act on immune and epithelial cells to promote gastric metaplasia during autoimmune gastritis

Abstract Chronic inflammation in the stomach can lead to peptic ulcers and is the highest independent risk factor for developing gastric cancer. Autoimmune gastritis (AIG) and infection with Helicobacter pylori are the two major causes of chronic gastritis. Cytokines released during chronic inflammation likely regulate the degree of tissue damage and the emergence of metaplasia, a precancerous condition believed to be the origin of gastric cancer. We recently discovered that mice with AIG that lack a receptor for IL-4/IL-13 (Il4ra−/−) developed mild gastritis but failed to develop gastric metaplasia. The objective of this study was to determine how IL-4 and/or IL-13 regulate disease development and severity. Immune assays revealed that autoantibody titers were high in control mice with AIG yet were nearly absent in Il4ra−/− mice with AIG. Epithelial cell assays revealed that both IL-4 and IL-13 also act on the gastric epithelium to promote growth and induce transcriptional changes associated with metaplasia. Finally, neutralizing antibodies to IL-4 and IL-13 were effective at ameliorating disease and preventing gastric metaplasia in mice with AIG. Together these data demonstrate that IL-4 and IL-13 play critical and complex roles in exacerbating gastric disease severity and metaplasia development by increasing production of tissue-damaging autoantibodies and inducing gastric metaplasia. These novel findings identify IL-4 and IL-13 as potential therapeutic targets for treatment of diseases induced by chronic gastritis.

Notch signaling drives development of Barrett\u2019s metaplasia from Dclk1-positive epithelial tuft cells in the murine gastric mucosa

Barrett’s esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC), but its cellular origin and mechanism of neoplastic progression remain unresolved. Notch signaling, which plays a key role in regulating intestinal stem cell maintenance, has been implicated in a number of cancers. The kinase Dclk1 labels epithelial post-mitotic tuft cells at the squamo-columnar junction (SCJ), and has also been proposed to contribute to epithelial tumor growth. Here, we find that genetic activation of intracellular Notch signaling in epithelial Dclk1-positive tuft cells resulted in the accelerated development of metaplasia and dysplasia in a mouse model of BE (pL2.Dclk1.N2IC mice). In contrast, genetic ablation of Notch receptor 2 in Dclk1-positive cells delayed BE progression (pL2.Dclk1.N2fl mice), and led to increased secretory cell differentiation. The accelerated BE progression in pL2.Dclk1.N2IC mice correlated with changes to the transcriptomic landscape, most notably for the activation of oncogenic, proliferative pathways in BE tissues, in contrast to upregulated Wnt signalling in pL2.Dclk1.N2fl mice. Collectively, our data show that Notch activation in Dclk1-positive tuft cells in the gastric cardia can contribute to BE development.

Analysis of the prevalence of Helicobacter pylori infection and the effectiveness of eradication schemes in patients with the upper gastrointestinal tract disorders (according to the results of 13C-urea breath tests for 2006–2019)

IntroductionThe problem of Helicobacter pylori is relevant due to the high frequency of stomach and duodenum erosions and ulcers, as well as the possible development of metaplasia and gastric cancer. Therefore, it is especially important to study the dynamics of H. pylori infection and monitor the effectiveness of eradication schemes in different regions of Ukraine.AimTo study the dynamics of H. pylori infection and to evaluate the effectiveness of H. pylori eradication schemes in patients with upper gastrointestinal tract disorders – residents of the Vinnytsia region.Material and methodsWe retrospectively analysed 2205 results of 13C-urea breath tests, performed during 2006–2019 in the National Pirogov Memorial Medical University, Vinnytsya on an infrared analyser.ResultsIt was found that patients with upper gastrointestinal tract disorders since 2009 had significantly reduced primary H. pylori infection. Among the schemes designed according to the Maastricht recommendations, the most effective were as follows: proton pump inhibitor (PPI) + clarithromycin (Clar) + amoxicillin (Amox) – 81.6%, PPI + Clar + Amox + bismuth subcitrate (Bi) – 87%, and PPI + tetracycline (TC) + metronidazole derivatives (MNZ) + Bi – 83.9%. The lowest efficiency was recorded for the scheme PPI + Clar + MNZ, at 68.1%.ConclusionsDespite the gradual decrease in H. pylori infection in the general population, its prevalence remains quite high among the elderly. This dictates that a thorough examination be carried out for patients with disorders of the upper G.I. tract to detect the presence of H. pylori infection, and if infection is detected, the correct selection of eradication therapy.

COPD: Perspectives of Immune Peptide Therapy and Lung Cancer Prevention

Background: Chronic obstructive pulmonary disease (COPD) occurs due to chronic inflammation, which leads to thickening of the airway walls, increased mucus production and, ultimately, permanent changes in lung structure. Meta-analysis indicates an increased risk of lung cancer in patients with COPD, so timely and comprehensive cancer prevention is extremely important. Objective: Determine the mechanisms of interaction between immune peptides and immunocompetent cells, which lead to the elimination of pathogens and prevent the development of metaplasia on the background of chronic inflammation. Methods: Selection and analysis of open access scientific publications. Results: Restoring the ability of secretory cells to synthesize IgA and maintaining this synthesis at the appropriate level can provide the necessary protection of the respiratory system from infection. Strengthening immune surveillance over the mucous membrane promotes not only the elimination of pathogens, but also to the destruction and removal of disabled and infected cells and cells that have undergone metaplasia - this is how the immunity program is implemented to counteract infection and prevent cancer. Conclusion: The use of exogenous anti-infective peptides for the treatment and prevention of exacerbations of COPD in the context of antibiotic resistance, to stimulate airway immune function and to prevent cancer is currently considered a promising area in clinical pulmonology.

Dysregulated Immune Responses by ASK1 Deficiency Alter Epithelial Progenitor Cell Fate and Accelerate Metaplasia Development during H. pylori Infection.

The mechanism of H. pylori-induced atrophy and metaplasia has not been fully understood. Here, we demonstrate the novel role of Apoptosis signal-regulating kinase 1 (ASK1) and downstream MAPKs as a regulator of host immune responses and epithelial maintenance against H. pylori infection. ASK1 gene deficiency resulted in enhanced inflammation with numerous inflammatory cells including Gr-1+CD11b+ myeloid-derived suppressor cells (MDSCs) recruited into the infected stomach. Increase of IL-1β release from apoptotic macrophages and enhancement of TH1-polarized immune responses caused STAT1 and NF-κB activation in epithelial cells in ASK1 knockout mice. Dysregulated immune and epithelial activation in ASK1 knockout mice led to dramatic expansion of gastric progenitor cells and massive metaplasia development. Bone marrow transplantation experiments revealed that ASK1 in inflammatory cells is critical for inducing immune disorder and metaplastic changes in epithelium, while ASK1 in epithelial cells regulates cell proliferation in stem/progenitor zone without changes in inflammation and differentiation. These results suggest that H. pylori-induced immune cells may regulate epithelial homeostasis and cell fate as an inflammatory niche via ASK1 signaling.

Evaluation of the chemopreventive potentials of ezetimibe and aspirin in a novel mouse model of gallbladder preneoplasia.

Gallbladder stones (cholecystolithiasis) are the main risk factor for gallbladder cancer (GBC), a lethal biliary malignancy with poor survival rates worldwide. Gallbladder stones are thought to damage the gallbladder epithelium and trigger chronic inflammation. Preneoplastic lesions that arise in such an inflammatory microenvironment can eventually develop into invasive carcinoma, through mechanisms that are not fully understood. Here, we developed a novel gallbladder preneoplasia mouse model through the administration of two lithogenic diets (a low- or a high-cholesterol diet) in wild-type C57BL/6 mice over a period of 9months. Additionally, we evaluated the chemopreventive potentials of the anti-inflammatory drug aspirin and the cholesterol absorption inhibitor ezetimibe. Both lithogenic diets induced early formation of gallbladder stones, together with extensive inflammatory changes and widespread induction of metaplasia, an epithelial adaptation to tissue injury. Dysplastic lesions were presented only in mice fed with high-cholesterol diet (62.5%) in late stages (9th month), and no invasive carcinoma was observed at any stage. The cholesterol absorption inhibitor ezetimibe inhibited gallbladder stone formation and completely prevented the onset of metaplasia and dysplasia in both lithogenic diets, whereas aspirin partially reduced metaplasia development only in the low-cholesterol diet setting. This model recapitulates several of the structural and inflammatory findings observed in human cholecystolithiasic gallbladders, making it relevant for the study of gallbladder carcinogenesis. In addition, our results suggest that the use of cholesterol absorption inhibitors and anti-inflammatory drugs can be evaluated as chemopreventive strategies to reduce the burden of GBC among high-risk populations.

Group 2 Innate Lymphoid Cells Coordinate Damage Response in the Stomach

Severe injury to the lining of the stomach leads to changes in the epithelium (reprogramming) that protect and promote repair of the tissue, including development of spasmolytic polypeptide-expressing metaplasia (SPEM) and tuft and foveolar cell hyperplasia. Acute gastric damage elicits a type-2 inflammatory response that includes production of type-2 cytokines and infiltration by eosinophils and alternatively activated macrophages. Stomachs of mice that lack interleukin 33 (IL33) or interleukin 13 (IL13) did not undergo epithelial reprogramming after drug-induced injury. We investigated the role of group 2 innate lymphoid cells (ILC2s) in gastric epithelial repair. Acute gastric injury was induced in C57BL/6J mice (wild-type and RAG1 knockout) by administration of L635. We isolated ILC2s by flow cytometry from stomachs of mice that were and were not given L635 and performed single-cell RNA sequencing. ILC2s were depleted from wild-type and RAG1-knockout mice by administration of anti-CD90.2. We assessed gastric cell lineages, markers of metaplasia, inflammation, and proliferation. Gastric tissue microarrays from patients with gastric adenocarcinoma were analyzed by immunostaining. There was a significant increase in the number of GATA3-positive ILC2s in stomach tissues from wild-type mice after L635-induced damage, but not in stomach tissues from IL33-knockout mice. We characterized a marker signature of gastric mucosal ILC2s and identified a transcription profile of metaplasia-associated ILC2s, which included changes in expression of Il5, Il13, Csf2, Pd1, and Ramp3; these changes were validated by quantitative polymerase chain reaction and immunocytochemistry. Depletion of ILC2s from mice blocked development of metaplasia after L635-induced injury in wild-type and RAG1-knockout mice and prevented foveolar and tuft cell hyperplasia and infiltration or activation of macrophages after injury. Numbers of ILC2s were increased in stomach tissues from patients with SPEM compared with patients with normal corpus mucosa. In analyses of stomach tissues from mice with gastric tissue damage and patients with SPEM, we found evidence of type 2 inflammation and increased numbers of ILC2s. Our results suggest that ILC2s coordinate the metaplastic response to severe gastric injury.

Helicobacter pylori-related precancerous lesions in Turkey: a retrospective endoscopic surveillance study

AimTo assess the relationship between Helicobacter pylori (H. pylori) infection and atrophic gastritis (AG) and intestinal metaplasia (IM) development and to assess the rate of dysplasia or gastric cancer development in patients with AG and/or IM.MethodsThis retrospective endoscopic follow-up study enrolled 2214 patients. The patients were followed for at least five years between 2007 and 2017 at the Department of Endoscopy at Antalya Ataturk Government Hospital. The results of third-year and five-year surveillance biopsy were assessed.ResultsThe mean follow-up time was 7.77 ± 2.78 years. H. pylori was histologically assessed in 1417 (64.6%) patients. Of 198 patients with severe H. pylori infection, 32 (16%) and 139 (70.3%) developed extensive AG and extensive IM, respectively. There was a significant relationship between H. pylori density and AG and IM degrees. High grade dysplasia, early gastric cancer, and advanced gastric cancer were diagnosed in 73 patients with median age 58.2 (28-80) years, and the incidence rate was 3.29% (73/2214). The annual incidence of gastric neoplastic lesions was 0.46% in total, 0.08% for early GC, and 0.02% for advanced gastric cancer.ConclusionsH. pylori infection has an important role in the development of AG and IM. H. pylori density is directly related to atrophy and metaplasia degree.

Switches of SOX17 and SOX2 expression in the development of squamous metaplasia and squamous intraepithelial lesions of the uterine cervix.

AimsThe dynamics and topographical distribution of SOX17 and SOX2 expression was studied in the transformation zone (TZ) of the uterine cervix. This TZ is a dynamic area where switches from glandular into squamous epithelium can be recognized, new squamocolumnar junctions are formed, and premalignant lesions originate. SOX17 and SOX2 show mutually exclusive expression patterns in the normal uterine cervix, with SOX2 being exclusively found in squamous epithelium, while SOX17 is detected in endocervical columnar cells and reserve cells.Methods and ResultsNormal cervices and squamous intraepithelial lesions (SIL) were studied with immunohistochemistry, methylation of SOX17, human papilloma virus (HPV) genotyping, and in situ hybridization. In the TZ squamous metaplasia originating from these reserve cells can still show SOX17 expression, while also remnants of SOX17‐positive immature metaplasia can be recognized in the normal squamous epithelium. SOX17 expression is gradually lost during maturation, resulting in the exclusive expression of SOX2 in the majority of (SIL). This loss of SOX17 expression is independent of methylation of the CpG island in its promotor region. HPV can be detected in SOX17‐positive immature metaplastic regions in the immediate vicinity of SOX2‐positive SIL, suggesting that switches in SOX17 and 2 expression can occur upon HPV infection.ConclusionsThis switch in expression, and the strong association between the distribution of reserve cells and squamous areas within the columnar epithelium in the TZ, suggests that reserve cell proliferations, next to basal cells in the squamous epithelium, are potential targets for the formation of squamous lesions upon viral infection.