Intestinal Dysplasia Research Articles

Cyclomodulins-harboring Escherichia coli isolated from obese and normal-weight subjects induces intestinal dysplasia in a mouse model.

Recently, cyclomodulins have been identified in Escherichia coli (E. coli), which can induce dysplastic damage. This work aimed to determine the dysplastic activity of cyclomodulin-harboring E. coli isolated from CRC patients, obese and normal-weight subjects in a mouse model. Forty-two mice were pretreated with streptomycin, azoxymethane, and dextran sodium sulfate. Mice were infected with E. coli pks + isolated from a CRC patient, with E. coli pks + cif + isolated from obese or normal-weight subjects, or with E. coli HB101. The presence of cyclomodulin-harboring E. coli in the feces, weight loss, changes in fecal consistency, and the presence of blood in the feces were monitored and used to assess the disease activity index (DAI). After 62 days, the mice were sacrificed to evaluate the presence of intestinal polyps and dysplastic damage by histologic sections. Cyclomodulin-harboring E. coli colonized the mice; these mice exhibited weight loss and watery diarrhea, and isolated normal-weight E. coli had a higher DAI. Polyps were observed in mice infected with cyclomodulin-harboring E. coli in the ileum but to a greater extent in obese isolates. E. coli isolated from CRC showed more significant endothelial damage associated with dysplasia in the ileum in equal proportions from obese and normal-weight isolates. In conclusion, E. coli harboring cyclomodulins isolated from CRC, obesity, or normal weight can cause dysplastic damage in the ileum of mice and may be a risk factor for CRC development.

Altering Trends in Pathological Spectrum of Cholecystectomy Specimen: Time to be More Vigilant

Abstract Background: Gall bladder cancer is a rare, most common and aggressive malignancy of the biliary tree, accounting for 80%–90% of biliary tract cancers. Gallstones are one of the major causes of the development of cholecystitis and long-term malignancy in developing countries. Cholecystectomy specimens have a great value in documenting various entities with clinical significance. Early detection is the most important step in improving the prognosis of gall bladder carcinoma (GBC) screening. Aim: Clinico- pathological spectrum of cholecystectomy specimen and Incidence of malignancy and its precursor lesion with gallstones. Patient and Methods: We conducted a retrospective analysis of all gall bladder specimens (cholecystectomy, laparoscopic, open or radical) from the period of January 2019–January 2022, including demographic data of the patients such as age and sex. Additional findings, such as the presence of gallstones, cholesterolosis, gastric or intestinal metaplasia, dysplasia and histopathological type of GBC, were documented. Results: A total of 1221 gall bladder specimens were received, with a higher female preponderance and a female-to-male ratio of 2.6:1. The mean age of presentation was 45 years. The most common histopathological diagnosis made was chronic cholecystitis (97%), and malignant cases accounted for 3% of the total cases. Conclusions: The high propensity of GBC with non-cholelithiasis cases, more than half of cases with metaplasia and increased incidence of adenosquamous carcinoma indicate a high burden of tumours, alerting the clinician as well as the pathologist.

Bromodomain containing 4 inhibition combats gastric precancerous lesions via modulating macrophage polarization

ObjectiveGastric precancerous lesions (GPL), characterized by intestinal metaplasia and dysplasia, marks a pivotal juncture in the transformation from gastritis to gastric cancer. Research on GPL could offer fresh perspectives on preventing cancer occurrence. MethodsThis study employed 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) to establish GPL rat models and knocked BRD4 down in vivo to assess its impact on the lesions and macrophage morphology. Following that, the impacts of BRD4 knockdown on the malignant phenotypes of human gastric epithelial GES-1 cells were determined. Moreover, conditioned medium from macrophage was gathered and used for GES-1 cell culture. The involvement of macrophage polarization in the BRD4 regulatory mechanism in GES-1 cells was assessed. ResultsThis study elucidated that MNNG induced an increase level of BRD4 in the rat models. BRD4 knockdown reduced lesions based on pathological sections and immunohistochemistry to detect proliferative antigens. Western blotting and immunofluorescence showed that BRD4 knockdown suppressed epithelial-mesenchymal transition and macrophage M2 polarization. In in vitro experiments, BRD4 knockdown inhibited the malignant phenotype of GES-1 cells and the differentiation of THP-1 cells into M2 macrophages, respectively. The conditioned medium from M2 macrophages with BRD4 knockdown was co-incubated with GES-1 cells, which attenuated the malignant phenotypes compared with the medium from M2 macrophages. ConclusionThrough in vivo and in vitro experiments, BRD4 upregulation was found to already occur during GPL, affecting macrophage polarization and epithelial cell cancerization. This finding provides an experimental basis for strategies targeting BRD4 inhibition at this critical stage.

The molecular profile of gastric intraepithelial foveolar type neoplasia based on somatic copy number alterations and multiple mutation analysis

BackgroundGastric foveolar type neoplasia is a rare histological variant of gastric tumors. It is very difficult to differentiate between benign and malignant intraepithelial foveolar neoplasia (IFN). Although limited molecular alterations have been identified in IFNs, somatic copy number alterations (SCNAs), which are linked to tumor progression, have not been systematically evaluated in IFN.MethodsThe aim of the present study was to comprehensively examine SCNAs using a SNP array in 37 cases of IFN, compared with intestinal type dysplasia, including 39 low grade (LGD) and 32 high grade dysplasia (HGD) cases. In addition, gene mutations were evaluated using a gene panel. Finally, we attempted to determine molecular profiles using a hierarchical clustering analysis.ResultsTwo patterns could be categorized according to the SCNAs in 108 tumors examined: high (subgroup 1) and low (subgroup 2) frequencies of SCNAs. Although IFN and LGD were associated with subgroup 2, HGD was found in both subgroups. The median numbers of total SCNAs and copy number gains were higher in IFN or HGD than in LGD. In addition, the IFN genotype was characterized by altered genes located at 4p13–4q35.2, including RAP1GDS1 and LEF1, which may be associated with IFN development. Finally, no significant mutations were found in IFNs using a gene panel.ConclusionsThe current molecular profiles of IFN may help elucidate the mechanisms of IFN development.

Yiqi Jiedu Huayu decoction inhibits precancerous lesions of chronic atrophic gastritis by inhibiting NLRP3 inflammasome-mediated pyroptosis.

Chronic atrophic gastritis (CAG) is a prevalent chronic gastritis usually accompanied by precancerous lesions such as intestinal metaplasia and dysplasia. The increasing application of traditional Chinese medicine in CAG treatment has shown promising results with low side effects and significant efficacy. To investigate the pharmacological effects of Yiqi Jiedu Huayu decoction (YJHD) on precancerous lesions of CAG. A CAG rat model was established by Helicobacter pylori bacteria solution combined with N-methyl-N'-nitro-N-nitrosoguanidine. Histopathological measurements were conducted by hematoxylin-eosin and alcian blue and periodic acid-Schiff staining. Serum levels of inflammatory factors and gastric mucosal-related factors were examined using enzyme-linked immunosorbent assay. Protein and mRNA levels were quantified via western blot and quantitative real-time polymerase chain reaction analysis, respectively. Molecular interaction was verified by chromatin immunoprecipitation (ChIP) assay. YJHD greatly attenuated pathological changes in the gastric mucosa and precancerous lesions in CAG rats. Meanwhile, YJHD treatment reduced serum levels of inflammatory factors [interleukin (IL)-6, tumor necrosis factor-α and C-reactive protein] and increased serum levels of gastric mucosal-related factors (gastrin, pepsin, somatostatin and prostaglandin E2) in CAG rats. In addition, YJHD administration suppressed NLRP3 inflammasome-mediated cell pyroptosis, as well as the activation of TLR4/NF-κB and IL-6/STAT3 signaling pathways. Mechanically, ChIP experiments confirmed that NLRP3 transcription was regulated by TLR4/NF-κB and IL-6/STAT3 signaling. Taken together, YJHD alleviated NLRP3 inflammasome formation and pyroptosis of epithelial cells in CAG, potentially through the inactivation of TLR4/NF-κB and IL-6/STAT3 pathways.

The Goblet Cell: Is It Needed for a Diagnosis of Barrett’s Esophagus and Does It Impact Surveillance and Treatment?—CON

Esophageal intestinal metaplasia generally is required for a diagnosis of Barrett’s esophagus (BE) and, in clinical practice, that intestinal metaplasia is identified by the presence of goblet cells. However, if BE is defined conceptually as an esophageal metaplasia that predisposes to adenocarcinoma, then the goblet cell becomes a very imperfect marker for that condition. False-positive diagnoses of BE can result from failure to distinguish true goblet cells from pseudogoblet cells, and false-negative diagnoses can result from inadequate biopsy sampling that misses goblet cells, which often are patchy in distribution. Furthermore, evidence is accumulating that there is a gastric foveolar pathway to esophageal adenocarcinoma that can occur in the absence of goblet cells, and that might be even more common and more aggressive than the familiar intestinal dysplasia pathway.

Viral infection disrupts intestinal homeostasis via Sting-dependent NF-κB signaling in Drosophila

Host-microbe interactions influence intestinal stem cell (ISC) activity to modulate epithelial turnover and composition. Here, we investigated the functional impacts of viral infection on intestinal homeostasis and the mechanisms by which viral infection alters ISC activity. We report that Drosophila A virus (DAV) infection disrupts intestinal homeostasis in Drosophila by inducing sustained ISC proliferation, resulting in intestinal dysplasia, loss of gut barrier function, and reduced lifespan. We found that additional viruses common in laboratory-reared Drosophila also promote ISC proliferation. The mechanism of DAV-induced ISC proliferation involves progenitor-autonomous epidermal growth factor receptor (EGFR) signaling, c-Jun N-terminal kinase (JNK) activity in enterocytes, and requires Sting-dependent nuclear factor κB (NF-κB) (Relish) activity. We further demonstrate that activating Sting-Relish signaling is sufficient to induce ISC proliferation, promote intestinal dysplasia, and reduce lifespan in the absence of infection. Our results reveal that viral infection can significantly disrupt intestinal physiology, highlight a novel role for Sting-Relish signaling, and support a role for viral infection in aging.

Trained Immunity and Trained Tolerance: The Case of Helicobacter pylori Infection.

Trained immunity is a concept in immunology in which innate immune cells, such as monocytes and macrophages, exhibit enhanced responsiveness and memory-like characteristics following initial contact with a pathogenic stimulus that may promote a more effective immune defense following subsequent contact with the same pathogen. Helicobacter pylori, a bacterium that colonizes the stomach lining, is etiologically associated with various gastrointestinal diseases, including gastritis, peptic ulcer, gastric adenocarcinoma, MALT lymphoma, and extra gastric disorders. It has been demonstrated that repeated exposure to H. pylori can induce trained immunity in the innate immune cells of the gastric mucosa, which become more responsive and better able to respond to subsequent H. pylori infections. However, interactions between H. pylori and trained immunity are intricate and produce both beneficial and detrimental effects. H. pylori infection is characterized histologically as the presence of both an acute and chronic inflammatory response called acute-on-chronic inflammation, or gastritis. The clinical outcomes of ongoing inflammation include intestinal metaplasia, gastric atrophy, and dysplasia. These same mechanisms may also reduce immunotolerance and trigger autoimmune pathologies in the host. This review focuses on the relationship between trained immunity and H. pylori and underscores the dynamic interplay between the immune system and the pathogen in the context of gastric colonization and inflammation.

Pathogenesis and potential reversibility of intestinal metaplasia - a milestone in gastric carcinogenesis.

Non-cardia gastric cancer remains a major cause of cancer-related mortality worldwide, despite declining incidence rates in many industrialized countries. The development of intestinal-type gastric cancer occurs through a multistep process in which normal mucosa is sequentially transformed into hyperproliferative epithelium, followed by metaplastic processes leading to carcinogenesis. Chronic infection with Helicobacter pylori is the primary etiological agent that causes chronic inflammation of the gastric mucosa, induces atrophic gastritis, and can lead to intestinal metaplasia and dysplasia. Both intestinal metaplasia and dysplasia are precancerous lesions, in which gastric cancer is more likely to occur. Atrophic gastritis often improves after eradication of Helicobacter pylori; however, the occurrence of intestinal metaplasia has been traditionally regarded as "the point of no return" in the carcinogenesis sequence. Helicobacter pylori eradication heals non-atrophic chronic gastritis, may lead to regression of atrophic gastritis, and reduces the risk of gastric cancer in patients with these conditions. In this article, we discuss the pathogenesis, epigenomics, and reversibility of intestinal metaplasia and briefly touch upon potential treatment strategy. Gastric intestinal metaplasia no longer appears to be an irreversible precancerous lesion. However, there are still many controversies regarding the improvement of intestinal metaplasia after Helicobacter pylori eradication.

Rates of Recurrent Intestinal Metaplasia and Dysplasia After Successful Endoscopic Therapy of Barrett's Neoplasia by Endoscopic Mucosal Resection vs Endoscopic Submucosal Dissection and Ablation: A Large North American Multicenter Cohort.

Endoscopic eradication therapy (EET) combining endoscopic resection (ER) with endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) followed by ablation is the standard of care for the treatment of dysplastic Barrett's esophagus (BE). We have previously shown comparable rates of complete remission of intestinal metaplasia (CRIM) with both approaches. However, data comparing recurrence after CRIM are lacking. We compared rates of recurrence after CRIM with both techniques in a multicenter cohort. Patients undergoing EET achieving CRIM at 3 academic institutions were included. Demographic and clinical data were abstracted. Outcomes included rates and predictors of any BE and dysplastic BE recurrence in the 2 groups. Cox-proportional hazards models and inverse probability treatment weighting (IPTW) analysis were used for analysis. A total of 621 patients (514 EMR and 107 ESD) achieving CRIM were included in the recurrence analysis. The incidence of any BE (15.7, 5.7 per 100 patient-years) and dysplastic BE recurrence (7.3, 5.3 per 100 patient-years) were comparable in the EMR and ESD groups, respectively. On multivariable analyses, the chances of BE recurrence were not influenced by ER technique (hazard ratio 0.87; 95% confidence interval 0.51-1.49; P = 0.62), which was also confirmed by IPTW analysis (ESD vs EMR: hazard ratio 0.98; 95% confidence interval 0.56-1.73; P = 0.94). BE length, lesion size, and history of cigarette smoking were independent predictors of BE recurrence. Patients with BE dysplasia/neoplasia achieving CRIM, initially treated with EMR/ablation, had comparable recurrence rates to ESD/ablation. Randomized trials are needed to confirm these outcomes between the 2 ER techniques.

Clinicopathological and molecular genetic features of Crohn's disease

Objective: To investigate the clinicopathological and molecular genetic characteristics of Crohn's disease (CD). Methods: A retrospective analysis was conducted on 52 CD patients who underwent surgical resection at the First Affiliated Hospital of Nanjing Medical University between January 2014 and June 2023. Clinical presentations and histopathological features were assessed. Whole-genome sequencing was performed on 17 of the samples, followed by sequencing and pathway enrichment analyses. Immunohistochemistry was used to assess the expression of frequently mutated genes. Results: Among the 52 patients, 34 were males and 18 were females, male-to-female ratio was 1.9∶1.0, with a median age of 45 years at surgery and 35 years at diagnosis. According to the Montreal classification, A3 (51.9%,27/52), B2 (61.5%, 32/52), and L3 (50.0%,26/52) subtypes were the most predominant. Abdominal pain and diarrhea were the common symptoms. Histopathological features seen in all 52 patients included transmural inflammation, disruption of cryptal architecture, lymphoplasmacytic infiltration, varying degrees of submucosal fibrosis and thickening, increased enteric nerve fibers and neuronal proliferation. Mucosal defects, fissure ulcers, abscesses, pseudopolyps, and adenomatous proliferation were also observed in 51 (98.1%), 38 (73.1%), 28 (53.8%), 45 (86.5%), and 28 (53.8%) cases, respectively. Thirty-one (59.6%) cases had non-caseating granulomas, and 3 (5.8%) cases had intestinal mucosal glandular epithelial dysplasia. Molecular analysis showed that 12/17 CD patients exhibited mutations in at least one mucin family gene (MUC2, MUC3A, MUC4, MUC6, MUC12, MUC17), and MUC4 was the most frequently mutated in 7/17 of cases. Immunohistochemical stains showed reduced MUC4 expression in epithelial cells, with increased MUC4 expression in the epithelial surface, particularly around areas of inflammatory cell aggregation; and minimal expression in the lower half of the epithelium. Conclusions: CD exhibits diverse clinical and pathological features, necessitating a comprehensive multidimensional analysis for diagnosis. Mutations and expression alterations in mucin family genes, particularly MUC4, may play crucial roles in the pathogenesis of CD.

Thyroid hormone deprival and TSH/TSHR signaling deficiency lead to central hypothyroidism-associated intestinal dysplasia

BackgroundCentral hypothyroidism (CH) is characterized by low T4 levels and reduced levels or bioactivity of circulating TSH. However, there is a lack of studies on CH-related intestinal maldevelopment. In particular, the roles of TH and TSH/TSHR signaling in CH-related intestinal maldevelopment are poorly understood. Herein, we utilized Tshr−/− mice as a congenital hypothyroidism model with TH deprival and absence of TSHR signaling. MethodsThe morphological characteristics of intestines were determined by HE staining, periodic acid–shiff staining, and immunohistochemical staining. T4 was administrated into the offspring of homozygous mice from the fourth postnatal day through weaning or administrated after weaning. RT-PCR was used to evaluate the expression of markers of goblet cells and intestinal digestive enzymes. Single-cell RNA-sequencing analysis was used to explore the cell types and gene profiles of metabolic alternations in early-T4-injected Tshr−/− mice. Key findingsTshr deletion caused significant growth retardation and intestinal maldevelopment, manifested as smaller and more slender small intestines due to reduced numbers of stem cells and differentiated epithelial cells. Thyroxin supplementation from the fourth postnatal day, but not from weaning, significantly rescued the abnormal intestinal structure and restored the decreased number of proliferating intestinal cells in crypts of Tshr−/− mice. Tshr−/− mice with early-life T4 injections had more early goblet cells and impaired metabolism compared to Tshr+/+ mice. SignificanceTH deprival leads to major defects of CH-associated intestinal dysplasia while TSH/TSHR signaling deficiency promotes the differentiation of goblet cells and impairs nutrition metabolism.

Solobacterium moorei promotes the progression of adenomatous polyps by causing inflammation and disrupting the intestinal barrier

BackgroundAdenomatous polyps (APs) with inflammation are risk factors for colorectal cancer. However, the role of inflammation-related gut microbiota in promoting the progression of APs is unknown.MethodsSequencing of the 16S rRNA gene was conducted to identify characteristic bacteria in AP tissues and normal mucosa. Then, the roles of inflammation-related bacteria were clarified by Spearman correlation analysis. Furthermore, colorectal HT-29 cells, normal colon NCM460 cells, and azoxymethane-treated mice were used to investigate the effects of the characteristic bacteria on progression of APs.ResultsThe expression levels of inflammation-related markers (diamine oxidase, d-lactate, C-reactive protein, tumor necrosis factor-α, interleukin-6 and interleukin-1β) were increased, whereas the expression levels of anti-inflammatory factors (interleukin-4 and interleukin-10) were significantly decreased in AP patients as compared to healthy controls. Solobacterium moorei (S. moorei) was enriched in AP tissues and fecal samples, and significantly positively correlated with serum inflammation-related markers. In vitro, S. moorei preferentially attached to HT-29 cells and stimulated cell proliferation and production of pro-inflammatory factors. In vivo, the incidence of intestinal dysplasia was significantly increased in the S. moorei group. Gavage of mice with S. moorei upregulated production of pro-inflammatory factors, suppressed proliferation of CD4+ and CD8+cells, and disrupted the integrity of the intestinal barrier, thereby accelerating progression of APs.ConclusionsS. moorei accelerated the progression of AP in mice via activation of the NF-κB signaling pathway, chronic low-grade inflammation, and intestinal barrier disruption. Targeted reduction of S. moorei presents a potential strategy to prevent the progression of APs.

A125 DIAGNOSTIC ACCURACY OF ARTIFICIAL INTELLIGENCE IN THE DIAGNOSIS OF INTESTINAL METAPLASIA AND DYSPLASIA IN PATIENTS WITH BARRETT'S ESOPHAGUS: A DIAGNOSTIC TEST ACCURACY META-ANALYSIS

Abstract Background Diagnosing dysplasia in patients with Barrett’s Esophagus is crucial in preventing esophageal cancer but challenging in clinical practice. Artificial Intelligence (AI) could potentially be utilized during endoscopy to provide better diagnostic accuracy. Aims The primary aim of this systematic review is to determine the diagnostic accuracy of AI in detecting intestinal metaplasia and dysplasia in adults with Barrett's esophagus using gastroscopy images. Methods A comprehensive electronic search was conducted of cross-sectional studies examining the accuracy of AI in diagnosing intestinal metaplasia or dysplasia using endoscopic images. Study selection, data extraction and quality assessment were completed by two authors independently. When a study used several models, the model with the highest sensitivity was used in meta-analysis. The Quality Assessment of Diagnostic Accuracy (QUADAS-2) tool was used to assess risk of bias and applicability. Meta-analysis was performed using a bivariate model to obtain summary estimates of sensitivity, specificity, and diagnostic odds ratio. Results Of the 1479 articles reviewed, 23 were included. The diagnosis of dysplasia by AI per endoscopic image obtained had a sensitivity of 0.92 (CI 0.85-0.96), specificity of 0.84 (CI 0.78-0.88) and diagnostic odds ratio (DOR) of 59 (CI 22-161). The diagnosis of dysplasia in volumetric laser endomicroscopy images interpreted by AI had an overall sensitivity of 0.83 (CI 0.70-0.91), specificity of 0.77 (0.67-0.85) and a DOR of 16 (CI 2-30). Subgroup analysis did not show a statistically significant difference when comparing studies conducted in Europe to those outside of Europe or studies published before 2020 to those published after 2020. A sensitivity analysis by removing the largest studies did not change the overall accuracy of AI. Conclusions AI algorithms seem to be accurate at detecting the presence of intestinal metaplasia and dysplasia. Further research into using artificial intelligence should be carried out to evaluate its use in combination with endoscopist’s opinion as a clinical decision-making tool to target areas of dysplasia for biopsies. Funding Agencies None

Primary mucinous adenocarcinoma of the ureter and renal pelvis: A case report.

Primary adenocarcinoma rarely occurs in the upper urinary tract and accounts for less than 1% of the urothelial tumors. Here we present a case report of a 45-year-old female patient who presented with a lump in the abdomen and pain in the right lumbar region for 2 months. Various radiological investigations revealed right-sided hydronephrosis with enhancing masses in the right proximal ureter and renal pelvis associated with multiple calculi. A gross examination of the right nephrectomy specimen revealed multiple cystic areas filled with mucinous material and papillary projections in the renal pelvis. A necrotic growth was observed in the right proximal ureter in association with the staghorn calculus in the renal pelvis. Histological examination of the ureteric mass and solid areas from the renal pelvis showed acini and papillary projections lined by pseudostratified columnar epithelium showing malignant changes. Surrounding areas also revealed intestinal metaplasia with moderate to marked dysplasia in some places. The ureteric malignancy was observed to infiltrate the inner two-thirds of the wall of the ureteric muscular layer and extend until the margin of excision. Thus, a diagnosis of mucinous adenocarcinoma of the ureter and renal pelvis with intestinal metaplasia and dysplasia that occurred in association with a large staghorn calculus was made.

Liquid nitrogen spray cryotherapy for eradication of dysplastic Barrett’s esophagus: results from a multicenter prospective registry

Liquid nitrogen spray cryotherapy (SCT) is an alternative to radiofrequency ablation (RFA) for eradication of dysplastic Barrett's esophagus (BE). We aimed to assess the safety, efficacy, and durability of SCT in a multicenter U.S. registry. This is a multicenter prospective registry of adults with BE treated with truFreeze Spray Cryotherapy (Steris, Mentor, Ohio, USA) (4 community and 11 academic sites, 2013-2022). Complete eradication of intestinal metaplasia (CEIM) and dysplasia (CED) were assessed in BE with dysplasia or intramucosal adenocarcinoma. Kaplan-Meier analysis of CEIM and CED was performed. Hazard ratios for CEIM stratified by baseline risk factors were calculated. Among 138 subjects with low-grade dysplasia (24%), high-grade dysplasia (49%), and intramucosal adenocarcinoma (27%), 34% received prior RFA therapy. Subjects received a median of 2 SCT sessions. Adverse events were uncommon, with 5.5% reporting strictures and 0.7% a perforation. Rates of CEIM and CED, respectively, were 66% and 84% after 2 years and 67% and 92% after 3 years. In RFA-naïve patients, CEIM was 77% and CED was 96% at 3 years. Increasing BE length (per centimeter: adjusted hazard ratio, 0.90; 95% confidence interval, 0.83-0.96) and prior treatment with RFA (adjusted hazard ratio, 0.39; 95% confidence interval, 0.22-0.69) were associated with a lower rate of CEIM. Recurrence occurred in 8.8% (n= 6) at a mean follow-up of 2.5 years after CEIM. In this largest reported prospective cohort, liquid nitrogen SCT was safe and effective for the treatment of dysplastic and neoplastic BE. Response was lower in those with prior failed RFA; in that cohort, approximately 50% attained CEIM at 3 years.

Trametinib ameliorates aging-associated gut pathology in Drosophila females by reducing Pol III activity in intestinal stem cells

Pharmacological therapies are promising interventions to slow down aging and reduce multimorbidity in the elderly. Studies in animal models are the first step toward translation of candidate molecules into human therapies, as they aim to elucidate the molecular pathways, cellular mechanisms, and tissue pathologies involved in the anti-aging effects. Trametinib, an allosteric inhibitor of MEK within the Ras/MAPK (Ras/Mitogen-Activated Protein Kinase) pathway and currently used as an anti-cancer treatment, emerged as a geroprotector candidate because it extended lifespan in the fruit fly Drosophila melanogaster. Here, we confirm that trametinib consistently and robustly extends female lifespan, and reduces intestinal stem cell (ISC) proliferation, tumor formation, tissue dysplasia, and barrier disruption in guts in aged flies. In contrast, pro-longevity effects of trametinib are weak and inconsistent in males, and it does not influence gut homeostasis. Inhibition of the Ras/MAPK pathway specifically in ISCs is sufficient to partially recapitulate the effects of trametinib. Moreover, in ISCs, trametinib decreases the activity of the RNA polymerase III (Pol III), a conserved enzyme synthesizing transfer RNAs and other short, non-coding RNAs, and whose inhibition also extends lifespan and reduces gut pathology. Finally, we show that the pro-longevity effect of trametinib in ISCs is partially mediated by Maf1, a repressor of Pol III, suggesting a life-limiting Ras/MAPK-Maf1-Pol III axis in these cells. The mechanism of action described in this work paves the way for further studies on the anti-aging effects of trametinib in mammals and shows its potential for clinical application in humans.

Cryotherapy versus radiofrequency ablation in the treatment of dysplastic Barrett's esophagus with or without early esophageal neoplasia: a systematic review and meta-analysis.

Radiofrequency ablation (RFA) is the first-line therapy for dysplastic Barrett's esophagus (BE). Therefore, cryotherapy has emerged as an alternative treatment option. This study aimed to compare the efficacies of these two techniques based on the rates of complete eradication of intestinal metaplasia (CE-IM) and dysplasia (CE-D). Adverse events and recurrence have also been reported. An electronic search was conducted using the Medline (PubMed), Embase, LILACS, and Google Scholar databases until December 2022. Studies were included comparing cryotherapy and RFA for treating dysplastic BE with or without early esophageal neoplasia. This study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Three retrospective cohort studies involving 627 patients were included. Of these, 399 patients underwent RFA, and 228 were treated with cryotherapy. There was no difference in CE-IM (risk difference [RD], -0.03; 95% confidence interval [CI], -0.25 to 0.19; p=0.78; I2=86%) as well as in CE-D (RD, -0.03; 95% CI, -0.15 to 0.09; p=0.64; I2=70%) between the groups. The absolute number of adverse events was low, and there was no difference in the recurrence rate. Cryotherapy and RFA were equally effective in treating dysplastic BE, with or without early esophageal neoplasia.

Characterization of sessile serrated adenomas with dysplasia including intramucosal adenocarcinoma and colorectal carcinoma with a microsatellite instability phenotype

Recent studies have shown that sessile serrated lesions (SSLs) lead to the development of colorectal cancer (CRC) with a microsatellite instability (MSI) phenotype via a dysplasia-carcinoma sequence. However, the pathological and molecular mechanisms of SSL with dysplasia (SSLD) are unclear. Here, we aimed to examine the clinicopathological and molecular alterations in SSLD and to evaluate the significance of such alterations with regard to lesion progression. Fifty-four SSLDs (20 serrated dysplasia cases and 17 intestinal dysplasia cases, including 30 low-grade dysplasia [LGD] cases, 7 high-grade dysplasia [HGD] cases, and 17 intramucosal adenocarcinomas [IMAs]) were evaluated. Molecular alterations, including immunohistochemical expression of various markers, DNA methylation status, and multiple genetic mutations (using next-generation sequencing), were assessed. Additionally, such alterations were also investigated in 41 CRCs with an MSI phenotype (invasion beyond submucosa). The frequency of mismatch repair (MMR) deficiency in SSLD was 12 of 39 cases (32.4 %), whereas the MMR proficient type was observed in 17 of 39 SSLD cases. SSLD with serrated dysplasia showed a significantly higher frequency of loss of MMR protein expression and methylation status. Moreover, loss of MMR protein expression differed significantly between LGD and IMA. Furthermore, the frequency of TP53 mutation was significantly higher in IMA than in LGD. The current findings demonstrated that SSL with serrated dysplasia may be associated with an increased risk of malignant transformation compared with intestinal dysplasia. Loss of MMR proteins and mutation of TP53 may play important roles in tumor progression from dysplasia to carcinomatous lesions.

Unveiling HuB genes and drug design against Helicobacter pylori infection by network biology and biophysics techniques

Helicobacter pylori (H. pylori) is mainly considered for causing chronic gastritis, which can lead to several secondary complications like peptic ulcer and pre-malignant lesions for example atrophic gastritis, intestinal dysplasia and metaplasia, with the etiological factor of developing gastric cancer. Recent research demonstrates that H.pylori colonizes the stomach mucosa of more than fifty populations around the globe. This research focuses on unveiling hub genes, and diagnostic and drug targets against said organism by utilizing various types of networking biology and biophysical approaches. In data retrieval, the GSE19826 dataset was obtained from the gene expression omnibus database and microarray data set from array express. Geo2r analysis predicted a total number of 7 DEGs and 10 hub genes, next functional protein association network analysis (STRING) unveiled that among 10 Hub genes only 3 genes were found more interactive with other genes and involved in pathogenesis, The shortlisted three genes were further analyzed for survival analysis using Gene Expression Profiling Interactive Analysis (GEPIA) and predicted the survival rate of targeted genes. Moreover, functional enchainment analysis was done using the ToppFun server, the server predicted that COL11A1 and COL10A1 were more involved in the pathogenesis of the H. pylori infection. Furthermore, the COL10A1 gene was subjected to protein structure prediction. In molecular docking analysis, the asinex antibacterial library was screened for potential inhibitors, and one compound was predicted as a strong inhibitor with the best binding at −10.23 kcal/mol. The docking results were further validated through molecular dynamic simulation analysis and the MD simulation analysis evaluated the dynamic movement of the docked complex in various nanoseconds, the MD simulation results predicted that the docked complexes are stable throughout the simulation and can be used as a potential inhibitor against the said pathogen, however experimental study is required to further validate the predicted results and design drug against targeted pathogen.