Transcription factor-mediated intestinal metaplasia and the role of a shadow enhancer

Barrett's esophagus (BE) and gastric intestinal metaplasia are related premalignant conditions in which areas of human stomach epithelium express mixed gastric and intestinal features. Intestinal transcription factors (TFs) are expressed in both conditions, with unclear causal roles and cis-regulatory mechanisms. Ectopic CDX2 reprogrammed isogenic mouse stomach organoid lines to a hybrid stomach–intestinal state transcriptionally similar to clinical metaplasia; squamous esophageal organoids resisted this CDX2-mediated effect. Reprogramming was associated with induced activity at thousands of previously inaccessible intestine-restricted enhancers, where CDX2 occupied DNA directly. HNF4A, a TF recently implicated in BE pathogenesis, induced weaker intestinalization by binding a novel shadow Cdx2 enhancer and hence activating Cdx2 expression. CRISPR/Cas9-mediated germline deletion of that cis-element demonstrated its requirement in Cdx2 induction and in the resulting activation of intestinal genes in stomach cells. dCas9-conjugated KRAB repression mapped this activity to the shadow enhancer's HNF4A binding site. Altogether, we show extensive but selective recruitment of intestinal enhancers by CDX2 in gastric cells and that HNF4A-mediated ectopic CDX2 expression in the stomach occurs through a conserved shadow cis-element. These findings identify mechanisms for TF-driven intestinal metaplasia and a likely pathogenic TF hierarchy.

Immunohistochemical Analysis of Myofibroblasts Using α- SMA in Oral Submucous Fibrosis Turning into Malignancy- A Case Report and Review

Oral submucous fibrosis is a premalignant condition, characterized by fibrosis in oral mucosa causing stiffness of mucosa and leading to reduced mouth opening. The malignant transformation of oral submucous fibrosis is very high among the rest of the premalignant conditions. Chronic chewing of arecanut causes production of myofibroblasts. These myofibroblasts plays an important role in neoangiogenesis as well as disintegration of the basement membrane at the tumor invasive front leading to carcinoma. Here, we are doing an Immunohistochemical study using alpha SMA for proper microscopic visulizations of myofibroblastic activity in an OSF patient, encompassing the pathogenesis and malignant potentiality of the disease.

MicroRNAs as a Potential New Preventive Approach in the Transition from Asymptomatic to Symptomatic Multiple Myeloma Disease

Multiple myeloma (MM) is a hematological malignancy characterised by proliferation of clonal plasma cells (PCs) within the bone marrow (BM). Myelomagenesis is a multi-step process which goes from an asymptomatic phase, defined as monoclonal gammopathy of undetermined significance (MGUS), to a smouldering myeloma (SMM) stage, to a final active MM disease, characterised by hypercalcemia, renal failure, bone lesions anemia, and higher risk of infections. Overall, microRNAs (miRNAs) have shown to significantly impact on MM tumorigenesis, as a result of miRNA-dependent modulation of genes involved in pathways known to be crucial for MM pathogenesis and disease progression. We aim to revise the literature related to the role of miRNAs as potential diagnostic and prognostic biomarkers, thus highlighting their key role as novel players within the field of MM and related premalignant conditions.

Premalignant Conditions of Larynx

Premalignant conditions of larynx encompass a variety of lesions that have the potential to evolve into malignant changes. The dysplastic premalignant epithelial changes of larynx have significantly increased Risk of developing in cancer than the hyperplastic stage of epithelial changes and this transformation significantly depends on the grade of dysplasia. Therefore, early diagnosis & prompt treatment should thus prevent the development of invasive carcinoma requiring more debilitating surgical resection. The histopathological examination is diagnostic & the evolution of advanced laryngoscopic surgical procedures including CO2 laser and newer treatment methods such as photodynamic therapy has shown promising results in their management.

Esophagogastric premalignant conditions. A literature review

Esophagogastric cancers are serious malignancies with high mortality and low overall survival for advanced tumors. Detection of premalignant lesions and early treatment of malignant lesions are of paramount importance. Precancerous esophagogastric conditions develop from interaction between environmental and genetic factors. Chronic irritation and inflammation may result in metaplasia, increased mutations, cellular atypia, and altered function (dysplasia). Helicobacter pylori (HP) infection is one of the most important risk factors for gastric carcinogenesis, but other environmental factors (e.g. alcohol, tobacco, nitrites, infection) and autoimmune disorders play a role as well. Esophageal adenocarcinoma (EAC) usually arises in the distal esophagus and is linked to obesity, gastroesophageal reflux disease (GERD) and Barrett’s esophagus (BE). Squamous cell carcinoma (ESCC) typically occurs in the presence of risk factors causing chronic inflammation (e.g. tobacco, alcohol abuse, achalasia, tylosis). Highquality endoscopic imaging is of primary importance in the diagnosis and assessment of premalignant and early malignant esophagogastric lesions. Biological markers such as aberrant p53 protein expression may be associated with increased risk of malignant transformation of precancerous lesions; however, none of those biomarkers has been validated for either diagnosis or risk stratification yet.