macrophage-differentiation-polarization-into-an-m2-like-phenotype

Macrophage Differentiation and Polarization into an M2-Like Phenotype using a Human Monocyte-Like THP-1 Leukemia Cell Line

Tumor-associated macrophages (TAM) can switch their expression and cytokine profile according to external stimuli. This remarkable plasticity enables TAM ...

University of Louisville

Significant evidence suggests that a promoter polymorphism within the gene SLC11A1 is involved in susceptibility to both autoimmune and infectious disorders. The aim of this study was to evaluate whether SLC11A1 has a role in the susceptibility to inflammatory bowel disease (IBD) by characterizing a promoter polymorphism within the gene and two short tandem repeat (STR) markers in genetic proximity to SLC11A1.

Evaluation of SLC11A1 as an inflammatory bowel disease candidate gene.

Fundamental differences exist between ulcerative colitis (UC)-associated and sporadic forms of colorectal cancer, including preexisting inflammation, type of dysplasia, and timing of molecular events in carcinogenesis. Transcriptional alterations that occur in UC-associated neoplasia in the progression from normal mucosa through dysplastic epithelium to invasive cancer have not been described. We used Affymetrix U95Av2 microarrays to assess differential gene expression in the neoplastic progression of UC tissue from the colonic mucosa of individuals with benign UC, UC-dysplasia-associated lesions or masses, and UC adenocarcinoma. By correlating transcript alterations across tissue types using a mixed statistical model, we identified 699 genes exhibiting altered expression with dysplasia development. A different expression profile was observed in progression to adenocarcinoma with 392 transcripts exhibiting differential expression. There were 224 transcripts common to both dysplasia and adenocarcinoma. Most of the differentially expressed genes described herein were not previously known to play a role in neoplastic progression in UC, including transcripts affecting cell proliferation and apoptosis, signal transduction and signaling, and DNA repair. The altered expression of five transcripts was confirmed by quantitative real-time reverse-transcription polymerase chain reaction. Based on comparisons with previous studies on sporadic colorectal carcinoma, several similarities were found. There were, however, important differences that suggest that different molecular events may occur in the development of UC-associated neoplasia. Several of these genes demonstrated similar changes in dysplastic and cancerous tissue and may be involved in early cancer formation. Identification of these genes as potential clinical biomarkers may lead to improved early disease diagnosis.

Molecular profiling of ulcerative colitis-associated neoplastic progression.

Crohn's disease (CD) and ulcerative colitis (UC), the two main types of inflammatory bowel disease (IBD), are multifactorial conditions of unknown etiology. The objective of this study is to examine the combined gene-environment interactions influencing IBD susceptibility in a well-defined Caucasian cohort in rural mid-America.

Clinical predictors of inflammatory bowel disease in a genetically well-defined Caucasian population.

Many patients with rectal cancer undergo preoperative neoadjuvant chemoradiation, with approximately 70% exhibiting pathologic downstaging in response to treatment. Currently, there is no accurate test to predict patients who are likely to be complete responders to therapy. 5-Fluorouracil is used regularly in the neoadjuvant treatment of rectal cancer. Genetic polymorphisms affect the activity of thymidylate synthase, an enzyme involved in 5-Fluorouracil metabolism, which may account for observed differences in response to neoadjuvant treatment between patients. Detection of genetic polymorphisms might identify patients who are likely to have a complete response to neoadjuvant therapy and perhaps allow them to avoid operation.

Genetic polymorphisms in 5-Fluorouracil-related enzymes predict pathologic response after neoadjuvant chemoradiation for rectal cancer.

To develop a plasma-based microRNA (miRNA) diagnostic assay specific for colorectal neoplasms, building upon our prior work.

A Highly Predictive Model for Diagnosis of Colorectal Neoplasms Using Plasma MicroRNA: Improving Specificity and Sensitivity.

This study aimed to determine whether manipulation of the microRNA-200 (miR-200) family could influence colon adenocarcinoma cell behavior. The miR-200 family has a significant role in tumor suppression and functions as an oncogene.  studies on gain and loss of function with small interfering RNA demonstrated that the miR-200 family could regulate RASSF2 expression. Knockdown of the miR-200 family in the HT-29 colon cancer cell line increased KRAS expression but decreased signaling in the MAPK/ERK signaling pathway through reduced ERK phosphorylation. Increased expression of the miR-200 family in the CCD-841 colon epithelium cell line increased KRAS expression and led to increased signaling in the MAPK/ERK signaling pathway but increased ERK phosphorylation. Functionally, knockdown of the miR-200 family led to decreased cell proliferation in the HT-29 cells; therefore, increased miR-200 family expression could increase cell proliferation in the CCD-841 cell line. The present study included a large paired miR array dataset (n=632), in which the miR-200 family was significantly found to be increased in colon cancer when compared with normal adjacent colon epithelium. In a miR-seq dataset (n=199), the study found that miR-200 family expression was increased in localized colon cancer compared with metastatic disease. Decreased expression was associated with poorer overall survival. The miR-200 family directly targeted RASSF2 and was inversely correlated with RASSF2 expression (n=199, all P<0.001). Despite the well-defined role of the miR-200 family in tumor suppression, the present findings demonstrated a novel function of the miR-200 family in tumor proliferation.

The microRNA-200 family acts as an oncogene in colorectal cancer by inhibiting the tumor suppressor RASSF2.

The analysis of plasma microRNAs (miRNAs) has been widely used as a method for finding potential biomarkers for human diseases, especially those with a link to cancer. Methods of analyzing plasma miRNA have been thoroughly discussed from sample extraction to data modeling. However, some issues exist within the process that have rarely been talked about. Rice et al. discussed some issues in plasma miRNA studies, such as the lack of standard methodology including the use of different cycle threshold, time to plasma extraction, among others. These issues can lead to inconsistent data, and thus impact the result and assay reproducibility. Other external issues, such as batch effect and operator effect, may also indirectly impact the statistical analysis. Here, we discuss issues in plasma miRNA studies from a statistical point of view. The interaction effect of different ways of calculating fold-change, the choice of housekeeping genes, and methods of normalization are among the issues we discuss, with data demonstrations.  values are calculated and compared to determine the effect of those issues on statistical conclusions. Statistical methods such as analysis of variance and analysis of covariance are crucial in the analysis of miRNA but investigators are often confused about them; therefore, a brief explanation of these statistical methods is also included. In addition, 3-group classification is discussed, as it is often challenging, compared with 2-group classification.

Statistical Issues and Group Classification in Plasma MicroRNA Studies With Data Application.

Ileal pouch-anal anastomosis (IPAA) is a common surgical treatment for ulcerative colitis. Afferent limb stenosis is an infrequent complication following IPAA, suggesting underlying Crohn's disease (CD). We hypothesized that CD-related single nucleotide polymorphisms (SNPs) are associated with afferent limb stenosis.

Article	Year
Evaluation of SLC11A1 as an inflammatory bowel disease candidate gene. BMC medical genetics\| PubMed ID: 15757519	2005
Molecular profiling of ulcerative colitis-associated neoplastic progression. Experimental and molecular pathology\| PubMed ID: 16277983	2006
Clinical predictors of inflammatory bowel disease in a genetically well-defined Caucasian population. Journal of negative results in biomedicine\| PubMed ID: 22269043	2012
Genetic polymorphisms in 5-Fluorouracil-related enzymes predict pathologic response after neoadjuvant chemoradiation for rectal cancer. Surgery\| PubMed ID: 27423551	2016
A Highly Predictive Model for Diagnosis of Colorectal Neoplasms Using Plasma MicroRNA: Improving Specificity and Sensitivity. Annals of surgery\| PubMed ID: 27471839	2016
The microRNA-200 family acts as an oncogene in colorectal cancer by inhibiting the tumor suppressor RASSF2. Oncology letters\| PubMed ID: 31565080	2019
Statistical Issues and Group Classification in Plasma MicroRNA Studies With Data Application. Evolutionary bioinformatics online\| PubMed ID: 32313420	2020
Crohn's disease-related single nucleotide polymorphisms are associated with ileal pouch afferent limb stenosis. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract\| PubMed ID: 33443688	2021

Maurice R. Eichenberger

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