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Molecular Diagnostic Approaches in Infectious Disease
Published in Attila Lorincz, Nucleic Acid Testing for Human Disease, 2016
Leonard F. Peruski, Anne Harwood Peruski
For example, when examining host response to infection with intracellular C. pneumoniae, C. trachomatis, and S. typhimurium pathogens, distinct expression profiles could be detected, demonstrating the ability to characterize pathogenic agents via host profile analysis.158 C. trachomatis and C. pneumoniae infection induced CTGF, ETV4, NR4A2, DUSP4, DUSP5, GAS-1, EGR1 LIF, MIP-2, IER3, MCL-1, EPHA2, IL6, and IL8. C. trachomatis induced IL-11 Gro-alpha, GM-CSF, and fos-related antigen FRA- 1, while C. pneumoniae induced IL-8, ICAM-1, and prostaglandin endoperoxide-synthase 2 (Cox 2, PTGS2). Intracellular Salmonella infection caused major increases in IL-6 and IL-8 mRNA levels only.
The MAP kinase signal transduction pathway: promising therapeutic targets used in the treatment of melanoma
Published in Expert Review of Anticancer Therapy, 2020
Erin McClure, Michael J Carr, Jonathan S Zager
More specifically, this study reported gain-of-function mutations that reactivated the MAPK pathway, which included BRAF-V600E ultra-amplification and NRAS-G12 R amplification. Additionally, observed loss-of-function mutations consisted of PTEN-F127 V, deletions in PTEN, CDKN2A, and DUSP4. These genetic alterations were observed singly and in combination with each other. Supraphysiologic levels of BRAF-V600E were found to allosterically promote MAPK signaling via interactions with CRAF. There was also evidence that upregulated BRAF-V600E regulates MEK1 and 2 activation. Furthermore, MEK1 and MEK2 mutations residing in or near the A and C helices shared an improved ability to complex with BRAF-V600E. These findings suggest the presence of a BRAF-V600E-CRAF-MEK signaling complex easily upregulated by one or multiple convergent DNA or non-DNA alterations. [88]
Cell-type specific MyD88 signaling is required for intestinal tumor initiation and progression to malignancy
Published in OncoImmunology, 2018
Anne Holtorf, Anja Conrad, Bernhard Holzmann, Klaus-Peter Janssen
Next, we assessed the role of MyD88 for proliferation and self-renewal in premalignant epithelia. Ki67-staining of intestinal tissue revealed a significant reduction of the transit-amplifying compartment in MyD88LSL mice, compared to the parental Apc1638N/+ strain. This reduced proliferation was rescued by re-expression of MyD88 in intestinal epithelia, but not in myeloid cells (Fig. 2C). Next, we investigated the signaling pathways associated with IEC proliferation, notably the MAP-kinase cascade, and analyzed phosphorylation of ERK1/2 in intestinal tissue lysates. Phospho-ERK1/2 levels in normal jejunum were significantly reduced in globally MyD88-deficient animals, clearly rescued by re-expression of Myd88 in IECs, but not in myeloid cells (Fig. 2D). In contrast, canonical WNT-signaling, which is aberrantly activated in Apc1638N/+ tumors, was essentially unaffected by absence of MyD88. Expression of Ccnd1 (CyclinD1), Spp1 (osteopontin), and Dusp4, targets of the canonical WNT-pathway,20 was elevated in tumors, but independent of MyD88, similar to intratumoral β-Catenin protein levels (Fig. 2E). As expected, intratumoral activation of the NF-κB pathway was decreased upon MyD88-deficiency, rescued by re-expression of MyD88 both in intestinal epithelia, as well as in myeloid cells (Supplementary Fig. 2C).
Proteomic investigations into resistance in colorectal cancer
Published in Expert Review of Proteomics, 2020
David I. Cantor, Harish R. Cheruku, Jack Westacott, Joo-Shik Shin, Abidali Mohamedali, Seong Boem Ahn
One-notable application of ML to identify CpG methylation patterns in early-onset CRC was recently performed by Kel et al. [111], who developed a method to identify potential causal relationships between epigenetic methylations in gene regulatory regions that influence transcription factor binding sites and gene expression profiles. Named ‘Walking pathways’, Kel et al., have established this bioinformatic method to consider the changing topology (or ‘re-wiring’) of the signal transduction pathways involved and highlight the presence of positive feedback loops which induce the carcinogenic aberrations observed [111]. By analyzing data from two previously published studies, Kel et al., utilized the genomic data from 313 CRC and 30 normal colon mucosa samples, combined with methylation microarray analysis and Illimina HiSeq RNA-sequencing [111]. Kel et al., went on to perform promoter, composite module analyst with correlation analysis, and My-Genome-Enhancer-assisted TRANSPATH® analysis to identify master regulators of the differentially expressed genes [111]. This approach identified 47-potential CpG methylation loci for follow-up analysis, of which 9 loci in the regulatory regions of the ENO1, IGF2, CALCA, PDX1, ZNF43, FOSL2, TCF7, DUSP4, and MYC genes were confirmed to exhibit statistically significant differences between CRC patients and cancer-free controls [111]. From these results, Kel et al. utilized the support vector machine (SVM) method to construct a minimal combination of methylation biomarkers that would maintain a high diagnostic potential; ultimately creating a six-marker panel to differentiate stage I CRC patients from healthy controls [111].