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Clinical Trials: the Statistician's Role
Published in Trevor F. Cox, Medical Statistics for Cancer Studies, 2022
The translational medicine publication, GATA6 regulates EMT and tumour dissemination, and is a marker of response to adjuvant chemotherapy in pancreatic cancer [40], reports on the use of ESPAC3 data to show that the transcription factor GATA6 is associated with outcome and response to chemotherapy for pancreatic patients.
Esophageal Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Jennifer Kahan, Carys Morgan, Kieran Foley, Thomas Crosby
Junctional adenocarcinomas resembled the previously described chromosomally unstable variant (CIN) of gastric cancer, suggesting that this is one disease entity, although some differences were identified, such as increased DNA hypermethylation in the esophageal adenocarcinomas. ERBB2, VEGFA, and GATA4 and GATA6 were also more commonly amplified.29 The classification and understanding of the differences in pathophysiology may help in designing future studies and identifying new treatment approaches.
Respiratory System
Published in Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard, Toxicologic Pathology, 2018
Tom P. McKevitt, David J. Lewis
The development of the mammalian respiratory system involves interaction between epithelial cells derived from a ventral outpouching of foregut endoderm and mesenchymal cells from the splanchnic mesoderm, and it begins at embryonic day 9 to 9.5 in the mouse (Wan et al. 2004). Lung development is under the control of transcription factors, including multiple forkhead transcription factors, GATA-6, and thyroid transcription factor-1 (Costa et al. 2001, Wan et al. 2004). The process has been divided into five stages (embryonic, pseudoglandular, canalicular, saccular, and alveolar), all of which are potentially susceptible to modification by toxicants (Fanucchi and Plopper 1997). In humans, the first four stages occur prenatally, with only the final, alveolar stage of development occurring after term. This is not the case in all species. In the monkey, for example, the alveolar stage of development is complete at birth. This has implications for species selection for inhaled pediatric drug development, as it is critical that the appropriate stage of lung development (i.e., the alveolar stage) is examined during preclinial testing. This has lead to the selection of the rat and dog rather than the monkey as appropriate species for testing inhaled drugs for a pediatric population (Zoetis and Hurtt 2003).
MiR-23b targets GATA6 to down-regulate IGF-1 and promote the development of congenital heart disease
Published in Acta Cardiologica, 2022
Guo-Jin Huang, Xue-Liang Xie, Yong Zou
Numerous studies have corroborated that GATA6 is expressed during heart development [27,28]. At present, it has been found that GATA6 mutations in CHD include ASD, VSD, patent ductus arteriosus, pulmonary valve stenosis, persistent truncus arteriosus, and TOF [27,29]. GATA6 is indispensable to the normal expression of the transcription factor network during the development of cardiomyocytes. Kodo et al. [13] have confirmed that GATA6 can directly regulate the brain signal protein 3 C-plexus protein A2 signal pathway, affect the normal migration of cardiac neural crest cells, resulting in abnormal development of the cardiac outflow tract. Moreover, some studies have also confirmed that GATA6 may influence the development of the heart by regulating the signal of bone morphogenetic protein 4 [30,31]. In short, GATA6 can regulate downstream target genes, thus affecting cardiac development. In our research, we found that miR-23b can target the regulation of GATA6 in cardiomyocytes, thus affecting cell proliferation and apoptosis. As a growth hormone-dependent peptide, IGF-1 plays an indispensable role in tissue growth and differentiation. According to Carlos Stocco et al. [32] and Yvonne Y. Hui et al. [21], down-regulation of GATA6 can induce the decrease of IGF-1 expression. In this study, we also confirmed this regulatory mechanism in the CHD cells.
Reg3β: A Potential Therapeutic Target for Tissue Injury and Inflammation-Associated Disorders
Published in International Reviews of Immunology, 2022
Yuwen Cao, Yu Tian, Yueqin Liu, Zhaoliang Su
Emerging studies have focused on Reg3β-related molecules to further understand the functions and molecular mechanisms of Reg3β. GATA4 is identified as a transcriptional activator or repressor of Reg3β gene activity in the intestinal epithelium. It contains two conserved zinc finger domains and a C-terminal nuclear localization sequence as well as two N-terminal transcriptional activation domains [36]. Several endodermal tissues, such as pancreas, liver, kidney, heart, and intestine, express GATA4 [37]. GATA4 depletion identifies Reg3β as a putative GATA4 gene target by using an unbiased approach to gene expression profiling in intestinal epithelial cells. Co-transfection and RNA interference assays identified the complex roles of GATA4 in controlling Reg3β expression. Through the C-terminal zinc finger domain, GATA4, functionally in combination with Cdx2, regulates the rat Reg3β gene promoter. However, GATA4 interaction with FOG1 through the GATA4 N-terminal zinc finger domain represses the GATA4/Cdx2-dependent synergistic induction of Reg3β transcription. In vivo, GATA4 intestinal epithelial conditional knockout mice support the transcriptional regulation of Reg3β [38]. GATA6 is also expressed in several endodermal tissues [39]. GATA6 and GATA4 have overlapping functions in regulating crypt cell proliferation, secretory cell differentiation, and absorptive enterocyte gene expression [40]. GATA6 is identified as a transcriptional activator of Reg4 in colon cancer cells, and the GATA6/Reg4 pathway is essential for colorectal tumorigenesis. It remains unclear whether Reg3β is a transcriptional target of GATA6 [41].
Refining targeted therapeutic approaches in pancreatic cancer: from histology and molecular pathology to the clinic
Published in Expert Opinion on Therapeutic Targets, 2022
Paola Mattiolo, Valentyna Kryklyva, Lodewijk A. Brosens, Andrea Mafficini, Rita T. Lawlor, Michele Milella, Aldo Scarpa, Vincenzo Corbo, Claudio Luchini
Consortium-based approaches have significantly expanded our knowledge of the molecular pathology of PDAC through comprehensive analyses of bulk tissues from patients with treatment-naïve and surgically resectable diseases. Of note, transcriptomic-based studies have opened new important perspectives. Based on gene expression profiling, indeed, two consensus molecular subtypes of PDAC have been proposed: classical/progenitor (hereafter referred to as classical) and basal-like/squamous (henceforth basal-like) [18]. Despite being mostly inferred from analysis of bulk tissues, the two subtypes largely reflect two main cell lineages that differ in the degree of fidelity to pancreatic endodermal gene programs. Classical PDAC tumors are characterized by expression of endodermal transcription factors, enrichment for SMAD4 alterations, and a lipogenic metabolic profile [18]. Of the transcription factors involved in maintaining pancreatic cell fate, GATA6 has been proved to be a critical driver of the classical gene programs and, accordingly, a reliable surrogate biomarker of the classical subtype [19].