Increased burden of familial-associated early-onset cancer risk among minority americans compared to non-latino whites

Background: The role of race/ethnicity in genetic predisposition of early-onset cancers can be estimated by comparing family-based cancer concordance rates among ethnic groups. Methods: We used linked California health registries to evaluate the relative cancer risks for first-degree relatives of patients diagnosed between ages 0 and 26, and the relative risks of developing distinct second primary malignancies (SPMs). From 1989 to 2015, we identified 29,631 cancer patients and 62,863 healthy family members. We calculated the standardized incident ratios (SIRs) of early-onset primary cancers diagnosed in proband siblings and mothers, as well as SPMs detected among early-onset patients. Analyses were stratified by self-identified race/ethnicity. Results: Given probands with cancer, there were increased relative risks of any cancer for siblings and mothers (SIR = 3.32; 95% confidence interval [CI]: 2.85–3.85) and of SPMs (SIR = 7.27; 95% CI: 6.56–8.03). Given a proband with solid cancer, both Latinos (SIR = 4.98; 95% CI: 3.82–6.39) and non-Latino Blacks (SIR = 7.35; 95% CI: 3.36–13.95) exhibited significantly higher relative risk of any cancer in siblings and mothers when compared to non-Latino White subjects (SIR = 3.02; 95% CI: 2.12–4.16). For hematologic cancers, higher familial risk was evident for Asian/Pacific Islanders (SIR = 7.56; 95% CI: 3.26–14.90) compared to non-Latino whites (SIR = 2.69; 95% CI: 1.62–4.20). Conclusions: The data support a need for increased attention to the genetics of early-onset cancer predisposition and environmental factors in race/ethnic minority families in the United States.</p

HOXB4 Gene Expression Is Regulated by CDX2 in Intestinal Epithelial Cells

The mammalian Caudal-related homeobox transcription factor 2 (CDX2) plays a key role in the homeobox regulatory network and is essential in regulating the expression of several homeobox (HOX) genes during embryonic development, particularly in the gut. Genome-wide CDX2 chromatin immunoprecipitation analysis and expression data from Caco2 cells also suggests a role for CDX2 in the regulation of HOXB4 gene expression in the intestinal epithelium. Thus, the aim of this study was to investigate whether HOXB4 gene expression is regulated by CDX2 in the intestinal epithelium. We demonstrated binding of CDX2 to four different CDX2 binding sites in an enhancer region located upstream of the HOXB4 transcription start site. Mutations in the CDX2 binding sites reduced HOXB4 gene activity, and knock down of endogenous CDX2 expression by shRNA reduced HOXB4 gene expression. This is the first report demonstrating the CDX2 regulation of HOXB4 gene expression in the developed intestinal epithelium, indicating a possible role for HOXB4 in intestinal homeostasis

Heterochronic Shift in Hox-Mediated Activation of Sonic hedgehog Leads to Morphological Changes during Fin Development

We explored the molecular mechanisms of morphological transformations of vertebrate paired fin/limb evolution by comparative gene expression profiling and functional analyses. In this study, we focused on the temporal differences of the onset of Sonic hedgehog (Shh) expression in paired appendages among different vertebrates. In limb buds of chick and mouse, Shh expression is activated as soon as there is a morphological bud, concomitant with Hoxd10 expression. In dogfish (Scyliorhinus canicula), however, we found that Shh was transcribed late in fin development, concomitant with Hoxd13 expression. We utilized zebrafish as a model to determine whether quantitative changes in hox expression alter the timing of shh expression in pectoral fins of zebrafish embryos. We found that the temporal shift of Shh activity altered the size of endoskeletal elements in paired fins of zebrafish and dogfish. Thus, a threshold level of hox expression determines the onset of shh expression, and the subsequent heterochronic shift of Shh activity can affect the size of the fin endoskeleton. This process may have facilitated major morphological changes in paired appendages during vertebrate limb evolution

What’s retinoic acid got to do with it? Retinoic acid regulation of the neural crest in craniofacial and ocular development

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151310/1/dvg23308.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151310/2/dvg23308_am.pd

Use of a conditional Ubr5 mutant allele to investigate the role an N-end rule ubiquitin-protein ligase in Hedgehog signalling and embryonic limb development

Hedgehog (Hh) signalling is a potent regulator of cell fate and function. While much is known about the events within a Hh-stimulated cell, far less is known about the regulation of Hh-ligand production. Drosophila Hyperplastic Discs (Hyd), a ubiquitin-protein ligase, represents one of the few non-transcription factors that independently regulates both hh mRNA expression and pathway activity. Using a murine embryonic stem cell system, we revealed that shRNAi of the mammalian homologue of hyd, Ubr5, effectively prevented retinoic-acid-induced Sonic hedgehog (Shh) expression. We next investigated the UBR5:Hh signalling relationship in vivo by generating and validating a mouse bearing a conditional Ubr5 loss-of-function allele. Conditionally deleting Ubr5 in the early embryonic limb-bud mesenchyme resulted in a transient decrease in Indian hedgehog ligand expression and decreased Hh pathway activity, around E13.5. Although Ubr5-deficient limbs and digits were, on average, shorter than control limbs, the effects were not statistically significant. Hence, while loss of UBR5 perturbed Hedgehog signalling in the developing limb, there were no obvious morphological defects. In summary, we report the first conditional Ubr5 mutant mouse and provide evidence for a role for UBR5 in influencing Hh signalling, but are uncertain to whether the effects on Hedgehog signaling were direct (cell autonomous) or indirect (non-cell-autonomous). Elaboration of the cellular/molecular mechanism(s) involved may help our understanding on diseases and developmental disorders associated with aberrant Hh signalling

Mesenchymal Stem Cells from Different Organs are Characterized by Distinct Topographic Hox Codes

Mesenchymal stem cells (MSC) are multipotent cells found as part of the stromal compartment of the bone marrow and in many other organs. They can be identified in vitro as CFU-F (colony forming unit-fibroblast) based on their ability to form adherent colonies of fibroblast-like cells in culture. MSC expanded in vitro retain characteristics appropriate to their tissue of origin. This is reflected in their propensity for differentiating towards specific lineages, and their capacity to generate, upon retransplantation in vivo, a stroma supporting typical lineages of hematopoietic cells. Hox genes encode master regulators of regional specification and organ development in the embryo and are widely expressed in the adult. We investigated whether they could be involved in determining tissue-specific properties of MSC. Hox gene expression profiles of individual CFU-F colonies derived from various organs and anatomical locations were generated, and the relatedness between these profiles was determined using hierarchical cluster analysis. This revealed that CFU-F have characteristic Hox expression signatures that are heterogeneous but highly specific for their anatomical origin. The topographic specificity of these Hox codes is maintained during differentiation, suggesting that they are an intrinsic property of MSC. Analysis of Hox codes of CFU-F from vertebral bone marrow suggests that MSC originate over a large part of the anterioposterior axis, but may not originate from prevertebral mesenchyme. These data are consistent with a role for Hox proteins in specifying cellular identity of MSC

Primary structure of the glycoprotein E2 of coronavirus MHV-A59 and identification of the trypsin cleavage site

The nucleotide sequence of the peplomer (E2) gene of MHV-A59 was determined from a set of overlapping cDNA clones. The E2 gene encodes a protein of 1324 amino acids including a hydrophobic signal peptide. A second large hydrophobic domain is found near the COOH terminus and probably represents the membrane anchor. Twenty glycosylation sites are predicted. Cleavage of the E2 protein results in two different 90K species, 90A and 90B ([Sturman et al., 1985]J. Virol. 56, 904–911), and activates cell fusion. Protein sequencing of the trypsin-generated N-terminus revealed the position of the cleavage site. 90A and 90B could be identified as the C-terminal and the N-terminal parts, respectively. Amino acid sequence comparison of the A59 and 1HM E2 proteins showed extensive homology and revealed a stretch of 89 amino acids in the 90B region of the A59 E2 protein that is absent in JHM