BackgroundGenomic microarrays have been used as the first-tier cytogenetic diagnostic test for patients with developmental delay/intellectual disability, autism spectrum disorders and/or multiple congenital anomalies. The use of SNP arrays has revealed regions of homozygosity in the genome which can lead to identification of uniparental disomy and parental consanguinity in addition to copy number variations. Consanguinity is associated with an increased risk of birth defects and autosomal recessive disorders. However, the frequency of parental consanguinity in children with developmental disabilities is unknown, and consanguineous couples may not be identified during doctor’s visit or genetic counseling without microarray.ResultsWe studied 607 proband pediatric patients referred for developmental disorders using a 4 × 180 K array containing both CGH and SNP probes. Using 720, 360, 180, and 90 Mb as the expected sizes of homozygosity for an estimated coefficient of inbreeding (F) 1/4, 1/8, 1/16, 1/32, parental consanguinity was detected in 21cases (3.46%).ConclusionParental consanguinity is not uncommon in children with developmental problems in our study population, and can be identified by use of a combined CGH and SNP chromosome microarray. Identification of parental consanguinity in such cases can be important for further diagnostic testing.
Transforming growth factor-1 (TGF-1) has been implicated as a major negative regulator of lung branching morphogenesis. Since connective tissue growth factor (CTGF) is a downstream mediator of TGF-1 effects on mesenchymal cells, we hypothesized that TGF-1 induces CTGF expression in mouse embryonic lung explants and that CTGF mediates TGF-1 inhibition of branching morphogenesis. We show that addition of TGF-1 to the serum-free medium of embryonic day (E)12.5 lung explant cultures inhibited branching morphogenesis and induced CTGF mRNA expression in time-and dose-dependent manners. In contrast to basal endogenous CTGF protein, which was exclusively localized in the distal airway epithelium, TGF-1-induced CTGF protein was localized in both the epithelium and the mesenchyme. Addition of exogenous CTGF to culture medium directly inhibited branching morphogenesis. To identify the signal transduction pathway through which TGF-1 induces CTGF, we used SB431542, a specific inhibitor for TGF- type I receptor (TRI)/ALK-5 to block TGF-1-induced Smad2/3 phosphorylation. Consequently, SB431542 stimulated normal branching morphogenesis and blocked TGF-1 inhibition of branching. Furthermore, SB-431542 blocked both endogenous and TGF-1-induced expression of CTGF mRNA and protein. These results demonstrate for the first time that TGF-1 induces CTGF expression in mouse embryonic lung explants, that CTGF inhibits branching morphogenesis, and that both endogenous and TGF-1-induced CTGF expression are mediated by the TRI/ALK-5-dependent Smad2 signaling pathway. Keywords: connective tissue growth factor; TGF-1; ALK-5; Smad2; lung Normal lung development is highly coordinated by autocrine/ paracrine signaling, and by cell-extracellular matrix (ECM) and cell-cell interactions between the epithelium and mesenchyme (1-3). Peptide growth factors and transcriptional factors play an important role during the processes of lung branching morphogenesis (4). Small changes in the temporal or spatial expression of growth factors or transcriptional factors can lead to significant alterations in the final architecture of the lung and severe defects in the pulmonary function.Multiple lines of evidence have indicated that TGF-s are key negative regulators for lung branching morphogenesis. TGF-s belong to a family of closely related peptides, including TGF-1,
The status of human epidermal growth factor receptor 2 (HER2, ERBB2) determines the eligibility of breast cancer patients to receive HER2-targeted therapy. The majority of HER2 testing in the U.S. is performed using a combination of immunohistochemistry (IHC) screening followed by fluorescence in situ hybridization (FISH) for IHC equivocal cases. In 2013, the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) updated the guideline for HER2 testing. This study evaluates the impact of the 2013 ASCO/CAP updated guideline on final HER2 FISH classification of breast cancers with an equivocal IHC result. For each case, we reported a FISH result according to the 2013 updated guideline and recorded a separated result using the 2007 guideline for investigational purpose. McNemar's test and Bowker's symmetry test were used to compare the classifications by the two guidelines. Among 172 HER2 IHC 2+ equivocal cases, use of the 2103 guideline changed classifications in 36 cases (21 %) when compared with the results expected by use of the 2007 guideline, and yielded a higher proportion of positive (28.5 vs. 23.3 %) and equivocal (16.3 vs. 4.1 %), and a lower proportion of negative (55.2 vs. 72.7 %) cases (p < 0.001). The major classification change with use of the updated guideline is from the HER2 FISH negative to equivocal in 26 cases (15 %). Our study has shown that implementation of the 2013 ASCO/CAP updated guideline has significant impact on HER2 classification for breast cancers with an equivocal HER2 IHC result and therefore increased the use of HER2-targeted therapy. Our data have also shown that reflex FISH is effective for final classification of the IHC equivocal cases and that polysomy 17 (CEP17 copy number ≥3/cell) is present in a significantly higher proportion of cases with an equivocal HER2 FISH classification.
High tidal volume (V T ) ventilation plays a key role in ventilator induced lung injury and bronchopulmonary dysplasia. However, little is known about the effect of high V T on expression of growth factors that are critical to lung development. In a previous study, we demonstrated that connective tissue growth factor (CTGF) inhibits branching morphogenesis. In this study, we investigated the effect of high V T on CTGF expression in newborn rat lungs. Newborn rats were ventilated with normal V T (10 mL/kg) or high V T (25 mL/kg) for 6 h. Nonventilated animals served as controls. We found that high V T upregulated CTGF expression. To identify the potential signaling pathways mediating high V T induction of CTGF, newborn rats were ventilated with high V T for 1 or 3 h. Temporal expression of TGF-s, p-Smad2, Smad7, and CTGF was analyzed. High V T ventilation did not change gene expression of TGF-s and Smad7 but induced rapid and sustained expression of p-Smad2 that precedes increased CTGF expression. CTGF and p-Smad2 were localized in bronchiolar epithelial cells, alveolar walls and septa. These data suggest that high V T ventilation activates the Smad2 pathway, which may be responsible for downstream induction of CTGF expression in newborn rat lungs. M echanical ventilation is essential for managing prematurely born infants with respiratory failure. However, ventilation with high tidal volume (V T ) can lead to ventilator induced lung injury (VILI) and bronchopulmonary dysplasia (BPD) (1-3). The lung pathology of BPD is characterized by fewer and larger alveoli, dysmorphic and decreased capillary network, and variable interstitial fibrosis, suggesting abnormal lung development and injury repair processes (4,5). Most of the studies in VILI and BPD have been focused on high V T induced lung proinflammatory response (6 -9). Little is known about the effect of high V T on expression of growth factors that are key to lung development and injury repair in neonatal lungs.Connective tissue growth factor (CTGF) belongs to the CCN family of early gene products with a high degree of amino acid sequence homology and 38 conserved cysteine residues (10,11). CTGF promotes fibroblast proliferation, extracellular matrix (ECM) production, myofibroblast differentiation, and cell adhesion and migration (12-16). CTGF is a potent profibrotic cytokine and its mRNA and protein levels have been correlated with the degree of lung fibrosis in bleomycin-treated mice and in human fibrotic lung disorders (17)(18)(19). Previous studies have demonstrated that mechanical stress drastically induces CTGF expression in cultured fibroblasts (20,21). CTGF is closely linked to TGF-. Studies have demonstrated that TGF- is a major inducer of CTGF expression in a variety of tissues and organs including the lung (11,(22)(23)(24). Activation of the Smad pathway plays a key role in TGF- induction of CTGF expression (25,26). TGF- stimulation of fibroblast proliferation, collagen synthesis, and myofibroblast differentiation is mediated via a CTG...
IntroductIon:Oxygen exposure plays an important role in the pathogenesis of bronchopulmonary dysplasia (BPD). The phosphodiesterase inhibitor pentoxifylline (PTX) has antiinflammatory and antifibrotic effects in multiple organs. It was hypothesized that PTX would have a protective effect on hyperoxia-induced lung injury (hILI). Methods: Newborn sprague-Dawley rats were exposed to >95% oxygen (O 2 ) and injected subcutaneously with normal saline (Ns) or PTX (75 mg/kg) twice a day for 9 d. Ns-injected, room air-exposed pups were controls. at days 4 and 9, lung tissue was collected to assess edema, antioxidant enzyme (aOe) activities, and vascular endothelial growth factor (VeGF) expression. at day 9, pulmonary macrophage infiltration, vascularization, and alveolarization were also examined. results: at day 9, treatment with PTX significantly increased survival from 54% to 88% during hyperoxia. Treatment with PTX significantly decreased lung edema and macrophage infiltration. PTX treatment increased lung aOe activities including those of superoxide dismutase (sOD), catalase (caT), and glutathione peroxidase (GPX). Furthermore, PTX treatment also increased the gene expression of VeGF189 and VeGF165, increased VeGF protein expression, and improved pulmonary vascularization. dIscussIon: These data indicate that the reduced lung edema and inflammation, increased aOe activities, and improved vascularization may be responsible for the improved survival with PTX during hyperoxia. PTX may be a potential therapy in reducing some of the features of BPD in preterm newborns.
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