Purpose:The basic fibroblast growth factor (FGF-2) gene is bidirectionally transcribed to generate overlapping sense and antisense (FGF-AS) mRNAs. FGF-AS has been implicated in the posttranscriptional regulation of FGF-2 expression. The aim of this study was to characterize FGF-2 and FGF-AS in esophageal cancer and to correlate their expression with clinicopathologic findings and outcome. Experimental Design: Reverse transcription-PCR was used to study FGF-2 and FGF-AS mRNA expression (normalized to glyceraldehyde-3-phosphate dehydrogenase) in 48 esophageal cancers relative to matched histologically normal esophageal epithelia (internal control). We used Cox proportional hazards analysis to calculate hazard ratios for recurrence and survival of patients with underexpression relative to the overexpression of FGF-2 and/or FGF-AS. Results: Overexpression of FGF-2 mRNA, by comparison with tumors underexpressing FGF-2, was associated with significantly increased risk for tumor recurrence (hazard ratio, 3.80; 95% confidence interval, 1.64-8.76) and reduced overall survival (hazard ratio, 2.11; 95% confidence interval, 1.0-4.58). When the effects of FGF-2 and FGF-AS were considered simultaneously, the association of FGF-2 mRNA overexpression with recurrence and mortality was even more pronounced, whereas FGF-AS mRNA overexpression was associated with reduced risk for recurrence and improved survival. Conclusions: Overexpression of FGF-2 mRNA is associated with tumor recurrence and reduced survival after surgical resection of esophageal cancer and that these risks are reduced in tumors coexpressing the FGF-AS mRNA. These data support the hypothesis that FGF-AS is a novel tumor suppressor that modulates the effect of FGF-2 expression and may have potential clinical application to the development of novel therapeutic strategies.

A positive correlation has been shown between dietary intake of long-chain omega-3 fatty acids in late pregnancy and gestation length in pregnant women and experimental animals. To determine whether omega-3 fatty acids have an effect on preterm labor in sheep, a fish oil concentrate emulsion was continuously infused to six pregnant ewes from 124 days gestational age. At 125 days, betamethasone was administered to the fetus to produce preterm labor. Both the onset of labor and the time of delivery were delayed by the fish oil emulsion. Two of the omega-3-infused ewes reverted from contractions to nonlabor, an effect never previously observed for experimental glucocorticoid-induced preterm labor in sheep. Maternal plasma estradiol and maternal and fetal prostaglandin E2 rose in control ewes but not in those infused with omega-3 fatty acid. The ability of omega-3 fatty acids to delay premature delivery in sheep indicates their possible use as tocolytics in humans. Premature labor is the major cause of neonatal death and long-term disability, and these studies present information that may lead to a novel therapeutic regimen for the prevention of preterm delivery in human pregnancy.

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Connective tissue growth factor (CTGF) is a mediator of growth factor activity, and Ctgf knockouts die at birth from respiratory failure due to skeletal dysplasia. Previous microarray analysis revealed Ctgf downregulation in the hypoplastic lungs of amyogenic mouse embryos. This study, therefore, examined pulmonary development in Ctgf؊/؊ mouse fetuses to investigate if respiration could also have been impaired by lung abnormalities. The Ctgf؊/؊ lungs were hypoplastic, with reduced cell proliferation and increased apoptosis. PDGF-B, its receptor and IGF-I, were markedly attenuated and the TTF-1 gradient lost. Type II pneumocyte differentiation was perturbed, the cells depicting excessive glycogen retention and diminished lamellar body and nuclear size, though able to synthesize surfactant-associated protein. However, type I pneumocyte differentiation was not affected by Ctgf deletion. Our findings indicate that the absence of Ctgf and/or its protein product, CTGF, may induce pulmonary hypoplasia by both disrupting basic lung developmental processes and restricting thoracic expansion. Developmental Dynamics 237: 485-493, 2008.

(NPRs), which can either activate guanylyl cyclase (NPRA and NPRB) or inhibit adenylyl cyclase (NPRC) to modulate intracellular cGMP or cAMP, respectively. During cardiac development, ANP serves as an early maker of differentiating atrial and ventricular chamber myocardium. As development proceeds, expression of ANP persists in the atria but declines in the ventricles. Currently, it is not known whether ANP is secreted or the ANP-NPR signaling system plays any active role in the developing ventricles. Thus the primary aims of this study were to 1) examine biological activity of ANP signaling systems in embryonic ventricular myocardium, and 2) determine whether ANP signaling modulates proliferation/differentiation of undifferentiated cardiac progenitor cells (CPCs) and/or cardiomyocytes. Here, we provide evidence that ANP synthesized in embryonic day (E)11.5 ventricular myocytes is actively secreted and processed to its biologically active form. Notably, NPRA and NPRC were detected in E11.5 ventricles and exogenous ANP stimulated production of cGMP in ventricular cell cultures. Furthermore, we showed that exogenous ANP significantly decreased cell number and DNA synthesis of CPCs but not cardiomyocytes and this effect could be reversed by pretreatment with the NPRA receptorspecific inhibitor A71915. ANP treatment also led to a robust increase in nuclear p27 levels in CPCs compared with cardiomyocytes. Collectively, these data provide evidence that in the developing mammalian ventricles ANP plays a local paracrine role in regulating the balance between CPC proliferation and differentiation via NPRA/ cGMP-mediated signaling pathways. embryonic heart; ANP; natriuretic peptide receptors; gene expression; cardiac progenitor cells; cardiomyocytes; lineage tracking; knockin mice; cell proliferation and differentiation ATRIAL NATRIURETIC PEPTIDE (ANP) is a 28 amino acid peptide that is synthesized and stored primarily in secretory granules of atrial cardiomyocytes in the adult heart. Ligand binding of ANP to its cognate natriuretic peptide receptors (NPRs) can either activate guanylyl cyclase (NPRA and NPRB) or inhibit adenylyl cyclase (NPRC) to modulate intracellular cGMP or cAMP, respectively. The primary stimulus for ANP secretion from atrial cardiomyocytes is mechanical stretch of the atrial wall (15). In addition to mechanical stimuli, several vasoconstrictor peptides including endothelin-1 (ET-1) (36) and angiotensin II (9), as well as a variety of neurohormones, growth factors, and cytokines, have been shown to modulate natriuretic peptide secretion (10). Once in the circulation, ANP acts in a true endocrine fashion by stimulating NPRA receptors in the kidneys, adrenal cortex, and vasculature to regulate fluid homeostasis and maintain blood pressure via diuretic, natriuretic and vasorelaxant effects (29). In the ventricles of the adult heart, the levels of ANP protein are normally ϳ1,000-fold lower than in the atria and secretory granules are rarely observed (31).In contrast to the adult heart, developmental stud...