Cardiotoxicity among adult survivors suffered from childhood malignancies.

Late cardiotoxicity following treatment of malignancy diseases has been long established. Cancer therapeutics-related cardiac dysfunction (CTRCD), acute arrhythmias, pericardial disease, valvopathies and early atherosclerotic Cardiovascular Disease (CVD), are the clinical presentations of cardiotoxicity. Although these clinical modalities can affect adults treated for malignancies, they are more common to present in the pediatric survivors as improvement of prognosis, nowadays exists. Studies have shown that CVD can present earlier than thirty years, post treatment. If adding on this the early and late effect of cardiotoxicity on the developing in childhood cardiovascular system, we are then faced with a new Risk Factor (RF) for CVD. Anthracyclines and its derivatives have served for over fifty years as the road model of studding early, mid and late term cardiotoxicity. Today a vast number of chemical agents are used, many of them with very good results in treating the existing malignancies. Unfortunate, little or even less are known on their potential mechanism of derived cardiotoxicity when used by their own or combined with others and/or radiotherapy (RT). The 2013 existing guidelines by ACC/AHA on surveillance of the cardiovascular health of oncology survivors, are mostly addressing early cardiac adverse effects and CTRCD. Little is mentioned about the development of early CVD, its subclinical diagnosis, prevention and the need of early intervention before clinical events are present. The aim of this paper is to review the exist knowledge and practice on this condition with growing numbers of survivors facing the risk of early atherosclerotic CVD.

Isolation, cloning, and characterization of a new mammalian coronin family member, coroninse, which is regulated within the protein kinase C signaling pathway.

In order to understand the regulatory role of protein kinase C (PKC) in secretory epithelia, it is necessary to identify and characterize specific downstream targets. We previously identified one such protein in studies of gastric parietal cells. This protein was referred to as pp66 because it migrated with an apparent molecular mass of 66 kDa on SDS-polyacrylamide gels. The phosphorylation of pp66 is increased by the cholinergic agonist, carbachol, and by the PKC activator, phorbol-12-myristate-13-acetate, in a calcium-independent manner. In this study, we have purified pp66 to homogeneity and cloned the complete open reading frame. GenBankTM searches revealed a 45% homology with the Dictyostelium actin-binding protein, coronin, and approximately 67% homology with the previously cloned human and bovine coronin-like homologue, p57. pp66 appears to be most highly expressed in the gastrointestinal mucosa and in kidney and lung. Confocal microscopic studies of an enhanced green fluorescent protein fusion construct of pp66 in cultured parietal cells and in Madin-Darby canine kidney cells indicate that pp66 preferentially localizes in F-actin-rich regions. On the basis of our findings, we propose that pp66 may play an important, PKC-dependent role in regulating membrane/cytoskeletal rearrangements in epithelial cells. We have tentatively named this protein coroninse, because it appears to be highly expressed in secretory epithelia.

Purification, cloning, and expression of a novel, endogenous, calcium-sensitive, 28-kDa phosphoprotein.

In gastric parietal cells, cholinergically induced increases in intracellular free calcium concentrations have been well characterized, but little is known about the signaling events beyond the initial rise in intracellular calcium. In the present study, we report the isolation of a 28-kDa protein, which is rapidly phosphorylated in intact, enriched parietal cells in response to both the cholinergic agonist, carbachol, and the calcium ionophore, ionomycin. A combination of in situ 32P labeling and one- and two-dimensional gel electrophoresis was used to acquire sufficient quantities of protein to obtain partial amino acid sequence. Cloning of the pp28 cDNA revealed a novel protein which we have named CSPP28 based on its calcium-sensitive phosphorylation. There are three CSPP28 mRNA species (1.7, 2.2, and 3.3 kilobases) that are widely distributed throughout a variety of rabbit tissues. Recombinant CSPP28 was phosphorylated by both crude parietal cell homogenate and purified CaM kinase II in a calcium/calmodulin-dependent manner. We propose that CSPP28 may play an important and ubiquitous role in the calcium signaling pathway.

Multiple actions of epidermal growth factor and TGF-alpha on rabbit gastric parietal cell function.

Parietal cells in primary culture and freshly isolated parietal cells were used to compare acute and chronic effects of epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) on acid-secretory related activity, measured as accumulation of the weak base, [14C]aminopyrine (AP). EGF and TGF-alpha chronically enhanced basal and agonist-stimulated AP accumulation (mean effective concentration 0.6-0.8 nM) but acutely inhibited responses to histamine and carbachol (half-maximal inhibitory concentration approximately 4 nM). Pertussis toxin (250 ng/ml, 4 h) suppressed acute EGF inhibition of histamine-stimulated AP accumulation but not the chronic enhancement. A subclass of tyrosine kinase inhibitors suppressed chronic EGF effects (genistein > tyrphostin B56 >>> tyrphostin B42), whereas tyrphostin A25, lavendustin A, and the inactive genistein analogue, daidzein, had no significant effect. In contrast, histamine-stimulated AP accumulation was acutely potentiated by genistein, daidzein, and tyrphostin B42, but not tyrphostin B56. Reduced phosphorylation of a 44- to 45-kDa protein with an isoelectric point of approximately 7 [phosphoprotein (pp) 44] was correlated with chronic inhibition but not with acute potentiation by specific tyrosine kinase inhibitors. Preliminary data indicate that pp44 is a member of the mitogen-activated protein kinase family of tyrosine/threonine kinases (also known as extracellular signal-related kinases). We propose that 1) EGF and/or TGF-alpha modulates parietal cell function by multiple signaling pathways, 2) a soluble tyrosine kinase may be involved in the mediation of the chronic effects of EGF, and 3) acute potentiation of histamine-stimulated AP accumulation by certain tyrosine kinase inhibitors and daidzein is probably not mediated by receptor-associated tyrosine kinases.

Effect of short-term treatment with gastrin and related peptides on gastrointestinal histamine H2-receptors.

The effects of short-term, 7-day, treatment with synthetic 15-leucine human gastrin I, pentagastrin or sulfated cholecystokinin-8 on the activity of histamine (HA)-stimulated adenylate cyclase in membranes isolated from guinea pig gastric mucosa and H2-receptor-mediated contractions of isolated ilea were evaluated. Treatment with each of the peptides produced a decrease in the maximal rate of HA-stimulated adenylate cyclase. The decreases in the maximal rate occurred without any effect on the potency of HA or any effect on basal rates of activity. In animals treated with pentagastrin, but not with cholecystokinin octapeptide sulfate, the contractile activity of dimaprit, a selective H2-agonist, was decreased. In animals treated with pentagastrin, the contractile actions of pentagastrin on isolated ileal preparations were increased. A 7-day treatment with the H2-antagonist, tiotidine, did not alter the potency of or the maximal response for HA-stimulated adenylate cyclase activity. Co-treatment with tiotidine prevented the effects of pentagastrin on gastric mucosal HA-stimulated adenylate cyclase. Treatment with pentagastrin did not alter the sensitivity of the gastric mucosal H2-receptor to inhibition by tiotidine. The effects of treatment with gastrin on NaF-stimulated adenylate cyclase activity also were determined. Treatment with gastrin did not alter the actions of NaF, suggesting that the coupling between the Gs subunit and the catalytic subunit of adenylate cyclase was not altered.(ABSTRACT TRUNCATED AT 250 WORDS)

Thapsigargin potentiates histamine-stimulated HCl secretion in gastric parietal cells but does not mimic cholinergic responses.

The role of calcium in control of HCl secretion by the gastric parietal cell was examined using a recently available intracellular calcium-releasing agent, thapsigargin, which has been shown, in some cell types, to induce sustained elevation of intracellular calcium ([Ca2+]i), an action that appears to be independent of inositol lipid breakdown and protein kinase C activation and to be mediated, at least partially, by selective inhibition of endoplasmic reticulum Ca2(+)-ATPase. Using the calcium-sensitive fluorescent probe, fura-2, in combination with digitized video image analysis of single cells as well as standard fluorimetric techniques, we found that thapsigargin induced sustained elevation of [Ca2+]i in single parietal cells and in parietal cells populations. Chelation of medium calcium led to a transient rise and fall in [Ca2+]i, indicating that the sustained elevation in [Ca2+]i in response to thapsigargin was due to both intracellular calcium release and influx. Although thapsigargin appeared to affect the same calcium pool(s) regulated by the cholinergic agonist, carbachol, and the pattern of thapsigargin-induced increases in [Ca2+]i were similar to the plateau phase of the cholinergic response, thapsigargin did not induce acid secretory responses of the same magnitude as those initiated by carbachol (28 vs 600% of basal). The protein kinase C activator, 12-O-tetradecanoyl phorbol-13-acetate (TPA) potentiated the secretory response to thapsigargin but this combined response also did not attain the same magnitude as the maximal cholinergic response. In the presence but not the absence of medium calcium, thapsigargin potentiated acid secretory responses to histamine, which elevate both cyclic AMP (cAMP) and [Ca2+]i in parietal cells, as well as forskolin and cAMP analogues but had no effect on submaximal and an inhibitory effect on maximal cholinergic stimulation. Furthermore, thapsigargin did not fully mimic potentiating interactions between histamine and carbachol, either in magnitude or in the pattern of temporal response. Assuming that the action of thapsigargin is specific for intracellular calcium release mechanisms, these data suggest that 1) sustained influx of calcium is necessary but not sufficient for cholinergic activation of parietal cell HCl secretion and for potentiating interactions between cAMP-dependent agonists and carbachol; 2) mechanisms in addition to elevated [Ca2+]i and protein kinase C activation may be involved in cholinergic regulation; and 3) increases in [Ca2+]i in response to histamine are not directly involved in the mechanism of histamine-stimulated secretion.

Aromatase inhibition depresses ultrasound production and copulation in male hamsters.

Rates of ultrasound production and copulatory behavior were observed in castrated male hamsters maintained on 100 micrograms/day of injected testosterone propionate (TP). Groups matched on their initial levels of behavior received either continued treatment with TP alone, or TP together with 6 mg/day injections of the aromatase inhibitor 1,4,6-androstatriene-3,17-dione (ATD). Testing at 11-15 days after the start of these treatments revealed deficits in the sexual behaviors of the subjects in the latter group. Specifically, these males showed lower rates of ultrasound production and intromission during, as opposed to before, treatment with ATD. These results support previous work suggesting that aromatization plays significant roles in the mediation of androgenic effects on both the courtship and copulatory behaviors of male hamsters.