Hemangiomas revisited: the useful,the unusual and the new Part 2: endangering hemangiomas and treatment

Hemangiomas, although benign tumors, can when located in particular regions threaten vital structures or in certain clinical circumstances be associated with other abnormalities, carrying significant morbidity and mortality. We review these endangering hemangiomas. We also discuss briefly the treatment with emphasis on the recent use of propranolol.     

p53-dependent and p53-independent anticancer effects of different histone deacetylase inhibitors

Background:

Histone deacetylase inhibitors (HDACi) are promising antineoplastic agents, but their precise mechanisms of actions are not well understood. In particular, the relevance of p53 for HDACi-induced effects has not been fully elucidated. We investigated the anticancer effects of four structurally distinct HDACi, vorinostat, entinostat, apicidin and valproic acid, using isogenic HCT-116 colon cancer cell lines differing in p53 status.

Methods:

Effects were assessed by MTT assay, flow-cytometric analyses of propidium iodide uptake, mitochondrial depolarisation and cell-cycle distribution, as well as by gene expression profiling.

Results:

Vorinostat was equally effective in p53 wild-type and null cells, whereas entinostat was less effective in p53 null cells. Histone deacetylase inhibitors treatment suppressed the expression of MDM2 and increased the abundance of p53. Combination treatments showed that vorinostat enhanced the cytotoxic activity of TRAIL and bortezomib, independent of the cellular p53 status. Investigations into the effects of an inhibitor of the sirtuin class of HDAC, tenovin-1, revealed that tenovin-1-mediated cell death hinged on p53.

Conclusion:

These results demonstrate that vorinostat activates p53, but does not require p53 for inducing its anticancer action. Yet they also demonstrate that entinostat-induced cytotoxic effects partially depend on p53, indicating that different HDACi have a different requirement for p53.     

Anticancer effects of the p53 activator nutlin-3 in Ewing's sarcoma cells

Mutation of p53 is rare in Ewing’s sarcoma (ES), suggesting that targeting and activation of wild-type p53 may be an effective therapeutic strategy for ES. The recently developed small-molecule MDM2 inhibitor nutlin-3 restores wild-type p53 function, resulting in the inhibition of cancer cell growth and the induction of apoptosis. In the present study, we explored the responsiveness of ES cell lines with wild-type or mutated p53 to nutlin-3. We found that treatment with nutlin-3 increased p53 level and induced p53 target gene expression (MDM2, p21, PUMA) in ES cells with wild-type p53, but not in ES cells with mutated p53. Consistently, nutlin-3 elicited apoptosis only in wild-type p53 cells, as assessed by caspase-3 activity assay and flow cytometric analyses of mitochondrial depolarisation and DNA fragmentation. In addition, we found nutlin-3 to evoke cellular senescence, indicating that nutlin-3 induces pleiotropic anticancer effects in ES. Furthermore, combined treatment with nutlin-3 and an inhibitor of NF-κB produced synergistic antineoplastic activity in ES cells. Our findings suggest that the direct activation of p53 by nutlin-3 treatment may be a useful new therapeutic approach for patients with ES.     

Bursts and hyperexcitability in non-myelinated axons of the rat hippocampus

Strict control over the initiation of action potentials is the primary task of a neuron. One way to lose proper spike control is to create several spikes, a burst, when only one should be initiated. We describe a new site for burst initiation in rat hippocampal CA3 neurons: the Schaffer collateral axons. These axons lack myelin, are long, extremely thin, and form synapses along their entire paths, features typical for many, if not most cortical axons in the mammalian brain. We used hippocampal slices and recorded from individual Schaffer collateral axons. We found that single action potentials were converted into bursts of two to six action potentials after blocking 4-aminopyridine (4-AP) sensitive K⁺ channels. The CA3 somata and initial part of their axons were surgically removed in these experiments, leading to the conclusion that the bursts were initiated far out in the axons. This conclusion was supported by two additional kinds of experiments. First, local application of 4-AP to one out of two stimulated axonal branches of the same neuron showed bursting only at the 4-AP exposed branch. Second, intracellular recordings from CA3 somata showed that some spontaneously occurring bursts were resistant to somatic hyperpolarization. We then investigated a hyperexcitable period that follows individual spikes in the Schaffer collaterals. With extracellular excitability testing, we showed that the time course of this hyperexcitability was compatible with that of the bursts, so this hyperexcitability could be the underlying cause of the bursts. Furthermore, the hyperexcitability was enhanced by low doses of 4-AP (20 μM), α-dendrotoxin (α-DTX) or margatoxin (MgTX). Kv1.2 containing channels may therefore dampen the hyperexcitability, but because bursting was observed only at high 4-AP concentration (1 mM), other channels may be needed to prevent axonal bursting.     

Studies on screening, isolation and purification of a fibrinolytic protease from an isolate (VK12) of Ganoderma lucidum and evaluation of its antithrombotic activity

Antithrombotic activity of a protease purified from a medicinal mushroom, Ganoderma lucidum, has been evaluated platelet aggregation in vitro and pulmonary thrombosis in vivo. The purified protease exhibited concentration dependent inhibitory effects on platelet aggregation induced by ADP (adenosine diphosphate), with an IC(50) value of 2.4 mg/mL. The purified protease protected mice against thrombotic death or paralysis induced by collagen and epinephrine in a dose dependent manner when administered orally. It produced a significant inhibition of thrombotic death or paralysis at 60 μg/kg body weight, while aspirin produced a significant inhibition of thrombosis at 10-20 mg/kg body weight. The purified protease also has showed fibrinolytic activity and alters coagulation parameters such as activated partial thromboplastin time (APTT), and thrombin time (TT) in rat platelet. These results suggested that the antithrombotic activity of Ganoderma lucidum protease might be due to antiplatelet activity rather than anticoagulation activity.     

Real-world experience of selexipag titration in pulmonary arterial hypertension

Selexipag is an oral selective prostacyclin-receptor agonist that was approved for use in patients with World Health Organisation (WHO) functional class II–III pulmonary arterial hypertension (PAH). Treatment with individualised doses of selexipag resulted in significant reductions in the composite end point of death or a complication related to PAH in the phase III GRIPHON (Prostacyclin [PGI2] Receptor Agonist In Pulmonary Arterial Hypertension) study. In order to better understand the real-world approach to selexipag titration and to establish the individualised maintenance regimens used in our centre, we performed this retrospective study of the first 20 patients prescribed selexipag. Baseline characteristics differed from the GRIPHON study, with more combination therapy and comorbidities at drug initiation. Maintenance doses were stratified as low-dose in 10% (n=2), medium-dose in 70% (n=14) and high-dose in 20% (n=4). This study highlights that selexipag can be safely initiated, titrated and transitioned in an outpatient setting to achieve an individualised dosing regimen.Key words: prostacyclin, pulmonary circulation, pulmonary hypertension, selexipag