The right atrium in idiopathic hypereosinophilic syndrome : Insights from the 3D speckle tracking echocardiographic MAGYAR-Path Study.

BACKGROUND: Idiopathic hypereosinophilic syndrome is characterized by a persistent eosinophil blood count of >1.5 × 109 cells/l and organ damage, independent of the primary and secondary causes of eosinophilia. The purpose of the present study was to assess the three-dimensional speckle tracking echocardiography-derived right atrial volumetric and functional properties between hypereosinophilic syndrome patients and matched controls. METHODS: A total of 11 patients with idiopathic hypereosinophilic syndrome and 22 age- and gender-matched healthy controls were enrolled in the study. Three-dimensional speckle tracking echocardiography was used for calculation of right atrial volumes, volume-based functional properties, and strain parameters. RESULTS: Significantly increased right atrial maximum (68.7 ± 33.1 ml vs. 40.3 ± 12.1 ml, respectively; p = 0.001) and minimum volumes (48.3 ± 31.0 ml vs. 28.3 ± 9.4 ml, respectively; p = 0.009), as well as right atrial volume before atrial contraction (58.6 ± 27.3 ml vs. 34.5 ± 11.8 ml, respectively; p = 0.001), were found in hypereosinophilic syndrome patients compared with controls. Total and passive right atrial stroke volumes proved to be significantly increased in hypereosinophilic syndrome patients. However, global and mean segmental strain parameters did not differ significantly between the groups. CONCLUSION: Increased cyclic right atrial volumes and mild alterations in right atrial functional properties could be demonstrated in idiopathic hypereosinophilic syndrome patients.

Cytotoxic efficacy of an anthraquinone linked platinum anticancer drug.

Platinum complexes are widely used in cancer chemotherapy; however, they are associated with toxicity, high "non-specific" reactivity and relatively poor pharmacokinetic profiles. In particular, their low cellular uptake and rapid metabolic inactivation means that the amount of "active" drug reaching the nuclear compartment is low. Our strategy to facilitate nuclear accumulation was to introduce a hydrophobic anthraquinone (1C3) moiety to the Pt-complex. Anthraquinones are known to readily intercalate into DNA strands and hence, the Pt-1C3 complex may represent an effective system for the delivery of the platinum moiety to nuclear DNA. Efficacy of the complex was determined by measuring the extent and potency of cytotoxicity in comparison to cisplatin and an anthraquinone based anticancer drug, doxorubicin. The Pt-1C3 complex generated higher levels of cytotoxicity than cisplatin, with a potency of 19 +/- 4 microM in the DLD-1 cancer cell line. However, this potency was not significantly different to that of the 1C3 moiety alone. To examine the reason for the apparent lack of platinum related cytotoxicity, the cellular distribution was characterised. Confocal fluorescence microscopy indicated that the Pt-1C3 complex was rapidly sequestered into lysosomes, in contrast to the nuclear localisation of doxorubicin. In addition, there was negligible DNA associated Pt following administration of the novel complex. Thus, the addition of a 1C3 moiety generated sequestration of the complex to lysosomes, thereby preventing localisation to the nucleus.

The influence of tumour microenvironmental factors on the efficacy of cisplatin and novel platinum(IV) complexes.

The chemotherapeutic drug cisplatin is an important treatment for many types of solid tumours, in particular non-small cell lung cancer (NSCLC). Platinum(IV) complexes offer several advantages to cisplatin due to their requirement for reduction to the active platinum(II) form to elicit cytotoxicity. This should minimise non-specific effects and facilitate higher amounts of the active complexes reaching the target DNA. Hypoxia and a quiescent cell population are features of the tumour microenvironment known to lead to resistance to many chemotherapeutic agents. It is unclear how these microenvironmental factors will impact on the efficacy of novel platinum(IV) complexes. Consequently, the cytotoxicities of several platinum drugs were determined in monolayer and tumour spheroid cultures derived from NSCLC lines. Platinum(IV) reduction potential correlated well with cytotoxicity. The complex containing a chloro axial ligand demonstrated the greatest potency and the drug with the hydroxy ligand was the least effective. Although drug cytotoxicity was not enhanced under hypoxic conditions, both cisplatin and the platinum(IV) complexes retained full potency. In addition, all of the platinum drugs retained the ability to evoke apoptosis in quiescent cells. In summary, unlike many anticancer drugs, the platinum(IV) complexes retain cytotoxic potency under resistance-inducing tumour microenvironmental conditions and warrant further investigation as more selective alternatives to current platinum-based therapy for the treatment of solid tumours.

Transport kinetics of four- and six-coordinate platinum compounds in the multicell layer tumour model.

Four-coordinate (Pt(II)) platinum-based anticancer drugs are widely used in primary or palliative chemotherapy and produce considerable efficacy in certain clinical applications, for example testicular cancer. However, in many cancers the Pt(II) drugs are beset by poor efficacy mainly due to suboptimal pharmacokinetic properties. Consequently, the six-coordinate (Pt(IV)) class of Pt drugs were developed to improve platinum efficacy by (i) increasing stability, (ii) reducing reactivity, (iii) increasing lipophilicity, and (iv) nuclear targeting. However, comparatively little information is available on the pharmacokinetic properties of these compounds within solid tumour tissue. In the present study, the distribution and fluxes of [(14)C]-labelled [PtCl(2)(en)] (where en stands for ethane-1,2-diamine) and cis,trans-[PtCl(2)(OH)(2)(en)] drugs were determined in the multicell layer (MCL) tumour model comprising colon cancer cells. Flux data were analysed by mathematical modelling of drug diffusion and cellular uptake in the transport system. The flux of the Pt(IV) compound through the MCL was not significantly different to that of the Pt(II) drug nor were the diffusion coefficient or tissue uptake; the latter confirmed with elemental imaging analysis by synchrotron radiation induced X-ray emission. However, the flux of the Pt(IV) through the MCL was increased by hydrostatic pressure, thereby demonstrating the potential to target cancer cells further away from the vessels with six-coordinate platinum drugs.

Host-versus-graft disease in mice after the induction of neonatal transplantation tolerance by two different methods.

Newborn A mice were injected either with a single i.v. dose (Group A) or with repeated doses of (B10 x A)F1 semiallogeneic spleen cells (SSC) (Group B). A similar degree of partial transplantation tolerance (TT) to B10 skin allografts was revealed in both groups. No signs of acute, rapidly fatal host-versus-graft disease (HVGD) (anemia, leukocytosis, severe thrombocytopenia, hepatic infarcts, gastrointestinal bleedings) were found, rather a chronic HVGD developed [moderate thrombocytopenia, autoimmune antithymocyte antibodies (ATA)] in both groups. The mortality due to lymphoproliferative disorders (LPD) was significantly higher in Group A. Thus, repeated perinatal injections of (B10 x A)F1 SSC into A mice did not increase the tolerogenic and the LPD-inducing effect either, and they did not elicit acute HVGD in contrast to observations in other F1 donor-recipient combinations [1]. Consequently, the development of acute HVGD depends on immunogenetic factors and not on the repeated administration of SSC.