Mapping of the RXRalpha binding elements involved in retinoic acid induced transcriptional activation of the human SOX3 gene

Sox3/SOX3 gene is implicated in the control of nervous system development and is considered to be one of the earliest neural markers. Expression of human SOX3 gene is modulated during the RA-induced neuronal differentiation cascade of NT2/D1 cells. Our present results demonstrate that the sequences responsible for RA-induced activation of SOX3 gene are localized within the 0.4 kb of its 5'-flanking region and implicate RXRalpha involvement in this regulation. The active RA/RXRalpha responsive region is pinned down to two regulatory elements. Only in the presence of both elements full RA/RXRalpha inducibility is achieved, suggesting they act synergistically. These elements comprise two unique G-rich boxes, separated by 49 bp, that could be considered as a novel, atypical RA-response element. Here, for the first time, we have demonstrated direct interaction of RXRalpha and SOX3 control elements. Furthermore, the functional in vivo analysis revealed that liganded RXRalpha is a potent activator of endogenous SOX3 protein expression. Since it is proven that Sox3 is critical determinant of neurogenesis our data may help in providing new insight into complex regulatory networks involved in retinoic acid induced neural differentiation of NT2/D1 cells.     

Multinodular and vacuolating neuronal tumour of the cerebrum: a rare neuroimaging incidentaloma or a potentially treatable cause of focal epilepsy?

Multinodular and vacuolating neuronal tumour (MVNT) of the cerebrum is a relatively new, well defined histopathological and neuroradiological entity, in many cases associated with an early adult‐onset epilepsy. These lesions have an indolent course and resemble both malformative and neoplastic processes, combining a focal developmental anomaly and a low‐grade tumour. Herein, we report a case of a 48‐year‐old female patient with left temporal lobe epilepsy associated with MVNT. In addition, a comprehensive review of all the previously published cases is provided with a focus on seizure‐related cases, surgical treatment, and postoperative outcome.     

Use of software applications to improve medication adherence and achieve more integrated disease management in heart failure

The treatment and management of heart failure is associated with high mortality rates and treatment costs. Poor medication adherence is a major barrier to improving care and traditional interventions addressing non-adherence have not consistently demonstrated improvement in health care outcomes like readmission. The reasons for non-adherence are complicated and illustrate the broader challenges patients face when managing a complex disease like heart failure. In this review, a digitally enabled heart failure management platform consisting of medical digital tools and software solutions that are designed to be patient-facing and continuously accessed is explored as a way to integrate the multiple components of heart failure care and deliver personalized patient management tools.     

Sleep apnoea and hypertension

This review article provides an update on two major issues. First, the most recent evidence supporting the occurrence of an association between obstructive sleep apnoea syndrome, or more generally sleep-disordered breathing, and arterial hypertension in humans is summarized and discussed. This includes an evaluation of both cross-sectional and longitudinal studies. Second, new insights into the mechanisms responsible for the appearance of chronic hypertension in individuals suffering from recurrent nocturnal apnoeic episodes are provided, based both on experimental studies in animals and on clinical studies in humans. The relevance of these data for the clinical management of hypertensive patients with sleep-disordered breathing, and the possibility of obtaining a reduction in blood pressure through the application of nasal continuous positive air pressure, is also addressed.     

Cytotoxicity, cellular uptake, and DNA interactions of new monodentate ruthenium(II) complexes containing terphenyl arenes

We have compared the cancer cell cytotoxicity, cell uptake, and DNA binding properties of the isomeric terphenyl complexes [(eta(6)-arene)Ru(en)Cl](+), where the arene is ortho- (2), meta- (3), or para-terphenyl (1) (o-, m-, or p-terp). Complex 1, the X-ray crystal structure of which confirms that it has the classical "piano-stool" geometry, has a similar potency to cisplatin but is not cross-resistant and has a much higher activity than 2 or 3. The extent of Ru uptake into A2780 or A2780cis cells does not correlate with potency. Complex 1 binds to DNA rapidly and quantitatively, preferentially to guanine residues, and causes significant DNA unwinding. Circular and linear dichroism, competitive binding experiments with ethidium bromide, DNA melting, and surface-enhanced Raman spectroscopic data are consistent with combined intercalative and monofunctional (coordination) binding mode of complex 1. This unusual DNA binding mode may therefore make a major contribution to the high potency of complex 1.     

Tumor microvasculature supports proliferation and expansion of glioma‐propagating cells

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. The identification of ‘cancer stem cells’ (CSC) has shed new light on the potential mechanism of therapy resistance of these tumors. Because these cells appear to be more resistant to conventional treatments, they are thought to drive tumor regrowth after therapy. Therefore, novel therapeutic approaches that target these cells are needed. Tumor cells interact with their microenvironment. It has been reported that close contact between CSCs and tumor microvascular endothelium in GBM is important for CSCs to preserve their undifferentiated state and self‐renewal ability. However, our understanding of this interaction is still rudimentary. This is in part due to a lack of suitable in vitro models that accurately represent the in vivo situation. Therefore, we set up a co‐culture system consisting of primary brain tumor microvascular endothelial cells (tMVECs) and glioma propagating cells (GPCs) derived from biopsies of GBM patients. We found that tMVECs support the growth of GPCs resulting in higher proliferation rates comparing to GPCs cultured alone. This effect was dependent on direct contact between the 2 cell types. In contrast to GPCs, the FCS‐cultured cell line U87 was stimulated by culturing on tMVEC‐derived ECM alone, suggesting that both cell types interact different with their microenvironment. Together, these results demonstrate the feasibility and utility of our system to model the interaction of GPCs with their microenvironment. Identification of molecules that mediate this interaction could provide novel targets for directed therapy for GBM. © 2009 UICC