Stem-like and highly invasive prostate cancer cells expressing CD44v8-10 marker originate from CD44-negative cells

In human prostate cancer (PCa), the neuroendocrine cells, expressing the prostate cancer stem cell (CSC) marker CD44, may be resistant to androgen ablation and promote tumor recurrence. During the study of heterogeneity of the highly aggressive neuroendocrine PCa cell lines PC3 and DU-145, we isolated and expanded in vitro a minor subpopulation of very small cells lacking CD44 (CD44neg). Unexpectedly, these sorted CD44neg cells rapidly and spontaneously converted to a stable CD44high phenotype specifically expressing the CD44v8-10 isoform which the sorted CD44high subpopulation failed to express. Surprisingly and potentially interesting, in these cells expression of CD44v8-10 was found to be induced in stem cell medium. CD44 variant isoforms are known to be more expressed in CSC and metastatic cells than CD44 standard isoform. In agreement, functional analysis of the two sorted and cultured subpopulations has shown that the CD44v8-10pos PC3 cells, resulting from the conversion of the CD44neg subpopulation, were more invasive in vitro and had a higher clonogenic potential than the sorted CD44high cells, in that they produced mainly holoclones, known to be enriched in stem-like cells. Of interest, the CD44v8-10 is more expressed in human PCa biopsies than in normal gland. The discovery of CD44v8-10pos cells with stem-like and invasive features, derived from a minoritarian CD44neg cell population in PCa, alerts on the high plasticity of stem-like markers and urges for prudency on the approaches to targeting the putative CSC

Activation of 5-HT7 receptor stimulates neurite elongation through mTOR, Cdc42 and actin filaments dynamics.

Recent studies have indicated that the serotonin receptor subtype 7 (5-HT7R) plays a crucial role in shaping neuronal morphology during embryonic and early postnatal life. Here we show that pharmacological stimulation of 5-HT7R using a highly selective agonist, LP-211, enhances neurite outgrowth in neuronal primary cultures from the cortex, hippocampus and striatal complex of embryonic mouse brain, through multiple signal transduction pathways. All these signaling systems, involving mTOR, the Rho GTPase Cdc42, Cdk5, and ERK, are known to converge on the reorganization of cytoskeletal proteins that subserve neurite outgrowth. Indeed, our data indicate that neurite elongation stimulated by 5-HT7R is modulated by drugs affecting actin polymerization. In addition, we show, by 2D Western blot analyses, that treatment of neuronal cultures with LP-211 alters the expression profile of cofilin, an actin binding protein involved in microfilaments dynamics. Furthermore, by using microfluidic chambers that physically separate axons from the soma and dendrites, we demonstrate that agonist-dependent activation of 5-HT7R stimulates axonal elongation. Our results identify for the first time several signal transduction pathways, activated by stimulation of 5-HT7R, that converge to promote cytoskeleton reorganization and consequent modulation of axonal elongation. Therefore, the activation of 5-HT7R might represent one of the key elements regulating CNS connectivity and plasticity during development

Некоторые подходы к совершенствованию регионально-институциональной основы курортно-гостиничных услуг в Автономной республике Крым

Рассмотрены подходы (институциональный, региональный, проблемно-ориентированный и маркетинговый) к разработке регионально-институциональной модели курортно-гостиничного хозяйства как одной из важнейших составляющих институциональной модели курортно-рекреационного комплекса Автономной Республики Крым.Розглядаються підходи (інституційний, регіональний, проблемно-орієнтований і маркетинговий) до розробки регіонально-інституційної моделі курортно-готельного господарства як однієї з найважливіших складових інституційної моделі курортно-рекреаційного комплексу Автономної Республіки Крим

Experimental system to displace radioisotopes from upper to deeper soil layers: chemical research

BACKGROUND: Radioisotopes are introduced into the environment following nuclear power plant accidents or nuclear weapons tests. The immobility of these radioactive elements in uppermost soil layers represents a problem for human health, since they can easily be incorporated in the food chain. Preventing their assimilation by plants may be a first step towards the total recovery of contaminated areas. METHODS: The possibility of displacing radionuclides from the most superficial soil layers and their subsequent stabilisation at lower levels were investigated in laboratory trials. An experimental system reproducing the environmental conditions of contaminated areas was designed in plastic columns. A radiopolluted soil sample was treated with solutions containing ions normally used in fertilisation (NO(3)(-), NH(4)(+), PO(4)(--- )and K(+)). RESULTS: Contaminated soils treated with an acid solution of ions NO(3)(-), PO(4)(--- )and K(+), undergo a reduction of radioactivity up to 35%, after a series of washes which simulate one year's rainfall. The capacity of the deepest soil layers to immobilize the radionuclides percolated from the superficial layers was also confirmed. CONCLUSION: The migration of radionuclides towards deeper soil layers, following chemical treatments, and their subsequent stabilization reduces bioavailability in the uppermost soil horizon, preventing at the same time their transfer into the water-bearing stratum

Multiple thromboembolism with multiple causes in a 69-year-old woman: a case report

<p>Abstract</p> <p>Introduction</p> <p>Aggressive, recurrent embolisms require accurate etiologic diagnosis. We describe the case of a 69-year-old Italian Caucasian woman with recurrent arterial embolisms in whom several sources and triggers of thrombosis were detected.</p> <p>Case presentation</p> <p>The patient, a 69-year-old Italian Caucasian woman, presented with a systemic embolism that was initially attributed to atrial fibrillation. The recurrence of embolisms despite anti-thrombotic therapy prompted a re-evaluation of the clinical presentation. New potential causes of thrombosis emerged in this patient, including thrombocytosis associated with the <it>JAK2 V617F </it>mutation and the very rare mural thrombosis of the descending aorta. A mural thrombus in the pulmonary artery was detected contiguous with the aortic mural thrombosis, raising the possibility of a clinically silent ductus Botalli as the initiating event. The patient was treated with warfarin, aspirin, hydroxyurea, and surgery.</p> <p>Conclusions</p> <p>The diagnosis was achieved via systematic use of imaging procedures and reconsideration of blood tests performed to explore the diagnosis of thrombosis. This allowed a deeper and more detailed analysis of the case beyond the conventional approach, which would have aimed to identify one cause for the condition at hand, in this case, atrial fibrillation. The broader approach that we used resulted in the diagnosis of multiple embolisms from multiple sites and multiple causes.</p

The Evolution of Compact Binary Star Systems

We review the formation and evolution of compact binary stars consisting of white dwarfs (WDs), neutron stars (NSs), and black holes (BHs). Binary NSs and BHs are thought to be the primary astrophysical sources of gravitational waves (GWs) within the frequency band of ground-based detectors, while compact binaries of WDs are important sources of GWs at lower frequencies to be covered by space interferometers (LISA). Major uncertainties in the current understanding of properties of NSs and BHs most relevant to the GW studies are discussed, including the treatment of the natal kicks which compact stellar remnants acquire during the core collapse of massive stars and the common envelope phase of binary evolution. We discuss the coalescence rates of binary NSs and BHs and prospects for their detections, the formation and evolution of binary WDs and their observational manifestations. Special attention is given to AM CVn-stars -- compact binaries in which the Roche lobe is filled by another WD or a low-mass partially degenerate helium-star, as these stars are thought to be the best LISA verification binary GW sources.Comment: 105 pages, 18 figure

Treatment of recurrent malignant gliomas with fotemustine monotherapy: impact of dose and correlation with MGMT promoter methylation

<p>Abstract</p> <p>Background</p> <p>In recurrent malignant gliomas (MGs), a high rate of haematological toxicity is observed with the use of fotemustine at the conventional schedule (100 mg/m²weekly for 3 consecutive weeks followed by triweekly administration after a 5-week rest period). Also, the impact of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status on fotemustine activity has never been explored in the clinical setting.</p> <p>Methods</p> <p>40 patients with recurrent pretreated MG were identified as being treated with fotemustine at doses ranging from 65 mg/m²to 100 mg/m². Patients were classified into 3 groups according to the dose of fotemustine received, from the lowest dosage received in group A, to the highest in group C. Analysis of MGMT promoter methylation in tumor tissue was successfully performed in 19 patients.</p> <p>Results</p> <p>Overall, 20% of patients responded to treatment, for a disease control rate (DCR, responses plus stabilizations) of 47.5%. Groups A and B experienced a response rate of 40% and 26.5% respectively, while the corresponding value for group C was 10%. Out of 19 patients, MGMT promoter was found methylated in 12 cases among which a DCR of 66.5% was observed. All 7 patients with unmethylated MGMT promoter were progressive to fotemustine.</p> <p>Conclusion</p> <p>Low-dose fotemustine at 65–75 mg/m²(induction phase) followed by 75–85 mg/m²(maintenance phase) has an activity comparable to that of the conventional schedule. By determination of the MGMT promoter methylation status patients might be identified who are more likely to benefit from fotemustine chemotherapy.</p

Pyrazolo-triazolo-pyrimidines as adenosine receptor antagonists: Effect of the N-5 bond type on the affinity and selectivity at the four adenosine receptor subtypes

In the last few years, many efforts have been made to search for potent and selective human A3 adenosine antagonists. In particular, one of the most promising human A3 adenosine receptor antagonists is represented by the pyrazolo-triazolo-pyrimidine family. This class of compounds has been strongly investigated from the point of view of structure-activity relationships. In particular, it has been observed that fundamental requisites for having both potency and selectivity at the human A3 adenosine receptors are the presence of a small substituent at the N8 position and an unsubstitued phenyl carbamoyl moiety at the N5 position. In this study, we report the role of the N5-bond type on the affinity and selectivity at the four adenosine receptor subtypes. The observed structure-activity relationships of this class of antagonists are also exhaustively rationalized using the recently published ligand-based homology modeling approach

Determinants of the Spatiotemporal Dynamics of the 2009 H1N1 Pandemic in Europe: Implications for Real-Time Modelling

Influenza pandemics in the last century were characterized by successive waves and differences in impact and timing between different regions, for reasons not clearly understood. The 2009 H1N1 pandemic showed rapid global spread, but with substantial heterogeneity in timing within each hemisphere. Even within Europe substantial variation was observed, with the UK being unique in experiencing a major first wave of transmission in early summer and all other countries having a single major epidemic in the autumn/winter, with a West to East pattern of spread. Here we show that a microsimulation model, parameterised using data about H1N1pdm collected by the beginning of June 2009, explains the occurrence of two waves in UK and a single wave in the rest of Europe as a consequence of timing of H1N1pdm spread, fluxes of travels from US and Mexico, and timing of school vacations. The model provides a description of pandemic spread through Europe, depending on intra-European mobility patterns and socio-demographic structure of the European populations, which is in broad agreement with observed timing of the pandemic in different countries. Attack rates are predicted to depend on the socio-demographic structure, with age dependent attack rates broadly agreeing with available serological data. Results suggest that the observed heterogeneity can be partly explained by the between country differences in Europe: marked differences in school calendars, mobility patterns and sociodemographic structures. Moreover, higher susceptibility of children to infection played a key role in determining the epidemiology of the 2009 pandemic. Our work shows that it would have been possible to obtain a broad-brush prediction of timing of the European pandemic well before the autumn of 2009, much more difficult to achieve with simpler models or pre-pandemic parameterisation. This supports the use of models accounting for the structure of complex modern societies for giving insight to policy makers