ACQUIRED ALTERATIONS OF SPHINGOSINE-1-PHOSPHATE METABOLISM CONFER STEMNESS AND DRUG RESISTANCE PROPERTIES ON GLIOBLASTOMA MULTIFORME: A NEW POTENTIAL TARGET FOR A COMBINED APPROACH TO TREAT BRAIN CANCER

The eradication of glioblastoma multiforme (GBM) (WHO grade 4) remains a tremendous clinical challenge in human oncology. Indeed, this tumor accounts for the most common, aggressive and lethal primary brain cancer in adults, exhibiting a dismal prognosis, despite extensive surgical resection and adjuvant radio- and chemo-therapy. The finding that GBM contains functional subsets of cells with stem-like properties named glioblastoma stem cells (GSCs) has opened up novel opportunities and promises for the development of new therapies for this devastating cancer. GSCs are self-renewing, multipotent cells, with the capacity to establish and maintain glioma tumors at the clonal level, leading to the hypothesis that they are tumor-initiating cells. Moreover, these rare subpopulations of cells possess an elevated proliferative potential, and intrinsic resistance to therapy, being thus considered a key determinant driving tumor growth, and relapse after resection and therapy. In serum free culture conditions, GSCs form neurospheres. free-floating cell aggregates with a spheroid morphology. These neurospheres preserve many of the important characteristics of the parent tumor, as cell heterogeneity and the ability to drive the parent tumor\u2019s cell invasiveness, when transplanted in murine brain. In addition, GSCs possess the capacities to give rise to a heterogeneous population of cells such as endothelial cells (glioblastoma endothelial cells, GECs) which may directly participate in the vascularization, a critical step in tumors, particularly in malignant GBM, one of the most vascularized/angiogenic tumor described. Moreover, it has been observed that microvasculature structures are the regions responsible for the localization and the maintenance of GSCs. Different molecules, including lipid mediators appear to play a key role in the GBM microenvironment. Among lipid mediators involved in GSC properties, ceramide (Cer) and sphingosine-1-phosphate (S1P) has recently emerged as key signals, able to control growth, invasion, and therapy resistance in various human cancers, including GBMs. Of relevance, the presence of S1P in both glioma cell lines and human gliomas is critical for tumor cell proliferation and survival, a down-regulation of sphingosine kinase 1 (SK1) suppressed growth of human GBM cells and xenografts, and a higher expression of S1P receptor 1 (S1PR1) in GBM has been correlated with poor prognosis. However, little is known on the role of Cer and S1P in GSCs. Recent studies reported that S1P acts as an invasive signal in GSCs, and that the inhibition of SKs, or the administration of a S1PR antagonist, results in GSC death. Very recently it was reported that GSCs derived from U87GBM cells, and those isolated from a human GBM specimen can release S1P extracellularly, and that S1P acts as a first messenger to enhance GSC chemoresistance to Temozolomide. In GSC invasiveness and chemoresistance very little is known about autocrine machinery controlling GSC proliferation and particularly on the significance of S1P in these events. In order to expand previous investigation on S1P and to better understand its role on GSC activity and chemoresistance in this project I focused on the pivotal role of S1P on GSC stemness properties

Lämmermast mit verschiedenen Rassen auf extensivem Grünland: erste Ergebnisse

Ziel dieser Studie ist es, die mögliche Nutzung von extensivem Grünland für die Mast von Merino-Lämmern und reinrassigen Waldschaf-Lämmern unter verschiedenen Besatzraten zu untersuchen. Während der ersten Weidemonate im Jahr 2017 wurden Merino-Lämmer unter Ausnutzung der hohen Graswachstumsintensität geweidet. Die Waldschaf-Lämmer wurden in der zweiten Hälfte der Vegetationsperiode im Jahr 2017 mit geringerer Wachstumsintensität der Weide bis zum Ende dieser Weidezeit geweidet. Beide Rassen wurden in zwei getrennten Paddocks mit unterschiedlichen Besatzraten und Graswachstumshöhen beweidet. Das gleiche Verfahren wird im Jahr 2018 wiederholt. Ergebnisse des ersten Jahres 2017 werden vorgestellt

Efficient Memory-Enhanced Transformer for Long-Document Summarization in Low-Resource Regimes

Long document summarization poses obstacles to current generative transformer-based models because of the broad context to process and understand. Indeed, detecting long-range dependencies is still challenging for today’s state-of-the-art solutions, usually requiring model expansion at the cost of an unsustainable demand for computing and memory capacities. This paper introduces Emma, a novel efficient memory-enhanced transformer-based architecture. By segmenting a lengthy input into multiple text fragments, our model stores and compares the current chunk with previous ones, gaining the capability to read and comprehend the entire context over the whole document with a fixed amount of GPU memory. This method enables the model to deal with theoretically infinitely long documents, using less than 18 and 13 GB of memory for training and inference, respectively. We conducted extensive performance analyses and demonstrate that Emma achieved competitive results on two datasets of different domains while consuming significantly less GPU memory than competitors do, even in low-resource settings

Reduced motor planning underlying inhibition of prepotent responses in children with ADHD

To flexibly regulate their behavior, children’s ability to inhibit prepotent responses arises from cognitive and motor mechanisms that have an intertwined developmental trajectory. Subtle differences in planning and control can contribute to impulsive behaviors, which are common in Attention Deficit and Hyperactivity Disorder (ADHD) and difficult to be assessed and trained. We adapted a Go/No-Go task and employed a portable, low-cost kinematic sensor to explore the different strategies used by children with ADHD or typical development to provide a prepotent response (dominant condition) or inhibit the prepotent and select an alternative one (non-dominant condition). Although no group difference emerged on accuracy levels, the kinematic analysis of correct responses revealed that, unlike neurotypical children, those with ADHD did not show increased motor planning in non-dominant compared to dominant trials. Future studies should investigate whether motor control could help children with ADHD compensate for planning difficulties. This strategy might make inhibition harder in naturalistic situations that involve complex actions. Combining cognitive and kinematic measures is a potential innovative method for assessment and intervention of subtle differences in executive processes such as inhibition, going deeper than is possible based on accuracy outcomes alone

Sphingosine-1-Phosphate in the Tumor Microenvironment: A Signaling Hub Regulating Cancer Hallmarks

As a key hub of malignant properties, the cancer microenvironment plays a crucial role intimately connected to tumor properties. Accumulating evidence supports that the lysophospholipid sphingosine-1-phosphate acts as a key signal in the cancer extracellular milieu. In this review, we have a particular focus on glioblastoma, representative of a highly aggressive and deleterious neoplasm in humans. First, we highlight recent advances and emerging concepts for how tumor cells and different recruited normal cells contribute to the sphingosine-1-phosphate enrichment in the cancer microenvironment. Then, we describe and discuss how sphingosine-1-phosphate signaling contributes to favor cancer hallmarks including enhancement of proliferation, stemness, invasion, death resistance, angiogenesis, immune evasion and, possibly, aberrant metabolism. We also discuss the potential of how sphingosine-1-phosphate control mechanisms are coordinated across distinct cancer microenvironments. Further progress in understanding the role of S1P signaling in cancer will depend crucially on increasing knowledge of its participation in the tumor microenvironment

On the Comparison of Two Vehicular Safety Systems in Realistic Highway Scenarios

Abstract The application of wireless VANET technology to accident warning systems is gaining an increasing interest. These systems can significantly increase the safety of daily driving and are based on a technology that is steadily becoming mature. We present an experimental comparison between two effective approaches that cope with realistic scenarios. Both rapidly broadcast alert messages throughout platoons of vehicles, and are based on wireless vehicle-to-vehicle (V2V) communications. However, with one approach an alert message propagates through the farthest relay at each hop, whereas with the other it propagatesusing the farthest spanning relay (i.e., the relay that can retransmit farthest away an alert message). With this study we will see retransmitting through the farthest spanning relay at each hop can improve the performance by a factor of two in terms of propagation delay, in comparison to choosing the farthest relay

RANTES correlates with inflammatory activity and synaptic excitability in multiple sclerosis

BACKGROUND: Alterations of synaptic transmission induced by inflammatory activity have been linked to the pathogenic mechanisms of multiple sclerosis (MS). Regulated upon activation, normal T-cell expressed, and secreted (RANTES) is a pro-inflammatory chemokine involved in MS pathophysiology, potentially able to regulate glutamate release and plasticity in MS brains, with relevant consequences on the clinical manifestations of the disease. OBJECTIVE: To assess the role of RANTES in the regulation of cortical excitability. METHODS: We explored the association of RANTES levels in the cerebrospinal fluid (CSF) of newly diagnosed MS patients with magnetic resonance imaging (MRI) and laboratory measures of inflammatory activity, as well its role in the control of cortical excitability and plasticity explored by means of transcranial magnetic stimulation (TMS), and in hippocampal mouse slices in vitro. RESULTS: CSF levels of RANTES were remarkably high only in active MS patients and were correlated with the concentrations of interleukin-1β. RANTES levels were associated with TMS measures of cortical synaptic excitability, but not with long-term potentiation (LTP)-like plasticity. Similar findings were obtained in mouse hippocampal slices in vitro, where we observed that RANTES enhanced basal excitatory synaptic transmission with no effect on LTP. CONCLUSION: RANTES correlates with inflammation and synaptic excitability in MS brains