Loss of Rb Cooperates with Ras to Drive Oncogenic Growth in Mammalian Cells

Background The p53, Rb, and Ras/PI3K pathways are implicated in the development of the majority of human cancers. A number of studies have established that these pathways cooperate at the level of the cell cycle leading to loss of normal proliferative controls. Here we have investigated how these signals influence a second critical component of tumor formation—cell growth. Results We find that oncogenic Ras is sufficient to drive growth via the canonical growth pathway, PI3K-AKT-TOR; however, it does so relatively weakly and p53 loss does not drive cell growth at all. Importantly, we identify a novel role for the Rb family of tumor suppressors in directing cell growth via a signaling pathway distinct from PI3K-AKT-TOR and via an E2F-independent mechanism. However, we find that strong, sustained growth requires Rb loss together with Ras signaling, identifying an additional mechanism by which these oncogenic pathways cooperate and a critical role for Ras in preserving the uptake of extracellular nutrients required for biogenesis. Conclusions We have identified a new role for the Rb family in cell biogenesis and show that, as for other processes associated with tumor development, oncogenic cell growth is dependent on cooperating oncogenes

Loss of Rb Cooperates with Ras to Drive Oncogenic Growth in Mammalian Cells

SummaryBackgroundThe p53, Rb, and Ras/PI3K pathways are implicated in the development of the majority of human cancers. A number of studies have established that these pathways cooperate at the level of the cell cycle leading to loss of normal proliferative controls. Here we have investigated how these signals influence a second critical component of tumor formation—cell growth.ResultsWe find that oncogenic Ras is sufficient to drive growth via the canonical growth pathway, PI3K-AKT-TOR; however, it does so relatively weakly and p53 loss does not drive cell growth at all. Importantly, we identify a novel role for the Rb family of tumor suppressors in directing cell growth via a signaling pathway distinct from PI3K-AKT-TOR and via an E2F-independent mechanism. However, we find that strong, sustained growth requires Rb loss together with Ras signaling, identifying an additional mechanism by which these oncogenic pathways cooperate and a critical role for Ras in preserving the uptake of extracellular nutrients required for biogenesis.ConclusionsWe have identified a new role for the Rb family in cell biogenesis and show that, as for other processes associated with tumor development, oncogenic cell growth is dependent on cooperating oncogenes

Current guidelines for the management of non-alcoholic fatty liver disease: A systematic review with comparative analysis

The current epidemic of non-alcoholic fatty liver disease (NAFLD) is reshaping the field of hepatology all around the world. The widespread diffusion of metabolic risk factors such as obesity, type2-diabetes mellitus, and dyslipidemia has led to a worldwide diffusion of NAFLD. In parallel to the increased availability of effective anti-viral agents, NAFLD is rapidly becoming the most common cause of chronic liver disease in Western Countries, and a similar trend is expected in Eastern Countries in the next years. This epidemic and its consequences have prompted experts from all over the word in identifying effective strategies for the diagnosis, management, and treatment of NAFLD. Different scientific societies from Europe, America, and Asia-Pacific regions have proposed guidelines based on the most recent evidence about NAFLD. These guidelines are consistent with the key elements in the management of NAFLD, but still, show significant difference about some critical points. We reviewed the current literature in English language to identify the most recent scientific guidelines about NAFLD with the aim to find and critically analyse the main differences. We distinguished guidelines from 5 different scientific societies whose reputation is worldwide recognised and who are representative of the clinical practice in different geographical regions. Differences were noted in: the definition of NAFLD, the opportunity of NAFLD screening in high-risk patients, the noninvasive test proposed for the diagnosis of NAFLD and the identification of NAFLD patients with advanced fibrosis, in the follow-up protocols and, finally, in the treatment strategy (especially in the proposed pharmacological management). These difference have been discussed in the light of the possible evolution of the scenario of NAFLD in the next years

Thermal mapping as a valuable tool for road weather forecast and winter road maintenance: an example from the Italian Alps

During the winter period ice is likely to form on roads, making pavement surfaces slippery and increasing accident risk. Road surface temperature (RST) is one of the most important parameters in ice formation. The LIFE+ “CLEANROADS” project aims to forecast RSTs in advance in order to support road maintenance services in the timely and effective preparation of preventive anti-icing measures. This support is provided through a novel MDSS (Maintenance Decision Support System). The final goal of the project is to quantitatively demonstrate that the implemented MDSS is capable to minimize the consumption of chemical anti-icing reagents (e.g. sodium chloride) and the associated environmental (water and air) impact while maintaining the current high levels of road safety. In the CLEAN-ROADS system RSTs have been forecast by applying the numerical model METRo (Model of the Environment and Temperature of Roads) to a network of RWIS (Road Weather Information System) stations installed on a test route in the Adige Valley (Italy). This forecast is however local and does not take into account typical peculiarities along road network, such as the presence of road sections that are particularly prone to ice formation. Thermal mapping, i.e. the acquisition of mobile RST measurements through infrared thermometry, permits to (i) identify and map those sections, and (ii) extend the forecast from a RWIS station to adjacent areas. The processing of thermal mapping signals is however challenging because of random variations in the road surface emissivity. To overcome this we have acquired several thermal mapping traces along the test route during winter seasons 2014-2015 and 2015-2016. We have then defined a “characteristic” thermal fingerprint as a function of all its historical thermal mapping signals, and used it to spatialize local METRo forecasts. Preliminary results suggest the high potential of such a technique for winter road applications

Toll-Like Receptor 4 Modulates Small Intestine Neuromuscular Function through Nitrergic and Purinergic Pathways

Objective: Toll-like receptors (TLRs) play a pivotal role in the homeostatic microflora-host crosstalk. TLR4-mediated modulation of both motility and enteric neuronal survival has been reported mainly for colon with limited information on the role of TLR4 in tuning structural and functional integrity of enteric nervous system (ENS) and in controlling small bowel motility. Methods: Male TLR4 knockout (TLR4-/-, 9 \ub1 1 weeks old) and sex- and age-matched wild-type (WT) C57BL/6J mice were used for the experiments. Alterations in ENS morphology and neurochemical code were assessed by immunohistochemistry whereas neuromuscular function was evaluated by isometric mechanical activity of ileal preparations following receptor and non-receptor-mediated stimuli and by gastrointestinal transit. Results: The absence of TLR4 induced gliosis and reduced the total number of neurons, mainly nNOS+ neurons, in ileal myenteric plexus. Furthermore, a lower cholinergic excitatory response with an increased inhibitory neurotransmission was found together with a delayed gastrointestinal transit. These changes were dependent on increased ileal non-adrenergic non-cholinergic (NANC) relaxations mediated by a complex neuronal-glia signaling constituted by P2X7 and P2Y1 receptors, and NO produced by nNOS and iNOS. Conclusion: We provide novel evidence that TLR4 signaling is involved in the fine-tuning of P2 receptors controlling ileal contractility, ENS cell distribution, and inhibitory NANC neurotransmission via the combined action of NO and adenosine-5\u2032-triphosphate (ATP). For the first time, this study implicates TLR4 at regulating the crosstalk between glia and neurons in small intestine and helps to define its role in gastrointestinal motor abnormalities during dysbiosis

Pediatric Obesity and Eating Disorders Symptoms: The Role of the Multidisciplinary Treatment. A Systematic Review

The prevalence of obesity in children/adolescents has increased worldwide during the past 30 years, becoming a significant public health concern; prevention, and management of pediatric obesity onset is one of the most critical public health goals for both industrialized and developing countries. Pediatric obesity has been identified as a risk factor for various psychopathologies, including eating disorders (ED). Although it has been demonstrated that a comprehensive multidisciplinary treatment (MT), with small steps and practical approaches to lifestyle change, can be an effective treatment for children and adolescents with obesity, to the best of our knowledge, this is the first systematic review investigating the effect of MT on the development, progression or decrease of ED symptoms (EDS) in this target population. PubMed and Web of Science databases were searched (last search on 18 February 2019) according to a predetermined search strategy, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines and Statement. Original studies published in English examining the effect of MT on pediatric overweight/obesity, paying particularly attention at the development of EDS, were eligible for inclusion. Seven hundred and forty-four records have been identified; nine articles with study quality ranging from weak to moderate have been included. MTs were heterogeneous in nature including length, number, frequency and type of sessions, parent-involvement and use of technology, besides several psychometric questionnaires were used to screen for EDS, since there are no standardized criteria. In 3 studies there was a significant decrease in external and emotional eating and in four studies a significant increase in restraint eating post MT. Two studies found a significant decrease of binge eating symptoms and other two studies showed an improvement of self-perception, weight, and shape concern. A statistical significant decrease in BMI, BMIz, BMISDS, and adjusted BMI was observed after all MTs, except one. A narrative summary of the evidences reported highlighted the positive impact of MT on the EDS. Moreover, since weight loss post MTs was not necessarily related to EDS, clinicians should also look for the presence of EDS and treat them accordingly

The Venular Side of Cerebral Amyloid Angiopathy: Proof of Concept of a Neglected Issue.

Small vessel diseases (SVD) is an umbrella term including several entities affecting small arteries, arterioles, capillaries, and venules in the brain. One of the most relevant and prevalent SVDs is cerebral amyloid angiopathy (CAA), whose pathological hallmark is the deposition of amyloid fragments in the walls of small cortical and leptomeningeal vessels. CAA frequently coexists with Alzheimer's Disease (AD), and both are associated with cerebrovascular events, cognitive impairment, and dementia. CAA and AD share pathophysiological, histopathological and neuroimaging issues. The venular involvement in both diseases has been neglected, although both animal models and human histopathological studies found a deposition of amyloid beta in cortical venules. This review aimed to summarize the available information about venular involvement in CAA, starting from the biological level with the putative pathomechanisms of cerebral damage, passing through the definition of the peculiar angioarchitecture of the human cortex with the functional organization and consequences of cortical arteriolar and venular occlusion, and ending to the hypothesized links between cortical venular involvement and the main neuroimaging markers of the disease

Microwave tomography enhanced GPR surveys in Centaur's Domus, Regio VI of Pompeii, Italy

The archaeological area of Pompeii (Naples, Italy) is worldwide known as one of the most remarkable examples of a Roman Empire town, but its origins are prior to the Roman age and there is a huge archeological interest in discovering the history of the forma urbis. With respect to this framework, the paper presents results achieved by Microwave Tomography enhanced Ground Penetrating Radar surveys carried out in the Centaur's Domus - Regio VI, one of the most ancient housing area of Pompeii. The GPR prospections aimed at addressing and driving the archeological excavation campaign performed in this area in October 2010. The results of the stratigraphic assays are herein taken into account to assess the reliability of the achieved tomographic images

Characterization of the structure and control of the blood-nerve barrier identifies avenues for therapeutic delivery

The blood barriers of the nervous system protect neural environments but can hinder therapeutic accessibility. The blood-brain barrier (BBB) is well characterized, consisting of endothelial cells with specialized tight junctions and low levels of transcytosis, properties conferred by contacting pericytes and astrocytes. In contrast, the blood-nerve barrier (BNB) of the peripheral nervous system is poorly defined. Here, we characterize the structure of the mammalian BNB, identify the processes that confer barrier function, and demonstrate how the barrier can be opened in response to injury. The homeostatic BNB is leakier than the BBB, which we show is due to higher levels of transcytosis. However, the barrier is reinforced by macrophages that specifically engulf leaked materials, identifying a role for resident macrophages as an important component of the BNB. Finally, we demonstrate the exploitation of these processes to effectively deliver RNA-targeting therapeutics to peripheral nerves, indicating new treatment approaches for nervous system pathologies