HMGB1-Induced Cross Talk between PTEN and miRs 221/222 in Thyroid Cancer

High mobility group box 1 (HMGB1) is an ubiquitous protein that plays different roles in the nucleus, cytoplasm and extra-cellular space. It is an important DAMP molecule that allows communication between damaged or tumor cells and the immune system. Tumor cells exploit HMGB1’s ability to activate intracellular pathways that lead to cell growth and migration. Papillary thyroid cancer is a well differentiated tumor and is often used to study relationships between cells and the inflammatory microenvironment as the latter is characterized by high levels of inflammatory cells and cytokines. Anaplastic thyroid cancer is one of the most lethal human cancers in which many microRNAs and tumor suppressor genes are de-regulated. Up-regulation of microRNAs 221 and 222 has been shown to induce the malignant phenotype in many human cancers via inhibition of PTEN expression. In this study we suggest that extracellular HMGB1 interaction with RAGE enhances expression of oncogenic cluster miR221/222 that in turn inhibits tumor suppressor gene PTEN in two cell lines derived from human thyroid anaplastic and papillary cancers. The newly identified pathway HMGB1/RAGE/miR 221/222 may represent an effective way of tumor escape from immune surveillance that could be used to develop new therapeutic strategies against anaplastic tumors

Effects of granulocyte-macrophage colony-stimulating factor and cyclic AMP interaction on human neutrophil apoptosis.

The current study was undertaken to evaluate the effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) and cyclic AMP (cAMP) signaling interaction on human neutrophil apoptosis, either occurring spontaneously or induced by Fas antigen activation. Results show that GM-CSF, dibutyryl cAMP (a cAMP analog) and forskolin (an adenylate cyclase activator) are all able to suppress spontaneous neutrophil cell death. Of note however, when GM-CSF is used in combination with cAMP-elevating agents, an additive effect on neutrophil survival is observed with dibutyryl cAMP only, whereas supplementation of cell cultures with GM-CSF and forskolin results in a progressive reduction of antiapoptotic effects exerted by the single compounds. Moreover, although dibutyryl cAMP and forskolin do not affect Fas-triggered apoptotic events, they are still able to modulate the GM-CSF capacity to prolong neutrophil survival following anti-Fas IgM cell challenge, with effects similar to those respectively exerted on spontaneous neutrophil apoptosis. The data indicate that GM-CSF may negatively modulate the cAMP-mediated antiapoptotic pathway in human neutrophils, likely via the inhibition of adenylate cyclase activity. This would prevent an abnormal neutrophil survival as a result of cAMP signaling stimulation, which provides a novel insight into the role of GM-CSF as a physiological regulator of myeloid cell turnover

Recommendations for headache service organisation and delivery in Europe.

Headache disorders are a major public-health priority, and there is pressing need for effective solutions to them. Better health care for headache—and ready access to it—are central to these solutions; therefore, the organisation of headache-related services within the health systems of Europe becomes an important focus. These recommendations are the result of collaboration between the European Headache Federation and Lifting The Burden: the Global Campaign against Headache. The process of development included wide consultation. To meet the very high level of need for headache care both effectively and efficiently, the recommendations formulate a basic three-level model of health-care organisation rationally spread across primary and secondary health-care sectors, taking account of the different skills and expertise in these sectors. They recognise that health services are differently structured in countries throughout Europe, and not always adequately resourced. Therefore, they aim to be adaptable to suit these differences. They are set out in five sections: needs assessment, description of the model, adaptation, standards and educational implications

Building an ecologically valid facial expression database – Behind the scenes

Artificial Intelligence (AI) algorithms, together with a general increased computational performance, allow nowadays exploring the use of Facial Expression Recognition (FER) as a method of recognizing human emotion through the use of neural networks. The interest in facial emotion and expression recognition in real-life situations is one of the current cutting-edge research challenges. In this context, the creation of an ecologically valid facial expression database is crucial. To this aim, a controlled experiment has been designed, in which thirty-five subjects aged 18–35 were asked to react spontaneously to a set of 48 validated images from two affective databases, IAPS and GAPED. According to the Self-Assessment Manikin, participants were asked to rate images on a 9-points visual scale on valence and arousal. Furthermore, they were asked to select one of the six Ekman’s basic emotions. During the experiment, an RGB-D camera was also used to record spontaneous facial expressions aroused in participants storing both the color and the depth frames to feed a Convolutional Neural Network (CNN) to perform FER. In every case, the prevalent emotion pointed out in the questionnaires matched with the expected emotion. CNN obtained a recognition rate of 75.02%, computed comparing the neural network results with the evaluations given by a human observer. These preliminary results have confirmed that this experimental setting is an effective starting point for building an ecologically valid database

An Overview of the Treatment Options for Acute Migraine

Migraine is a primary headache disorder associated with a high socioeconomic burden. The first step in effective migraine management, following confirmation of the diagnosis, is patient education: the condition is carefully explained, to ensure that it is properly understood, and realistic expectations are set. The choice of acute treatment has changed over time as the available therapeutic options have increased. Abortive migraine therapy can be either specific (ergot derivatives and triptans) or non-specific (analgesics and non-steroidal anti-inflammatory drugs). Even though acute symptomatic therapy can be optimised, migraine remains a chronic and potentially progressive conditio

Application of unmanned aerial vehicle data and discrete fracture network models for improved rockfall simulations

In this research, we present a new approach to define the distribution of block volumes during rockfall simulations. Unmanned aerial vehicles (UAVs) are utilized to generate high-accuracy 3D models of the inaccessible SW flank of the Mount Rava (Italy), to provide improved definition of data gathered from conventional geomechanical surveys and to also denote important changes in the fracture intensity. These changes are likely related to the variation of the bedding thickness and to the presence of fracture corridors in fault damage zones in some areas of the slope. The dataset obtained integrating UAV and conventional surveys is then utilized to create and validate two accurate 3D discrete fracture network models, representative of high and low fracture intensity areas, respectively. From these, the ranges of block volumes characterizing the in situ rock mass are extracted, providing important input for rockfall simulations. Initially, rockfall simulations were performed assuming a uniform block volume variation for each release cell. However, subsequent simulations used a more realistic nonuniform distribution of block volumes, based on the relative block volume frequency extracted from discrete fracture network (DFN) models. The results of the simulations were validated against recent rockfall events and show that it is possible to integrate into rockfall simulations a more realistic relative frequency distribution of block volumes using the results of DFN analyse

Meeting patient expectations in migraine treatment: what are the key endpoints?

Clinical outcomes of migraine treatment are generally based on two major endpoints: acute pain resolution and effects on quality of life (QOL). Resolution of acute pain can be evaluated in a number of ways, each increasingly challenging to achieve; pain relief, pain freedom at 2 h, sustained pain-freedom, and SPF plus no adverse events (SNAE, the most challenging). QOL questionnaires help assess the burden of migraine and identify optimal treatments. Pain resolution and improved QOL form the basis of the ultimate target-meeting patient expectations, to achieve patient satisfaction. To achieve this, it is crucial to choose appropriate endpoints that reflect realistic treatment goals for individual patients. Moreover, SNAE can help discriminate between triptans, with almotriptan having the highest SNAE score. Kaplan-Meier plots are also relevant when evaluating migraine treatments. The use of symptomatic medication may lead to the paradoxical development of medication-overuse headache. In general practice, patients should use simple tools for pain measurement (e.g. headache diary) and a QOL questionnaire. A composite endpoint of pain resolution and QOL restoration would constitute a step forward in migraine management

Migraine and psychiatric comorbidity: a review of clinical findings.

Migraine is an extremely common disorder. The underlying mechanisms of this chronic illness interspersed with acute symptoms appear to be increasingly complex. An important aspect of migraine heterogeneity is comorbidity with other neurological diseases, cardiovascular disorders, and psychiatric illnesses. Depressive disorders are among the leading causes of disability worldwide according to WHO estimation. In this review, we have mainly considered the findings from general population studies and studies on clinical samples, in adults and children, focusing on the association between migraine and psychiatric disorders (axis I of the DSM), carried over after the first classification of IHS (1988). Though not easily comparable due to differences in methodology to reach diagnosis, general population studies generally indicate an increased risk of affective and anxiety disorders in patients with migraine, compared to non-migrainous subjects. There would also be a trend towards an association of migraine with bipolar disorder, but not with substance abuse/dependence. With respect to migraine subtypes, comorbidity mainly involves migraine with aura. Patients suffering from migraine, however, show a decreased risk of developing affective and anxiety disorders compared to patients with daily chronic headache. It would also appear that psychiatric disorders prevail in patients with chronic headache and substance use than in patients with simple migraine. The mechanisms underlying migraine psychiatric comorbidity are presently poorly understood, but this topic remains a priority for future research. Psychiatric comorbidity indeed affects migraine evolution, may lead to chronic substance use, and may change treatment strategies, eventually modifying the outcome of this important disorder