miR-15a targets the HSP90 co-chaperone Morgana in chronic myeloid leukemia.

Morgana is a ubiquitous HSP90 co-chaperone protein coded by the CHORDC1 gene. Morgana heterozygous mice develop with age a myeloid malignancy resembling human atypical myeloid leukemia (aCML), now renamed MDS/MPN with neutrophilia. Patients affected by this pathology exhibit low Morgana levels in the bone marrow (BM), suggesting that Morgana downregulation plays a causative role in the human malignancy. A decrease in Morgana expression levels is also evident in the BM of a subgroup of Philadelphia-positive (Ph+) chronic myeloid leukemia (CML) patients showing resistance or an incomplete response to imatinib. Despite the relevance of these data, the mechanism through which Morgana expression is downregulated in patients' bone marrow remains unclear. In this study, we investigated the possibility that Morgana expression is regulated by miRNAs and we demonstrated that Morgana is under the control of four miRNAs (miR-15a/b and miR-26a/b) and that miR-15a may account for Morgana downregulation in CML patients.

Transcranial magnetic stimulation on the right dorsal attention network modulates the center-surround profile of the attentional focus.

Psychophysical observations indicate that the spatial profile of visuospatial attention includes a central enhancement around the attentional focus, encircled by a narrow zone of reduced excitability in the immediate surround. This inhibitory ring optimally amplifies relevant target information, likely stemming from top-down frontoparietal recurrent activity modulating early visual cortex activations. However, the mechanisms through which neural suppression gives rise to the surrounding attenuation and any potential hemispheric specialization remain unclear. We used transcranial magnetic stimulation to evaluate the role of two regions of the dorsal attention network in the center-surround profile: the frontal eye field and the intraparietal sulcus. Participants performed a psychophysical task that mapped the entire spatial attentional profile, while transcranial magnetic stimulation was delivered either to intraparietal sulcus or frontal eye field on the right (Experiment 1) and left (Experiment 2) hemisphere. Results showed that stimulation of right frontal eye field and right intraparietal sulcus significantly changed the center-surround profile, by widening the inhibitory ring around the attentional focus. The stimulation on the left frontal eye field, but not left intraparietal sulcus, induced a general decrease in performance but did not alter the center-surround profile. Results point to a pivotal role of the right dorsal attention network in orchestrating inhibitory spatial mechanisms required to limit interference by surrounding distractors.

Look at me now! Enfacement illusion over computer-generated faces.

According to embodied cognition research, one's bodily self-perception can be illusory and temporarily shifted toward an external body. Similarly, the so-called "enfacement illusion" induced with a synchronous multisensory stimulation over the self-face and an external face can result in implicit and explicit changes in the bodily self. The present study aimed to verify (i) the possibility of eliciting an enfacement illusion over computer-generated faces and (ii) which multisensory stimulation condition was more effective. A total of 23 participants were asked to look at a gender-matched avatar in three synchronous experimental conditions and three asynchronous control conditions (one for each stimulation: visuotactile, visuomotor, and simple exposure). After each condition, participants were asked to complete a questionnaire assessing both the embodiment and the enfacement sensations to address different facets of the illusion. Results suggest a stronger effect of synchronous vs. asynchronous stimulation, and the difference was more pronounced for the embodiment items of the questionnaire. We also found a greater effect of visuotactile and visuomotor stimulations as compared to the simple exposure condition. These findings support the enfacement illusion as a new paradigm to investigate the ownership of different face identities and the specific role of visuotactile and visuomotor stimulations with virtual reality stimuli.

Upstaging nodal status in colorectal cancer using ex vivo fluorescence sentinel lymph node mapping: preliminary results.

BACKGROUND: Sentinel lymph node (SLN) mapping using near-infrared fluorescence (NIRF) imaging is a recent technique to improve nodal staging in several tumors. The presence of colorectal cancer (CRC) micro-metastases has recently been defined as N1 disease and no longer as N1mi, determining the need for adjuvant chemotherapy. In CRC, the reported rate of SLN micro-metastases detected by ultrastaging techniques is as high as 30%. The aim of this prospective study is to report the preliminary results of the sensitivity analysis of NIRF imaging for ex vivo SLN mapping and the research of micro-metastases in CRC, in patients with node-negative disease (NND). MATERIAL AND METHODS: On the specimen of 22 CRC patients, 1 mL of ICG (5 mg/mL) was injected submucosally around the tumor to identify SLNs. NND SLNs were further investigated with ultrastaging techniques. RESULTS: Three-hundred and sixty-three lymph nodes were retrieved (59 SLNs; mean per case: 2.7). The detection, sensitivity and false-negative rate were 100%, 100% and 0% respectively. Ultrastaging investigations showed no micro-metastases in the NND SLNs. CONCLUSIONS: The ex vivo SLN fluorescence-based detection in CRC was confirmed to be easy to perform and reliable. In this preliminary results report of an ongoing study, the SLN assay was congruent with the nodal status, as confirmed by histological investigations.

"Help! I Need Somebody": Music as a Global Resource for Obtaining Wellbeing Goals in Times of Crisis.

Music can reduce stress and anxiety, enhance positive mood, and facilitate social bonding. However, little is known about the role of music and related personal or cultural (individualistic vs. collectivistic) variables in maintaining wellbeing during times of stress and social isolation as imposed by the COVID-19 crisis. In an online questionnaire, administered in 11 countries (Argentina, Brazil, China, Colombia, Italy, Mexico, the Netherlands, Norway, Spain, the UK, and USA, N = 5,619), participants rated the relevance of wellbeing goals during the pandemic, and the effectiveness of different activities in obtaining these goals. Music was found to be the most effective activity for three out of five wellbeing goals: enjoyment, venting negative emotions, and self-connection. For diversion, music was equally good as entertainment, while it was second best to create a sense of togetherness, after socialization. This result was evident across different countries and gender, with minor effects of age on specific goals, and a clear effect of the importance of music in people's lives. Cultural effects were generally small and surfaced mainly in the use of music to obtain a sense of togetherness. Interestingly, culture moderated the use of negatively valenced and nostalgic music for those higher in distress.

[Fluorescence-guided detection of lymph node metastases of gastrointestinal tumors]. / Fluoreszenzgesteuerte Detektion von Lymphknotenmetastasen bei gastrointestinalen Tumoren.

A correct lymph node (LN) staging is essential in oncological surgery. Indocyanine green (ICG) near-infrared fluorescence (NIRF) guided sentinel lymph node (SLN) navigation is a relatively novel technique. The aim of this review is to analyze the impact of ICG-NIRF on identification of LN metastases of gastrointestinal tumors. The Scopus and PubMed/MEDLINE literature databases were searched and 20 studies were included. The ICG-NIRF navigation of LN has been shown to enable and improve LN detection in gastrointestinal tumors; however, the mean detection, sensitivity, accuracy and false negative rates show substantial variation. This could be due to both the heterogeneous techniques applied and to the low retention of ICG by lymph nodes. Fluorescence imaging to identify LN drainage is a promising tool to improve oncological outcomes. Nonetheless, the technique requires further development in terms of hardware, software and fluorophores, which are currently being investigated.

Quality of life in patients with loco-regional rectal cancer after ELRR by TEM versus VLS TME after nChRT: long-term results.

BACKGROUND: Endoluminal loco-regional resection (ELRR) by transanal endoscopic microsurgery (TEM) may be an alternative treatment option to Laparoscopic total mesorectal excision (LTME), in selected patients with N0 rectal cancer. Post-operative quality of life (QoL) evaluation is an important parameter of outcomes related to high percentage of functional sequelae. We reported, in a previous paper, the short and medium term results of QoL in patients who underwent ELRR or LTME. The aim is to evaluate the 3 year QoL in patients with iT2-T3 N0/+ rectal cancer who underwent ELRR by TEM or LTME after neoadjuvant radio-chemotherapy (nChRT) in a retrospective analysis of prospectively collected data. METHODS: We enrolled in this study, 39 patients with iT2-T3 rectal cancer who underwent ELRR (n = 19) or LTME (n = 20), according to predefined criteria. QoL was evaluated by EORTC QLQ-C30 and QLQ-CR38 questionnaires at admission, after n-RCT and 1, 6, 12, and 36 months after surgery. RESULTS: No statistically significant differences in QoL evaluation were observed between the two groups, both at admission and after n-RCT. In short term (1-6 months) period, significantly better results were observed in ELRR group by QLQ-C30 in global health status (p = 0.03), physical functioning (p = 0.026), role functioning (p = 0.04), emotional functioning (p = 0.04), cognitive functioning, fatigue (p < 0.05), dyspnoea (p < 0.001), insomnia (p < 0.05), appetite loss (p < 0.05), constipation (≤ 0.05), and by QLQ-CR38 in: body image (p = 0.03) and defecation (p = 0.025). At 1 year, the two groups were homogenous as assessed by QLQ-C30, whereas the QLQCR38 still showed better results of ELRR versus LTME in body image (p = 0.006), defecation problems (p = 0.01), and weight loss (p = 0.005). At 3 years, no statistically significant differences were observed between the two groups. CONCLUSIONS: In selected patients with rectal cancer, who underwent ELRR by TEM or LTME, QoL tests at 3 years do not show any statistical differences on examined items.

Targeting few to help hundreds: JAK, MAPK and ROCK pathways as druggable targets in atypical chronic myeloid leukemia.

Atypical Chronic Myeloid Leukemia (aCML) is a myeloproliferative neoplasm characterized by neutrophilic leukocytosis and dysgranulopoiesis. From a genetic point of view, aCML shows a heterogeneous mutational landscape with mutations affecting signal transduction proteins but also broad genetic modifiers and chromatin remodelers, making difficult to understand the molecular mechanisms causing the onset of the disease. The JAK-STAT, MAPK and ROCK pathways are known to be responsible for myeloproliferation in physiological conditions and to be aberrantly activated in myeloproliferative diseases. Furthermore, experimental evidences suggest the efficacy of inhibitors targeting these pathways in repressing myeloproliferation, opening the way to deep clinical investigations. However, the activation status of these pathways is rarely analyzed when genetic mutations do not occur in a component of the signaling cascade. Given that mutations in functionally unrelated genes give rise to the same pathology, it is tempting to speculate that alteration in the few signaling pathways mentioned above might be a common feature of pathological myeloproliferation. If so, targeted therapy would be an option to be considered for aCML patients.

The IKK/NF-κB signaling pathway requires Morgana to drive breast cancer metastasis.

NF-κB is a transcription factor involved in the regulation of multiple physiological and pathological cellular processes, including inflammation, cell survival, proliferation, and cancer cell metastasis. NF-κB is frequently hyperactivated in several cancers, including triple-negative breast cancer. Here we show that NF-κB activation in breast cancer cells depends on the presence of the CHORDC1 gene product Morgana, a previously unknown component of the IKK complex and essential for IκBα substrate recognition. Morgana silencing blocks metastasis formation in breast cancer mouse models and this phenotype is reverted by IκBα downregulation. High Morgana expression levels in cancer cells decrease recruitment of natural killer cells in the first phases of tumor growth and induce the expression of cytokines able to attract neutrophils in the primary tumor, as well as in the pre-metastatic lungs, fueling cancer metastasis. In accordance, high Morgana levels positively correlate with NF-κB target gene expression and poor prognosis in human patients.

Dorsomedial prefrontal cortex and cerebellar contribution to in-group attitudes: a transcranial magnetic stimulation study.

We tend to express more positive judgments and behaviors toward individuals belonging to our own group compared to other (out-) groups. In this study, we assessed the role of the cerebellum and of the dorsomedial prefrontal cortex (dmPFC) - two regions critically implicated in social cognition processes - in mediating implicit valenced attitudes toward in-group and out-group individuals. To this aim, we used transcranial magnetic stimulation (TMS) in combination with a standard attitude priming task, in which Caucasian participants had to categorize the valence of a series of adjectives primed by either an in-group or an out-group face. In two behavioral experiments, we found an in-group bias (i.e. faster categorization of positive adjectives when preceded by in-group faces) but no evidence of an out-group bias. Interestingly, TMS over both the dmPFC and over the (right) cerebellum significantly interfered with the modulation exerted by group membership on adjective valence classification, abolishing the in-group bias observed at baseline. Overall, our data suggest that both the dmPFC and the cerebellum play a causal role in mediating implicit social attitudes.

Modeling myeloproliferative neoplasms: From mutations to mouse models and back again.

Myeloproliferative neoplasms (MPNs) are defined according to the 2008 World Health Organization (WHO) classification and the recent 2016 revision. Over the years, several genetic lesions have been associated with the development of MPNs, with important consequences for identifying unique biomarkers associated with specific neoplasms and for developing targeted therapies. Defining the genotype-phenotype relationship in MPNs is essential to identify driver somatic mutations that promote MPN development and maintenance in order to develop curative targeted therapies. While studies with human samples can identify putative driver mutations, murine models are mandatory to demonstrate the causative role of mutations and for pre-clinical testing of specific therapeutic interventions. This review focuses on MPN mouse models specifically developed to assess the pathogenetic roles of gene mutations found in human patients, as well as murine MPN-like phenotypes identified in genetically modified mice.

The double face of Morgana in tumorigenesis.

Morgana is a chaperone protein able to bind to ROCK I and II and to inhibit their kinase activity. Rho kinases are multifunctional proteins involved in different cellular processes, including cytoskeleton organization, centrosome duplication, cell survival and proliferation. In human cancer samples Morgana appears to be either downregulated or overexpressed, and experimental evidence indicate that Morgana behaves both as an oncosuppressor and as a proto-oncogene. Our most recent findings demonstrated that if on the one hand low Morgana expression levels, by inducing ROCK II hyperactivation, cause centrosome overduplication and genomic instability, on the other hand, Morgana overexpression induces tumor cell survival and chemoresistance through the ROCK I-PTEN-AKT axis. Therefore, Morgana belongs to a new class of proteins, displaying both oncogenic and oncosuppressor features, depending on the specific cellular context.

Morgana acts as an oncosuppressor in chronic myeloid leukemia.

We recently described morgana as an essential protein able to regulate centrosome duplication and genomic stability, by inhibiting ROCK. Here we show that morgana (+/-) mice spontaneously develop a lethal myeloproliferative disease resembling human atypical chronic myeloid leukemia (aCML), preceded by ROCK hyperactivation, centrosome amplification, and cytogenetic abnormalities in the bone marrow (BM). Moreover, we found that morgana is underexpressed in the BM of patients affected by atypical CML, a disorder of poorly understood molecular basis, characterized by nonrecurrent cytogenetic abnormalities. Morgana is also underexpressed in the BM of a portion of patients affected by Philadelphia-positive CML (Ph(+) CML) caused by the BCR-ABL oncogene, and in this condition, morgana underexpression predicts a worse response to imatinib, the standard treatment for Ph(+) CML. Thus, morgana acts as an oncosuppressor with different modalities: (1) Morgana underexpression induces centrosome amplification and cytogenetic abnormalities, and (2) in Ph(+) CML, it synergizes with BCR-ABL signaling, reducing the efficacy of imatinib treatment. Importantly, ROCK inhibition in the BM of patients underexpressing morgana restored the efficacy of imatinib to induce apoptosis, suggesting that ROCK inhibitors, combined with imatinib treatment, can overcome suboptimal responses in patients in which morgana is underexpressed.

Morgana acts as a proto-oncogene through inhibition of a ROCK-PTEN pathway.

Morgana/CHP-1 is a ubiquitously expressed protein able to inhibit ROCK II kinase activity. We have previously demonstrated that morgana haploinsufficiency leads to multiple centrosomes, genomic instability, and higher susceptibility to tumour development. While a large fraction of human cancers has shown morgana down-regulation, a small subset of tumours was shown to express high morgana levels. Here we demonstrate that high morgana expression in different breast cancer subtypes correlates with high tumour grade, mitosis number, and lymph node positivity. Moreover, morgana overexpression induces transformation in NIH-3T3 cells and strongly protects them from various apoptotic stimuli. From a mechanistic point of view, we demonstrate that morgana causes PTEN destabilization, by inhibiting ROCK activity, hence triggering the PI3K/AKT survival pathway. In turn, morgana down-regulation in breast cancer cells that express high morgana levels increases PTEN expression and leads to sensitization of cells to chemotherapy.

Mechanisms contributing to the thermal analysis of waste incineration bottom ash and quantification of different carbon species.

The focus of this study was to identify the main compounds affecting the weight changes of bottom ash (BA) in conventional loss on ignition (LOI) tests and to obtain a better understanding of the individual processes in heterogeneous (waste) materials such as BA. Evaluations were performed on BA samples from a refuse derived fuel incineration (RDF-I) plant and a hospital waste incineration (HW-I) plant using thermogravimetric analysis and subsequent mass spectrometry (TG-MS) analysis of the gaseous thermal decomposition products. Results of TG-MS analysis on RDF-I BA indicated that the LOI measured at 550°C was due to moisture evaporation and dehydration of Ca(OH)(2) and hydrocalumite. Results for the HW-I BA showed that LOI at 550°C was predominantly related to the elemental carbon (EC) content of the sample. Decomposition of CaCO(3) around 700°C was identified in both materials. In addition, we have identified reaction mechanisms that underestimate the EC and overestimate the CaCO(3) contents of the HW-I BA during TG-MS analyses. These types of artefacts are expected to occur also when conventional LOI methods are adopted, in particular for materials that contain CaO/Ca(OH)(2) in combination with EC and/or organic carbon, such as e.g. municipal solid waste incineration (MSWI) bottom and fly ashes. We suggest that the same mechanisms that we have found (i.e. in situ carbonation) can also occur during combustion of the waste in the incinerator (between 450 and 650°C) demonstrating that the presence of carbonate in bottom ash is not necessarily indicative for weathering. These results may also give direction to further optimization of waste incineration technologies with regard to stimulating in situ carbonation during incineration and subsequent potential improvement of the leaching behavior of bottom ash.

Characterisation of major component leaching and buffering capacity of RDF incineration and gasification bottom ash in relation to reuse or disposal scenarios.

Thermal treatment of refuse derived fuel (RDF) in waste-to-energy (WtE) plants is considered a promising solution to reduce waste volumes for disposal, while improving material and energy recovery from waste. Incineration is commonly applied for the energetic valorisation of RDF, although RDF gasification has also gained acceptance in recent years. In this study we focused on the environmental properties of bottom ash (BA) from an RDF incineration (RDF-I, operating temperature 850-1000°C) and a RDF gasification plant (RDF-G, operating temperature 1200-1400°C), by evaluating the total composition, mineralogy, buffering capacity, leaching behaviour (both at the material's own pH and as a function of pH) of both types of slag. In addition, buffering capacity results and pH-dependence leaching concentrations of major components obtained for both types of BA were analysed by geochemical modelling. Experimental results showed that the total content of major components for the two types of BA was fairly similar and possibly related to the characteristics of the RDF feedstock. However, significant differences in the contents of trace metals and salts were observed for the two BA samples as a result of the different operating conditions (i.e. temperature) adopted by the two RDF thermal treatment plants. Mineralogy analysis showed in fact that the RDF-I slag consisted of an assemblage of several crystalline phases while the RDF-G slag was mainly made up by amorphous glassy phases. The leached concentrations of major components (e.g. Ca, Si) at the natural pH of each type of slag did not reflect their total contents as a result of the partial solubility of the minerals in which these components were chemically bound. In addition, comparison of total contents with leached concentrations of minor elements (e.g. Pb, Cu) showed no obvious relationship for the two types of BA. According to the compliance leaching test results, the RDF-G BA would meet the limits of the Italian legislation for reuse and the European acceptance criteria for inert waste landfilling. RDF-I BA instead would meet the European acceptance criteria for non hazardous waste landfilling. A new geochemical modelling approach was followed in order to predict the leaching behaviour of major components and the pH buffering capacity of the two types of slags on the basis of independent mineralogical information obtained by XRD analysis and the bulk composition of the slag. It was found that the combined use of data regarding the mineralogical characterization and the buffering capacity of the slag material can provide an independent estimate of both the identity and the amount of minerals that contribute to the leaching process. This new modelling approach suggests that only a limited amount of the mineral phases that control the pH, buffering capacity and major component leaching from the solid samples is available for leaching, at least on the time scale of the applied standard leaching tests. As such, the presented approach can contribute to gain insights for the identification of the types and amounts of minerals that control the leaching properties and pH buffering capacity of solid residues such as RDF incineration and gasification bottom ash.