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To form a proper mitotic spindle, centrosomes must be duplicated and driven poleward in a timely and controlled fashion. Improper timing of centrosome separation and errors in mitotic spindle assembly may lead to chromosome instability, a hallmark of cancer. Protein kinase C epsilon (PKCϵ) has recently emerged as a regulator of several cell-cycle processes associated with the resolution of mitotic catenation during the metaphase–anaphase transition and in regulating the abscission checkpoint. However, an engagement of PKCϵ in earlier (pre)mitotic events has not been addressed. Here, we now establish that PKCϵ controls prophase-to-metaphase progression by coordinating centrosome migration and mitotic spindle assembly in transformed cells. This control is exerted through cytoplasmic dynein function. Importantly, it is also demonstrated that the PKCϵ dependency of mitotic spindle organization is correlated with the nonfunctionality of the TOPO2A-dependent G2 checkpoint, a characteristic of many transformed cells. Thus, PKCϵ appears to become specifically engaged in a programme of controls that are required to support cell-cycle progression in transformed cells, advocating for PKCϵ as a potential cancer therapeutic target.Implications: The close relationship between PKCϵ dependency for mitotic spindle organization and the nonfunctionality of the TOPO2A-dependent G2 checkpoint, a hallmark of transformed cells, strongly suggests PKCϵ as a therapeutic target in cancer. Mol Cancer Res; 16(1); 3–15. ©2017 AACR.

This figure show that Ciliobrevin treatment results in mitotic spindle defects, delay of centrosome movement and bending phenotype.

Here are described the Supplementary Figures from Figure S1 to Figure S4.

Snow, as a fundamental reservoir of freshwater, is a crucial natural resource. Specifically, knowledge of snow density spatial and temporal variability could improve modelling of snow water equivalent, which is relevant for managing freshwater resources in context of ongoing climate change. The possibility of estimating snow density from remote sensing has great potential, considering the availability of satellite data and their ability to generate efficient monitoring systems from space. In this study, we present an innovative method that combines meteorological parameters, satellite data and field snow measurements to estimate thermal inertia of snow and snow density at a catchment scale. Thermal inertia represents the responsiveness of a material to variations in temperature and depends on the thermal conductivity, density and specific heat of the medium. By exploiting Landsat 8 data and meteorological modelling, we generated multitemporal thermal inertia maps in mountainous catchments in the Western European Alps (Aosta Valley, Italy), from incoming shortwave radiation, surface temperature and snow albedo. Thermal inertia was then used to develop an empirical regression model to infer snow density, demonstrating the possibility of mapping snow density from optical and thermal observations from space. The model allows for estimation of snow density with R2CV and RMSECV of 0.59 and 82 kg m−3, respectively. Thermal inertia and snow density maps are presented in terms of the evolution of snow cover throughout the hydrological season and in terms of their spatial variability in complex topography. This study could be considered a first attempt at using thermal inertia toward improved monitoring of the cryosphere. Limitations of and improvements to the proposed methods are also discussed. This study may also help in defining the scientific requirements for new satellite missions targeting the cryosphere. We believe that a new class of Earth Observation missions with the ability to observe the Earth's surface at high spatial and temporal resolution, with both day and night-time overpasses in both optical and thermal domain, would be beneficial for the monitoring of seasonal snowpacks around the globe.

Initially, stressed plates are widely used in modern fabrication techniques, such as additive manufacturing and UV lithography, for their tunable morphology by application of external stimuli. In this work, we propose a formal asymptotic derivation of the Föppl–von Kármán equations for an elastic plate with initial stresses, using the constitutive theory of nonlinear elastic solids with initial stresses under the assumptions of incompressibility and material isotropy. Compared to existing works, our approach allows us to determine the morphological transitions of the elastic plate without prescribing the underlying target metric of the unstressed state of the elastic body. We explicitly solve the derived FvK equations in some physical problems of engineering interest, discussing how the initial stress distribution drives the emergence of spontaneous curvatures within the deformed plate. The proposed mathematical framework can be used to tailor shape on demand, with applications in several engineering fields ranging from soft robotics to four-dimensional printing.

T cell-mediated adaptive immunity is designed to respond to non-self antigens and pathogens through the activation and proliferation of various T cell populations. T helper 1 (Th1), Th2, Th17 and Treg cells finely orchestrate cellular responses through a plethora of paracrine and autocrine stimuli that include cytokines, autacoids, and hormones. Hydrogen sulfide (H2S) is one of these mediators able to induce/inhibit immunological responses, playing a role in inflammatory and autoimmune diseases, neurological disorders, asthma, acute pancreatitis, and sepsis. Both endogenous and exogenous H2S modulate numerous important cell signaling pathways. In monocytes, polymorphonuclear, and T cells H2S impacts on activation, survival, proliferation, polarization, adhesion pathways, and modulates cytokine production and sensitivity to chemokines. Here, we offer a comprehensive review on the role of H2S as a natural buffer able to maintain over time a functional balance between Th1, Th2, Th17 and Treg immunological responses.

Sulphurous thermal water inhalations have been traditionally used in the treatment of airway diseases. In vivo and in vitro studies reported that they ameliorate mucus rheology, mucociliary clearance and reduce inflammation. Cigarette smoking induces an inflammatory damage, with consequent remodeling of respiratory airways, which in turn affect pulmonary functions. Despite the anti-inflammatory effects of H2S are clinically documented in several airway inflammatory diseases, data on the effects of sulphurous thermal water treatment on pulmonary function and biomarkers of airways inflammation in smokers are still scant. Therefore, we investigated whether a conventional cycle of sulphurous thermal water inhalation produced changes in markers of respiratory inflammation and function. A cohort of 504 heavy current and former smokers underwent 10-day cycles of sulphurous thermal water inhalation. Pulmonary function and metabolic analyses on exhaled breath condensate were then performed at day 0 and after the 10-day treatment. Spirometric data did not change after spa therapy, while exhaled breath condensate analysis revealed that a single 10-day cycle of sulphurous water inhalation was sufficient to induce a statistically significant increase of citrulline levels along with a decrease in ornithine levels, thus shifting arginine metabolism towards a reduced nitric oxide production, i.e. an anti-inflammatory profile. Overall, sulphurous thermal water inhalation impacts on arginine catatabolic intermediates of airways cells, shifting their metabolic balance towards a reduction of the inflammatory activity, with potential benefits for smokers.

Single nucleotide polymorphisms (SNPs) can modify the individual pro-inflammatory background and may therefore have relevant implications in the MPN setting, typified by aberrant cytokine production. In a cohort of 773 primary myelofibrosis (PMF), we determined the contribution of the rs1024611 SNP of CCL2—one of the most potent immunomodulatory chemokines—to the clinical and biological characteristics of the disease, demonstrating that male subjects carrying the homozygous genotype G/G had an increased risk of PMF and that, among PMF patients, the G/G genotype is an independent prognostic factor for reduced overall survival. Functional characterization of the SNP and the CCL2-CCR2 axis in PMF showed that (i) homozygous PMF cells are the highest chemokine producers as compared to the other genotypes, (ii) PMF CD34+ cells are a selective target of CCL2, since they uniquely express CCR2 (CCL2 receptor), (iii) activation of the CCL2-CCR2 axis boosts pro-survival signals induced by driver mutations via Akt phosphorylation, (iv) ruxolitinib effectively counteracts CCL2 production and down-regulates CCR2 expression in PMF cells. In conclusion, the identification of the role of the CCL2/CCR2 chemokine system in PMF adds a novel element to the pathophysiological picture of the disease, with clinical and therapeutic implications.

Mechanisms underlying the resistance of acute lymphoblastic leukemia (ALL) blasts to l-asparaginase are still incompletely known. Here we demonstrate that human primary bone marrow mesenchymal stromal cells (MSCs) successfully adapt to l-asparaginase and markedly protect leukemic blasts from the enzyme-dependent cytotoxicity through an amino acid trade-off. ALL blasts synthesize and secrete glutamine, thus increasing extracellular glutamine availability for stromal cells. In turn, MSCs use glutamine, either synthesized through glutamine synthetase (GS) or imported, to produce asparagine, which is then extruded to sustain asparagine-auxotroph leukemic cells. GS inhibition prevents mesenchymal cells adaptation to l-asparaginase, lowers glutamine secretion by ALL blasts, and markedly hinders the protection exerted by MSCs on leukemic cells. The pro-survival amino acid exchange is hindered by the inhibition or silencing of the asparagine efflux transporter SNAT5, which is induced in mesenchymal cells by ALL blasts. Consistently, primary MSCs from ALL patients express higher levels of SNAT5 (P < .05), secrete more asparagine (P < .05), and protect leukemic blasts (P

Reactive Oxygen Species (ROS) are molecules naturally produced by cells. If their levels are too high, the cellular antioxidant machinery intervenes to bring back their quantity to physiological conditions. Since aging often induces malfunctioning in this machinery, ROS are considered an effective cause of age-associated diseases. Exercise stimulates ROS production on one side, and the antioxidant systems on the other side. The effects of exercise on oxidative stress markers have been shown in blood, vascular tissue, brain, cardiac and skeletal muscle, both in young and aged people. However, the intensity and volume of exercise and the individual subject characteristics are important to envisage future strategies to adequately personalize the balance of the oxidant/antioxidant environment. Here, we reviewed the literature that deals with the effects of physical activity on redox balance in young and aged people, with insights into the molecular mechanisms involved. Although many molecular pathways are involved, we are still far from a comprehensive view of the mechanisms that stand behind the effects of physical activity during aging. Although we believe that future precision medicine will be able to transform exercise administration from wellness to targeted prevention, as yet we admit that the topic is still in its infancy.

A rapid differential diagnosis of the clinical conditions underlying chest pain is a relevant clinical issue. Specifically, a fast rule-in or -out of acute myocardial infarction (AMI) is mandatory to improve diagnostic outcome and cost-effectiveness of patient management. We demonstrated that Protein Kinase C (PKC) epsilon is selectively expressed by platelets from AMI patients, accounting for increased platelet activation. Thus, we hypothesized that PKCepsilon-expressing platelets may represent a pathophysiological marker of AMI that could be utilized in combination with troponin-I, the conventional marker of cardiac injury, to add diagnostic information in chest pain workup. In 94 chest pain patients consecutively admitted to Parma University Hospital, we tested the diagnostic performance of flow-cytometric detection of PKCepsilon expressing platelets in discriminating AMI vs. non-AMI conditions. We demonstrated that PKCepsilon-expressing platelets were significantly higher in patients with AMI. Flow cytometry detection of PKCepsilon-expressing platelets showed high sensitivity and specificity (87.5% and 84.4%, respectively) and good diagnostic accuracy (AUC: 0.875). The combination of PKCepsilon expressing platelets and cardiac troponin clearly discriminates patients with 100% and 0% of probability to be affected by AMI. Overall, we highlighted a dual marker strategy potentially useful for a rapid rule-in or -out of myocardial infarction in chest pain patients.

The clear evidence of cardiovascular benefits in cardiovascular outcome trials of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in type 2 diabetes might suggest an effect on atherosclerotic plaque vulnerability and/or thrombosis, in which myeloid angiogenic cells (MAC) and platelets (PLT) are implicated. We tested the effects of SGLT2i on inflammation and oxidant stress in a model of stearic acid (SA)-induced lipotoxicity in MAC and on PLT activation. The possible involvement of the Na+/H+ exchanger (NHE) was also explored., info:eu-repo/semantics/published

PKCe is implicated in T cell activation and proliferation and is overexpressed in CD4+ -T cells from patients with autoimmune Hashimoto's thyroiditis. Although this might induce the suspicion that PKCe takes part in autoimmunity, its role in the molecular pathophysiology of immune-mediated disorders is still largely unknown. We studied PKCe expression in circulating CD4+ -T cells from patients with psoriasis, a skin disorder characterized by an increased amount of Th17 cells, a CD4+ subset that is critical in the development of autoimmunity. Although the mechanisms that underlie Th17 differentiation in humans are still unclear, we here show that: (i) PKCe is overexpressed in CD4+ -T cells from psoriatic patients, and its expression positively correlates with the severity of the disease, being reduced by effective phototherapy; (ii) PKCe interacts with Stat3 during Th17 differentiation and its overexpression results in an enhanced expression of Stat3 and pStat3(Ser727); iii) conversely, when PKCe is forcibly downregulated, CD4+ -T cells show lower levels of pStat3(Ser727) expression and defective in vitro expansion into the Th17-lineage. These data provide a novel insight into the molecular mechanisms of Th17 cell polarization that is known to play a crucial role in autoimmunity, pinpointing PKCe as a potential target in Th17-mediated diseases.

To form a proper mitotic spindle, centrosomes must be duplicated and driven poleward in a timely and controlled fashion. Improper timing of centrosome separation and errors in mitotic spindle assembly may lead to chromosome instability, a hallmark of cancer. Protein kinase C epsilon (PKCϵ) has recently emerged as a regulator of several cell-cycle processes associated with the resolution of mitotic catenation during the metaphase–anaphase transition and in regulating the abscission checkpoint. However, an engagement of PKCϵ in earlier (pre)mitotic events has not been addressed. Here, we now establish that PKCϵ controls prophase-to-metaphase progression by coordinating centrosome migration and mitotic spindle assembly in transformed cells. This control is exerted through cytoplasmic dynein function. Importantly, it is also demonstrated that the PKCϵ dependency of mitotic spindle organization is correlated with the nonfunctionality of the TOPO2A-dependent G2 checkpoint, a characteristic of many transformed cells. Thus, PKCϵ appears to become specifically engaged in a programme of controls that are required to support cell-cycle progression in transformed cells, advocating for PKCϵ as a potential cancer therapeutic target. Implications: The close relationship between PKCϵ dependency for mitotic spindle organization and the nonfunctionality of the TOPO2A-dependent G2 checkpoint, a hallmark of transformed cells, strongly suggests PKCϵ as a therapeutic target in cancer. Mol Cancer Res; 16(1); 3–15. ©2017 AACR.

Natural killer (NK) cells are pivotal effectors of the innate immunity protecting an individual from microbes. They are the first line of defense against invading viruses, given their substantial ability to directly target infected cells without the need for specific antigen presentation. By establishing cellular networks with a variety of cell types such as dendritic cells, NK cells can also amplify and modulate antiviral adaptive immune responses. In this review, we will examine the role of NK cells in SARS-COV2 infections causing the ongoing COVID19 pandemic, keeping in mind the controversial role of NK cells specifically in viral respiratory infections and in inflammatory-driven lung damage. We discuss lessons learnt from previous coronavirus outbreaks in humans (caused by SARS-CoV-1 and MERS-COV).

Acute myocardial infarction is primarily due to coronary atherosclerotic plaque rupture and subsequent thrombus formation. Platelets play a key role in the genesis and progression of both atherosclerosis and thrombosis. Since platelets are anuclear cells that inherit their mRNA from megakaryocyte precursors and maintain it unchanged during their life span, gene expression profiling at the time of an acute myocardial infarction provides information concerning the platelet gene expression preceding the coronary event. In ST-segment elevation myocardial infarction (STEMI), a gene-by-gene analysis of the platelet gene expression identified five differentially expressed genes: FKBP5, S100P, SAMSN1, CLEC4E and S100A12. The logistic regression model used to combine the gene expression in a STEMI vs healthy donors score showed an AUC of 0.95. The same five differentially expressed genes were externally validated using platelet gene expression data from patients with coronary atherosclerosis but without thrombosis. Platelet gene expression profile highlights five genes able to identify STEMI patients and to discriminate them in the background of atherosclerosis. Consequently, early signals of an imminent acute myocardial infarction are likely to be found by platelet gene expression profiling before the infarction occurs.

Reactive oxygen species (ROS) and mitochondria play a pivotal role in regulating platelet functions. Platelet activation determines a drastic change in redox balance and in platelet metabolism. Indeed, several signaling pathways have been demonstrated to induce ROS production by NAPDH oxidase (NOX) and mitochondria, upon platelet activation. Platelet-derived ROS, in turn, boost further ROS production and consequent platelet activation, adhesion and recruitment in an auto-amplifying loop. This vicious circle results in a platelet procoagulant phenotype and apoptosis, both accounting for the high thrombotic risk in oxidative stress-related diseases. This review sought to elucidate molecular mechanisms underlying ROS production upon platelet activation and the effects of an altered redox balance on platelet function, focusing on the main advances that have been made in platelet redox biology. Furthermore, given the increasing interest in this field, we also describe the up-to-date methods for detecting platelets, ROS and the platelet bioenergetic profile, which have been proposed as potential disease biomarkers.

Primary myelofibrosis (PMF) is the most aggressive Philadelphia-negative myeloproliferative neoplasm. Heterogeneity in disease phenotype and outcome led to investigate the influence of germline host genetic variations on disease onset and evolution. We recently found that patients with secondary myelofibrosis are enriched in the polymorphic allele variant of the -2518 A/G SNP of the Monocyte Chemoattractant Protein-1 (MCP-1), and that this SNP correlates with disease severity (Masselli E. et al, Leukemia 2018). Here, we examined the interactive effects of MCP-1 allele variants with the baseline phenotype in PMF, and how these variants impact the disease progression. MCP-1 -2518 SNP genotyping was performed by TaqMan Predesigned SNP Genotyping Assays on DNA extracted from peripheral blood granulocytes of 201 PMF patients and 249 matched local control subjects (CTRL). One-hundred and nineteen out of 201 PMF were males (59.2%). Median age was 52y (18-80y). N.103 patients (51.2%) were pre-fibrotic PMF. Driver mutations occurred as follows: 123 (61.2%) harbored a JAK2V617F mutation, 47 (23.4%) had CALR mutations, 20 (9.9%) were triple negative and n.8 (4%) had MPL mutations. Three patients had both JAK2V617F and CALR mutation. After a median follow-up of 84.7 months, 37 patients (18.4%) died, 38 (18%) experienced blast transformation (BT) and 23 patients (11.4%) received allogeneic hematopoietic stem cell transplantation (ASCT). Median age of CTRL was 64y (28-85y), and 132/249 (53%) were males. Consistently with our previous report, PMF displayed similar genotypic and allelic frequencies of the local control population (O.R., 1.04). The G allele distribution was also similar in JAK2V617Fpos vs. JAK2V617Fneg PMF and did not correlate with the allele burden (O.R., 1.29 and 1.51, respectively). After verifying that PMF with only 1 copy of the risk allele (A/G), had a similar risk of the reference group with 0 copies (A/A), we used a recessive genetic model to compare PMF with 2 copies of the risk variant (G/G, hereby referred as the MCP-1 high-risk group) vs. A/A+A/G PMF (the MCP-1 low-risk group). Genotype-phenotype correlations with disease parameters at the time of diagnosis were performed by χ2/Fisher exact test. We found that the MCP-1 high risk group displayed a significantly higher frequency, at the time of diagnosis, of severe anemia, massive splenomegaly, elevated LDH and higher levels of hs-CRP (high-sensitivity C-reactive protein) (see Table). These results indicate that MCP-1 high-risk variant has a role in determining the disease phenotype and the pro-inflammatory microenvironment of PMF. Additionally, we assessed whether the MCP-1 high-risk variant could predispose the acquisition of risk factors in PMF. On the basis of the recessive genetic model, we found that the MCP-1 high-risk group was about four times as likely to progress to leukocytosis as was the reference group (HR, 4.16; 95% CI; 1.37 to 12.5; P=0.011). To weight the clinical relevance of our findings, we tested whether the MCP-1 high-risk variant might affect the disease progression. ASCT occurrence resulted significantly higher in the high-risk group as compared to the low-risk (HR = 3.22; 95% CI, 1.06 to 10; P=0.038). In the composite endpoint model that considered death for any cause, BT or ASCT, PMF carrying the high-risk genotype presented a shorter time to event as compared to the low-risk group (HR, 2.56; 95% CI, 1.19 to 5.55; P=0.016). In conclusion, the MCP-1 SNP appears to identify PMF patients at higher chance to present with adverse hematological features and more likely to progress rapidly to either death, BT or ASCT. Table. Disclosures No relevant conflicts of interest to declare.

Introduction: Host genetic variations have an essential role in the mutational landscape of Philadelphia-negative myeloproliferative neoplasm (MPNs), with JAK2 46/1 and TERT rs2736100 polymorphisms predisposing to disease onset (Tapper W et al, Nat Commun. 2015). However, the contribution of inherited factors in disease phenotype and evolution is poorly characterized. We recently demonstrated that the -2518 A/G SNP of the Monocyte Chemoattractant Protein-1 (MCP-1, rs1024611) is an inherited host genetic factor associated with secondary myelofibrosis (sMF) and a biomarker of disease severity in MF, correlating with adverse hematologic characteristics at the time of diagnosis, such as higher IPSS risk category (Masselli E et al, Leukemia 2018). Here we aimed to: i) provide a correlation between MF patients' genetic readout, chemokine expression/production and hematopoietic progenitor differentiation, ii) correlate MCP-1 levels with disease subtype and severity. Methods: 16 MF patients were genotyped for MCP-1 SNP by TaqMan Predesigned SNP Genotyping Assays and added to our previously reported dataset (Masselli E et al, Leukemia 2018), reaching 81 MF (20 prePMF, 36 overtPMF and 25 sMF). Samples from 15 therapy-naïve MF were dedicated to in vitro-experiments. Eleven healthy subjects and 4 apheresis bags were utilized as controls (CTRL). MF were stratified according to their rs1024611 genotype in A/A (wild types), A/G and G/G (polymorphics). Peripheral blood mononuclear cells (MNCs) were isolated by Ficoll-Hypaque gradient, in part pelleted (resting, T0) and in part seeded in RPMI-1640 medium and activated with 1.1 ng/ml of IL-1β for 20h (T1). CD34+-cells were purified from MF peripheral blood and from apheresis by immunomagnetic selection and differentiated toward the MK lineage as described in Masselli E et al, Leukemia 2015, up to 14 days. MK differentiation was assessed by CD41-flow cytometric expression. MCP-1 levels were evaluated by real-time PCR and western blot. Results: We confirmed, in a cohort of 81 MF patients, that polymorphic subjects were significantly more frequent in sMF vs. PMF (17/25, 68% vs. 21/56, 37.5%, respectively, P=.011, Fig.1A). Of note, sMF was significantly more frequent in A/G and G/G individuals than either prePMF (6/20, 30%, P=.011) or overtPMF (15/36, 41.7%, P=.034, Fig.1B). In overall MF patients, a higher frequency of allele-G carriers was also confirmed in IPSS int-2/high vs. low/int-1 risk group (17/25, 68% vs. 19/51, 37.3%, respectively, P=.011, Fig.1C - all comparisons made by Χ2 test). We proved that MF MNCs significantly over-expressed MCP-1 mRNA and protein as compared to CTRL MNCs at basal state (P=.04 and P=.006 by t-test, respectively, Fig.1D-E), consistently with reports from Tefferi et al. on serum ELISA (Tefferi A et al, JCO 2011). Of note, basal MCP-1 mRNA levels in MF correlated with genotypes, with polymorphic patients displaying significantly higher transcript levels vs. wild types (~20-times higher 2-ΔΔCT, P=.018 by t-test). When MF MNCs were stimulated ex-vivo with IL-1β, a dose-dependent effect of the SNP on MCP-1 expression was observed, with A/G patients displaying >20-times higher and G/G patients showing >60-times-higher fold-increase in MCP-1 expression as compared to wild types (P Conclusions: Our data proved a dose-dependent effect of the rs1024611 SNP on MCP-1 production in MF and establish a correlation between patients' genetic readout and chemokine levels. These results suggest that MF patients harboring the G allele - and thus producing more MCP-1 - are genetically prone to a higher inflammatory burden, to display a more severe disease and abnormal MK differentiation. Disclosures Aversa: Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria; Astellas: Honoraria; Basilea: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees.

International audience; In the big data era, huge amount of data are created in digital forms. Due to the frequent technological changes and developments that are happening in this era, organisations need to constantly match with market changes. Therefore they need to develop dynamic capabilities based on digital data, in order to reach valuable outputs. Specifically, this study examines whether the development of the Digital Data Genesis dynamic capability in firms leads to valuable outputs: data quality and data accessibility. We empirically test our model using a questionnaire-based survey answered by 125 sales managers. Results suggest that firms able to develop dynamic capabilities based on digital data obtain higher outputs in terms of data quality and accessibility. Managerial implications of our results are finally offered.

International audience; Although the Business Model (BM) concept provides a convenient unit for analyzing business practices, BM research in the Information Systems (IS) field reveals that there is a lack of consensus about definitions of the BM concept, and divergences and blurriness about the structure of such models. The aim of this paper is to provide a comprehensive state of the art review of BM research in the IS domain, and so highlight important research avenues. We review the titles and abstracts of 115 papers, examine a subset of 54 significant papers, and code 28 separate definitions of the BM concept. Our work makes three main contributions. First, it up-dates previous literature analysis in BM in the IS discipline. Second, it helps alleviate the fuzziness associated with BM definitions, identifying BM essence, components, characteristics and functions as fundamental dimensions of the BM definition. Third it defines four main BM uses, so enriching research on BMs from different angles.

Protein Kinase Cs (PKCs) are a family of 10 isoenzymes with critical roles in cell physiological processes like proliferation, differentiation, apoptosis. Muscular dystrophies are a heterogenous group of genetic degenerative diseases that affect skeletal and cardiac muscles. In the development of muscular dystrophies, several transduction pathways have been studied. A possible link between muscular dystrophies and PKCs have been recently proposed. After a brief description of the possible transduction pathways that are involved in the development of these genetic diseases, we summarize recent evidence on the role of PKC proteins in muscular dystrophies, with the aim to review possible candidates in molecular therapy of these pathologies.

Background: Myelofibrosis (MF) is the most aggressive Philadelphia-negative chronic myeloproliferative neoplasm (MPN) with high morbidity and mortality due to thrombo-hemorrhagic complications and leukemic transformation. MF is characterized by profound alterations of megakaryocytopoiesis, with consequent abnormalities in platelet number and function. We recently showed that the overexpression of the oncoprotein PKCepsilon plays a key role in the aberrant differentiation of MF megakaryocyte clone and that its levels correlate with disease burden. Moreover, our group previously demonstrated that PKCepsilon is over-expressed in platelets from patients with acute myocardial infarction (MI) and accounts for their increased reactivity. On these bases, we investigated here the activation state and PKCepsilon expression of MF platelets, testing potential correlations with thrombotic risk and disease aggressiveness. Methods: Platelets were isolated from peripheral blood samples of MF patients and healthy donors (HDs). Patients were stratified according to the IPSS/DIPSS risk category and history of cardiovascular events. Platelet activation was assessed by flow cytometry. PKCepsilon mRNA and protein levels were determined by real time-PCR and western blot. Results: MF platelets circulate in an activated status and display significantly higher levels of PKCepsilon compared to HDs. In MF patients, PKCepsilon platelet levels were associated with high-risk disease as well as with a positive history of major cardiovascular events. Conclusions: PKCepsilon is configuring as the common denominator of neoplastic transformation and thrombus formation in MF. Overall, our data pinpoint PKCepsilon as a potential novel biomarker of disease aggressiveness and thrombotic risk in this hematologic neoplasm.