Functionally Relevant Cytokine/Receptor Axes in Myelofibrosis.

Dysregulated inflammatory signaling is a key feature of myeloproliferative neoplasms (MPNs), most notably of myelofibrosis (MF). Indeed, MF is considered the prototype of onco-inflammatory hematologic cancers. While increased levels of circulatory and bone marrow cytokines are a well-established feature of all MPNs, a very recent body of literature is intriguingly pinpointing the selective overexpression of cytokine receptors by MF hematopoietic stem and progenitor cells (HSPCs), which, by contrast, are nearly absent or scarcely expressed in essential thrombocythemia (ET) or polycythemia vera (PV) cells.

Interplay between Protein Kinase C Epsilon and Reactive Oxygen Species during Myogenic Differentiation.

Reactive oxygen species (ROS) are currently recognized as a key driver of several physiological processes. Increasing evidence indicates that ROS levels can affect myogenic differentiation, but the molecular mechanisms still need to be elucidated. Protein kinase C (PKC) epsilon (PKCe) promotes muscle stem cell differentiation and regeneration of skeletal muscle after injury.

Evolution led humans to bipedalism, but we live in a sedentary society: Will "Sunday running" protect us from NCDs at no cost?

Evolution led humans to bipedal stance and movement. However, we live in a sedentary society that strongly challenges our willingness to be physically active. We (mis)understand that being at least a Sunday runner could protect us from sedentary-related diseases, but what if this compromises the healthier life expectancy anyway? Citing Paul Gauguin, we know where we come from and what we are, the question arises about where we are going.

Tracking fibrosis in myeloproliferative neoplasms by CCR2 expression on CD34 cells.

In myeloproliferative neoplasm (MPNs), bone marrow fibrosis - mainly driven by the neoplastic megakaryocytic clone - dictates a more severe disease stage with dismal prognosis and higher risk of leukemic evolution. Therefore, accurate patient allocation into different disease categories and timely identification of fibrotic transformation are mandatory for adequate treatment planning. Diagnostic strategy still mainly relies on clinical/laboratory assessment and bone marrow histopathology, which, however, requires an invasive procedure and frequently poses challenges also to expert hemopathologists.

Buffering Adaptive Immunity by Hydrogen Sulfide.

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 (HS) 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.

The Genetic Makeup of Myeloproliferative Neoplasms: Role of Germline Variants in Defining Disease Risk, Phenotypic Diversity and Outcome.

Myeloproliferative neoplasms are hematologic malignancies typified by a substantial heritable component. Germline variants may affect the risk of developing a MPN, as documented by GWAS studies on large patient cohorts. In addition, once the MPN occurred, inherited host genetic factors can be responsible for tuning the disease phenotypic presentation, outcome, and response to therapy.

Hydrogen Sulfide Inhibits TMPRSS2 in Human Airway Epithelial Cells: Implications for SARS-CoV-2 Infection.

The COVID-19 pandemic has now affected around 190 million people worldwide, accounting for more than 4 million confirmed deaths. Besides ongoing global vaccination, finding protective and therapeutic strategies is an urgent clinical need. SARS-CoV-2 mostly infects the host organism via the respiratory system, requiring angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) to enter target cells.

Ruxolitinib rechallenge in resistant or intolerant patients with myelofibrosis: Frequency, therapeutic effects, and impact on outcome.

Background: After ruxolitinib discontinuation, the outcome of patients with myelofibrosis (MF) is poor with scarce therapeutic possibilities.

Methods: The authors performed a subanalysis of an observational, retrospective study (RUX-MF) that included 703 MF patients treated with ruxolitinib to investigate 1) the frequency and reasons for ruxolitinib rechallenge, 2) its therapeutic effects, and 3) its impact on overall survival.

Results: A total of 219 patients (31.

Cytokine Profiling in Myeloproliferative Neoplasms: Overview on Phenotype Correlation, Outcome Prediction, and Role of Genetic Variants.

Among hematologic malignancies, the classic Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are considered a model of inflammation-related cancer development. In this context, the use of immune-modulating agents has recently expanded the MPN therapeutic scenario. Cytokines are key mediators of an auto-amplifying, detrimental cross-talk between the MPN clone and the tumor microenvironment represented by immune, stromal, and endothelial cells.

NK cells: A double edge sword against SARS-CoV-2.

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.

ROS in Platelet Biology: Functional Aspects and Methodological Insights.

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.

Sodium-glucose cotransporter 2 inhibitors antagonize lipotoxicity in human myeloid angiogenic cells and ADP-dependent activation in human platelets: potential relevance to prevention of cardiovascular events.

Background: 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.

Sighting acute myocardial infarction through platelet gene expression.

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.

Muscle Activation in Traditional and Experimental Barbell Bench Press Exercise: A Potential New Tool for Fitness Maintenance.

Background: The bench press exercise (BP) is commonly practiced in both recreational and professional training. The weight is lowered from a position where the elbows are at a 90° angle at the start and <90° at the end of eccentric phase, and then returned to the elbows extended position. In order to focus the exercise more on the triceps brachii (TB) rather than the pectoralis major (PM), the inter-handle distance (IHD) is decreased diminishing the involvement of the PM in favor of the TB.

Sulphurous thermal water inhalation impacts respiratory metabolic parameters in heavy smokers.

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.

Combination of Platelet expression of PKCepsilon and cardiac troponin-I for early diagnosis of chest pain patients in the emergency department.

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.

PKCε promotes human Th17 differentiation: Implications in the pathophysiology of psoriasis.

PKCε 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 PKCε takes part in autoimmunity, its role in the molecular pathophysiology of immune-mediated disorders is still largely unknown. We studied PKCε 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.

Protein Kinase C Epsilon Is a Key Regulator of Mitochondrial Redox Homeostasis in Acute Myeloid Leukemia.

The intracellular redox environment of acute myeloid leukemia (AML) cells is often highly oxidized compared to healthy hematopoietic progenitors and this is purported to contribute to disease pathogenesis. However, the redox regulators that allow AML cell survival in this oxidized environment remain largely unknown. Utilizing several chemical and genetically-encoded redox sensing probes across multiple human and mouse models of AML, we evaluated the role of the serine/threonine kinase PKC-epsilon (PKCε) in intracellular redox biology, cell survival and disease progression.

PKCε Controls Mitotic Progression by Regulating Centrosome Migration and Mitotic Spindle Assembly.

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.

Platelet expression of PKCepsilon oncoprotein in myelofibrosis is associated with disease severity and thrombotic risk.

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.

Human thrombopoiesis depends on Protein kinase Cδ/protein kinase Cε functional couple.

A deeper understanding of the molecular events driving megakaryocytopoiesis and thrombopoiesis is essential to regulate in vitro and in vivo platelet production for clinical applications. We previously documented the crucial role of PKCε in the regulation of human and mouse megakaryocyte maturation and platelet release. However, since several data show that different PKC isoforms fulfill complementary functions, we targeted PKCε and PKCδ, which show functional and phenotypical reciprocity, at the same time as boosting platelet production in vitro.