The bone marrow niche landscape: a journey through aging, extrinsic and intrinsic stressors in the haemopoietic milieu

Inflammation and its effects in the bone marrow microenvironment represent a paradigmatic condition in which the hematopoietic niche and the immune systems, thought to properly sustain blood cell production and distinguish between friend and foe, can actively sustain a corrupted neighborhood within a chronic aberrant inflamed state. The bone marrow niche hijacks the physiologic hematopoiesis. The interactions between the hematopoietic stem cells and the niche in the bone marrow are critical determinants of quiescence. We examined several approaches to confront the available evidence; three key points emerged, pointing to the chronic inflammation process, especially the chronic infection and systemic inflammatory states, as leading causes of hematopoietic stem cell depletion. Clonal hematopoiesis, defined as a relative expansion of individual clones, is caused by somatic alterations in essential hematopoietic genes, which increase stem cell fitness. Moreover, terminal differentiation plays a significant role in progenitor loss and inflammatory signaling, promoting clonal selection and clonal hematopoiesis conditions. Specific myeloid malignancies as paradigmatic examples are discussed as a condition associated with inflammation, including the 5q-syndrome, Philadelphia negative myeloproliferative neoplasms, and chronic myeloid leukemia. Aging with increased fitness and hematopoietic stem cell attrition, extrinsic stress, enhanced stressor-specific fitness, and intrinsic defect across the hematopoietic process represent the route for novel insights in defective hematopoiesis. The discussion in this review also points out that the hematopoietic niches' inflammatory stimulation may affect differentiation patterns and the function of downstream cells

Design of superconducting magnets for power applications

A three-year research project, called DRYSMES4GRID, was recently funded by the Italian Minister of Economic Development, Italy. The project is aimed to demonstrate the feasibility of cost-competitive SMES based on magnesium diboride (MgB2) with a cryogen-free cooling by means of the manufacturing and the testing of a demonstrator with an objective rating of 500 kJ/200 kW. The preliminary design, concerning the definition the geometry of the coil and the reference MgB2 conductor based on the functional requirements of the system, is first discussed. The detailed design of the coil, aimed at producing the information and the technical drawings needed for the manufacturing of the coil, is then presented. The mechanical behavior of the coil during cool down and successive energization up to the nominal transport current is analyzed and the compatibility of stress and strain with allowable limits of the conductor is verified. The distribution of electrical stress on the coil during the switching of the power electronic converters is also calculated for the proper design of electrical insulation. Results of quench analysis are also presented showing that the maximum hot spot temperature reached when the coil is discharged is within the design value. Evaluation of the thermal load due to radiation, conduction through the supports, current leads and AC loss is presented. The same methodology has been applied on another superconducting application in order to design the SC coil of a Saturated Iron superconductive Fault Current Limiter (SI-SFCL) at Changwon National University, South Korea. The SI-SFCL consists of three main parts: one magnetic iron-core, one normal conductive primary coil (CPC), and one superconducting secondary coil (SSC). The design of the SSC was based on the terms of shape, wire types, required fault current limit and protection aspects

Angiogenesis and Antiangiogenesis in Multiple Myeloma

Multiple myeloma progression is characterized by a dense interaction between cancer cells and bone marrow microenvironment. The interactions of myeloma cells with various stromal cells and extracellular matrix components are the main regulator of the biological processes that underlie the progression of the disease and of the classic symptomatology correlated. The bone marrow of myeloma patients has recognized autocrine and paracrine loops that regulate multiple signaling pathways and the malignant phenotype of plasma cells. One of the pivotal biological processes which are responsible for myeloma progression is the formation of new vessels from existing ones, known as angiogenesis. It represents a constant hallmark of disease progression and a characteristic feature of the active phase of the disease. Near angiogenesis, other two ancestral processes were active in the bone marrow: vasculogenesis and vasculogenic mimicry. These processes are mediated by the angiogenic cytokines, interleukins, and inflammatory cytokines directly secreted by plasma cells and stromal cells. Neovascularization is also mediated by direct interaction between plasma cells and the various components of bone marrow microenvironment. The observation of the increased bone marrow angiogenesis in multiple myeloma and its correlation with disease activity and overall survival led to consider angiogenesis as a new target in the treatment of multiple myeloma

Origin Of Fluorescence In 11-cis Locked Bovine Rhodopsin

The excited state lifetime of bovine rhodopsin (Rh) increases from ca. 100 fs to 85 ps when the C11=C12 bond of its chromophore is locked by a cyclopentene moiety (Rh5). To explain such an increase, we employed ab initio multiconfigurational quantum chemistry to construct computer models of Rh and Rh5 and to investigate the shape of their excited state potential energy surfaces in a comparative way. Our results show that the observed Rh5 fluorescence (lambda(f)(max) = 620 nm) is due to a previously unreported locally excited intermediate whose lifetime is controlled by a small energy barrier. The analysis of the properties and decay path of such an intermediate provides useful information for engineering rhodopsin variants with augmented fluorescence efficiencies

Mapping The Excited State Potential Energy Surface Of A Retinal Chromophore Model With Multireference And Equation-of-motion Coupled-cluster Methods

The photoisomerization of the retinal chromophore of visual pigments proceeds along a complex reaction coordinate on a multidimensional surface that comprises a hydrogen-out-of-plane (HOOP) coordinate, a bond length alternation (BLA) coordinate, a single bond torsion and, finally, the reactive double bond torsion. These degrees of freedom are coupled with changes in the electronic structure of the chromophore and, therefore, the computational investigation of the photochemistry of such systems requires the use of a methodology capable of describing electronic structure changes along all those coordinates. Here, we employ the penta-2,4-dieniminium (PSB3) cation as a minimal model of the retinal chromophore of visual pigments and compare its excited state isomerization paths at the CASSCF and CASPT2 levels of theory. These paths connect the cis isomer and the trans isomer of PSB3 with two structurally and energetically distinct conical intersections (CIs) that belong to the same intersection space. MRCISD+Q energy profiles along these paths provide benchmark values against which other ab initio methods are validated. Accordingly, we compare the energy profiles of MRPT2 methods (CASPT2, QD-NEVPT2, and XMCQDPT2) and EOM-SF-CC methods (EOM-SF-CCSD and EOM-SF-CCSD(dT)) to the MRCISD+Q reference profiles. We find that the paths produced with CASSCF and CASPT2 are topologically and energetically different, partially due to the existence of a locally excited region on the CASPT2 excited state near the Franck-Condon point that is absent in CASSCF and that involves a single bond, rather than double bond, torsion. We also find that MRPT2 methods as well as EOM-SF-CCSD(dT) are capable of quantitatively describing the processes involved in the photoisomerization of systems like PSB3

Right Heart Changes Impact on Clinical Phenotype of Amyloid Cardiac Involvement: A Single Centre Study

Amyloidosis is due to deposition of an excessive amount of protein in many parenchymal tissues, including myocardium. The onset of cardiac Amyloidosis (CA) is an inauspicious prognostic factor, which can lead to sudden death. We retrospectively analyzed 135 patients with systemic amyloidosis, admitted to our ward between 1981 and 2019. Among them, 54 patients (46.30% F/53.70% M, aged 63.95 ± 12.82) presented CA at baseline. In 53 patients, it was associated with a multiorgan involvement, while in one there was a primary myocardial deposition. As a control group, we enrolled 81 patients (49.30% F/50.70% M, aged 58.33 ± 15.65) who did not meet the criteria for CA. In 44/54 of patients CA was associated with AL, 5/54 with AA and 3/54 of patients with ATTR, and in 1/54 AL was related to hemodialysis and in 1/54 to Gel-Amyloidosis. The most common AL type was IgG (28/44); less frequent forms were either IgA (7/44) or IgD (2/44), while seven patients had a λ free light chain form. The 32 AL with complete Ig were 31 λ-chain and just one k-chain. CA patients presented normal BP (SBP 118.0 ± 8.4 mmHg; DBP 73.8 ± 4.9 mmHg), while those with nCA had an increased proteinuria (p = 0.02). TnI and NT-proBNP were significantly increased compared to nCA (p = 0.031 and p = 0.047, respectively). In CA patients we found an increased LDH compared to nCA (p = 0.0011). CA patients were also found to have an increased interventricular septum thickness compared to nCA (p = 0.002), a decreased Ejection Fraction % (p = 0.0018) and Doppler velocity E/e' ratio (p = 0.0095). Moreover, CA patients had an enhanced right atrium area (p = 0.0179), right ventricle basal diameter (p = 0.0112) and wall thickness (p = 0.0471) compared to nCA, and an increased inferior cava vein diameter (p = 0.0495) as well. TAPSE was the method chosen to evaluate systolic function of the right heart. In CA subjects very poor TAPSE levels were found compared to nCA patients (p = 0.0495). Additionally, we found a significant positive correlation between TAPSE and lymphocyte count (r = 0.47; p = 0.031) as well as Gamma globulins (r = 0.43, p = 0.033), Monoclonal components (r = 0.72; p = 0.047) and IgG values (r = 0.62, p = 0.018). Conversely, a significant negative correlation with LDH (r = -0.57, p = 0.005), IVS (r = -0.51, p = 0.008) and diastolic function evaluated as E/e' (r = -0.60, p = 0.003) were verified. CA patients had very poor survival rates compared to controls (30 vs. 66 months in CA vs. nCA, respectively, p = 0.15). Mean survival of CA individuals was worse also when stratified according to NT-proBNP levels, using 2500 pg/mL as class boundary (174 vs. 5.5 months, for patients with lower vs. higher values than the median, respectively p = 0.013). In much the same way, a decreased right heart systolic function was correlated with a worse prognosis (18.0 months median survival, not reached in subjects with lower values than 18 mm, p = 0.0186). Finally, our data highlight the potential prognostic and predictive value of right heart alterations characterizing amyloidosis, as a novel clinical parameter correlated to increased LDH and immunoglobulins levels. Overall, we confirm the clinical relevance of cardiac involvement suggests that right heart evaluation may be considered as a new marker for clinical risk stratification in patients with amyloidosis

Prognostic and therapeutic role of angiogenic microenvironment in thyroid cancer

Thyroid cancer is the most common endocrine malignancy, with a typically favorable prognosis following standard treatments, such as surgical resection and radioiodine therapy. A subset of thyroid cancers progress to refractory/metastatic disease. Understanding how the tumor microenvironment is transformed into an angiogenic microenvironment has a role of primary importance in the aggressive behavior of these neoplasms. During tumor growth and progression, angiogenesis represents a deregulated biological process, and the angiogenic switch, characterized by the formation of new vessels, induces tumor cell proliferation, local invasion, and hematogenous metastases. This evidence has propelled the scientific community’s effort to study a number of molecular pathways (proliferation, cell cycle control, and angiogenic processes), identifying mediators that may represent viable targets for new anticancer treatments. Herein, we sought to review angiogenesis in thyroid cancer and the potential role of proangiogenic cytokines for risk stratification of patients. We also present the current status of treatment of advanced differentiated, medullary, and poorly differentiated thyroid cancers with multiple tyrosine kinase inhibitors, based on the rationale of angiogenesis as a potential therapeutic target

Vγ9Vδ2 T Cells as Strategic Weapons to Improve the Potency of Immune Checkpoint Blockade and Immune Interventions in Human Myeloma

The advent of immune checkpoint (ICP) blockade has introduced an unprecedented paradigm shift in the treatment of cancer. Though very promising, there is still a substantial proportion of patients who do not respond or develop resistance to ICP blockade. In vitro and in vivo models are eagerly needed to identify mechanisms to maximize the immune potency of ICP blockade and overcome primary and acquired resistance to ICP blockade. Vγ9Vδ2 T cells isolated from the bone marrow (BM) from multiple myeloma (MM) are excellent tools to investigate the mechanisms of resistance to PD-1 blockade and to decipher the network of mutual interactions between PD-1 and the immune suppressive tumor microenvironment (TME). Vγ9Vδ2 T cells can easily be interrogated to dissect the progressive immune competence impairment generated in the TME by the long-lasting exposure to myeloma cellss. BM MM Vγ9Vδ2 T cells are PD-1+ and anergic to phosphoantigen (pAg) stimulation; notably, single agent PD-1 blockade is insufficient to fully recover their anti-tumor activity in vitro indicating that additional players are involved in the anergy of Vγ9Vδ2 T cells. In this mini-review we will discuss the value of Vγ9Vδ2 T cells as investigational tools to improve the potency of ICP blockade and immune interventions in MM

MicroRNAs as a Potential New Preventive Approach in the Transition from Asymptomatic to Symptomatic Multiple Myeloma Disease

Multiple myeloma (MM) is a hematological malignancy characterised by proliferation of clonal plasma cells (PCs) within the bonemarrow (BM). Myelomagenesis is a multi-step process which goes from an asymptomatic phase, defined as monoclonal gammopathy of undetermined significance (MGUS), to a smouldering myeloma (SMM) stage, to a final active MM disease, characterised by hypercalcemia, renal failure, bone lesions anemia, and higher risk of infections. Overall, microRNAs (miRNAs) have shown to significantly impact onMMtumorigenesis, as a result of miRNA-dependent modulation of genes involved in pathways known to be crucial for MM pathogenesis and disease progression. We aim to revise the literature related to the role of miRNAs as potential diagnostic and prognostic biomarkers, thus highlighting their key role as novel players within the field of MM and related premalignant conditions