The bone marrow microenvironment contains a heterogeneous population of stromal cells organized into niches that support hematopoietic stem cells (HSCs) and other lineage-committed hematopoietic ...progenitors. The stem cell niche generates signals that regulate HSC self-renewal, quiescence, and differentiation. Here, we review recent studies that highlight the heterogeneity of the stromal cells that comprise stem cell niches and the complexity of the signals that they generate. We highlight emerging data that stem cell niches in the bone marrow are not static but instead are responsive to environmental stimuli. Finally, we review recent data showing that hematopoietic niches are altered in certain hematopoietic malignancies, and we discuss how these alterations might contribute to disease pathogenesis.
Non-structural elements represent most of the total construction cost of typical buildings. A significant portion of the total losses in recent earthquakes worldwide, has been attributed to damage to ...non-structural elements. Damage to non-structural elements occurs at low levels of ground shaking, and can significantly affect the post-earthquake functionality of buildings. However, in Europe, limited prescriptions are provided in the codes for seismic design of non-structural elements and this may partially explain why it is so common for these elements to perform poorly during earthquakes. This paper describes the observed damage to non-structural elements following the 2016 Central Italy earthquake. The most commonly damaged elements were partition walls, ceiling systems, non-structural vaults, chimneys, and storage racks. As a result, it was highlighted the need to introduce seismic regulations devoted to improving the seismic performance of non-structural elements and to reduce the associated economic losses, loss of functionality, and potential threats to life safety.
•Microenvironmental defects can initiate myeloid neoplasms, including myelodysplastic syndrome (MDS).•MDS induces functional alterations in microenvironmental cells.•Niche abnormalities impair normal ...hematopoiesis and facilitate MDS progression.•Aberrant inflammatory signaling contributes to pathologic features of MDS.•Vascular and endothelial abnormalities may contribute to MDS progression.
Myelodysplastic syndromes (MDSs) are clonal disorders of hematopoietic stem and progenitor cells and represent the most common cause of acquired marrow failure. Hallmarked by ineffective hematopoiesis, dysplastic marrow, and risk of transformation to acute leukemia, MDS remains a poorly treated disease. Although identification of hematopoietic aberrations in human MDS has contributed significantly to our understanding of MDS pathogenesis, evidence now identify the bone marrow microenvironment (BMME) as another key contributor to disease initiation and progression. With improved understanding of the BMME, we are beginning to refine the role of the hematopoietic niche in MDS. Despite genetic diversity in MDS, interaction between MDS and the BMME appears to be a common disease feature and therefore represents an appealing therapeutic target. Further understanding of the interdependent relationship between MDS and its niche is needed to delineate the mechanisms underlying hematopoietic failure and how the microenvironment can be targeted clinically. This review provides an overview of data from human MDS and murine models supporting a role for BMME dysfunction at several steps of disease pathogenesis. Although no models or human studies so far have combined all of these findings, we review current data identifying BMME involvement in each step of MDS pathogenesis organized to reflect the chronology of BMME contribution as the normal hematopoietic system becomes myelodysplastic and MDS progresses to marrow failure and transformation. Although microenvironmental heterogeneity and dysfunction certainly add complexity to this syndrome, data are already demonstrating that targeting microenvironmental signals may represent novel therapeutic strategies for MDS treatment.
Base isolation has emerged as one of the most effective high-tech strategies for protecting infrastructure under seismic loading. This review paper discusses the historical development of ...friction-based seismic isolation systems, focusing on systems that have successfully been deployed and used as seismic safety measures for structures located in Europe. The conception and implementation of the Friction Pendulum system, the development of low friction materials and the effects of heating, contact pressure and velocity are discussed in light of past and recent numerical and experimental evidence. The merits of multiple surface devices, namely the Double Curvature Friction Pendulum and the Triple Friction Pendulum are also discussed, along with current knowledge and research gaps. Two European case studies, the Bolu Viaduct and the C.A.S.E. Project, are presented to illustrate that sliding base isolators can be used to meet otherwise unachievable design objectives. Finally, existing problems such as the response to high vertical accelerations, the potential for bearing uplift and the relevance of residual displacement are analyzed.
•Development and application of friction-based isolation systems.•Performance of single and multi-surface base isolation systems.•Real European experience with base isolation systems: Bolu-Viaduct (1999) and L′Aquila (2009).•Open problems and research needs.
Pancytopenia is a major cause of morbidity in acute myeloid leukemia (AML), yet its cause is unclear. Normal osteoblastic cells have been shown to support hematopoiesis. To define the effects of ...leukemia on osteoblastic cells, we used an immunocompetent murine model of AML. Leukemic mice had inhibition of osteoblastic cells, with decreased serum levels of the bone formation marker osteocalcin. Osteoprogenitor cells and endosteal-lining osteopontin+ cells were reduced, and osteocalcin mRNA in CD45− marrow cells was diminished. This resulted in severe loss of mineralized bone. Osteoclasts were only transiently increased without significant increases in bone resorption, and their inhibition only partially rescued leukemia-induced bone loss. In vitro data suggested that a leukemia-derived secreted factor inhibited osteoblastic cells. Because the chemokine CCL-3 was recently reported to inhibit osteoblastic function in myeloma, we tested its expression in our model and in AML patients. Consistent with its potential novel role in leukemic-dependent bone loss, CCL-3 mRNA was significantly increased in malignant marrow cells from leukemic mice and from samples from AML patients. Based on these results, we propose that therapeutic mitigation of leukemia-induced uncoupling of osteoblastic and osteoclastic cells may represent a novel approach to promote normal hematopoiesis in patients with myeloid neoplasms.
Abstract Recently there has been increased interest in the regulatory interactions between osteoblasts and cells in the surrounding bone marrow microenvironment. The proximity of hematopoietic stem ...cells (HSCs) with osteoblastic cells first suggested regulatory interactions, and recent data have highlighted the role of osteoblastic cells in providing a HSC niche. Reports have indicated that direct contact is necessary to mediate the osteoblastic effects and that these effects could be mediated through Notch activation. Notch signaling is important throughout development and also appears to play a critical role in cellular maturation and differentiation of osteoblastic cells and hematopoietic cells as disregulation can lead to bone loss and leukemias, respectively. In this review we discuss the current understanding of Notch signaling and how it functions in hematopoiesis, osteoblastic cells, and the interactions between HSC and their osteoblastic niche.
The myelodysplastic syndromes (MDS) represent neoplasms derived from the expansion of mutated clonal hematopoietic cells which often demonstrate aberrant differentiation potential with resultant ...cytopenias and a propensity to evolve into acute myelogenous leukemia. While multiple mutations have been identified which may serve as drivers of the MDS clone, there is accumulating evidence that MDS clones and subclones are subject to modulation by the marrow microenvironment and its inflammatory milieu. There is also a strong link between autoimmune disorders and MDS. In this review, we examine the role of inflammatory cytokines, toll like receptors, pyroptosis, stromal cells, and cellular inflammatory mediators in MDS initiation, propagation, and progression. These contributions in a background of mutational, epigenetic, and aging changes in the marrow are also reviewed. Such inflammatory mediators may be subject to therapeutic agents which will enhance suppression of the MDS clone with potential to improve therapeutic outcomes in this disease which is usually incurable in aged patients not eligible for stem cell transplantation.
Risk assessment is affected by large uncertainties, depending on hazard, structure, damage, and loss analysis. Crucial problems and choices may refer to: (a) hazard parameters, including the ...definition of appropriate ground motion levels and of their probability to occur; (b) level of knowledge about materials, geometry, detailing; (c) assessed damage and failure modes; and (d) resulting potential for step changes in performances.
The cost of attaining a high level of knowledge may significantly reduce the remaining resources, it is therefore important to favor resilient solutions with a creative adoption of appropriate strengthening strategies.
In this framework, this article discusses the possible criteria for the mitigation of seismic risk and some of the alternative choices that may be adopted for strengthening, with reference to:
(a) the modification of damage and collapse modes strengthening individual elements or locallyincreasing the deformation capacity;
(b) the insertion of additional systems resisting to horizontal actions;
(c) the introduction of base isolation, with the objective of capacity-protecting the existingstructure;
(d) the reduction of displacement demand by added damping or introducing tuned masssystems.
Alternative strengthening choices lead to different protection levels and imply different performances that are, in general, represented by non linear or step functions of a cost parameter of the intervention. From these considerations, conceptual "structure driven" strengthening criteria, based on a logical use of resources, are discussed.
Stem cell fate is influenced by specialized microenvironments that remain poorly defined in mammals. To explore the possibility that haematopoietic stem cells derive regulatory information from bone, ...accounting for the localization of haematopoiesis in bone marrow, we assessed mice that were genetically altered to produce osteoblast-specific, activated PTH/PTHrP receptors (PPRs). Here we show that PPR-stimulated osteoblastic cells that are increased in number produce high levels of the Notch ligand jagged 1 and support an increase in the number of haematopoietic stem cells with evidence of Notch1 activation in vivo. Furthermore, ligand-dependent activation of PPR with parathyroid hormone (PTH) increased the number of osteoblasts in stromal cultures, and augmented ex vivo primitive haematopoietic cell growth that was abrogated by γ-secretase inhibition of Notch activation. An increase in the number of stem cells was observed in wild-type animals after PTH injection, and survival after bone marrow transplantation was markedly improved. Therefore, osteoblastic cells are a regulatory component of the haematopoietic stem cell niche in vivo that influences stem cell function through Notch activation. Niche constituent cells or signalling pathways provide pharmacological targets with therapeutic potential for stem-cell-based therapies.
Inv(3q26) and t(3:3)(q21;q26) are specific to poor-prognosis myeloid malignancies, and result in marked overexpression of EVI1, a zinc-finger transcription factor and myeloid-specific oncoprotein. ...Despite extensive study, the mechanism by which EVI1 contributes to myeloid malignancy remains unclear. Here we describe a new mouse model that mimics the transcriptional effects of 3q26 rearrangement. We show that EVI1 overexpression causes global distortion of hematopoiesis, with suppression of erythropoiesis and lymphopoiesis, and marked premalignant expansion of myelopoiesis that eventually results in leukemic transformation. We show that myeloid skewing is dependent on DNA binding by EVI1, which upregulates Spi1, encoding master myeloid regulator PU.1. We show that EVI1 binds to the -14 kb upstream regulatory element (-14kbURE) at Spi1; knockdown of Spi1 dampens the myeloid skewing. Furthermore, deletion of the -14kbURE at Spi1 abrogates the effects of EVI1 on hematopoietic stem cells. These findings support a novel mechanism of leukemogenesis through EVI1 overexpression.
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