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

peripheral blood progenitor cells mobilization in patients with multiple myeloma

Autologous stem cell transplantation (ASCT) is considered the standard therapy for younger patients with newly diagnosed symptomatic multiple myeloma (MM). The introduction into clinical practice of novel agents (i.e.: proteasome inhibitors and immunomodulatory derivatives [IMiDs]) has significantly contributed to major advances in MM therapy and prognosis. These novel agents are incorporated into induction regimens to enhance the depth of response before ASCT and further improve post-ASCT outcomes. Collection of adequate hematopoietic stem cells (HSCs) is necessary for successful autologous transplantation. The mobilizing regimen usually consists of cyclophosphamide or disease-specific agents, in combination with a hematopoietic cytokine, usually G-CSF, which mobilizes HPSCs into the bloodstream, in particular when administered after myelosuppressive chemotherapy. In some patients, the number of mobilized CD34+ cells is not sufficient to perform successful stem cell transplantation due to bone marrow damage by neoplastic proliferation and/or chemoradiotherapy. To improve the collection of CD34+ cells, the mobilization procedure can be repeated or an alternative chemotherapy regimen can be chosen. Recently, the new drug plerixafor (Mozobil®) has been introduced to increase the number of circulating CD34+ cells. Its use increases the level of functional HPCs in the peripheral blood, with long-term resettlemen

Cancer-Associated Angiogenesis: The Endothelial Cell as a Checkpoint for Immunological Patrolling

Cancer-associated neo vessels’ formation acts as a gatekeeper that orchestrates the entrance and egress of patrolling immune cells within the tumor milieu. This is achieved, in part, via the directed chemokines’ expression and cell adhesion molecules on the endothelial cell surface that attract and retain circulating leukocytes. The crosstalk between adaptive immune cells and the cancer endothelium is thus essential for tumor immune surveillance and the success of immune-based therapies that harness immune cells to kill tumor cells. This review will focus on the biology of the endothelium and will explore the vascular-specific molecular mediators that control the recruitment, retention, and trafficking of immune cells that are essential for effective antitumor immunity. The literature revision will also explore how abnormalities in the tumor endothelium impair crosstalk with adaptive immune cells and how targeting these abnormalities can improve the success of immune-based therapies for different malignancies, with a particular focus on the paradigmatic example represented by multiple myeloma. We also generated and provide two original bio-informatic analyses, in order to sketch the physiopathology underlying the endothelial–neoplastic interactions in an easier manner, feeding into a vicious cycle propagating disease progression and highlighting novel pathways that might be exploited therapeutically

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

The mandibular condyle as uncommon metastatic site of neuroendocrine carcinoma: Case report and review of literature

Temporo-mandibular joint (TMJ) metastases are a very rare event and only 73 cases are reported in literature. In about 40% of cases condylar metastases represent the first clinical manifestation of a tumor of elsewhere and may then allow an early diagnosis. However, the identification of this tumoral process can be difficult as in over 50% of the cases it has a nuanced clinical presentation that is very similar to temporo-mandibular disorders. The first case of metastatic neuroendocrine carcinoma (NEC) of the temporo-mandibular joint (TMJ) mimicking a temporo-mandibular joint disorder is presented in this report. Furthermore, an extensive review of the literature has been performed in order to establish a correct diagnosticâ\u80\u93therapeutic protocol for these oncologic patients

two dimensional two phase depth integrated model for transients over mobile bed

AbstractFast geomorphic transients may involve complex scenarios of sediment transport, occurring near the bottom as bed load (i.e., saltating, sliding, and rolling) or as suspended load in the upper portion of the flow. The two sediment transport modalities may even coexist or alternate each other during the same event, especially when the shear stress varies considerably. Modeling these processes is therefore a challenging task, for which the usual representation of the flow as a mixture may result in being unsatisfactory. In the present paper, a new two-phase depth-averaged model is presented that accounts for variable sediment concentration in both bed and suspended loads. Distinct phase velocities are considered for bed load, whereas the slip velocity between the two phases is neglected in the suspended load. It is shown that the resulting two-phase model is hyperbolic, and the analytical expression of the eigenvalues is provided. The entrainment/deposition of sediment between the bottom and the bed ..

Proteolytic Activity of Human Lymphoid Tumor Cells. Correlation with Tumor Progression

Matrix metalloproteinase (MMP) expression and production are associated with advanced-stage tumor and contribute to tumor progression, invasion and metastases. The current study was designed to determine the expression and production of MMP-2 (gelatinase A) and MMP-9 (gelatinase B) by human lymphoid tumor cells. Changes in expression and production were also investigated during tumor progression of multiple myeloma and mycosis fungoides. In situ hybridization analysis revealed that lymphoblastic leukemia B cells (SB cell line), multiple myeloma (MM) cells (U266 cell line) and lymphoblastic leukemia T cells (CEM and Jurkat cell lines) express constitutively the mRNA for MMP-2 and/or MMP-9. We demonstrated by gelatin-zymography of cell culture medium that both enzymes were secreted in their cleaved (activated) form. In situ hybridization of bone marrow plasma cells and gelatin- zymography of the medium showed that patients with active MM (diagnosis, relapse, leukemic progression) express higher levels of MMP-2 mRNA and protein than patients with non-active MM (complete/objective response, plateau) and with monoclonal gammopathies of undetermined significance (MGUS). MMP-9 expression and secretion was similar in all patient groups. In patients with mycosis fungoides (MF), the expression of MMP-2 and MMP-9 mRNAs was significantly upregulated with advancing stage, in terms of lesions both positive for one of two mRNAs and with the greatest intensity of expression. Besides MF cells, the MMP-2 and/or MMP-9 mRNAs were expressed by some stromal cell populations (microvascular endothelial cells, fibroblasts, macrophages), suggesting that these cells cooperate in the process of tumor invasion. Our studies identify MMPs as an important class of proteinases involved in the extracellular matrix (ECM) degradation by human lymphoid tumors, and suggest that MMPs inhibitors may lead to important new treatment for their control

The Employment of Leukotriene Antagonists in Cutaneous Diseases Belonging to Allergological Field

Leukotrienes (LTs) are potent biological proinflammatory mediators. LTC4, LTD4, and LTE4 are more frequently involved in chronic inflammatory responses and exert their actions binding to a cysteinyl-LT 1 (CysLT1) receptor and a cysteinyl-LT 2 (CysLT2) receptor. LTs receptor antagonists available for clinical use demonstrate high-affinity binding to the CysLT1 receptor. In this paper the employment of anti-LTs in allergic cutaneous diseases is analyzed showing that several studies have recently reported a beneficial effects of these agents (montelukast and zafirlukast as well as zileuton) for the treatment of some allergic cutaneous related diseases-like chronic urticaria and atopic eczema although their proper application remains to be established