Relative Energy Deficiency in sport (REDs): Endocrine manifestations, pathophysiology and treatments.

Research on lean, energy-deficient athletic and military cohorts has broadened the concept of the Female Athlete Triad into the Relative Energy Deficiency in Sport (REDs) syndrome. REDs represents a spectrum of abnormalities induced by low energy availability (LEA), which serves as the underlying cause of all symptoms described within the REDs concept, affecting exercising populations of either biological sex. Both short- and long-term LEA, in conjunction with other moderating factors, may produce a multitude of maladaptive changes that impair various physiological systems and adversely affect health, well-being, and sport performance. Consequently, the comprehensive definition of REDs encompasses a broad spectrum of physiological sequelae and adverse clinical outcomes related to LEA, such as neuroendocrine, bone, immune, and hematological effects, ultimately resulting in compromised health and performance. In this review, we discuss the pathophysiology of REDs and associated disorders. We briefly examine current treatment recommendations for REDs, primarily focusing on non-pharmacological, behavioral, and lifestyle modifications that target its underlying cause - energy deficit. We also discuss treatment approaches aimed at managing symptoms, such as menstrual dysfunction and bone stress injuries, and explore potential novel treatments that target the underlying physiology, emphasizing the roles of leptin and the activin-follistatin-inhibin axis, the roles of which remain to be fully elucidated, in the pathophysiology and management of REDs. In the near future, novel therapies leveraging our emerging understanding of molecules and physiological axes underlying energy availability or lack thereof may restore LEA-related abnormalities, thus preventing and/or treating REDs-related health complications, such as stress fractures, and improving performance.

Perspectives for the Use of Umbilical Cord Blood in Transplantation and Beyond: Initiatives for an Advanced and Sustainable Public Banking Program in Greece.

The umbilical cord blood (UCB) donated in public UCB banks is a source of hematopoietic stem cells (HSC) alternative to bone marrow for allogeneic HSC transplantation (HSCT). However, the high rejection rate of the donated units due to the strict acceptance criteria and the wide application of the haploidentical HSCT have resulted in significant limitation of the use of UCB and difficulties in the economic sustainability of the public UCB banks. There is an ongoing effort within the UCB community to optimize the use of UCB in the field of HSCT and a parallel interest in exploring the use of UCB for applications beyond HSCT i.e., in the fields of cell therapy, regenerative medicine and specialized transfusion medicine. In this report, we describe the mode of operation of the three public UCB banks in Greece as an example of an orchestrated effort to develop a viable UCB banking system by (a) prioritizing the enrichment of the national inventory by high-quality UCB units from populations with rare human leukocyte antigens (HLA), and (b) deploying novel sustainable applications of UCB beyond HSCT, through national and international collaborations. The Greek paradigm of the public UCB network may become an example for countries, particularly with high HLA heterogeneity, with public UCB banks facing sustainability difficulties and adds value to the international efforts aiming to sustainably expand the public UCB banking system.

An IL-10/DEL-1 axis supports granulopoiesis and survival from sepsis in early life.

The limited reserves of neutrophils are implicated in the susceptibility to infection in neonates, however the regulation of neutrophil kinetics in infections in early life remains poorly understood. Here we show that the developmental endothelial locus (DEL-1) is elevated in neonates and is critical for survival from neonatal polymicrobial sepsis, by supporting emergency granulopoiesis. Septic DEL-1 deficient neonate mice display low numbers of myeloid-biased multipotent and granulocyte-macrophage progenitors in the bone marrow, resulting in neutropenia, exaggerated bacteremia, and increased mortality; defects that are rescued by DEL-1 administration. A high IL-10/IL-17A ratio, observed in newborn sepsis, sustains tissue DEL-1 expression, as IL-10 upregulates while IL-17 downregulates DEL-1. Consistently, serum DEL-1 and blood neutrophils are elevated in septic adult and neonate patients with high serum IL-10/IL-17A ratio, and mortality is lower in septic patients with high serum DEL-1. Therefore, IL-10/DEL-1 axis supports emergency granulopoiesis, prevents neutropenia and promotes sepsis survival in early life.

Immunomodulatory actions of myeloid-derived suppressor cells in the context of innate immunity.

Myeloid-derived suppressor cells (MDSCs) are notable innate immune cells, which are further divided into two subpopulations, i.e., monocytic and granulocytic. These cells are traditionally considered to mainly suppress the T-cell responses. However, more updated data indicate that their properties are rather immunomodulatory than solely immunosuppressive. Indeed, MDSCs display extensive crosstalk with other either innate or adaptive immune cells, and, according to the situation under which they are triggered, they may enhance or attenuate the immune response. However, their positive role in host's defense mechanisms under specific conditions is rarely discussed in the literature. In this mini-review, the authors briefly summarise the mechanisms of action of MDSCs under distinct conditions, such as infections and malignancies, with a particular emphasis on their role as components of the innate immunity system.

Epithelial to mesenchymal transition (EMT) in metaplastic breast cancer and phyllodes breast tumors.

Epithelial-mesenchymal transition (EMT), a transdifferentiation program whereby epithelial cells acquire mesenchymal phenotype, is essential during embryonic development. EMT has also been implicated in cancer progression by conferring migratory and metastatic potential, as well as cell plasticity and stem cell like traits, to cancer cells. Metaplastic breast carcinoma (MBC) is a rare aggressive type of breast cancer characterized by the presence of heterologous elements, typically by the existence of epithelial and mesenchymal components. Phyllodes tumors (PTs) are uncommon fibroepithelial neoplasms consisting of epithelial and mesenchymal elements. Although various hypotheses have been proposed on the pathogenesis of these biphasic tumors, there is growing evidence supporting the theory that PTs and MBC could both correlate with cancer related EMT. This review summarizes the existing literature on the emerging role of EMT in the pathogenesis of MBC and PTs. Both malignant PTs and MBC are characterized by poor prognosis. Therefore, several anti-EMT targeting strategies such as blocking upstream signaling pathways, targeting the molecular drivers of EMT and targeting mesenchymal cells and the extracellular matrix, could potentially represent a promising therapeutic approach for patients suffering from these aggressive neoplasms.

Caplacizumab for immune thrombotic thrombocytopenic purpura: real-world multicenter data.

Given the limited real-world data of caplacizumab, our multicenter real-world study was designed to assess the safety and efficacy of caplacizumab in immune thrombotic thrombocytopenic pupura (iTTP), compared to historic controls. We have studied 70 patients: 23 in the caplacizumab and 47 in the historic control group. Plasma exchange was applied in all episodes except for two patients that denied plasma exchange. Rituximab as first-line treatment was more common in the caplacizumab group compared to historic control. Caplacizumab (10 mg daily) was given at a median on day 7 (1-43) from initial diagnosis for 32 (6-47) dosages. In the caplacizumab group, a median of 12 (8-23) patients required plasma exchange sessions versus 14 (6-32) in the control group. Caplacizumab administration did not produce any grade 3 complications or major hemorrhagic events. After a median of 19.0 (2.6-320) months since the iTTP diagnosis, 5 deaths occurred (4 in the control group and 1 in the caplacizumab group, p = 0.310). Caplacizumab patients achieved early platelet normalization and ADAMTS13 activity normalization at the end of treatment. Relapse was observed only in 2/23 (9%) caplacizumab patients, compared to 29/47 (62%) historic controls (p < 0.001). Overall, caplacizumab is safe and effective in treating iTTP, including cases refractory to plasma exchange, re-administration, and cases without previous plasma exchange treatment. No major hemorrhagic events were observed. Cessation of dosing guided by ADAMTS13 has ensured a low relapse rate.

The European Guidelines on Diagnosis and Management of Neutropenia in Adults and Children: A Consensus Between the European Hematology Association and the EuNet-INNOCHRON COST Action.

Neutropenia, as an isolated blood cell deficiency, is a feature of a wide spectrum of acquired or congenital, benign or premalignant disorders with a predisposition to develop myelodysplastic neoplasms/acute myeloid leukemia that may arise at any age. In recent years, advances in diagnostic methodologies, particularly in the field of genomics, have revealed novel genes and mechanisms responsible for etiology and disease evolution and opened new perspectives for tailored treatment. Despite the research and diagnostic advances in the field, real world evidence, arising from international neutropenia patient registries and scientific networks, has shown that the diagnosis and management of neutropenic patients is mostly based on the physicians' experience and local practices. Therefore, experts participating in the European Network for the Innovative Diagnosis and Treatment of Chronic Neutropenias have collaborated under the auspices of the European Hematology Association to produce recommendations for the diagnosis and management of patients across the whole spectrum of chronic neutropenias. In the present article, we describe evidence- and consensus-based guidelines for the definition and classification, diagnosis, and follow-up of patients with chronic neutropenias including special entities such as pregnancy and the neonatal period. We particularly emphasize the importance of combining the clinical findings with classical and novel laboratory testing, and advanced germline and/or somatic mutational analyses, for the characterization, risk stratification, and monitoring of the entire spectrum of neutropenia patients. We believe that the wide clinical use of these practical recommendations will be particularly beneficial for patients, families, and treating physicians.

The mesenchymal compartment in myelodysplastic syndrome: Its role in the pathogenesis of the disorder and its therapeutic targeting.

Myelodysplastic syndromes include a broad spectrum of malignant myeloid disorders that are characterized by dysplastic ineffective hematopoiesis, reduced peripheral blood cells counts and a high risk of progression to acute myeloid leukemia. The disease arises primarily because of accumulating chromosomal, genetic and epigenetic changes as well as immune-mediated alterations of the hematopoietic stem cells (HSCs). However, mounting evidence suggests that aberrations within the bone marrow microenvironment critically contribute to myelodysplastic syndrome (MDS) initiation and evolution by providing permissive cues that enable the abnormal HSCs to grow and eventually establish and propagate the disease. Mesenchymal stromal cells (MSCs) are crucial elements of the bone marrow microenvironment that play a key role in the regulation of HSCs by providing appropriate signals via soluble factors and cell contact interactions. Given their hematopoiesis supporting capacity, it has been reasonable to investigate MSCs' potential involvement in MDS. This review discusses this issue by summarizing existing findings obtained by in vitro studies and murine disease models of MDS. Furthermore, the theoretical background of targeting the BM-MSCs in MDS is outlined and available therapeutic modalities are described.

Adipokines and epithelial-mesenchymal transition (EMT) in cancer.

Obesity is a significant risk factor for cancer development. Within the tumor microenvironment, adipocytes interact with cancer cells, immune cells, fibroblasts and endothelial cells, and orchestrate several signaling pathways by secreting bioactive molecules, including adipokines. Adipokines or adipocytokines are produced predominantly by adipocytes and function as autocrine, paracrine and endocrine mediators. Adipokines can exert pro- and anti-inflammatory functions, and they play a pivotal role in the state of chronic low-grade inflammation that characterizes obesity. Epithelial-mesenchymal transition (EMT), a complex biological process whereby epithelial cells acquire the invasive, migratory mesenchymal phenotype is well-known to be implicated in cancer progression and metastasis. Emerging evidence suggests that there is a link between adipokines and EMT. This may contribute to the correlation that has been documented between obesity and cancer progression. This review summarizes the existing body of evidence supporting an association between the process of EMT in cancer and the adipokines leptin, adiponectin, resistin, visfatin/NAMPT, lipocalin-2/NGAL, as well as other newly discovered adipokines including chemerin, nesfatin-1/nucleobindin-2, AZGP1, SFRP5 and FABP4.

Autoimmune Neutropenias: Update on Clinical and Biological Features in Children and Adults.

The definition of autoimmune neutropenias (AIN) has been based on the demonstration of autoantibodies directed to various epitopes on blood neutrophils. However, this definition is probably too limited and excludes neutropenias (NPs) with a negative autoantibody test but with other phenomena that indicate an underlying autoimmune process. Examples of such AINs may be complete or incomplete systemic lupus erythematosus or other autoimmune diseases where NP is common but patients may not fulfill formal diagnostic criteria for a rheumatic disease. Recently, various inherited immune-dysregulation syndromes, such as those related to variants in, for example, TACI, BAFFR, ACKR1/DARC, LRBA, CTLA 4 genes, with dysregulated B- and T-lymphocyte functions, have been associated with concomitant AINs. Cellular immune mechanisms may also play a prominent role in the development of NP, in the presence or not of autoantibodies, in cases of large granular lymphocyte syndromes of T- and NK-cell types or in chronic idiopathic NP, particularly in adults with T-cell clonal populations. The course of AIN may differ according to age, being transient and rather uncomplicated in children, and chronic with treatment requirement in adolescents and adults. This review discusses current knowledge of AINs, including diagnostic procedures, treatments, and prognosis.

Glucagon-like Peptide-1 Receptor in the Human Hypothalamus Is Associated with Body Mass Index and Colocalizes with the Anorexigenic Neuropeptide Nucleobindin-2/Nesfatin-1.

Data on animals emphasize the importance of the neuronal glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) for feeding suppression, although it is unclear whether astrocytes participate in the transduction of anorectic GLP-1R-dependent signals. In humans, the brain circuitry underlying these effects remains insufficiently investigated. The present study aimed to explore GLP-1R protein expression in the human hypothalamus and its correlation with body mass index (BMI). Sections of hypothalamus from 28 autopsy cases, 11 with normal weight (BMI < 25 kg/m2) and 17 with non-normal weight (BMI ≥ 25 kg/m2), were examined using immunohistochemistry and double immunofluorescence labeling. Prominent GLP-1R immunoexpression was detected in neurons of several hypothalamic nuclei, including paraventricular, supraoptic, and infundibular nuclei; the lateral hypothalamic area (LH); and basal forebrain nuclei. Interestingly, in the LH, GLP-1R was significantly decreased in individuals with BMI ≥ 25 kg/m2 compared with their normal weight counterparts (p = 0.03). Furthermore, GLP-1R was negatively correlated (τb = −0.347, p = 0.024) with BMI levels only in the LH. GLP-1R extensively colocalized with the anorexigenic and antiobesogenic neuropeptide nucleobindin-2/nesfatin-1 but not with the astrocytic marker glial fibrillary acidic protein. These data suggest a potential role for GLP-1R in the regulation of energy balance in the human hypothalamus. In the LH, an appetite- and reward-related brain region, reduced GLP-1R immunoexpression may contribute to the dysregulation of homeostatic and/or hedonic feeding behavior. Possible effects of NUCB2/nesfatin-1 on central GLP-1R signaling require further investigation.

Real world data on the prognostic significance of monocytopenia in myelodysplastic syndrome.

Monocytopenia is a common finding in patients with myelodysplastic syndrome (MDS), but although monocytes may exhibit prognostic significance in MDS due to their role in innate immunity, they have not been incorporated in any prognostic scoring system for MDS. In this study, we analyzed national registry data from 1719 adults with MDS. Monocytopenia was present in 29.5% of the patients and was correlated with the presence of excess blasts and higher revised international prognostic scoring system categories. Univariate analysis showed that monocytopenia was prognostic of a lower overall survival [(OS), 32.0 versus 65.0 months, p < 0.001], while it retained its prognostic significance in a multivariate model comprising anemia, neutropenia and thrombocytopenia [hazard ratio (HR) for OS, 1.320, p < 0.001]. Moreover, it was prognostic of a lower leukemia free survival (LFS) both in univariate analysis and in a multivariate model comprising cytopenias, bone marrow blasts, and cytogenetic risk (HR for LFS 1.27, p = 0.031). The findings regarding OS and LFR were exclusive or more pronounced in lower risk patients, respectively. Moreover, monocytopenia could divide the low and intermediate risk groups of IPSS-R in prognostically distinct subgroups. Our results redefine the prognostic role of monocytes in MDS and set the basis for further studies to validate our results and expand our knowledge on the prognostic significance of monocytopenia in MDS.

New Perspectives on Myeloid-Derived Suppressor Cells and Their Emerging Role in Haematology.

Myeloid-derived suppressor cells (MDSCs) are immature cells of myeloid origin that have gained researchers' attention, as they constitute promising biomarkers and targets for novel therapeutic strategies (i.e., blockage of development, differentiation, depletion, and deactivation) in several conditions, including neoplastic, autoimmune, infective, and inflammatory diseases, as well as pregnancy, obesity, and graft rejection. They are characterised in humans by the typical immunophenotype of CD11b+CD33+HLA-DR-/low and immune-modulating properties leading to decreased T-cell proliferation, induction of T-regulatory cells (T-regs), hindering of natural killer (NK) cell functionality, and macrophage M2-polarisation. The research in the field is challenging, as there are still difficulties in defining cell-surface markers and gating strategies that uniquely identify the different populations of MDSCs, and the currently available functional assays are highly demanding. There is evidence that MDSCs display altered frequency and/or functionality and could be targeted in immune-mediated and malignant haematologic diseases, although there is a large variability of techniques and results between different laboratories. This review presents the current literature concerning MDSCs in a clinical point of view in an attempt to trigger future investigation by serving as a guide to the clinical haematologist in order to apply them in the context of precision medicine as well as the researcher in the field of experimental haematology.

Myeloid-Derived Suppressor Cells: New Insights into the Pathogenesis and Therapy of MDS.

Myelodysplastic syndromes (MDS) are hematopoietic malignancies characterized by the clonal expansion of hematopoietic stem cells, bone marrow failure manifested by cytopenias, and increased risk for evolving to acute myeloid leukemia. Despite the fact that the acquisition of somatic mutations is considered key for the initiation of the disease, the bone marrow microenvironment also plays significant roles in MDS by providing the right niche and even shaping the malignant clone. Aberrant immune responses are frequent in MDS and are implicated in many aspects of MDS pathogenesis. Recently, myeloid-derived suppressor cells (MDSCs) have gained attention for their possible implication in the immune dysregulation associated with MDS. Here, we summarize the key findings regarding the expansion of MDSCs in MDS, their role in MDS pathogenesis and immune dysregulation, as well their potential as a new therapeutic target for MDS.

The deadly cross-talk between Hippo pathway and epithelial-mesenchymal transition (EMT) in cancer.

Hippo signaling pathway is an evolutionarily conserved network that regulates organ size growth and tissue regeneration. Hippo signaling dysfunction results in uncontrolled cell proliferation and influences cell differentiation. Aberrant Hippo pathway signaling is implicated in cancer progression, by promoting cell proliferation, cancer stem cell properties, chemoresistance and metastatic capacity. Epithelial-mesenchymal transition (EMT) is also well known to be implicated in carcinogenesis. Loss of cell polarity, disruption of cell-cell junctions and cytoskeletal remodeling are essential during EMT. At the same time, signals related to intercellular contact, cell-extracellular matrix contact, polarity and mechanotransduction are included in the list of regulatory inputs into Hippo pathway. Therefore, the emerging association between Hippo pathway and EMT in cancer is not surprising. Recent studies have begun to unravel the mechanisms of interaction between Hippo signaling pathway and EMT. In this review, we describe the existing evidence of cross talk between Hippo signaling pathway key molecules and the process of EMT, with emphasis on the role of Hippo-EMT interplay in cancer.