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International Journal of Molecular... Jan 2015Reactive oxygen species (ROS) can be generated by defective endogenous reduction of oxygen by cellular enzymes or in the mitochondrial respiratory pathway, as well as by... (Review)
Review
Reactive oxygen species (ROS) can be generated by defective endogenous reduction of oxygen by cellular enzymes or in the mitochondrial respiratory pathway, as well as by exogenous exposure to UV or environmental damaging agents. Regulation of intracellular ROS levels is critical since increases above normal concentrations lead to oxidative stress and DNA damage. A growing body of evidence indicates that the inability to regulate high levels of ROS leading to alteration of cellular homeostasis or defective repair of ROS-induced damage lies at the root of diseases characterized by both neurodegeneration and bone marrow failure as well as cancer. That these diseases may be reflective of the dynamic ability of cells to respond to ROS through developmental stages and aging lies in the similarities between phenotypes at the cellular level. This review summarizes work linking the ability to regulate intracellular ROS to the hematopoietic stem cell phenotype, aging, and disease.
Topics: Anemia, Aplastic; Animals; Bone Marrow Diseases; Bone Marrow Failure Disorders; DNA Damage; DNA Repair; Genomic Instability; Hematopoietic Stem Cells; Hemoglobinuria, Paroxysmal; Humans; Oxidative Stress; Reactive Oxygen Species
PubMed: 25622253
DOI: 10.3390/ijms16022366 -
International Journal of Molecular... Apr 2023Bone marrow edema (BME), also termed bone marrow lesions, is a syndrome characterized by bone pain and the appearance of high signal intensity on T2 fat-suppressed and...
Bone marrow edema (BME), also termed bone marrow lesions, is a syndrome characterized by bone pain and the appearance of high signal intensity on T2 fat-suppressed and short tau inversion recovery (STIR) MRI sequences. BME can be related to trauma or a variety of non-traumatic diseases, and current treatment modalities include non-steroidal anti-inflammatory drugs (NSAIDS), bisphosphonates, denosumab, extracorporeal shockwave therapy (ESWT), the vasoactive prostacyclin analogue iloprost, and surgical decompression. Spontaneous BME is a subset that has been observed with no apparent causative conditions. It is most likely caused by venous outflow obstruction and intraosseous hypertension. These are mechanistically related to impaired perfusion and ischemia in several models of BME and are related to bone remodeling. The association of perfusion abnormalities and bone pain provides the pathophysiological rationale for surgical decompression. We present a case of spontaneous BME and a second case of spontaneous migratory BME treated with surgical decompression and demonstrate resolution of pain and the high signal intensity on MRI. This report provides an integration of the clinical syndrome, MR imaging characteristics, circulatory pathophysiology, and treatment. It draws upon several studies to suggest that both the bone pain and the MRI characteristics are related to venous stasis, and when circulatory pathologies are relieved by decompression or fenestration, both the bone pain and the MRI signal abnormalities resolve.
Topics: Humans; Bone Marrow; Bone Marrow Diseases; Bone Diseases; Edema; Decompression, Surgical; Magnetic Resonance Imaging; Musculoskeletal Pain; Perfusion
PubMed: 37047734
DOI: 10.3390/ijms24076761 -
Hematology. American Society of... Dec 2017Patients with inherited bone marrow failure syndromes (IBMFSs) classically present with specific patterns of cytopenias along with congenital anomalies and/or other... (Review)
Review
Patients with inherited bone marrow failure syndromes (IBMFSs) classically present with specific patterns of cytopenias along with congenital anomalies and/or other physical features that are often recognizable early in life. However, increasing application of genomic sequencing and clinical awareness of subtle disease presentations have led to the recognition of IBMFS in pediatric and adult populations more frequently than previously realized, such as those with early onset myelodysplastic syndrome (MDS). Given the well-defined differences in clinical management needs and outcomes for aplastic anemia, acute myeloid leukemia, and MDS in patients with an IBMFS vs those occurring sporadically, as well as nonhematologic comorbidities in patients with IBMFSs, it is critical for hematologists to understand how to approach screening for the currently known IBMFSs. This review presents a practical approach for the clinical hematologist that outlines when to suspect an IBMFS and how to use various diagnostic tools, from physical examination to screening laboratory tests and genomics, for the diagnosis of the most frequent IBMFSs: Fanconi anemia, telomere biology disorders, Diamond-Blackfan anemia, GATA2 deficiency syndrome, Shwachman-Diamond syndrome, and severe congenital neutropenia.
Topics: Bone Marrow Diseases; Genetic Diseases, Inborn; Genetic Testing; Humans; Syndrome
PubMed: 29222240
DOI: 10.1182/asheducation-2017.1.79 -
Cancer Apr 2017The current study was conducted to expedite international standardized reporting of bone marrow disease in children with neuroblastoma and to improve equivalence of care. (Review)
Review
Recommendations for the standardization of bone marrow disease assessment and reporting in children with neuroblastoma on behalf of the International Neuroblastoma Response Criteria Bone Marrow Working Group.
BACKGROUND
The current study was conducted to expedite international standardized reporting of bone marrow disease in children with neuroblastoma and to improve equivalence of care.
METHODS
A multidisciplinary International Neuroblastoma Response Criteria Bone Marrow Working Group was convened by the US National Cancer Institute in January 2012 with representation from Europe, North America, and Australia. Practical transferable recommendations to standardize the reporting of bone marrow disease were developed.
RESULTS
To the authors' knowledge, the current study is the first to comprehensively present consensus criteria for the collection, analysis, and reporting of the percentage area of bone marrow parenchyma occupied by tumor cells in trephine-biopsies. The quantitative analysis of neuroblastoma content in bone marrow aspirates by immunocytology and reverse transcriptase-quantitative polymerase chain reaction are revised. The inclusion of paired-like homeobox 2b (PHOX2B) for immunohistochemistry and reverse transcriptase-quantitative polymerase chain reaction is recommended. Recommendations for recording bone marrow response are provided. The authors endorse the quantitative assessment of neuroblastoma cell content in bilateral core needle biopsies-trephines and aspirates in all children with neuroblastoma, with the exception of infants, in whom the evaluation of aspirates alone is advised. It is interesting to note that 5% disease is accepted as an internationally achievable level for disease assessment.
CONCLUSIONS
The quantitative assessment of neuroblastoma cells is recommended to provide data from which evidence-based numerical criteria for the reporting of bone marrow response can be realized. This is particularly important in the minimal disease setting and when neuroblastoma detection in bone marrow is intermittent, where clinical impact has yet to be validated. The wide adoption of these harmonized criteria will enhance the ability to compare outcomes from different trials and facilitate collaborative trial design. Cancer 2017;123:1095-1105. © 2016 American Cancer Society.
Topics: Biopsy; Bone Marrow; Bone Marrow Diseases; Bone Marrow Examination; Humans; Immunohistochemistry; Neoplasm Invasiveness; Neoplasm Metastasis; Neuroblastoma; Polymerase Chain Reaction
PubMed: 27984660
DOI: 10.1002/cncr.30380 -
Stem Cells and Development Jan 2017When considering inherited diseases that can be treated by gene transfer into hematopoietic stem cells (HSCs), there are only two in which the HSC and progenitor cell... (Review)
Review
When considering inherited diseases that can be treated by gene transfer into hematopoietic stem cells (HSCs), there are only two in which the HSC and progenitor cell distribution inside the bone marrow and its microenvironment are exactly the same as in a healthy subject: metachromatic leukodystrophy (MLD) and adrenoleukodystrophy (ALD). In all other settings [X-linked severe combined immunodeficiency (X-SCID), adenosine deaminase deficiency, Wiskott-Aldrich syndrome, and β-hemoglobinopathies], the bone marrow content of the different stem and precursor cells and the cells' relationship with the stroma have very specific characteristics. These peculiarities can influence the cells' harvesting and behavior in culture, and the postgraft uptake and further behavior of the gene-modified hematopoietic/precursor cells. In the present mini-review, we shall briefly summarize these characteristics and outline the possible consequences and challenges.
Topics: Animals; Bone Marrow; Bone Marrow Diseases; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans
PubMed: 27750026
DOI: 10.1089/scd.2016.0230 -
Haematologica Oct 2023Shwachman-Diamond syndrome is a rare inherited bone marrow failure syndrome characterized by neutropenia, exocrine pancreatic insufficiency, and skeletal abnormalities....
Shwachman-Diamond syndrome is a rare inherited bone marrow failure syndrome characterized by neutropenia, exocrine pancreatic insufficiency, and skeletal abnormalities. In 10-30% of cases, transformation to a myeloid neoplasm occurs. Approximately 90% of patients have biallelic pathogenic variants in the SBDS gene located on human chromosome 7q11. Over the past several years, pathogenic variants in three other genes have been identified to cause similar phenotypes; these are DNAJC21, EFL1, and SRP54. Clinical manifestations involve multiple organ systems and those classically associated with the Shwachman-Diamond syndrome (bone, blood, and pancreas). Neurocognitive, dermatologic, and retinal changes may also be found. There are specific gene-phenotype differences. To date, SBDS, DNAJC21, and SRP54 variants have been associated with myeloid neoplasia. Common to SBDS, EFL1, DNAJC21, and SRP54 is their involvement in ribosome biogenesis or early protein synthesis. These four genes constitute a common biochemical pathway conserved from yeast to humans that involve early stages of protein synthesis and demonstrate the importance of this synthetic pathway in myelopoiesis.
Topics: Humans; Shwachman-Diamond Syndrome; Lipomatosis; Bone Marrow Diseases; Mutation; Exocrine Pancreatic Insufficiency; Signal Recognition Particle
PubMed: 37226705
DOI: 10.3324/haematol.2023.282949 -
Hematology/oncology Clinics of North... Aug 2018Clonal hematopoiesis as a hallmark of myelodysplastic syndrome (MDS) is mediated by the selective advantage of clonal hematopoietic stem cells in a context-specific... (Review)
Review
Clonal hematopoiesis as a hallmark of myelodysplastic syndrome (MDS) is mediated by the selective advantage of clonal hematopoietic stem cells in a context-specific manner. Although primary MDS emerges without known predisposing cause and is associated with advanced age, secondary MDS may develop in younger patients with bone marrow failure syndromes or after exposure to chemotherapy, respectively. This article discusses recent advances in the understanding of context-dependent clonal hematopoiesis in MDS with focus on clonal evolution in inherited and acquired bone marrow failure syndromes.
Topics: Anemia, Aplastic; Bone Marrow Diseases; Bone Marrow Failure Disorders; Clonal Evolution; Genetic Predisposition to Disease; Hemoglobinuria, Paroxysmal; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes
PubMed: 30047417
DOI: 10.1016/j.hoc.2018.03.005 -
Clinical & Developmental Immunology 2013Immune-mediated bone marrow failure syndromes (BMFS) are characterized by ineffective marrow haemopoiesis and subsequent peripheral cytopenias. Ineffective haemopoiesis... (Review)
Review
Immune-mediated bone marrow failure syndromes (BMFS) are characterized by ineffective marrow haemopoiesis and subsequent peripheral cytopenias. Ineffective haemopoiesis is the result of a complex marrow deregulation including genetic, epigenetic, and immune-mediated alterations in haemopoietic stem/progenitor cells, as well as abnormal haemopoietic-to-stromal cell interactions, with abnormal release of haemopoietic growth factors, chemokines, and inhibitors. Mesenchymal stem/stromal cells (MSCs) and their progeny (i.e., osteoblasts, adipocytes, and reticular cells) are considered as key cellular components of the bone marrow haemopoietic niche. MSCs may interfere with haemopoietic as well as immune regulation. Evidence suggests that bone marrow MSCs may be involved in immune-mediated BMFS underlying pathophysiology, harboring either native abnormalities and/or secondary defects, caused by exposure to activated marrow components. This review summarizes previous as well as more recent information related to the biologic/functional characteristics of bone marrow MSCs in myelodysplastic syndromes, acquired aplastic anemia, and chronic idiopathic neutropenia.
Topics: Anemia, Aplastic; Bone Marrow Diseases; Bone Marrow Failure Disorders; Cell Differentiation; Hemoglobinuria, Paroxysmal; Humans; Mesenchymal Stem Cells; Myelodysplastic Syndromes; Neutropenia
PubMed: 24386000
DOI: 10.1155/2013/265608 -
The Journal of Clinical Investigation May 2016Mammalian chromosomes terminate in stretches of repetitive telomeric DNA that act as buffers to avoid loss of essential genetic information during end-replication. A... (Review)
Review
Mammalian chromosomes terminate in stretches of repetitive telomeric DNA that act as buffers to avoid loss of essential genetic information during end-replication. A multiprotein complex known as shelterin prevents recognition of telomeric sequences as sites of DNA damage. Telomere erosion contributes to human diseases ranging from BM failure to premature aging syndromes and cancer. The role of shelterin telomere protection is less understood. Mutations in genes encoding the shelterin proteins TRF1-interacting nuclear factor 2 (TIN2) and adrenocortical dysplasia homolog (ACD) were identified in dyskeratosis congenita, a syndrome characterized by somatic stem cell dysfunction in multiple organs leading to BM failure and other pleiotropic manifestations. Here, we introduce the biochemical features and in vivo effects of individual shelterin proteins, discuss shelterin functions in hematopoiesis, and review emerging knowledge implicating the shelterin complex in hematological disorders.
Topics: Anemia, Aplastic; Animals; Bone Marrow Diseases; Bone Marrow Failure Disorders; Chromosomes, Human; DNA Damage; Dyskeratosis Congenita; Hematopoiesis; Hemoglobinuria, Paroxysmal; Humans; Mutation; Shelterin Complex; Telomere; Telomere-Binding Proteins
PubMed: 27135879
DOI: 10.1172/JCI84547 -
Osteoarthritis and Cartilage Jul 2017Whether meniscal extrusion and bone marrow lesions (BMLs) are independently associated with the risk of knee osteoarthritis (OA) is unknown. (Observational Study)
Observational Study
OBJECTIVE
Whether meniscal extrusion and bone marrow lesions (BMLs) are independently associated with the risk of knee osteoarthritis (OA) is unknown.
METHODS
Data was extracted from the Osteoarthritis Initiative (OAI) cohort. Participants were grouped according to the absence (Kellgren-Lawrence (KL) grade ≤ 1, n = 2120) or presence (KL ≥ 2, n = 2249) of radiographic OA (ROA). Baseline meniscal extrusion and tibial BMLs were assessed. Tibial plateau cartilage volume was assessed at baseline and 72 months, while radiographic disease was assessed at baseline and 48 months. Total knee replacement (TKR) was assessed at 72 months.
RESULTS
In those with ROA, the presence of a baseline meniscal extrusion (independent of BMLs) was associated with accelerated cartilage volume loss (medial tibia: -2.1%/annum vs -1.5%; lateral: -2.6%/annum vs -1.6%; both P < 0.001), progressive ROA and TKR (Odds ratio (OR) range 1.4-1.8; 95% CI range 1.1-2.9). The presence of a baseline BML was associated with accelerated cartilage volume loss (medial tibia: -2.1%/annum vs -1.6%; lateral: -1.9%/annum vs -1.6%; P ≤ 0.02), progressive ROA and joint replacement (OR range 1.5-2.4; 95% CI range 1.1-3.4). In those with no ROA, a baseline medial meniscal extrusion was associated with accelerated cartilage volume loss (medial tibia: -2.1%/annum vs -1.2%, P < 0.001), and a baseline medial BML with incident ROA (OR 1.7, 95% CI 1.1 to 2.9).
CONCLUSIONS
The presence of baseline meniscal extrusion and BMLs are associated with incident and progressive knee of each other (OA) and represent important structural targets for the treatment and prevention of knee OA.
Topics: Aged; Arthroplasty, Replacement, Knee; Bone Marrow Diseases; Cartilage Diseases; Cartilage, Articular; Disease Progression; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Menisci, Tibial; Middle Aged; Osteoarthritis, Knee; Range of Motion, Articular; Risk Assessment
PubMed: 28216311
DOI: 10.1016/j.joca.2017.02.792