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Environmental Health Perspectives Jun 1981Hematopoietic system toxicity is a major limiting factor in the use of aggressive combined modality therapy in the treatment of malignant disease. In this review, the... (Review)
Review
Hematopoietic system toxicity is a major limiting factor in the use of aggressive combined modality therapy in the treatment of malignant disease. In this review, the known drug-x-ray interactions using tissue culture systems are extended to the bone marrow compartment. Two hypotheses prevail for late bone marrow failure: (1) stromal damage to the vasculature with subsequent fibrosis and (2) irreversible stem cell depletion in the irradiated site. Clinical extensions of the experimental data for bone marrow kinetics in the animal model have not proven successful to date. The future strategies for therapy of malignancies in which both radiation and chemotherapy are employed may require dose modification or treatment planning to limit bone marrow toxicity.
Topics: Animals; Bone Marrow; Bone Marrow Diseases; Humans; Physical Phenomena; Physics; Radiation Injuries, Experimental
PubMed: 7016523
DOI: 10.1289/ehp.813959 -
Cartilage Oct 2019This study aimed to compile available data in medical literature about subchondral calcium phosphate injection, comparing results obtained with this technique, as well... (Review)
Review
PURPOSE
This study aimed to compile available data in medical literature about subchondral calcium phosphate injection, comparing results obtained with this technique, as well as indications, complications, and other important factors in treatment of bone marrow lesions.
DESIGNS
A literature review using PubMed and Medline database in order to identify works with terms "subchondral calcium phosphate injection," " subchondroplasty®," "bone marrow lesion," and "knee." Eight relevant articles were found.
RESULTS
A total of 164 patients with bone marrow lesion mainly on femoral condyle and tibial plateau recovered with significant functional improvement of knee after subchondral calcium phosphate treatment. Although 25% of them still had some type of pain complaint, they also showed improvement. There were few complications reported and return to activities occurred after 3 months on average.
CONCLUSIONS
Few studies evaluate the result of using subchondral calcium phosphate injection technique. However, all presented favorable results regarding pain and improvement of knee function. In addition, within 2 years, there was a 70% reduction in conversion to total knee arthroplasty in patients with previous surgical indication who choose calcium phosphate treatment.
Topics: Bone Marrow Diseases; Bone Substitutes; Calcium Phosphates; Humans; Injections, Intra-Articular; Knee Injuries; Knee Joint; Recovery of Function
PubMed: 29667853
DOI: 10.1177/1947603518770249 -
Molecular Therapy : the Journal of the... Dec 2015The combination of epigenetic reprogramming with advanced genome editing technologies opened a new avenue to study disease mechanisms, particularly of disorders with... (Review)
Review
The combination of epigenetic reprogramming with advanced genome editing technologies opened a new avenue to study disease mechanisms, particularly of disorders with depleted target tissue. Bone marrow failure syndromes (BMFS) typically present with a marked reduction of peripheral blood cells due to a destroyed or dysfunctional bone marrow compartment. Somatic and germline mutations have been etiologically linked to many cases of BMFS. However, without the ability to study primary patient material, the exact pathogenesis for many entities remained fragmentary. Capturing the pathological genotype in induced pluripotent stem cells (iPSCs) allows studying potential developmental defects leading to a particular phenotype. The lack of hematopoietic stem and progenitor cells in these patients can also be overcome by differentiating patient-derived iPSCs into hematopoietic lineages. With fast growing genome editing techniques, such as CRISPR/Cas9, correction of disease-causing mutations in iPSCs or introduction of mutations in cells from healthy individuals enable comparative studies that may identify other genetic or epigenetic events contributing to a specific disease phenotype. In this review, we present recent progresses in disease modeling of inherited and acquired BMFS using reprogramming and genome editing techniques. We also discuss the challenges and potential shortcomings of iPSC-based models for hematological diseases.
Topics: Anemia, Aplastic; Animals; Bone Marrow Diseases; Bone Marrow Failure Disorders; Disease Models, Animal; Epigenesis, Genetic; Genetic Engineering; Genetic Therapy; Hemoglobinuria, Paroxysmal; Humans; Induced Pluripotent Stem Cells
PubMed: 26435409
DOI: 10.1038/mt.2015.180 -
Molecular Genetics & Genomic Medicine May 2018ERCC6L2-associated disorder has recently been described and only five patients were reported so far. The described phenotype included bone marrow, cerebral, and... (Review)
Review
BACKGROUND
ERCC6L2-associated disorder has recently been described and only five patients were reported so far. The described phenotype included bone marrow, cerebral, and craniofacial abnormalities. The aim of this study was to further define the genetic and phenotypic spectrum of the disorder by summarizing the five published cases and an additional case that we identified through whole-exome sequencing performed at the University of Toronto.
METHODS
Clinical data was extracted from the Canadian Inherited Marrow Failure Registry. Whole exome sequencing was performed to identify causative mutations.
RESULTS
All six cases had homozygous truncating mutations either at or upstream of the helicase domain of ERCC6L2. All patients displayed bone marrow failure, learning or developmental delay and microcephaly. Our patient was unique in displaying features of cerebellar disease, including ataxia and dysmetria as well as an interval deterioration of the corpus callosum and generalized volume loss on MRI. Another unique feature of our patient was retinal dystrophy with macular involvement. Along with one other patient, our patient displayed craniofacial abnormalities by presenting with low-set prominent ears, a pointed prominent chin, and deep-set eyes. Leukemia is common among patients with inherited bone marrow failure, but thus far, none of the patients have developed this complication.
CONCLUSIONS
ERCC6L2-associated disorder is a multisystem disorder. The phenotype spectrum includes bone marrow failure, cerebral, and craniofacial abnormalities, as well as cerebellar and retinal abnormalities.
Topics: Adolescent; Adult; Anemia, Aplastic; Bone Marrow Diseases; Bone Marrow Failure Disorders; Canada; Child; Child, Preschool; Craniofacial Abnormalities; DNA Helicases; Developmental Disabilities; Exome; Female; Hemoglobinuria, Paroxysmal; Homozygote; Humans; Infant; Intellectual Disability; Male; Microcephaly; Mutation; Nervous System Malformations; Pedigree; Phenotype
PubMed: 29633571
DOI: 10.1002/mgg3.388 -
Frontiers in Immunology 2024Bone marrow failure (BMF) has become one of the most studied autoimmune disorders, particularly due to its prevalence both as an inherited disease, but also as a result... (Review)
Review
Bone marrow failure (BMF) has become one of the most studied autoimmune disorders, particularly due to its prevalence both as an inherited disease, but also as a result of chemotherapies. BMF is associated with severe symptoms such as bleeding episodes and susceptibility to infections, and often has underlying characteristics, such as anemia, thrombocytopenia, and neutropenia. The current treatment landscape for BMF requires stem cell transplantation or chemotherapies to induce immune suppression. However, there is limited donor cell availability or dose related toxicity associated with these treatments. Optimizing these treatments has become a necessity. Polymer-based materials have become increasingly popular, as current research efforts are focused on synthesizing novel cell matrices for stem cell expansion to solve limited donor cell availability, as well as applying polymer delivery vehicles to intracellularly deliver cargo that can aid in immunosuppression. Here, we discuss the importance and impact of polymer materials to enhance therapeutics in the context of BMF.
Topics: Humans; Polymers; Animals; Bone Marrow Diseases; Bone Marrow Failure Disorders; Biocompatible Materials
PubMed: 38694497
DOI: 10.3389/fimmu.2024.1396486 -
Blood Jan 2019Hematopoiesis is a dynamic system that requires balanced cell division, differentiation, and death. The 2 major modes of programmed cell death, apoptosis and...
Hematopoiesis is a dynamic system that requires balanced cell division, differentiation, and death. The 2 major modes of programmed cell death, apoptosis and necroptosis, share molecular machinery but diverge in outcome with important implications for the microenvironment; apoptotic cells are removed in an immune silent process, whereas necroptotic cells leak cellular contents that incite inflammation. Given the importance of cytokine-directed cues for hematopoietic cell survival and differentiation, the impact on hematopoietic homeostasis of biasing cell death fate to necroptosis is substantial and poorly understood. Here, we present a mouse model with increased bone marrow necroptosis. Deletion of the proapoptotic Bcl-2 family members Bax and Bak inhibits bone marrow apoptosis. Further deletion of the BH3-only member Bid (to generate triple-knockout [TKO] mice) leads to unrestrained bone marrow necroptosis driven by increased Rip1 kinase (Ripk1). TKO mice display loss of progenitor cells, leading to increased cytokine production and increased stem cell proliferation and exhaustion and culminating in bone marrow failure. Genetically restoring Ripk1 to wild-type levels restores peripheral red cell counts as well as normal cytokine production. TKO bone marrow is hypercellular with abnormal differentiation, resembling the human disorder myelodysplastic syndrome (MDS), and we demonstrate increased necroptosis in MDS bone marrow. Finally, we show that Bid impacts necroptotic signaling through modulation of caspase-8-mediated Ripk1 degradation. Thus, we demonstrate that dysregulated necroptosis in hematopoiesis promotes bone marrow progenitor cell death that incites inflammation, impairs hematopoietic stem cells, and recapitulates the salient features of the bone marrow failure disorder MDS.
Topics: Animals; BH3 Interacting Domain Death Agonist Protein; Bone Marrow; Bone Marrow Diseases; Cells, Cultured; Cytokines; Hematopoietic Stem Cells; Inflammation; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelodysplastic Syndromes; Necrosis; Receptor-Interacting Protein Serine-Threonine Kinases; bcl-2 Homologous Antagonist-Killer Protein
PubMed: 30413413
DOI: 10.1182/blood-2018-05-847335 -
Frontiers in Immunology 2021Immune phenomena are increasingly reported in myeloid neoplasms, and include autoimmune cytopenias/diseases and immunodeficiency, either preceding or complicating acute... (Review)
Review
Immune phenomena are increasingly reported in myeloid neoplasms, and include autoimmune cytopenias/diseases and immunodeficiency, either preceding or complicating acute myeloid leukemia, myelodysplastic syndromes (MDS), chronic myeloproliferative neoplasms, and bone marrow failure (BMF) syndromes. Autoimmunity and immunodeficiency are the two faces of a dysregulated immune tolerance and surveillance and may result, along with contributing environmental and genetic factors, in an increased incidence of both tumors and infections. The latter may fuel both autoimmunity and immune activation, triggering a vicious circle among infections, tumors and autoimmune phenomena. Additionally, alterations of the microbiota and of mesenchymal stem cells (MSCs) pinpoint to the importance of a permissive or hostile microenvironment for tumor growth. Finally, several therapies of myeloid neoplasms are aimed at increasing host immunity against the tumor, but at the price of increased autoimmune phenomena. In this review we will examine the epidemiological association of myeloid neoplasms with autoimmune diseases and immunodeficiencies, and the pivotal role of autoimmunity in the pathogenesis of MDS and BMF syndromes, including the paroxysmal nocturnal hemoglobinuria conundrum. Furthermore, we will briefly examine autoimmune complications following therapy of myeloid neoplasms, as well as the role of MSCs and microbiota in these settings.
Topics: Autoimmune Diseases; Bone Marrow Diseases; Humans; Mesenchymal Stem Cells; Microbiota; Primary Immunodeficiency Diseases
PubMed: 34659257
DOI: 10.3389/fimmu.2021.751630 -
Hematology. American Society of... Dec 2016Clonal progression to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) remains a dreaded complication for a subset of patients with bone marrow failure... (Review)
Review
Clonal progression to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) remains a dreaded complication for a subset of patients with bone marrow failure (BMF). Recognizing risk factors for the development of MDS or AML would inform individualized treatment decisions and identify patients who may benefit from early or upfront hematopoietic stem cell transplantation. Now that next-generation DNA sequencing is available in the clinical laboratory, research has focused on the implications of germ line and somatic mutations for diagnosing and monitoring patients with BMF. Most germ line genetic BMF disorders are characterized by a high propensity to develop MDS or AML. Many affected patients lack the physical stigmata traditionally associated with the inherited marrow failure syndromes. Although any single inherited marrow failure disorder is rare, multiplexed genetic sequencing that allows simultaneous evaluation of marrow failure genes en masse demonstrated that, as a group, these inherited disorders compose a significant subset (5% to 10%) of patients with BMF. Early diagnosis of a germ line genetic marrow failure disorder allows individualized monitoring and tailored therapy. Recent studies of somatic variants in marrow failure revealed a high frequency of clonal hematopoiesis with the acquisition of mutations in genes associated with MDS or AML. Investigation of somatic mutations in marrow failure revealed important insights into the mechanisms promoting clonal disease but also raised additional questions. This review will focus on the evaluation and implications of germ line and somatic mutations for the development of clonal disorders in patients with BMF. Challenges and limitations of clinical genetic testing will be explored.
Topics: Anemia, Aplastic; Genetic Diseases, Inborn; Germ-Line Mutation; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes
PubMed: 27913465
DOI: 10.1182/asheducation-2016.1.74 -
Experimental Hematology Feb 2020Cyclophosphamide (CP) is one of the commonly used anticancer drugs, but its use is limited by myelotoxicity. Nerolidol (NER) is a lipophilic, bioactive sesquiterpene...
Cyclophosphamide (CP) is one of the commonly used anticancer drugs, but its use is limited by myelotoxicity. Nerolidol (NER) is a lipophilic, bioactive sesquiterpene reported to have neuroprotective, cardioprotective, gastroprotective, and renal protective potential, but its myeloprotective potential is underexplored. This study was aimed at evaluating the myeloid-protective potential of NER in CP-induced myelotoxic mice. NER 200 and 400 mg/kg was given orally from the first to the 14th day. CP 200 mg/kg was administered intravenously on the seventh day. At the end of the study, mice were humanly killed, and blood and bone marrow were collected and stored for hematologic, biochemical and histopathologic estimations. Bone marrow analysis revealed reduced bone marrow cellularity, α-esterase activity, colony-forming unit granulocyte-macrophage (CFU-GM) levels, colony-forming unit erythroid (CFU-E) levels, and burst-forming unit-erythroid (BFU-E) levels. Hematologic findings revealed reduced peripheral blood count and granulocyte-colony stimulating factor (G-CSF) levels, whereas biochemical analysis revealed increased malondialdehyde (MDA), tumor necrosis factor α (TNF-α), interleukin (IL)-6, and IL-1β levels and reduced superoxide dismutase (SOD), catalase (CAT), and IL-10 levels. Histopathologic study further strengthened our findings. Treatment with NER significantly reversed the hematotoxic and myelotoxic aberrations and retained the structural integrity of bone marrow. Findings of the current study suggest that NER is a potential therapeutic molecule that can mitigate CP-induced hematotoxic and myelotoxic manifestations. However, more detailed studies are needed to explicate the mechanism underlying its protective effect.
Topics: Animals; Bone Marrow; Bone Marrow Diseases; Cyclophosphamide; Cytokines; Erythroid Precursor Cells; Male; Mice; Sesquiterpenes
PubMed: 31987924
DOI: 10.1016/j.exphem.2020.01.007 -
BMC Pediatrics Oct 2023Shwachman-Diamond syndrome (SDS) is an autosomal recessive disease which results in inherited bone marrow failure (IBMF) and is characterized by exocrine pancreatic...
BACKGROUND
Shwachman-Diamond syndrome (SDS) is an autosomal recessive disease which results in inherited bone marrow failure (IBMF) and is characterized by exocrine pancreatic dysfunction and diverse clinical phenotypes. In the present study, we reviewed the internationally published reports on SDS patients, in order to summarize the clinical features, epidemiology, and treatment of SDS.
METHODS
We searched the WangFang and China National Knowledge Infrastructure databases with the keywords "Shwachman-Diamond syndrome," "SDS," "SBDS gene" and "inherited bone marrow failure" for relevant articles published from January 2002 to October 2022. In addition, studies published from January 2002 to October 2022 were searched from the Web of Science, PubMed, and MEDLINE databases, using "Shwachman-diamond syndrome" as the keyword. Finally, one child with SDS treated in Tongji Hospital was also included.
RESULTS
The clinical features of 156 patients with SDS were summarized. The three major clinical features of SDS were found to be peripheral blood cytopenia (96.8%), exocrine pancreatic dysfunction (83.3%), and failure to thrive (83.3%). The detection rate of SDS mutations was 94.6% (125/132). Mutations in SBDS, DNAJC21, SRP54, ELF6, and ELF1 have been reported. The male-to-female ratio was approximately 1.3/1. The median age of onset was 0.16 years, but the diagnostic age lagged by a median age of 1.3 years.
CONCLUSIONS
Pancreatic exocrine insufficiency and growth failure were common initial symptoms. SDS onset occurred early in childhood, and individual differences were obvious. Comprehensive collection and analysis of case-related data can help clinicians understand the clinical characteristics of SDS, which may improve early diagnosis and promote effective clinical intervention.
Topics: Female; Humans; Infant; Male; Bone Marrow Diseases; Exocrine Pancreatic Insufficiency; Mutation; Phenotype; Shwachman-Diamond Syndrome; Signal Recognition Particle
PubMed: 37803383
DOI: 10.1186/s12887-023-04324-3