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Rheumatic Diseases Clinics of North... Nov 2023Deficiency of adenosine deaminase 2 (DADA2) is a monogenic vasculitis syndrome caused by biallelic mutations in the adenosine deaminase 2 gene. The diagnosis of DADA2 is... (Review)
Review
Deficiency of adenosine deaminase 2 (DADA2) is a monogenic vasculitis syndrome caused by biallelic mutations in the adenosine deaminase 2 gene. The diagnosis of DADA2 is confirmed by decreased enzymatic activity of ADA2 and genetic testing. Symptoms range from cutaneous vasculitis and polyarteritis nodosa-like lesions to stroke. The vasculopathy of DADA2 can affect many organ systems, including the gastrointestinal and renal systems. Hematologic manifestations occur early with hypogammaglobulinemia, lymphopenia, pure red cell aplasia, or pancytopenia. Treatment can be challenging. Tumor necrosis factor inhibitors are helpful to control inflammatory symptoms. Hematopoietic stem cell transplant may be needed to treat refractory cytopenias, vasculopathy, or immunodeficiency.
Topics: Humans; Adenosine Deaminase; Intercellular Signaling Peptides and Proteins; Polyarteritis Nodosa; Vasculitis; Mutation
PubMed: 37821195
DOI: 10.1016/j.rdc.2023.06.004 -
Journal of Clinical Immunology Aug 2023MECOM deficiency is a recently identified inborn error of immunity and inherited bone marrow failure syndrome caused by haploinsufficiency of the hematopoietic... (Review)
Review
MECOM deficiency is a recently identified inborn error of immunity and inherited bone marrow failure syndrome caused by haploinsufficiency of the hematopoietic transcription factor MECOM. It is unique among inherited bone marrow failure syndromes, many of which present during later childhood or adolescence, because of the early age of onset and severity of the pancytopenia, emphasizing the importance and gene dose dependency of MECOM during hematopoiesis. B-cell lymphopenia and hypogammaglobulinemia have been described in a subset of patients with MECOM deficiency. While the mechanisms underlying the B-cell deficiency are currently unknown, recent work has provided mechanistic insights into the function of MECOM in hematopoietic stem cell (HSC) maintenance. MECOM binds to regulatory enhancers that control the expression of a network of genes essential for HSC maintenance and self-renewal. Heterozygous mutations, as seen in MECOM-deficient bone marrow failure, lead to dysregulated MECOM network expression. Extra-hematopoietic manifestations of MECOM deficiency, including renal and cardiac anomalies, radioulnar synostosis, clinodactyly, and hearing loss, have been reported. Individuals with specific genotypes have some of the systemic manifestations with isolated mild thrombocytopenia or without hematologic abnormalities, highlighting the tissue specificity of mutations in some MECOM domains. Those infants with MECOM-associated bone marrow failure require HSC transplantation for survival. Here, we review the expanding cohort of patient phenotypes and accompanying genotypes resulting in MECOM deficiency, and the proposed mechanisms underlying MECOM regulation of human HSC maintenance and B-cell development.
Topics: Humans; Child; Pancytopenia; Transcription Factors; Bone Marrow Failure Disorders; Hematopoietic Stem Cells; Gene Expression Regulation; Congenital Bone Marrow Failure Syndromes; Thrombocytopenia; Hematopoiesis; MDS1 and EVI1 Complex Locus Protein
PubMed: 37407873
DOI: 10.1007/s10875-023-01545-0 -
Haematologica Oct 2023Clinical trials have shown that lentiviral-mediated gene therapy can ameliorate bone marrow failure (BMF) in nonconditioned Fanconi anemia (FA) patients resulting from...
Clinical trials have shown that lentiviral-mediated gene therapy can ameliorate bone marrow failure (BMF) in nonconditioned Fanconi anemia (FA) patients resulting from the proliferative advantage of corrected FA hematopoietic stem and progenitor cells (HSPC). However, it is not yet known if gene therapy can revert affected molecular pathways in diseased HSPC. Single-cell RNA sequencing was performed in chimeric populations of corrected and uncorrected HSPC co-existing in the BM of gene therapy-treated FA patients. Our study demonstrates that gene therapy reverts the transcriptional signature of FA HSPC, which then resemble the transcriptional program of healthy donor HSPC. This includes a down-regulated expression of TGF-β and p21, typically up-regulated in FA HSPC, and upregulation of DNA damage response and telomere maintenance pathways. Our results show for the first time the potential of gene therapy to rescue defects in the HSPC transcriptional program from patients with inherited diseases; in this case, in FA characterized by BMF and cancer predisposition.
Topics: Humans; Fanconi Anemia; Hematopoietic Stem Cells; Genetic Therapy; Transforming Growth Factor beta; Up-Regulation; Pancytopenia; Bone Marrow Failure Disorders
PubMed: 37021532
DOI: 10.3324/haematol.2022.282418 -
The Journal of the Association of... Jan 2024We found the article on "The Digital Technology in Clinical Medicine: From Calculators to ChatGPT" interesting. According to Kulkarni et al., humanity has witnesses four...
We found the article on "The Digital Technology in Clinical Medicine: From Calculators to ChatGPT" interesting. According to Kulkarni et al., humanity has witnesses four important social system changes, starting with the primitive huntersgatherers and progressing to horticultural, agricultural, industrial, and the current fifth, which is based on digital information technology and has altered the way we present, recognize, and utilize different factors of production. In clinical medicine, digital technology has advanced significantly since the days of computations. According to Kulkarni et al., we have to benefit from these advancements as we all improve the lives of our patients while being cautious not to overturn the doctor-patient relationship. If technology, clinical expertise, and humanistic values are properly balanced, Kulkarni et al. concluded that the future is quite glorious. Regulatory organizations are pushing for improvements through clinical trials as a result of recognition of the expanding influence of digital technology in healthcare delivery. The "World Health Organizations Guidelines for Digital Interventions" and the "Food and Drug Administration's Digital Health Center of Excellence" are only two of the projects that are currently being highlighted in the study as efforts to analyze and implement digital health services.
Topics: Humans; Pancytopenia; Folic Acid Deficiency; Folic Acid
PubMed: 38736088
DOI: 10.59556/japi.71.0443 -
Experimental and Therapeutic Medicine Oct 2023The present study aimed to study the efficacy and adverse effects of anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T (CAR-T) cell therapy in relapsed...
The present study aimed to study the efficacy and adverse effects of anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T (CAR-T) cell therapy in relapsed or refractory multiple myeloma. Patients were divided into three dose groups based on cell therapy concentration. After CAR-T cell therapy for 10 patients with recurrent or refractory multiple myeloma, the patients were monitored and evaluated regularly to observe the efficacy and adverse reactions of CAR-T cell therapy. At a median follow-up of 337 (253-504) days, one patient succumbed 24 days due to rapidly progressing disease. The overall response rate of nine patients was 88.9%, including 77.8% (7/9) with minimal residual disease negative complete remission (CR) and 11.1% (1/9) with partial remission. A total of three patients were maintained in remission state for more than a year and eight were maintained for more than six months. Among the three patients with extramedullary invasion, two extramedullary lesions disappeared and one was stable. The highest copy number of CAR-T cells in seven patients with CR was >1x10 copies/µl gDNA, and the best therapeutic effect can be achieved within 30 (7-30) days after the copy number of CAR-T cells reached 1x10 copies/µl genomic DNA. The median onset time in the nine patients was 43 (22-169) days, and the median progression-free survival was 337 (253-504). Among the 10 patients, nine (90%) had cytokine release syndrome, all of which were below grade II. There were nine (90%) patients with hematological adverse reactions, six (60%) patients with severe anemia, five (50%) patients with grade III and above leukopenia, five (50%) patients with granulocytopenia, four (40%) patients with grade III and above thrombocytopenia, and three (30%) patients with grade III and above pancytopenia. It was concluded that anti-BCMA CAR-T cell therapy is a promising treatment method for relapsed or refractory multiple myeloma and extramedullary invasion, with stable efficacy and controllable adverse effects.
PubMed: 37664681
DOI: 10.3892/etm.2023.12170 -
American Journal of Medical Genetics.... Jul 2023The MECOM gene encodes multiple protein isoforms that are essential for hematopoietic stem cell self-renewal and maintenance. Germline MECOM variants have been...
The MECOM gene encodes multiple protein isoforms that are essential for hematopoietic stem cell self-renewal and maintenance. Germline MECOM variants have been associated with congenital thrombocytopenia, radioulnar synostosis and bone marrow failure; however, the phenotypic spectrum of MECOM-associated syndromes continues to expand and novel pathogenic variants continue to be identified. We describe eight unrelated patients who add to the previously known phenotypes and genetic defects of MECOM-associated syndromes. As each subject presented with unique MECOM variants, the series failed to demonstrate clear genotype-to-phenotype correlation but may suggest a role for additional modifiers that affect gene expression and subsequent phenotype. Recognition of the expanded hematologic and non-hematologic clinical features allows for rapid molecular diagnosis, early identification of life-threatening complications, and improved genetic counseling for families. A centralized international publicly accessible database to share annotated MECOM variants would advance their clinical interpretation and provide a foundation to perform functional MECOM studies.
Topics: Humans; Bone Marrow Diseases; Syndrome; Bone Marrow Failure Disorders; Pancytopenia; Transcription Factors; Hematologic Diseases; Phenotype; MDS1 and EVI1 Complex Locus Protein
PubMed: 37067177
DOI: 10.1002/ajmg.a.63208 -
Current Research in Translational... 2023The 2019 coronavirus disease (COVID-19) is a respiratory infection caused by the SARS-CoV-2 virus with a significant impact on the hematopoietic system and homeostasis.... (Review)
Review
INTRODUCTION
The 2019 coronavirus disease (COVID-19) is a respiratory infection caused by the SARS-CoV-2 virus with a significant impact on the hematopoietic system and homeostasis. The effect of the virus on blood cells indicates the involvement of the bone marrow (BM) as the place of production and maturation of these cells by the virus and it reminds the necessity of investigating the effect of the virus on the bone marrow.
METHOD
To investigate the effects of COVID-19 infection in BM, we reviewed literature from the Google Scholar search engine and PubMed database up to 2022 using the terms "COVID-19; SARS-CoV-2; Bone marrow; Thrombocytopenia; Hemophagocytosis; Pancytopenia and Thrombocytopenia.
RESULTS
Infection with the SARS-CoV-2 virus is accompanied by alterations such as single-line cytopenia, pancytopenia, hemophagocytosis, and BM necrosis. The presence of factors such as cytokine release syndrome, the direct effect of the virus on cells through different receptors, and the side effects of current treatments such as corticosteroids are some of the important mechanisms in the occurrence of these alterations.
CONCLUSION
To our knowledge, this review is the first study to comprehensively investigate BM alterations caused by SAR-CoV-2 virus infection. The available findings show that the significant impact of this viral infection on blood cells and the clinical consequences resulting from them are deeper than previously thought and it may be rooted in the changes that the virus causes in the BM of patients.
PubMed: 37544028
DOI: 10.1016/j.retram.2023.103407 -
Acta Parasitologica Sep 2023In Turkey, the main causative agent of visceral leishmaniasis (VL) is Leishmania. infantum and the main causative agent of cutaneous leishmaniasis (CL) is Leishmania...
PURPOSE
In Turkey, the main causative agent of visceral leishmaniasis (VL) is Leishmania. infantum and the main causative agent of cutaneous leishmaniasis (CL) is Leishmania tropica. In this study, we aimed to discuss the possible mechanisms, clinical aspects, and threat of visceralizing L. tropica.
METHODS
This study includes seven cases of VL caused by L. tropica.Five patients were male (71%) and four were adults (57%).
RESULTS
All the VL patients complained of fever and splenomegaly. Fatigue, pancytopenia, and hepatomegaly were present in six patients each (86%), while weight loss and gastrointestinal system (GIS) symptoms were present in 5 patients (71%).
CONCLUSIONS
In this study, we have evaluated seven cases of visceralized L. tropica (VLT) in the context of the changing leishmaniasis epidemiology in Turkey. We have evaluated the possible mechanisms of visceralization; inter- and intraspecies genetic exchange with all the old world leishmaniasis agents present in the region, stress induced by inappropriate use of drugs, and possible ongoing adaptation mechanisms of Leishmania spp. The threat posed by VLT is significant as L. tropica is the most widespread and most common cause of leishmaniasis in Turkey. We do not know the vectorial capacity of the sand flies for the transmission of VLT strains or if these strains are in circulation in Turkey. Future studies should be carried out to investigate these issues as the transition of L. tropica from a mild disease-causing agent to a mortal one poses a significant public health concern for Turkey and Europe.
Topics: Male; Female; Humans; Leishmania tropica; Leishmaniasis, Visceral; Leishmaniasis, Cutaneous; Leishmania infantum; Turkey
PubMed: 37351773
DOI: 10.1007/s11686-023-00695-w -
Experimental Hematology 2023Aplastic anemia is a bone marrow failure (BMF) disorder characterized by pancytopenia and hypocellular marrow from an immune-mediated etiology. Regulatory T cells...
Aplastic anemia is a bone marrow failure (BMF) disorder characterized by pancytopenia and hypocellular marrow from an immune-mediated etiology. Regulatory T cells (Tregs) prevent autoimmunity by suppressing autoreactive T cells. We recently demonstrated the efficacy of ruxolitinib (RUX), a JAK 1/2 inhibitor, in attenuating murine BMF. Herein, we investigated the changes of Tregs in the context of RUX treatment for murine BMF. Tregs are conventionally identified by surface expression of CD4 and CD25, in addition to intracellular transcription factor FoxP3. RUX promoted the expansion of Tregs in BMF mice defined by increased expression of FoxP3 in CD4 T cells but suppressed expression of activation marker CD25 in CD4 and CD8 T cells. In this context, CD25 is no longer a reliable surface marker for Tregs. We observed strong co-expression of FoxP3 with surface marker GITR instead of CD25 in RUX-treated BMF mice. Fluorescence-activated cell sorting (FACS)-sorted CD4GITR cells showed high FoxP3 expression and intact suppressive function in vitro, suggesting GITR to be a surrogate marker for Tregs. In contrast to its expansive effect on Tregs in BMF, RUX suppressed Tregs in normal and sublethal irradiation conditions, indicating that the effects of RUX on Tregs are immune-context dependent.
Topics: Mice; Animals; T-Lymphocytes, Regulatory; Flow Cytometry; CD4-Positive T-Lymphocytes; Interleukin-2 Receptor alpha Subunit; Forkhead Transcription Factors
PubMed: 37468118
DOI: 10.1016/j.exphem.2023.07.004 -
The Journal of Pediatrics May 2024
PubMed: 38768892
DOI: 10.1016/j.jpeds.2024.114111