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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 -
Journal of Veterinary Internal Medicine Jan 2023After a strong epidemiological link to diet was established in an outbreak of pancytopenia in cats in spring 2021 in the United Kingdom, 3 dry diets were recalled....
BACKGROUND
After a strong epidemiological link to diet was established in an outbreak of pancytopenia in cats in spring 2021 in the United Kingdom, 3 dry diets were recalled. Concentrations of the hemato- and myelotoxic mycotoxins T-2, HT-2 and diacetoxyscirpenol (DAS) greater than the European Commission guidance for dry cat foods were detected in the recalled diets.
OBJECTIVES
To describe clinical and clinicopathological findings in cats diagnosed with suspected diet induced pancytopenia.
ANIMALS
Fifty cats presenting with pancytopenia after exposure to a recalled diet.
METHODS
Multicenter retrospective case series study. Cats with known exposure to 1 of the recalled diets were included if presented with bi- or pancytopenia and underwent bone marrow examination.
RESULTS
Case fatality rate was 78%. Bone marrow aspirates and biopsy examination results were available in 23 cats; 19 cats had a bone marrow aspirate, and 8 cats had a biopsy core, available for examination. Bone marrow hypo to aplasia-often affecting all cell lines-was the main feature in all 31 available core specimens. A disproportionately pronounced effect on myeloid and megakaryocytic cells was observed in 19 cats. Myelofibrosis or bone marrow necrosis was not a feature.
CONCLUSION AND CLINICAL IMPORTANCE
Mycotoxin induced pancytopenia should be considered as differential diagnosis in otherwise healthy cats presenting with bi- or pancytopenia and bone marrow hypo- to aplasia.
Topics: Cats; Animals; Pancytopenia; Retrospective Studies; Bone Marrow; Biopsy; Diet; Cat Diseases
PubMed: 36609843
DOI: 10.1111/jvim.16613 -
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 -
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 -
Journal of Clinical Oncology : Official... Jan 2020
Topics: Healthcare Disparities; Hispanic or Latino; Humans; Male; Middle Aged; Military Medicine; Narration; Pancytopenia; Primary Myelofibrosis; Stem Cell Transplantation
PubMed: 31664879
DOI: 10.1200/JCO.19.01497 -
Clinics in Liver Disease Nov 2019Idiopathic portal hypertension (IPH) and extrahepatic portal venous obstruction (EHPVO) are prototype noncirrhotic causes of portal hypertension (PHT), characterized by... (Review)
Review
Idiopathic portal hypertension (IPH) and extrahepatic portal venous obstruction (EHPVO) are prototype noncirrhotic causes of portal hypertension (PHT), characterized by normal hepatic venous pressure gradient, variceal bleeds, and moderate to massive splenomegaly with preserved liver synthetic functions. Infections, toxins, and immunologic, prothrombotic and genetic disorders are possible causes in IPH, whereas prothrombotic and local factors around the portal vein lead to EHPVO. Growth failure, portal biliopathy, and minimal hepatic encephalopathy are long-term concerns in EHPVO. Surgical shunts and transjugular intrahepatic portosystemic shunt resolve the complications secondary to PHT. Meso-Rex shunt is now the standard-of-care surgery in children with EHPVO.
Topics: Animals; Biliary Tract Diseases; Disease Management; Disease Models, Animal; Disease Progression; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Growth Disorders; Hepatic Encephalopathy; Humans; Hypertension, Portal; Liver Cirrhosis; Liver Transplantation; Metabolomics; Pancytopenia; Portal Vein; Portasystemic Shunt, Surgical; Portasystemic Shunt, Transjugular Intrahepatic; Quality of Life; Splenomegaly; Transcriptome; Venous Thrombosis; Idiopathic Noncirrhotic Portal Hypertension
PubMed: 31563222
DOI: 10.1016/j.cld.2019.07.006 -
Blood Jan 2023Immune aplastic anemia (AA) is a severe blood disease characterized by T-lymphocyte- mediated stem cell destruction. Hematopoietic stem cell transplantation and...
Immune aplastic anemia (AA) is a severe blood disease characterized by T-lymphocyte- mediated stem cell destruction. Hematopoietic stem cell transplantation and immunosuppression are effective, but they entail costs and risks, and are not always successful. The Janus kinase (JAK) 1/2 inhibitor ruxolitinib (RUX) suppresses cytotoxic T-cell activation and inhibits cytokine production in models of graft-versus-host disease. We tested RUX in murine immune AA for potential therapeutic benefit. After infusion of lymph node (LN) cells mismatched at the major histocompatibility complex [C67BL/6 (B6)⇒CByB6F1], RUX, administered as a food additive (Rux-chow), attenuated bone marrow hypoplasia, ameliorated peripheral blood pancytopenia, preserved hematopoietic progenitors, and prevented mortality, when used either prophylactically or therapeutically. RUX suppressed the infiltration, proliferation, and activation of effector T cells in the bone marrow and mitigated Fas-mediated apoptotic destruction of target hematopoietic cells. Similar effects were obtained when Rux-chow was fed to C.B10 mice in a minor histocompatibility antigen mismatched (B6⇒C.B10) AA model. RUX only modestly suppressed lymphoid and erythroid hematopoiesis in normal and irradiated CByB6F1 mice. Our data support clinical trials of JAK/STAT inhibitors in human AA and other immune bone marrow failure syndromes.
Topics: Mice; Humans; Animals; Pancytopenia; Anemia, Aplastic; Bone Marrow Failure Disorders; Bone Marrow; Bone Marrow Diseases; Janus Kinase 1
PubMed: 36130301
DOI: 10.1182/blood.2022015898 -
The Journal of the Association of... Apr 2022Pancytopenia is a common cause of hematological consultation. Common underlying causes include vitamin deficiency (vitamin B12, folic acid), drugs (hydroxyurea,... (Observational Study)
Observational Study
Pancytopenia is a common cause of hematological consultation. Common underlying causes include vitamin deficiency (vitamin B12, folic acid), drugs (hydroxyurea, phenytoin, methotrexate), and bone marrow failure syndrome. Aplastic anemia is one of the rarest hematological diseases and presents as pancytopenia. However, it is the most sinister one and is a hematological emergency that needs urgent medical attention. Absolute neutrophil count (ANC) is a measure of disease severity and is expected to be low in patients with pancytopenia of any cause. Aim & Objective: We aimed to analyze the absolute neutrophil count (ANC) level in patients presenting with pancytopenia. Material & Method: This prospective, observational study was conducted at a tertiary care hospital in northern India. We included patients with pancytopenia diagnosed at our center or reported to our center for therapy. ANC was measured before starting therapy. Observation: One hundred twenty-seven patients were included in this study. After evaluation, megaloblastic anemia was the commonest underlying cause in 42 (33%) patients followed by myelodysplastic syndrome in 31 (24.4%) patients. Twenty-three (18.1%) patients having pancytopenia were diagnosed with aplastic anemia. Other causes included leukemia, paroxysmal nocturnal hemoglobinuria and drugs. The median age was 37 years (range 18-75 years), and 67 (52.75%) were male. The mean hemoglobin was 5.5 g/dL (95% CI ±1.9). The median WBC was 2570/cmm (300-3130) and the median platelet was 36000/cmm (2000-92000). The median ANC in patients with aplastic anemia was 594/cmm (range 25- 3850). When compared, the ANC level was significantly lower in aplastic anemia than other causes of pancytopenia (p<0.001). Conclusion: On univariate and multivariate analysis ANC was significantly lower at baseline in patients of aplastic anemia. A longer follow-up of the patients will be required to assess the value of ANC in predicting response to therapy.
Topics: Adolescent; Adult; Aged; Anemia, Aplastic; Anemia, Megaloblastic; Female; Humans; Male; Middle Aged; Neutrophils; Pancytopenia; Prospective Studies; Young Adult
PubMed: 35443536
DOI: No ID Found -
BMJ Case Reports Jan 2023We present the case of a young female landscaper who presented to an Australian tertiary hospital with persistent fevers and new pancytopenia. Extensive initial workup...
We present the case of a young female landscaper who presented to an Australian tertiary hospital with persistent fevers and new pancytopenia. Extensive initial workup for her presenting illness did not identify a cause; however, a detailed history of her occupation revealed she worked heavily with soil on farms that had domestic livestock in addition to rodents. Hence, further serological testing for leptospirosis was performed, revealing a diagnosis of infection with Leptospira interrogans serovar Hardjo. Treatment covering leptospirosis was commenced, and she improved clinically, and her cell counts returned to normal. Pancytopenia is a rare manifestation of leptospirosis and has only been reported in a handful of case studies. We highlight that leptospirosis should be considered as a differential diagnosis in those with fever, and new pancytopaenia, particularly in patients with relevant risk factors for exposure.
Topics: Female; Humans; Pancytopenia; Australia; Leptospirosis; Leptospira interrogans; Risk Factors; Leptospira; Antibodies, Bacterial
PubMed: 36604107
DOI: 10.1136/bcr-2022-251506 -
[Rinsho Ketsueki] the Japanese Journal... 2022Inherited bone marrow failure syndrome (IBMFS) is a heterogeneous group of genetic disorders characterized by bone marrow failure, congenital anomalies, and an increased... (Review)
Review
Inherited bone marrow failure syndrome (IBMFS) is a heterogeneous group of genetic disorders characterized by bone marrow failure, congenital anomalies, and an increased risk of malignancy. The p53 tumor suppressor protein is a transcription factor activated in response to various cellular stresses and induces genes involved in apoptosis, cell cycle arrest, and DNA repair. Several lines of evidence suggest that p53 activation is central to the pathogenesis of IBMFS. We discovered germline TP53 activating mutations in IBMFS cases mimicking Diamond-Blackfan anemia using whole-exome sequencing. These cases were recognized as having a novel disorder, germline TP53 activation syndrome (bone marrow failure syndrome 5; OMIN). Recently, additional cases with the same TP53 mutations were reported, further clarifying the phenotype of this disease. This discovery confirms the hypothesis that p53 activation causes IBMFS. This review focuses on this novel IBMFS and discusses the link between p53 hyperactivation and IBMFS.
Topics: Anemia, Aplastic; Anemia, Diamond-Blackfan; Bone Marrow Diseases; Bone Marrow Failure Disorders; Congenital Bone Marrow Failure Syndromes; Hemoglobinuria, Paroxysmal; Humans; Mutation; Pancytopenia; Transcription Factors; Tumor Suppressor Protein p53
PubMed: 36198537
DOI: 10.11406/rinketsu.63.1115