-
Genes Aug 2022Hereditary myopathies are well documented in dogs, whereas hereditary dyserythropoietic anemias are rarely seen. The aim of this study was to further characterize the...
Hereditary myopathies are well documented in dogs, whereas hereditary dyserythropoietic anemias are rarely seen. The aim of this study was to further characterize the clinical and clinicopathological features of and to identify the causative genetic variant for a dyserythropoietic anemia and myopathy syndrome (DAMS) in English springer spaniel dogs (ESSPs). Twenty-six ESSPs, including five dogs with DAMS and two puppies that died perinatally, were studied. Progressive weakness, muscle atrophy-particularly of the temporal and pelvic muscles-trismus, dysphagia, and regurgitation due to megaesophagus were observed at all ages. Affected dogs had a non-regenerative, microcytic hypochromic anemia with metarubricytosis, target cells, and acanthocytes. Marked erythroid hyperplasia and dyserythropoiesis with non-orderly maturation of erythrocytes and inappropriate microcytic metarubricytosis were present. Muscle biopsies showed centralized nuclei, central pallor, lipocyte infiltrates, and fibrosis, which was consistent with centronuclear myopathy. The genome sequencing of two affected dogs was compared to 782 genomes of different canine breeds. A homozygous frameshift single-base deletion in was identified; this gene was not previously associated with DAMS. Pedigree analysis confirmed that the affected ESSPs were related. Variant genotyping showed appropriate complete segregation in the family, which was consistent with an autosomal recessive mode of inheritance. This study expands the known genotype-phenotype correlation of and the list of potential causative genes in dyserythropoietic anemias and myopathies in humans. deficiency was previously reported as perinatally lethal in humans and knockout mice. Our findings enable the genetic testing of ESSP dogs for early diagnosis and disease prevention through targeted breeding strategies.
Topics: Anemia; Animals; Dog Diseases; Dogs; Frameshift Mutation; Genetic Association Studies; Humans; Mice; Muscular Diseases; Syndrome
PubMed: 36140701
DOI: 10.3390/genes13091533 -
Biomolecules Jun 2022In patients, endometrial hyperplasia (EH) is often accompanied by abnormal uterine bleeding (AUB), which is prone to release large amounts of heme. However, the role of...
In patients, endometrial hyperplasia (EH) is often accompanied by abnormal uterine bleeding (AUB), which is prone to release large amounts of heme. However, the role of excess heme in the migration and infiltration of immune cells in EH complicated by AUB remains unknown. In this study, 45 patients with AUB were divided into three groups: a proliferative phase group (n = 15), a secretory phase group (n = 15) and EH (n = 15). We observed that immune cell subpopulations were significantly different among the three groups, as demonstrated by flow cytometry analysis. Of note, there was a higher infiltration of total immune cells and macrophages in the endometrium of patients with EH. Heme up-regulated the expression of heme oxygenase-1 (HO-1) and nuclear factor erythroid-2-related factor 2 (Nrf2) in endometrial epithelial cells (EECs) in vitro, as well as chemokine (e.g., CCL2, CCL3, CCL5, CXCL8) levels. Additionally, stimulation with heme led to the increased recruitment of THP-1 cells in an indirect EEC-THP-1 co-culture unit. These data suggest that sustained and excessive heme in patients with AUB may recruit macrophages by increasing the levels of several chemokines, contributing to the accumulation and infiltration of macrophages in the endometrium of EH patients, and the key molecules of heme metabolism, HO-1 and Nrf2, are also involved in this regulatory process.
Topics: Endometrial Hyperplasia; Female; Heme; Humans; Macrophages; NF-E2-Related Factor 2; Uterine Diseases; Uterine Hemorrhage
PubMed: 35740976
DOI: 10.3390/biom12060849 -
Molecular Carcinogenesis Jul 2013Previous clinical and epidemiological studies of vitamin E have used primarily α-tocopherol for the prevention of cancer. However, γ-tocopherol has demonstrated...
Dietary tocopherols inhibit cell proliferation, regulate expression of ERα, PPARγ, and Nrf2, and decrease serum inflammatory markers during the development of mammary hyperplasia.
Previous clinical and epidemiological studies of vitamin E have used primarily α-tocopherol for the prevention of cancer. However, γ-tocopherol has demonstrated greater anti-inflammatory and anti-tumor activity than α-tocopherol in several animal models of cancer. This study assessed the potential chemopreventive activities of a tocopherol mixture containing 58% γ-tocopherol (γ-TmT) in an established rodent model of mammary carcinogenesis. Female ACI rats were utilized due to their sensitivity to 17β-estradiol (E2 ) to induce mammary hyperplasia and neoplasia. The rats were implanted subcutaneously with sustained release E2 pellets and given dietary 0.3% or 0.5% γ-TmT for 2 or 10 wk. Serum E2 levels were significantly reduced by the treatment with 0.5% γ-TmT. Serum levels of inflammatory markers, prostaglandin E2 and 8-isoprostane, were suppressed by γ-TmT treatment. Histology of mammary glands showed evidence of epithelial hyperplasia in E2 -treated rats. Immunohistochemical analysis of the mammary glands revealed a decrease in proliferating cell nuclear antigen (PCNA), cyclooxygenase-2 (COX-2), and estrogen receptor α (ERα), while there was an increase in cleaved-caspase 3, peroxisome proliferator-activated receptor γ (PPARγ), and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in γ-TmT-treated rats. In addition, treatment with γ-TmT resulted in a decrease in the expression of ERα mRNA, whereas mRNA levels of ERβ and PPARγ were increased. In conclusion, γ-TmT was shown to suppress inflammatory markers, inhibit E2 -induced cell proliferation, and upregulate PPARγ and Nrf2 expression in mammary hyperplasia, suggesting that γ-TmT may be a promising agent for human breast cancer prevention.
Topics: Animals; Antioxidants; Biomarkers, Tumor; Blotting, Western; Cell Proliferation; Cell Transformation, Neoplastic; Diet; Estradiol; Estrogen Receptor alpha; Female; Gene Expression Regulation, Neoplastic; Hyperplasia; Immunoenzyme Techniques; Inflammation Mediators; Mammary Neoplasms, Experimental; Microsomes, Liver; NF-E2-Related Factor 2; PPAR gamma; RNA, Messenger; Rats; Rats, Inbred ACI; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Tocopherols
PubMed: 22389237
DOI: 10.1002/mc.21886 -
Journal of Blood Medicine 2022Hematological disorders are heterogeneous conditions ranging from malignant to non-malignant disorders. Hematological malignancies comprise a collection of heterogeneous...
BACKGROUND
Hematological disorders are heterogeneous conditions ranging from malignant to non-malignant disorders. Hematological malignancies comprise a collection of heterogeneous conditions originating from cells of the bone marrow and the lymphatic system. Therefore, this study aimed to determine the pattern of bone marrow confirmed malignant and non-malignant hematological disorders in patients with abnormal hematological parameters.
METHODS
Institutional-based cross-sectional study was conducted in Dessie town from April 2020 to June 2021. A total of 228 study participants who had abnormal hematological parameters and referred for bone marrow examination were included consecutively. About 1.5 mL of bone marrow sample and 3 mL of venous blood sample were collected for bone marrow examination, complete blood count analysis and peripheral blood morphology examination. Wright stain, Sudan black B, and Prussian blue stains were used for staining the bone marrow and peripheral blood smears. The result was expressed in mean and standard deviation and presented in texts and tables. Ratio, frequency, and percentage were used to express the magnitude of malignant and non-malignant hematological disorders.
RESULTS
The overall prevalence of hematological malignancies among the study participants was 11.4% with 8.8% in male patients. The prevalence of hematological malignancies were 3.5% CML, 2.6% AML, 1.8% CLL and MM, 0.9% ALL and undifferentiated acute leukemia. On the other hand, 57.0% of the study participants had non-malignant hematological disorders. Regarding non-malignant hematological cases, 24.6% were erythroid hyperplasia, 10.5% aplastic anemia, 8.8% concomitant IDA and MBA, 7.0% MBA, 3.5% leukemoid reaction, 1.8% IDA, and 0.9% visceral leishmaniasis. In patients with HM, 66.7% of AML, 100% of CML and CLL, and 75% of MM patients had increased total WBC count, whereas 66.7% of AML, 62.5% of CML, 75% of CLL, and 50% of MM patients had decreased hemoglobin level. On the other hand, 66.7% of AML, and 50% of CML, ALL, and CLL patients had decreased platelet count.
CONCLUSION
In this study, 11.4% of the patients had hematological malignant cases, whereas 57% of the patients had non-malignant hematological cases. Therefore, in patients with hematological abnormalities and where conclusive diagnosis could not be made through clinical and other laboratory investigations, bone marrow examination should be done for definitive diagnosis, management and prognosis.
PubMed: 35210892
DOI: 10.2147/JBM.S346091 -
Molecular and Cellular Biology Jun 2013During erythropoiesis, hemoglobin (Hb) synthesis increases from early progenitors to mature enucleated erythrocytes. Although Hb is one of the most extensively studied...
During erythropoiesis, hemoglobin (Hb) synthesis increases from early progenitors to mature enucleated erythrocytes. Although Hb is one of the most extensively studied proteins, the role of Hb in erythroid lineage commitment, differentiation, and maturation remains unclear. In this study, we generate mouse embryos and embryonic stem (ES) cells with all of the adult α and β globin genes deleted (Hb Null). While Hb Null embryos die in midgestation, adult globin genes are not required for primitive or definitive erythroid lineage commitment. In vitro differentiation of Hb Null ES cells generates viable definitive proerythroblasts that undergo apoptosis upon terminal differentiation. Surprisingly, all stages of Hb Null-derived definitive erythroblasts develop normally in vivo in chimeric mice, and Hb Null erythroid cells undergo enucleation to form reticulocytes. Free heme toxicity is not observed in Hb Null-derived erythroblasts. Transplantation of Hb Null-derived bone marrow cells provides short-term radioprotection of lethally irradiated recipients, whose progressive anemia results in an erythroid hyperplasia composed entirely of Hb Null-derived erythroblasts. This novel experimental model system enables the role played by Hb in erythroid cell enucleation, cytoskeleton maturation, and heme and iron regulation to be studied.
Topics: Animals; Bone Marrow Transplantation; Cell Differentiation; Embryonic Stem Cells; Erythroid Cells; Erythropoiesis; Fetal Death; Gestational Age; Heme; Hemoglobins; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Reticulocytes; alpha-Globins; beta-Globins
PubMed: 23530053
DOI: 10.1128/MCB.01734-12 -
International Journal of Molecular... Oct 2017Chronic ultraviolet (UV) exposure may cause skin damage, disrupt skin barrier function, and promote wrinkle formation. UV induces oxidative stress and inflammation,...
Chronic ultraviolet (UV) exposure may cause skin damage, disrupt skin barrier function, and promote wrinkle formation. UV induces oxidative stress and inflammation, which results in extracellular matrix degradation in the dermis and epidermal hyperplasia. Our previous study demonstrated that fisetin exerts photoprotective activity by inhibiting mitogen-activated protein kinase/activator protein-1/matrix metalloproteinases (MMPs) activation. In this study, fisetin was applied topically to investigate its antiphotodamage effects in hairless mice. The erythema index (a* values) and transepidermal water loss were evaluated to assess skin damage, and immunohistochemical staining was conducted to elucidate the photoprotective mechanism of fisetin. The results revealed that the topical application of fisetin reduced UVB-induced increase in the a* value and wrinkle formation. In addition, fisetin inhibited epidermal hyperplasia and increased the collagen content in the dermis. Fisetin exerted photoprotective activity by inhibiting the expression of MMP-1, MMP-2, and cyclooxygenase-2 and increasing the expression of nuclear factor erythroid 2-related factor. Furthermore, fisetin increased the expression of filaggrin to prevent UVB-induced barrier function disruption. Altogether, the present results provide evidence of the effects and mechanisms of fisetin's antiphotodamage and antiphotoinflammation activities.
Topics: Animals; Biomarkers; Erythema; Female; Flavonoids; Flavonols; Hyperplasia; Inflammation; Mice; Mice, Hairless; Models, Animal; NF-E2-Related Factor 2; Oxidative Stress; Skin; Skin Aging; Ultraviolet Rays
PubMed: 28994699
DOI: 10.3390/ijms18102118 -
Haematologica Dec 2018Chromosomal translocation t(8;21)(q22;q22) which leads to the generation of oncogenic RUNX1-RUNX1T1 (AML1-ETO) fusion is observed in approximately 10% of acute...
Chromosomal translocation t(8;21)(q22;q22) which leads to the generation of oncogenic RUNX1-RUNX1T1 (AML1-ETO) fusion is observed in approximately 10% of acute myelogenous leukemia (AML). To identify somatic mutations that co-operate with t(8;21)-driven leukemia, we performed whole and targeted exome sequencing of an Asian cohort at diagnosis and relapse. We identified high frequency of truncating alterations in along with recurrent mutations of , and in this subtype of AML. To investigate in depth the role of ASXL2 in normal hematopoiesis, we utilized a mouse model of ASXL2 deficiency. Loss of ASXL2 caused progressive hematopoietic defects characterized by myeloid hyperplasia, splenomegaly, extramedullary hematopoiesis, and poor reconstitution ability in transplantation models. Parallel analyses of young and >1-year old Asxl2-deficient mice revealed age-dependent perturbations affecting, not only myeloid and erythroid differentiation, but also maturation of lymphoid cells. Overall, these findings establish a critical role for ASXL2 in maintaining steady state hematopoiesis, and provide insights into how its loss primes the expansion of myeloid cells.
Topics: Acute Disease; Animals; Cell Differentiation; Cell Proliferation; Gene Expression Profiling; Hematopoiesis; Humans; Leukemia, Myeloid; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Myeloid Cells; Myelopoiesis; Repressor Proteins
PubMed: 30093396
DOI: 10.3324/haematol.2018.189928 -
The Journal of Pathology Oct 2020Activation of the nuclear factor (erythroid-derived 2)-like 2 (NFE2L2 or NRF2) transcription factor is a critical and evolutionarily conserved cellular response to...
Activation of the nuclear factor (erythroid-derived 2)-like 2 (NFE2L2 or NRF2) transcription factor is a critical and evolutionarily conserved cellular response to oxidative stress, metabolic stress, and xenobiotic insult. Deficiency of NRF2 results in hypersensitivity to a variety of stressors, whereas its aberrant activation contributes to several cancer types, most commonly squamous cell carcinomas of the esophagus, oral cavity, bladder, and lung. Between 10% and 35% of patients with squamous cell carcinomas display hyperactive NRF2 signaling, harboring activating mutations and copy number amplifications of the NFE2L2 oncogene or inactivating mutations or deletions of KEAP1 or CUL3, the proteins of which co-complex to ubiquitylate and degrade NRF2 protein. To better understand the role of NRF2 in tumorigenesis and more broadly in development, we engineered the endogenous Nfe2l2 genomic locus to create a conditional mutant LSL-Nrf2 mouse model. The E79Q mutation, one of the most commonly observed NRF2-activating mutations in human squamous cancers, codes for a mutant protein that does not undergo KEAP1/CUL3-dependent degradation, resulting in its constitutive activity. Expression of NRF2 E79Q protein in keratin 14 (KRT14)-positive murine tissues resulted in hyperplasia of squamous cell tissues of the tongue, forestomach, and esophagus, a stunted body axis, decreased weight, and decreased visceral adipose depots. RNA-seq profiling and follow-up validation studies of cultured NRF2 murine esophageal epithelial cells revealed known and novel NRF2-regulated transcriptional programs, including genes associated with squamous cell carcinoma (e.g. Myc), lipid and cellular metabolism (Hk2, Ppard), and growth factors (Areg, Bmp6, Vegfa). These data suggest that in addition to decreasing adipogenesis, KRT14-restricted NRF2 activation drives hyperplasia of the esophagus, forestomach, and tongue, but not formation of squamous cell carcinoma. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Topics: Adipose Tissue, White; Animals; Carcinogenesis; Carcinoma, Squamous Cell; Disease Models, Animal; Esophagus; Humans; Hyperplasia; Mice; Mutation; NF-E2-Related Factor 2; Precancerous Conditions; Tongue; Upper Gastrointestinal Tract
PubMed: 32619021
DOI: 10.1002/path.5504 -
Parasites & Vectors Dec 2014Bone marrow (BM) is a major hematopoietic organ that can harbour a variety of vector-borne pathogens; however, knowledge of BM pathological changes in dogs infected with...
BACKGROUND
Bone marrow (BM) is a major hematopoietic organ that can harbour a variety of vector-borne pathogens; however, knowledge of BM pathological changes in dogs infected with vector-borne pathogens is limited. Thus, the aim of the present study was to assess the pathological changes in canine BM associated with natural infections by four vector-borne pathogens, as well as to determine the relationships between such changes and abnormalities of the peripheral blood.
METHODS
Cytological disorders and pathological changes of the BM of 83 dogs naturally-infected with one or more of four vector-borne pathogens (i.e., Anaplasma platys, Leishmania infantum, Babesia vogeli and Hepatozoon canis) were evaluated and compared with the corresponding hematological findings.
RESULTS
Dysgranulopoiesis and dysmegakaryocytopoiesis were the most frequently observed BM abnormalities in infected dogs. Erythroid suppression, and lymphocytic, monocytic and macrophage hyperplasia were also observed. Interestingly, associations between suppression and hyperplasia of specific cell lines in the marrow and corresponding changes in numbers of circulating peripheral blood cells were not observed.
CONCLUSIONS
Infections with one or more of the vector-borne pathogens examined in this study should be considered as differential diagnoses for secondary dysmyelopoiesis.
Topics: Animals; Bacterial Infections; Bone Marrow; Bone Marrow Cells; Disease Vectors; Dog Diseases; Dogs; Female; Male; Parasitic Diseases, Animal
PubMed: 25441458
DOI: 10.1186/s13071-014-0534-2 -
Autopsy & Case Reports Apr 2021Myelodysplastic syndromes (MDS) mainly occur in the elderly but can rarely affect younger individuals too. The correct diagnosis relies on careful morphologic...
BACKGROUND
Myelodysplastic syndromes (MDS) mainly occur in the elderly but can rarely affect younger individuals too. The correct diagnosis relies on careful morphologic evaluation, cytogenetic/molecular results, and excluding reactive conditions mimicking MDS. We present the clinical, pathologic, cytogenetic, and molecular features of a case of MDS with excess blasts-2 (MDS-EB-2) in a 30-year-old male who was found to have pancytopenia during his hospitalization for coronavirus disease 2019 (COVID-19) and discuss the diagnostic challenges of MDS in patients with COVID-19.
CASE PRESENTATION
A 30-year-old man presented to an outside hospital with fever, chills, weakness, coughing spells, dizziness and shortness of breath and was diagnosed with bilateral pneumonia due to COVID-19. At the outside hospital, he was found to be pancytopenic, and a subsequent bone marrow aspiration and biopsy raised concern for a COVID-19 induced hemophagocytic lymphohistiocytosis. In addition, MDS could not be ruled out. The patient was thus referred to our institute for further management. The patient's peripheral blood showed pancytopenia with occasional dysplastic neutrophils and a few teardrop cells. Given the diagnostic uncertainty, a bone marrow aspiration and a biopsy were repeated revealing a hypercellular bone marrow with erythroid hyperplasia, megakaryocytic hyperplasia, trilineage dysplasia, increased blasts (13%), many ring sideroblasts, and mild to moderate myelofibrosis, consistent with MDS-EB-2. Chromosomal analysis revealed isochromosome 14. Next generation sequencing demonstrated SF3B1 K700E mutation.
DISCUSSION AND CONCLUSION
The diagnosis of MDS can be challenging, particularly in young patients. Cytopenia and myelodysplastic features have been reported in COVID-19 patients, making the diagnosis of MDS more elusive. A careful pathologic examination of the bone marrow with ancillary studies including flow cytometry, immunohistochemistry, and cytogenetic and molecular studies in combination with a thorough clinical evaluation, leads to the accurate diagnosis.
PubMed: 33968834
DOI: 10.4322/acr.2021.274