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INTRODUCTION: Type 1 diabetes (T1D) mellitus is an autoimmune disease in which immune cells, predominantly effector T cells, destroy insulin-secreting beta-cells. Beta-cell destruction led to various consequences ranging from retinopathy and nephropathy to neuropathy. Different strategies have been developed to achieve normoglycemia, including exogenous glucose compensation, whole pancreas transplantation, islet transplantation, and beta-cell replacement. AREAS COVERED: The last two decades of experience have shown that indigenous glucose compensation through beta-cell regeneration and protection is a peerless method for T1D therapy. Tremendous studies have tried to find an unlimited source for beta-cell regeneration, on the one hand, and beta-cell protection against immune attack, on the other hand. Recent advances in stem cell technology, gene editing methods, and immune modulation approaches provide a unique opportunity for both beta-cell regeneration and protection. EXPERT OPINION: Pluripotent stem cell differentiation into the beta-cell is considered an unlimited source for beta-cell regeneration. Devising engineered pancreas-specific regulatory T cells using Chimeric Antigen Receptor (CAR) technology potentiates an effective immune tolerance induction for beta-cell protection. Beta-cell regeneration using pluripotent stem cells and beta-cell protection using pancreas-specific engineered regulatory T cells promises to develop a curative protocol in T1D.
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Diabetes Mellitus Tipo 1 , Células Secretoras de Insulina , Transplante das Ilhotas Pancreáticas , Regeneração , Humanos , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 1/imunologia , Células Secretoras de Insulina/fisiologia , Transplante das Ilhotas Pancreáticas/métodos , Animais , Células-Tronco Pluripotentes , Transplante de Pâncreas/métodosRESUMO
OBJECTIVE: Neuroinflammation is the hallmark of amyotrophic lateral sclerosis (ALS) disease. Regulatory T cells (Tregs) are essential in immune tolerance and neuroinflammation prevention. It has been shown that a significant decrease in Treg and FoxP3 protein expression is observed in ALS patients. The main reason for the FoxP3+ Treg loss in ALS is unknown. In this study, the role of autophagy dysregulation in FoxP3+ Tregs in ALS was investigated. METHODS: Twenty-three ALS patients and 24 healthy controls were recruited for the study. Mononuclear cells (MNCs) were obtained from peripheral blood, and then Tregs were isolated. Isolated Tregs were stained with FoxP3 and LC3 antibodies and analyzed in flow cytometry to determine autophagy levels in FoxP3+ Tregs in patients and controls. RESULTS: The mean of FoxP3+ LC3+ cells, were 0.47 and 0.45 in patients and controls, respectively. The mean of FoxP3+ LC3- cells was 0.15 in patients and 0.20 in controls, p = 0.030 (p < 0.05). There is no significant correlation between ALSFRS-R decay rate and autophagy level in patients. Also, there is no significant difference between autophagy levels in FoxP3+ Tregs in patients with rapidly progressing ALS and slow-progressing ALS. CONCLUSION: Excessive autophagy levels in FoxP3+ Tregs in ALS patients can potentially be an explanation for an increased cell death and result in worsened neuroinflammation and disease onset. However, the disease progress is not attributable to autophagy levels in FoxP3+ Tregs.
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Esclerose Lateral Amiotrófica , Linfócitos T Reguladores , Humanos , Linfócitos T Reguladores/metabolismo , Esclerose Lateral Amiotrófica/metabolismo , Doenças Neuroinflamatórias , Autofagia , Fatores de Transcrição Forkhead/metabolismoRESUMO
Autosomal recessive osteopetrosis (ARO) is a rare genetic bone disease characterized by dense and fragile bone, caused by a defect in osteoclasts responsible for the bone destruction. In this study, we aimed to investigate the mutations in TCIRG1 and SNX10 that are responsible for 50% and 4% of the cases, respectively. All amplicons were sequenced by Sanger sequencing following PCR amplification. As a result, six different mutations of the TCIRG1 gene were found in five of the twelve unrelated cases. These include two novel mutations, namely c.630â¯+â¯1Gâ¯>â¯T mutation and c.1778_1779delTG mutation of the gene which are identified as homozygous. A compound heterozygosity of known mutations c.649_674del26 and c.1372Gâ¯>â¯A and homozygous presence of the known c.2235â¯+â¯1Gâ¯>â¯A mutation were also observed in different patients. In addition, as a result of the prenatal testing in a family with osteopetrosis infant, the c.1674-1Gâ¯>â¯A mutation was detected as homozygous for the fetus. In TCIRG1, c.166Câ¯>â¯T change, which is indicated as likely benign according to ClinVar database, was heterozygous. Several known polymorphisms; c.117â¯+â¯83â¯Tâ¯>â¯C, c.417â¯+â¯11Aâ¯>â¯G and c.714-19Câ¯>â¯A in TCIRG1 gene; c.24â¯+â¯36â¯Tâ¯>â¯A and c.112-84Gâ¯>â¯A in SNX10 gene were also detected. In conclusion, our study revealed that five of the twelve cases carry at least one mutation of TCIRG1 gene. Further studies with more patients and other genes would help better understanding of genetic etiology of the disease.
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Mutação , Osteopetrose/genética , Nexinas de Classificação/genética , ATPases Vacuolares Próton-Translocadoras/genética , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Domínios Proteicos/genética , Turquia , ATPases Vacuolares Próton-Translocadoras/químicaRESUMO
Childhood acute lymphoblastic leukemia (ALL) is the most common type of childhood leukemia. Specifically, ALL is a malignant disorder of the lymphoid progenitor cells, with a peak incidence among children aged 2-5 years. The t(12;21)(p13;q22) translocation occurs in 25 % of childhood B cell precursor ALL. In this study, bone marrow samples were obtained from 165 patients with childhood ALL. We analyzed the t(12;21) translocation and other related abnormalities using the fluorescent in situ hybridization (FISH) technique with the ETV6(TEL)/RUNX1(AML1) ES dual color translocation probe. Conventional cytogenetic analyses were also performed. ETV6 and RUNX1 related chromosomal abnormalities were found in 42 (25.5 %) of the 165 patients with childhood ALL. Among these 42 patients, structural changes were detected in 33 (78.6 %) and numerical abnormalities in 9 (21.4 %). The frequency of FISH abnormalities in pediatric ALL cases were as follows: 8.5 % for t(12;21)(p13;q22) ETV6/RUNX1 fusion, 6.0 % for RUNX1 amplification, 3.0 % for tetrasomy/trisomy 21, 1.8 % for ETV6 deletion, 1.21 % for ETV6 deletion with RUNX1 amplification, 1.21 % for ETV6 amplification with RUNX1 amplification, 0.6 % for polyploidy, 0.6 % for RUNX1 deletion, and 0.6 % for diminished ETV6 signal. The most common structural abnormality was the t(12;21) translocation, followed by RUNX1 amplification and ETV6 deletion, while the most commonly observed numerical abnormality was trisomy 21.
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Pure partial trisomy of chromosome 21 is a rare event. The patients with this aberration are very important for setting up precise karyotype-phenotype correlations particularly in Down syndrome phenotype. We present here a patient with Down syndrome with a de novo derivative chromosome 21. Karyotype of the patient was designated as 46,XY,der(21)(p13)dup(21)(q11.2q21.3)dup(21)(q22.2q22.3) with regard to cytogenetic, FISH and array-CGH analyses. Non-continuous monosomic, disomic and trisomic chromosomal segments through the derivative chromosome 21 were detected by array-CGH analysis. STR analyses revealed maternal origin of the de novo derivative chromosome 21. The dual-specificity tyrosine (Y)-phosphorylation regulated kinase 1A (DYRK1A) and Down Syndrome Critical Region 1 (DSCR1) genes that are located in Down syndrome critical region, are supposed to be responsible for most of the clinical findings of Down syndrome. However, our patient is the first patient with Down syndrome whose clinical findings were provided in detail, with a de novo derivative chromosome 21 resulting from multiple chromosome breaks excluding DYRK1A and DSCR1 gene regions.
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Cromossomos Humanos Par 21/genética , Síndrome de Down/genética , Bandeamento Cromossômico , Quebra Cromossômica , Hibridização Genômica Comparativa , Proteínas de Ligação a DNA , Humanos , Hibridização in Situ Fluorescente , Lactente , Peptídeos e Proteínas de Sinalização Intracelular/genética , Cariotipagem , Masculino , Proteínas Musculares/genética , Fenótipo , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Trissomia , Quinases DyrkRESUMO
Despite its rarity, donor cell leukemia (DCL) is a most intriguing entity. We report here the case of a 5 year-old girl with juvenile myelomonocytic leukemia and normal female karyotype who developed acute myeloblastic leukemia with a karyotype of 46, X, t(X; 7) (p21; p11.2), der(7) t(3; 7) (q13.3; q22) 5 months after peripheral blood hematopoietic stem cell transplantation from her HLA-matched sister. We performed the analysis of short tandem repeat sequence markers to DNA obtained from donor peripheral blood, patient's peripheral blood including leukemic blasts and patient's hair root. This analysis showed that the leukemic blood DNA matched the donor blood DNA and not the patient's DNA, thus confirming DCL. To our knowledge, this is the first case of DCL after peripheral blood SCT for juvenile myelomonocytic leukemia.
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Doadores de Sangue , Leucemia Mieloide Aguda/etiologia , Leucemia Mielomonocítica Crônica/terapia , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Quimeras de Transplante , Pré-Escolar , Aberrações Cromossômicas , Evolução Fatal , Feminino , Humanos , Leucemia Mielomonocítica Crônica/complicações , Leucemia Mielomonocítica Crônica/genética , Segunda Neoplasia Primária , Quimeras de Transplante/genética , Transplante HomólogoRESUMO
BACKGROUND: The precise genes involved in conferring prostate cancer risk in sporadic and familial cases are not fully known. OBJECTIVES: To evaluate the genetic profile within several candidate genes of unselected prostate cancer cases and to correlate this profile with disease parameters. METHODS: Jewish Israeli prostate cancer patients (n = 224) were genotyped for polymorphisms within candidate genes: p53, ER, VDR, GSTT1, CYP1A1, GSTP1, GSTM1, EPHX and HPC2/ELAC2, followed by analysis of the genotype with relevant clinical and pathologic parameters. RESULTS: The EPHX gene His113 allele was detected in 21.4% (33/154) of patients in whom disease was diagnosed above 61 years, compared with 5.7% (4/70) in earlier onset disease (P < 0.001). Within the group of late-onset disease, the same allele was noted in 5.5% (2/36) with grade I tumors compared with 18% (34/188) with grade II and up (P = 0.004). All other tested polymorphisms were not associated with a distinct clinical or pathologic feature in a statistically significant manner. CONCLUSIONS: In Israeli prostate cancer patients, the EPHX His113 allele is seemingly associated with a more advanced, late-onset disease. These preliminary data need to be confirmed by a larger and more ethnically diverse study.