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3.
Nat Med ; 25(6): 890-897, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31160821

RESUMO

Monogenic disorders occur at a high frequency in human populations and are commonly inherited through the germline. Unfortunately, once the mutation has been transmitted to a child, only limited treatment options are available in most cases. However, means of correcting disease-causing nuclear and mitochondrial DNA mutations in gametes or preimplantation embryos have now been developed and are commonly referred to as germline gene therapy (GGT). We will discuss these novel strategies and provide a path forward for safe, high-efficiency GGT that may provide a promising new paradigm for preventing the passage of deleterious genes from parent to child.


Assuntos
Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/terapia , Terapia Genética/métodos , Mutação em Linhagem Germinativa , Criança , Reparo do DNA , DNA Mitocondrial/genética , Feminino , Fertilização In Vitro , Conversão Gênica , Terapia Genética/ética , Terapia Genética/legislação & jurisprudência , Humanos , Masculino , Terapia de Substituição Mitocondrial , Gravidez , Diagnóstico Pré-Implantação , Segurança
6.
Hum Genet ; 138(10): 1117-1122, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31243543

RESUMO

The Israeli population mainly includes Jews, Muslim and Christian Arabs, and Druze. Data on genetic diseases present in the population have been systematically collected and are available online in the Israeli national genetic database. Among the Israeli Arabs in December 31 2018, the database included molecular data on six diseases relatively frequent in the whole population: thalassemia, familial Mediterranean fever (FMF), cystic fibrosis, deafness, phenylketonuria or congenital adrenal hyperplasia as well as data on 632 autosomal recessive diseases among Muslim Israeli Arabs, 52 among the Christian Arabs and 79 among Druze. A single variant was characterized in 590 out of the 771 genes causing disorders in which the molecular basis was known. Many of the variants reported among Arabs in Israel are novels, most being found in one community only. Some variants are ancient and for instance, consistent with the migration history, several variants are found in the Bedouins from the Negev as well as from the Arab peninsula. In the 181 other disorders more than one variant was characterized either in the same gene or in more than one gene. While it is probable that most of these cases represent random events in some cases the reason may be a selective advantage to the heterozygotes.


Assuntos
Árabes/genética , Genes Recessivos , Doenças Genéticas Inatas/epidemiologia , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Doenças Genéticas Inatas/diagnóstico , Variação Genética , Heterozigoto , Humanos , Israel/epidemiologia , Programas de Rastreamento , Vigilância da População
7.
Int J Lab Hematol ; 41 Suppl 1: 131-141, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31069978

RESUMO

Advances in molecular genetic sequencing techniques have contributed to the elucidation of previously unknown germline mutations responsible for inherited thrombocytopenia (IT). Regardless of age of presentation and severity of symptoms related to thrombocytopenia and/or platelet dysfunction, a subset of patients with IT are at increased risk of developing myeloid neoplasms during their life time, particularly those with germline autosomal dominant mutations in RUNX1, ANKRD26, and ETV6. Patients may present with isolated thrombocytopenia and megakaryocytic dysmorphia or atypia on baseline bone marrow evaluation, without constituting myelodysplasia (MDS). Bone marrow features may overlap with idiopathic thrombocytopenic purpura (ITP) or sporadic MDS leading to misdiagnosis. Progression to myelodysplastic syndrome/ acute myeloid leukemia (MDS/AML) may be accompanied by progressive bi- or pancytopenia, multilineage dysplasia, increased blasts, cytogenetic abnormalities, acquisition of bi-allelic mutations in the underlying gene with germline mutation, or additional somatic mutations in genes associated with myeloid malignancy. A subset of patients may present with MDS/AML at a young age, underscoring the growing concern for evaluating young patients with MDS/AML for germline mutations predisposing to myeloid neoplasm. Early recognition of germline mutation and predisposition to myeloid malignancy permits appropriate treatment, adequate monitoring for disease progression, proper donor selection for hematopoietic stem cell transplantation, as well as genetic counseling of the affected patients and their family members. Herein, we describe the clinical and diagnostic features of IT with germline mutations predisposing to myeloid neoplasms focusing on mutations involving RUNX1, ANKRD26, and ETV6.


Assuntos
Doenças Genéticas Inatas , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Proteínas de Neoplasias , Trombocitopenia , Aloenxertos , Genes Dominantes , Aconselhamento Genético , Doenças Genéticas Inatas/sangue , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/terapia , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Mutação , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/terapia , Trombocitopenia/sangue , Trombocitopenia/diagnóstico , Trombocitopenia/genética , Trombocitopenia/terapia
8.
Hum Genet ; 138(6): 673-679, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31069506

RESUMO

The study of Mendelian diseases and the identification of their causative genes are of great significance in the field of genetics. The evaluation of the pathogenicity of genes and the total number of Mendelian disease genes are both important questions worth studying. However, very few studies have addressed these issues to date, so we attempt to answer them in this study. We calculated the gene pathogenicity prediction (GPP) score by a machine learning approach (random forest algorithm) to evaluate the pathogenicity of genes. When we applied the GPP score to the testing gene set, we obtained an accuracy of 80%, recall of 93% and area under the curve of 0.87. Our results estimated that a total of 10,384 protein-coding genes were Mendelian disease genes. Furthermore, we found the GPP score was positively correlated with the severity of disease. Our results indicate that GPP score may provide a robust and reliable guideline to predict the pathogenicity of protein-coding genes. To our knowledge, this is the first trial to estimate the total number of Mendelian disease genes.


Assuntos
Algoritmos , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença/genética , Aprendizado de Máquina , Genes Dominantes/genética , Genes Recessivos/genética , Doenças Genéticas Inatas/diagnóstico , Humanos , Curva ROC
9.
Int J Mol Sci ; 20(9)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052252

RESUMO

Ectopic mineralization disorders comprise a broad spectrum of inherited or acquired diseases characterized by aberrant deposition of calcium crystals in multiple organs, such as the skin, eyes, kidneys, and blood vessels. Although the precise mechanisms leading to ectopic calcification are still incompletely known to date, various molecular targets leading to a disturbed balance between pro- and anti-mineralizing pathways have been identified in recent years. Vitamin K and its related compounds, mainly those post-translationally activated by vitamin K-dependent carboxylation, may play an important role in the pathogenesis of ectopic mineralization as has been demonstrated in studies on rare Mendelian diseases, but also on highly prevalent disorders, like vascular calcification. This narrative review compiles and summarizes the current knowledge regarding the role of vitamin K, its metabolism, and associated compounds in the pathophysiology of both monogenic ectopic mineralization disorders, like pseudoxanthoma elasticum or Keutel syndrome, as well as acquired multifactorial diseases, like chronic kidney disease. Clinical and molecular aspects of the various disorders are discussed according to the state-of-the-art, followed by a comprehensive literature review regarding the role of vitamin K in molecular pathophysiology and as a therapeutic target in both human and animal models of ectopic mineralization disorders.


Assuntos
Calcinose/metabolismo , Doenças Genéticas Inatas/metabolismo , Vitamina K/metabolismo , Anormalidades Múltiplas , Animais , Calcinose/genética , Doenças das Cartilagens , Doenças Genéticas Inatas/genética , Deformidades Congênitas da Mão , Humanos , Estenose da Valva Pulmonar , Vitamina K/genética
10.
Math Biosci Eng ; 16(3): 1376-1391, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30947425

RESUMO

For discovery of new usage of drugs, the function type of their target genes plays an important role, and the hypothesis of "Antagonist-GOF" and "Agonist-LOF" has laid a solid foundation for supporting drug repurposing. In this research, an active gene annotation corpus was used as training data to predict the gain-of-function or loss-of-function or unknown character of each human gene after variation events. Unlike the design of(entity, predicate, entity) triples in a traditional three way tensor, a four way and a five way tensor, GMFD-/GMAFD-tensor, were designed to represent higher order links among or among part of these entities: genes(G), mutations(M), functions(F), diseases( D) and annotation labels(A). A tensor decomposition algorithm, CP decomposition, was applied to the higher order tensor and to unveil the correlation among entities. Meanwhile, a state-of-the-art baseline tensor decomposition algorithm, RESCAL, was carried on the three way tensor as a comparing method. The result showed that CP decomposition on higher order tensor performed better than RESCAL on traditional three way tensor in recovering masked data and making predictions. In addition, The four way tensor was proved to be the best format for our issue. At the end, a case study reproducing two disease-gene-drug links(Myelodysplatic Syndromes-IL2RA-Aldesleukin, Lymphoma- IL2RA-Aldesleukin) presented the feasibility of our prediction model for drug repurposing.


Assuntos
Reposicionamento de Medicamentos/economia , Reposicionamento de Medicamentos/métodos , Variação Genética , Aprendizado de Máquina , Mutação , Algoritmos , Análise Custo-Benefício , Doenças Genéticas Inatas/genética , Humanos , Interleucina-2/análogos & derivados , Interleucina-2/uso terapêutico , Subunidade alfa de Receptor de Interleucina-2/genética , Linfoma/genética , Modelos Genéticos , Anotação de Sequência Molecular , Síndromes Mielodisplásicas/genética , Proteínas Recombinantes/uso terapêutico , Software
11.
Hum Genet ; 138(4): 389-409, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30887117

RESUMO

Incidence rates of Mendelian diseases vary among ethnic groups, and frequencies of variant types of causative genes also vary among human populations. In this study, we examined to what extent we can predict population frequencies of recessive disorders from genomic data, and explored better strategies for variant interpretation and classification. We used a whole-genome reference panel from 3552 general Japanese individuals constructed by the Tohoku Medical Megabank Organization (ToMMo). Focusing on 32 genes for 17 congenital metabolic disorders included in newborn screening (NBS) in Japan, we identified reported and predicted pathogenic variants through variant annotation, interpretation, and multiple ways of classifications. The estimated carrier frequencies were compared with those from the Japanese NBS data based on 1,949,987 newborns from a previous study. The estimated carrier frequency based on genomic data with a recent guideline of variant interpretation for the PAH gene, in which defects cause hyperphenylalaninemia (HPA) and phenylketonuria (PKU), provided a closer estimate to that by the observed incidence than the other methods. In contrast, the estimated carrier frequencies for SLC25A13, which causes citrin deficiency, were much higher compared with the incidence rate. The results varied greatly among the 11 NBS diseases with single responsible genes; the possible reasons for departures from the carrier frequencies by reported incidence rates were discussed. Of note, (1) the number of pathogenic variants increases by including additional lines of evidence, (2) common variants with mild effects also contribute to the actual frequency of patients, and (3) penetrance of each variant remains unclear.


Assuntos
Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Doenças do Recém-Nascido/diagnóstico , Doenças do Recém-Nascido/genética , Triagem Neonatal/métodos , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Estudos de Coortes , Feminino , Frequência do Gene , Doenças Genéticas Inatas/epidemiologia , Estudo de Associação Genômica Ampla/normas , Heterozigoto , Humanos , Incidência , Recém-Nascido , Doenças do Recém-Nascido/epidemiologia , Japão/epidemiologia , Masculino , Padrões de Referência
12.
Mol Genet Genomic Med ; 7(2): e00606, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30816028

RESUMO

Attention has been focused on the field of genetics and genomics in Iran in recent years and some efforts have been enforced and implemented. However, they are totally not adequate, considering the advances in medical genetics and genomics in the past two decades around the world. Overall, considering the lack of medical genetics residency programs in the Iranian health education system, big demand due to high consanguinity and intraethnic marriages, there is a lag in genetic services and necessity to an immediate response to fill this big gap in Iran. As clarified in the National constitution fundamental law and re-emphasized in the 6th National Development Plan, the Iranian government authority is in charge of providing the standard level of health including genetic services to all Iranian individuals who are in need.


Assuntos
Utilização de Instalações e Serviços , Doenças Genéticas Inatas/diagnóstico , Testes Genéticos/estatística & dados numéricos , Genética Médica/estatística & dados numéricos , Diagnóstico Pré-Natal/estatística & dados numéricos , Análise de Sequência de DNA/estatística & dados numéricos , Bases de Dados Genéticas , Doenças Genéticas Inatas/epidemiologia , Doenças Genéticas Inatas/genética , Testes Genéticos/economia , Testes Genéticos/legislação & jurisprudência , Genética Médica/economia , Genética Médica/legislação & jurisprudência , Genética Médica/organização & administração , Humanos , Irã (Geográfico) , Diagnóstico Pré-Natal/economia , Análise de Sequência de DNA/economia
13.
Exp Clin Transplant ; 17(Suppl 1): 31-37, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30777520

RESUMO

To avoid the ethical issues of embryonic stem cells, genome engineering has focused on inducible pluripotent stem cells, which can develop into all 3 germ layers. The ability to detect methylation patterns in these cells allows research into pluripotency markers. The recently developed CRISPR system has allowed widespread application of genome engineering techniques. The CRISPR-Cas9 system, a potent system for genome editing, can be used for gene knockout or knock-in genome manipulations through substitution of a target genetic sequence with a desired donor sequence. Two types of genome engineering can be initiated: homologous or nonhomologous DNA repair by the Cas9 nuclease. Delivery of the CRISPR-Cas9 and target donor vectors in human pluripotent stem cells can be accomplished via viral and nonviral delivery methods. Nonviral delivery includes lipid-mediated transfection and electroporation. It has become the most common and efficient in vitro delivery method for human pluripotent stem cells. The CRISPR-Cas9 system can be combined with inducible pluripotent stem cells to generate single or multiple gene knockouts, correct mutations, or insert reporter transgenes. Knockouts can also be utilized to investigate epigenetic roles and targets, such as investigation of DNA methylation. CRISPR could be combined with human pluripotent stem cells to explore genetic determinants of lineage choice, differentiation, and stem cell fate, allowing investigators to study how various genes or noncoding elements contribute to specific processes and pathways. The CRISPR-Cas9 system can also be used to create null or nucleasedead Cas9, which has no enzymatic activity but has been utilized through fusion with other functional protein domains. In conclusion, RNA-guided genome targeting will have broad implications for synthetic biology, direct perturbation of gene networks, and targeted ex vivo and in vivo gene therapy.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes/métodos , Doenças Genéticas Inatas/terapia , Genoma Humano , Células-Tronco Pluripotentes Induzidas/transplante , Transplante de Células-Tronco/métodos , Animais , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/imunologia , Predisposição Genética para Doença , Humanos , Células-Tronco Pluripotentes Induzidas/imunologia , Fenótipo , Transplante de Células-Tronco/efeitos adversos , Resultado do Tratamento
14.
Genome Res ; 29(3): 428-438, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30787035

RESUMO

In the last decade, noninvasive prenatal diagnosis (NIPD) has emerged as an effective procedure for early detection of inherited diseases during pregnancy. This technique is based on using cell-free DNA (cfDNA) and fetal cfDNA (cffDNA) in maternal blood, and hence, has minimal risk for the mother and fetus compared with invasive techniques. NIPD is currently used for identifying chromosomal abnormalities (in some instances) and for single-gene disorders (SGDs) of paternal origin. However, for SGDs of maternal origin, sensitivity poses a challenge that limits the testing to one genetic disorder at a time. Here, we present a Bayesian method for the NIPD of monogenic diseases that is independent of the mode of inheritance and parental origin. Furthermore, we show that accounting for differences in the length distribution of fetal- and maternal-derived cfDNA fragments results in increased accuracy. Our model is the first to predict inherited insertions-deletions (indels). The method described can serve as a general framework for the NIPD of SGDs; this will facilitate easy integration of further improvements. One such improvement that is presented in the current study is a machine learning model that corrects errors based on patterns found in previously processed data. Overall, we show that next-generation sequencing (NGS) can be used for the NIPD of a wide range of monogenic diseases, simultaneously. We believe that our study will lead to the achievement of a comprehensive NIPD for monogenic diseases.


Assuntos
Doenças Genéticas Inatas/genética , Testes Genéticos/métodos , Diagnóstico Pré-Natal/métodos , Teorema de Bayes , Ácidos Nucleicos Livres/genética , Doenças Genéticas Inatas/diagnóstico , Testes Genéticos/normas , Humanos , Mutação INDEL , Aprendizado de Máquina , Diagnóstico Pré-Natal/normas
16.
J Int Med Res ; 47(3): 1169-1178, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30732499

RESUMO

OBJECTIVE: High-throughput sequencing based on copy number variation (CNV-seq) is commonly used to detect chromosomal abnormalities including aneuploidy. This study provides evidence for the prevalence of chromosomal abnormalities in target populations. METHODS: A total of 160 samples, including 83 high-risk pregnancies, 37 spontaneous abortions, and 40 suspected genetic disorders, were analyzed by CNV-seq. Relationships between the incidence of these chromosomal abnormalities and risk factors (e.g. advanced maternal age, abnormal pregnancy history, and family history of congenital disease) were further analyzed by subgroup. RESULTS: A total of 37 (44.6%) high-risk pregnancies, 25 (67.6%) spontaneous abortions, and 22 (55%) suspected genetic disorders had chromosomal abnormalities including aneuploidy and CNVs. There was an increased risk association between the prevalence of aneuploidy and pathogenic-relevant CNV in the fetus or abortive tissue and advanced maternal age. Moreover, a family history of congenital disease was also positively correlated with fetal chromosomal abnormalities in high-risk pregnancies. CONCLUSION: A relatively high prevalence of chromosomal abnormalities was detected in high-risk pregnancies, spontaneous abortions, and suspected genetic disorders, indicating the importance of CNV detection in such populations.


Assuntos
Aborto Espontâneo/genética , Aberrações Cromossômicas , Variações do Número de Cópias de DNA , Doenças Genéticas Inatas/genética , Gravidez de Alto Risco/genética , Aborto Espontâneo/epidemiologia , Adolescente , Adulto , China/epidemiologia , Feminino , Seguimentos , Doenças Genéticas Inatas/epidemiologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cariotipagem , Gravidez , Prevalência , Prognóstico , Adulto Jovem
17.
Mol Diagn Ther ; 23(2): 291-299, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30712216

RESUMO

Non-invasive prenatal diagnosis (NIPD) is based on fetal DNA analysis starting from a simple peripheral blood sample, thus avoiding risks associated with conventional invasive techniques. During pregnancy, the fetal DNA increases to approximately 3-13% of the total circulating free DNA in maternal plasma. The very low amount of circulating cell-free fetal DNA (ccffDNA) in maternal plasma is a crucial issue, and requires specific and optimized techniques for ccffDNA purification from maternal plasma. In addition, highly sensitive detection approaches are required. In recent years, advanced ccffDNA investigation approaches have allowed the application of non-invasive prenatal testing (NIPT) to determine fetal sex, fetal rhesus D (RhD) genotyping, aneuploidies, micro-deletions and the detection of paternally inherited monogenic disorders. Finally, complex and innovative technologies such as digital polymerase chain reaction (dPCR) and next-generation sequencing (NGS) (exhibiting higher sensitivity and/or the capability to read the entire fetal genome from maternal plasma DNA) are expected to allow the detection, in the near future, of maternally inherited mutations that cause genetic diseases. The aim of this review is to introduce the principal ccffDNA characteristics and their applications as the basis of current and novel NIPT.


Assuntos
DNA/sangue , Diagnóstico Pré-Natal/métodos , Ácidos Nucleicos Livres/sangue , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Testes Genéticos , Humanos
19.
Stem Cell Res ; 35: 101398, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30772683

RESUMO

Fibroblasts of a patient with Infantile Liver Failure Syndrome 2 (OMIM #616483) due to a homozygous missense variant in the neuroblastoma amplified sequence gene (NBAS; c.[2708T>G]; c.[2708T>G]/p.[Leu903Arg]; p.[Leu903Arg]) were reprogrammed to iPSCs using the Cytotune®-iPS 2.0 Sendai Reprogramming Kit (Invitrogen) delivering the reprogramming factors Oct3/4, Sox2, c-Myc and Klf4. Cells showed a normal karyotype. Pluripotency of DHMCi004-A was proven using immunohistochemistry, RT-PCR analysis, flow cytometry and differentiation into all three germ layers using the STEMdiff™ Trilineage Differentiation Kit (Stemcell Technologies). DHMCi004-A represents the first iPS-based cell model system to elucidate the pathomechanism underlying this disease.


Assuntos
Linhagem Celular , Doenças Genéticas Inatas , Células-Tronco Pluripotentes Induzidas , Falência Hepática , Mutação de Sentido Incorreto , Proteínas de Neoplasias , Pré-Escolar , Feminino , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/metabolismo , Doenças Genéticas Inatas/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Falência Hepática/genética , Falência Hepática/patologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Síndrome
20.
Nat Rev Genet ; 20(7): 377-388, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30737492

RESUMO

The derivation of induced pluripotent stem cells (iPSCs) over a decade ago sparked widespread enthusiasm for the development of new models of human disease, enhanced platforms for drug discovery and more widespread use of autologous cell-based therapy. Early studies using directed differentiation of iPSCs frequently uncovered cell-level phenotypes in monogenic diseases, but translation to tissue-level and organ-level diseases has required development of more complex, 3D, multicellular systems. Organoids and human-rodent chimaeras more accurately mirror the diverse cellular ecosystems of complex tissues and are being applied to iPSC disease models to recapitulate the pathobiology of a broad spectrum of human maladies, including infectious diseases, genetic disorders and cancer.


Assuntos
Doenças Transmissíveis/terapia , Doenças Genéticas Inatas/terapia , Células-Tronco Pluripotentes Induzidas/citologia , Modelos Biológicos , Neoplasias/terapia , Engenharia Tecidual/métodos , Animais , Diferenciação Celular , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Quimera/genética , Quimera/imunologia , Doenças Transmissíveis/genética , Doenças Transmissíveis/imunologia , Doenças Transmissíveis/patologia , Descoberta de Drogas/métodos , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/imunologia , Doenças Genéticas Inatas/patologia , Terapia Genética/métodos , Humanos , Células-Tronco Pluripotentes Induzidas/imunologia , Células-Tronco Pluripotentes Induzidas/transplante , Modelos Animais , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Organoides/citologia , Organoides/efeitos dos fármacos , Organoides/imunologia , Transplante de Tecidos/métodos , Transplante Heterólogo
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