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1.
Proc Natl Acad Sci U S A ; 118(22)2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34050017

RESUMO

CRISPR-Cas9 nuclease-based gene drives have been developed toward the aim of control of the human malaria vector Anopheles gambiae Gene drives are based on an active source of Cas9 nuclease in the germline that promotes super-Mendelian inheritance of the transgene by homology-directed repair ("homing"). Understanding whether CRISPR-induced off-target mutations are generated in Anopheles mosquitoes is an important aspect of risk assessment before any potential field release of this technology. We compared the frequencies and the propensity of off-target events to occur in four different gene-drive strains, including a deliberately promiscuous set-up, using a nongermline restricted promoter for SpCas9 and a guide RNA with many closely related sites (two or more mismatches) across the mosquito genome. Under this scenario we observed off-target mutations at frequencies no greater than 1.42%. We witnessed no evidence that CRISPR-induced off-target mutations were able to accumulate (or drive) in a mosquito population, despite multiple generations' exposure to the CRISPR-Cas9 nuclease construct. Furthermore, judicious design of the guide RNA used for homing of the CRISPR construct, combined with tight temporal constriction of Cas9 expression to the germline, rendered off-target mutations undetectable. The findings of this study represent an important milestone for the understanding and managing of CRISPR-Cas9 specificity in mosquitoes, and demonstrates that CRISPR off-target editing in the context of a mosquito gene drive can be reduced to minimal levels.


Assuntos
Anopheles/genética , Sistemas CRISPR-Cas , Edição de Genes , Genoma de Inseto , Malária , Mosquitos Vetores/genética , Animais , Humanos
2.
Nature ; 529(7587): 490-5, 2016 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-26735016

RESUMO

CRISPR-Cas9 nucleases are widely used for genome editing but can induce unwanted off-target mutations. Existing strategies for reducing genome-wide off-target effects of the widely used Streptococcus pyogenes Cas9 (SpCas9) are imperfect, possessing only partial or unproven efficacies and other limitations that constrain their use. Here we describe SpCas9-HF1, a high-fidelity variant harbouring alterations designed to reduce non-specific DNA contacts. SpCas9-HF1 retains on-target activities comparable to wild-type SpCas9 with >85% of single-guide RNAs (sgRNAs) tested in human cells. Notably, with sgRNAs targeted to standard non-repetitive sequences, SpCas9-HF1 rendered all or nearly all off-target events undetectable by genome-wide break capture and targeted sequencing methods. Even for atypical, repetitive target sites, the vast majority of off-target mutations induced by wild-type SpCas9 were not detected with SpCas9-HF1. With its exceptional precision, SpCas9-HF1 provides an alternative to wild-type SpCas9 for research and therapeutic applications. More broadly, our results suggest a general strategy for optimizing genome-wide specificities of other CRISPR-RNA-guided nucleases.


Assuntos
Proteínas Associadas a CRISPR/genética , Proteínas Associadas a CRISPR/metabolismo , Sistemas CRISPR-Cas/fisiologia , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Endonucleases/metabolismo , Engenharia Genética , Genoma Humano/genética , Sequência de Bases , DNA/genética , DNA/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Endonucleases/genética , Humanos , Mutação , Ligação Proteica , RNA/genética , Reprodutibilidade dos Testes , Análise de Sequência de DNA , Streptococcus pyogenes/enzimologia , Streptococcus pyogenes/genética , Especificidade por Substrato
3.
Clin Infect Dis ; 70(6): 1215-1221, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-31044232

RESUMO

BACKGROUND: Anaplasmosis presents with fever, headache, and laboratory abnormalities including leukopenia and thrombocytopenia. Polymerase chain reaction (PCR) is the preferred diagnostic but is overutilized. We determined if routine laboratory tests could exclude anaplasmosis, improving PCR utilization. METHODS: Anaplasma PCR results from a 3-year period, with associated complete blood count (CBC) and liver function test results, were retrospectively reviewed. PCR rejection criteria, based on white blood cell (WBC) and platelet (PLT) counts, were developed and prospectively applied in a mock stewardship program. If rejection criteria were met, a committee mock-refused PCR unless the patient was clinically unstable or immunocompromised. RESULTS: WBC and PLT counts were the most actionable routine tests for excluding anaplasmosis. Retrospective review demonstrated that rejection criteria of WBC ≥11 000 cells/µL or PLT ≥300 000 cells/µL would have led to PCR refusal in 428 of 1685 true-negative cases (25%) and 3 of 66 true-positive cases (5%) involving clinically unstable or immunocompromised patients. In the prospective phase, 155 of 663 PCR requests (23%) met rejection criteria and were reviewed by committee, which endorsed refusal in 110 of 155 cases (71%) and approval in 45 (29%), based on clinical criteria. PCR was negative in all 45 committee-approved cases. Only 1 of 110 mock-refused requests yielded a positive PCR result; this patient was already receiving doxycycline at the time of testing. CONCLUSIONS: A CBC-based stewardship algorithm would reduce unnecessary Anaplasma PCR testing, without missing active cases. Although the prospectively evaluated screening approach involved medical record review, this was unnecessary to prevent errors and could be replaced by a rejection comment specifying clinical situations that might warrant overriding the algorithm.


Assuntos
Anaplasma phagocytophilum , Anaplasmose , Anaplasma phagocytophilum/genética , Anaplasmose/diagnóstico , Animais , Contagem de Células Sanguíneas , Técnicas e Procedimentos Diagnósticos , Humanos , Estudos Prospectivos , Estudos Retrospectivos
5.
Nat Methods ; 11(4): 429-35, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24531420

RESUMO

Although transcription activator-like effector nucleases (TALENs) can be designed to cleave chosen DNA sequences, TALENs have activity against related off-target sequences. To better understand TALEN specificity, we profiled 30 unique TALENs with different target sites, array length and domain sequences for their abilities to cleave any of 10(12) potential off-target DNA sequences using in vitro selection and high-throughput sequencing. Computational analysis of the selection results predicted 76 off-target substrates in the human genome, 16 of which were accessible and modified by TALENs in human cells. The results suggest that (i) TALE repeats bind DNA relatively independently; (ii) longer TALENs are more tolerant of mismatches yet are more specific in a genomic context; and (iii) excessive DNA-binding energy can lead to reduced TALEN specificity in cells. Based on these findings, we engineered a TALEN variant that exhibits equal on-target cleavage activity but tenfold lower average off-target activity in human cells.


Assuntos
DNA/metabolismo , Desoxirribonucleases/metabolismo , Engenharia de Proteínas/métodos , Especificidade por Substrato/fisiologia , Sequência de Bases , Sítios de Ligação , Linhagem Celular , Desoxirribonucleases/genética , Marcação de Genes , Humanos , Ligação Proteica
6.
Nat Chem Biol ; 11(5): 316-8, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25848930

RESUMO

Directly modulating the activity of genome-editing proteins has the potential to increase their specificity by reducing activity following target locus modification. We developed Cas9 nucleases that are activated by the presence of a cell-permeable small molecule by inserting an evolved 4-hydroxytamoxifen-responsive intein at specific positions in Cas9. In human cells, conditionally active Cas9s modify target genomic sites with up to 25-fold higher specificity than wild-type Cas9.


Assuntos
Endonucleases/genética , Genoma/efeitos dos fármacos , Proteínas de Bactérias/efeitos dos fármacos , Proteínas de Bactérias/genética , Células Cultivadas , Endonucleases/efeitos dos fármacos , Células HEK293 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Ligantes , Modelos Moleculares , Conformação Proteica , Bibliotecas de Moléculas Pequenas , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacologia
7.
10.
Nucleic Acids Res ; 41(19): e181, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23945932

RESUMO

Gene-editing nucleases enable targeted modification of DNA sequences in living cells, thereby facilitating efficient knockout and precise editing of endogenous loci. Engineered nucleases also have the potential to introduce mutations at off-target sites of action. Such unintended alterations can confound interpretation of experiments and can have implications for development of therapeutic applications. Recently, two improved methods for identifying the off-target effects of zinc finger nucleases (ZFNs) were described-one using an in vitro cleavage site selection method and the other exploiting the insertion of integration-defective lentiviruses into nuclease-induced double-stranded DNA breaks. However, application of these two methods to a ZFN pair targeted to the human CCR5 gene led to identification of largely non-overlapping off-target sites, raising the possibility that additional off-target sites might exist. Here, we show that in silico abstraction of ZFN cleavage profiles obtained from in vitro cleavage site selections can greatly enhance the ability to identify potential off-target sites in human cells. Our improved method should enable more comprehensive profiling of ZFN specificities.


Assuntos
Clivagem do DNA , Desoxirribonucleases/metabolismo , Dedos de Zinco , Inteligência Artificial , Sequência de Bases , Simulação por Computador , DNA/química , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Receptores CCR5/genética , Análise de Sequência de DNA , Fator A de Crescimento do Endotélio Vascular/genética
11.
Nat Methods ; 8(9): 765-70, 2011 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-21822273

RESUMO

Engineered zinc-finger nucleases (ZFNs) are promising tools for genome manipulation, and determining off-target cleavage sites of these enzymes is of great interest. We developed an in vitro selection method that interrogates 10(11) DNA sequences for cleavage by active, dimeric ZFNs. The method revealed hundreds of thousands of DNA sequences, some present in the human genome, that can be cleaved in vitro by two ZFNs: CCR5-224 and VF2468, which target the endogenous human CCR5 and VEGFA genes, respectively. Analysis of identified sites in one cultured human cell line revealed CCR5-224-induced changes at nine off-target loci, though this remains to be tested in other relevant cell types. Similarly, we observed 31 off-target sites cleaved by VF2468 in cultured human cells. Our findings establish an energy compensation model of ZFN specificity in which excess binding energy contributes to off-target ZFN cleavage and suggest strategies for the improvement of future ZFN design.


Assuntos
DNA/metabolismo , Endodesoxirribonucleases/metabolismo , Especificidade por Substrato , Dedos de Zinco , Sequência de Bases , Sítios de Ligação , Células Cultivadas , Proteínas de Ligação a DNA/metabolismo , Humanos , Células K562 , Dedos de Zinco/genética
12.
Drug Des Devel Ther ; 17: 333-339, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36785760

RESUMO

Uveal melanoma (UM) is a rare type of melanoma with distinct features from cutaneous melanoma, low response rates to immune checkpoint inhibition, and poor survival rates. Tebentafusp, a bispecific antibody engaging T cells with gp 100 on HLA-A*02:01, was recently approved by the FDA as the first drug of its class and the first treatment approved by the FDA to treat UM. In this review, we summarize the preclinical and clinical data on tebentafusp for UM. We additionally discuss patient selection and the relevant challenges. For the literature search, PubMed search and relevant articles presented at international conferences were used.


Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/patologia , Seleção de Pacientes
13.
Hum Immunol ; 84(4): 278-285, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36868898

RESUMO

Although rare, infection and vaccination can result in antibodies to human leukocyte antigens (HLA). We analyzed the effect of SARS-CoV-2 infection or vaccination on HLA antibodies in waitlisted renal transplant candidates. Specificities were collected and adjudicated if the calculated panel reactive antibodies (cPRA) changed after exposure. Of 409 patients, 285 (69.7 %) had an initial cPRA of 0 %, and 56 (13.7 %) had an initial cPRA > 80 %. The cPRA changed in 26 patients (6.4 %), 16 (3.9 %) increased, and 10 (2.4 %) decreased. Based on cPRA adjudication, cPRA differences generally resulted from a small number of specificities with subtle fluctuations around the borderline of the participating centers' cutoff for unacceptable antigen listing. All five COVID recovered patients with an increased cPRA were female (p = 0.02). In summary, exposure to this virus or vaccine does not increase HLA antibody specificities and their MFI in approximately 99 % of cases and 97 % of sensitized patients. These results have implications for virtual crossmatching at the time of organ offer after SARS-CoV-2 infection or vaccination, and these events of unclear clinical significance should not influence vaccination programs.


Assuntos
COVID-19 , Transplante de Rim , Humanos , Feminino , Masculino , Doadores de Tecidos , Teste de Histocompatibilidade/métodos , Transplante de Rim/métodos , SARS-CoV-2 , Anticorpos , Antígenos HLA , Vacinação , Isoanticorpos
14.
bioRxiv ; 2023 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-37292647

RESUMO

Gene editing the BCL11A erythroid enhancer is a validated approach to fetal hemoglobin (HbF) induction for ß-hemoglobinopathy therapy, though heterogeneity in edit allele distribution and HbF response may impact its safety and efficacy. Here we compared combined CRISPR-Cas9 endonuclease editing of the BCL11A +58 and +55 enhancers with leading gene modification approaches under clinical investigation. We found that combined targeting of the BCL11A +58 and +55 enhancers with 3xNLS-SpCas9 and two sgRNAs resulted in superior HbF induction, including in engrafting erythroid cells from sickle cell disease (SCD) patient xenografts, attributable to simultaneous disruption of core half E-box/GATA motifs at both enhancers. We corroborated prior observations that double strand breaks (DSBs) could produce unintended on- target outcomes in hematopoietic stem and progenitor cells (HSPCs) such as long deletions and centromere-distal chromosome fragment loss. We show these unintended outcomes are a byproduct of cellular proliferation stimulated by ex vivo culture. Editing HSPCs without cytokine culture bypassed long deletion and micronuclei formation while preserving efficient on-target editing and engraftment function. These results indicate that nuclease editing of quiescent hematopoietic stem cells (HSCs) limits DSB genotoxicity while maintaining therapeutic potency and encourages efforts for in vivo delivery of nucleases to HSCs.

15.
Mol Ther Nucleic Acids ; 28: 450-461, 2022 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-35505961

RESUMO

Presenilin 1 (PS1) is a central component of γ-secretase, an enzymatic complex involved in the generation of the amyloid-ß (Aß) peptide that deposits as plaques in the Alzheimer's disease (AD) brain. The M146L mutation in the PS1 gene (PSEN1) leads to an autosomal dominant form of early-onset AD by promoting a relative increase in the generation of the more aggregation-prone Aß42. This change is evident not only in the brain but also in peripheral cells of mutation carriers. In this study we used the CRISPR-Cas9 system from Streptococcus pyogenes to selectively disrupt the PSEN1 M146L allele in human fibroblasts. A disruption of more than 50% of mutant alleles was observed in all CRISPR-Cas9-treated samples, resulting in reduced extracellular Aß42/40 ratios. Fluorescence resonance energy transfer-based conformation and western blot analyses indicated that CRISPR-Cas9 treatment also affects the overall PS1 conformation and reduces PS1 levels. Moreover, our guide RNA did not lead to any detectable editing at the highest-ranking candidate off-target sites identified by ONE-seq and CIRCLE-seq. Overall, our data support the effectiveness of CRISPR-Cas9 in selectively targeting the PSEN1 M146L allele and counteracting the AD-associated phenotype. We believe that this system could be developed into a therapeutic strategy for patients with this and other dominant mutations leading to early-onset AD.

16.
Front Immunol ; 13: 838985, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35281011

RESUMO

Introduction: Studies have shown reduced antiviral responses in kidney transplant recipients (KTRs) following SARS-CoV-2 mRNA vaccination, but data on post-vaccination alloimmune responses and antiviral responses against the Delta (B.1.617.2) variant are limited. Materials and methods: To address this issue, we conducted a prospective, multi-center study of 58 adult KTRs receiving mRNA-BNT162b2 or mRNA-1273 vaccines. We used multiple complementary non-invasive biomarkers for rejection monitoring including serum creatinine, proteinuria, donor-derived cell-free DNA, peripheral blood gene expression profile (PBGEP), urinary CXCL9 mRNA and de novo donor-specific antibodies (DSA). Secondary outcomes included development of anti-viral immune responses against the wild-type and Delta variant of SARS-CoV-2. Results: At a median of 85 days, no KTRs developed de novo DSAs and only one patient developed acute rejection following recent conversion to belatacept, which was associated with increased creatinine and urinary CXCL9 levels. During follow-up, there were no significant changes in proteinuria, donor-derived cell-free DNA levels or PBGEP. 36% of KTRs in our cohort developed anti-wild-type spike antibodies, 75% and 55% of whom had neutralizing responses against wild-type and Delta variants respectively. A cellular response against wild-type S1, measured by interferon-γ-ELISpot assay, developed in 38% of KTRs. Cellular responses did not differ in KTRs with or without antibody responses. Conclusions: SARS-CoV-2 mRNA vaccination in KTRs did not elicit a significant alloimmune response. About half of KTRs who develop anti-wild-type spike antibodies after two mRNA vaccine doses have neutralizing responses against the Delta variant. There was no association between anti-viral humoral and cellular responses.


Assuntos
Vacina de mRNA-1273 contra 2019-nCoV/imunologia , Vacina BNT162/imunologia , Rejeição de Enxerto/diagnóstico , Transplante de Rim , Monitorização Fisiológica/métodos , SARS-CoV-2/imunologia , Idoso , Anticorpos Antivirais/sangue , ELISPOT , Feminino , Humanos , Imunidade Celular , Isoanticorpos/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Transplante Homólogo , Vacinação
17.
CRISPR J ; 4(1): 19-24, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33571044

RESUMO

Gene drives hold promise for use in controlling insect vectors of diseases, agricultural pests, and for conservation of ecosystems against invasive species. At the same time, this technology comes with potential risks that include unknown downstream effects on entire ecosystems as well as the accidental or nefarious spread of organisms that carry the gene drive machinery. A code of ethics can be a useful tool for all parties involved in the development and regulation of gene drives and can be used to help ensure that a balanced analysis of risks, benefits, and values is taken into consideration in the interest of society and humanity. We have developed a code of ethics for gene drive research with the hope that this code will encourage the development of an international framework that includes ethical guidance of gene drive research and is incorporated into scientific practice by gaining broad agreement and adherence.


Assuntos
Códigos de Ética , Tecnologia de Impulso Genético , Ecossistema , Edição de Genes , Humanos , Espécies Introduzidas , Princípios Morais , Saúde Pública
18.
RNA ; 14(4): 657-65, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18359781

RESUMO

We developed self-quenching reporter molecules (SQRMs), oligodeoxynucleotides with fluorophore and quencher moieties at the 5' and 3' ends respectively, to probe mRNAs for single-stranded, hybridization accessible sequences. SQRMs and their homologous antecedents, Molecular Beacons (MB), are designed with the assumption that they adopt a stem-loop structure thought critical for regulating their reporter function. Recently, we observed that stem-loop structures are not required for SQRM function, and on this basis proposed that these reporter molecules be classified according to whether they were stemmed (Type I) or not (Type II). This finding further stimulated us to investigate whether Type I SQRMs, and by extension MBs, actually adopt a stem-loop configuration under physiologic conditions. Accordingly, we synthesized Type I and Type II SQRMs and studied the thermodynamic characteristics of each by fluorescence melting analysis. The results of these studies suggested that the majority of stem-loop Type I SQRMs are unstructured at 37 degrees C, while some of the stemless Type II SQRMs are, surprisingly, structured. These results were not predicted by the mfold computer program. Type I and II SQRMs were then employed to "map" the mRNA secondary structure of a gene encoding a tyrosine kinase receptor, c-kit. Neither experimentally determined melting temperatures nor mfold-"predicted" thermodynamic parameters were useful in predicting the fluorescence signal-to-noise ratios obtained for SQRMs incubated with c-kit mRNA. We conclude that stem-loop reporter molecules are in fact unlikely to adopt their presumed structures at 37 degrees C, and this design consideration may be dispensed when their use is contemplated under physiologic conditions.


Assuntos
Corantes Fluorescentes/química , Conformação de Ácido Nucleico , Sondas de Oligonucleotídeos/química , RNA Mensageiro/química , Sequência de Bases , Simulação por Computador , Modelos Moleculares , Desnaturação de Ácido Nucleico , Sondas de Oligonucleotídeos/genética , Proteínas Proto-Oncogênicas c-kit/genética , RNA Mensageiro/genética , Termodinâmica
19.
J Invest Dermatol ; 140(5): 995-1002, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31669059

RESUMO

Keratinocyte carcinoma (KC), defined as squamous cell carcinoma and basal cell carcinoma, is the most common malignancy among white, non-Hispanic renal transplant recipients. Although recent genome-wide association studies reported that class II HLA is associated with KC risk, epidemiologic data on HLA type and KC risk in renal transplant recipients is limited. Using an institutional cohort of white, non-Hispanic renal transplant recipients transplanted between 1993 and 2017, we examined the association between pretransplant molecular HLA types and KC risk. Posttransplant KCs were captured using the International Classification of Diseases codes and validated using pathology reports. Cox proportional hazards regression models were used to estimate hazard ratios of incident KC, squamous cell carcinoma, and basal cell carcinoma, adjusting for age, male sex, history of KC, Charlson comorbidity index, HLA mismatch, transplant type, year of transplant, and the type of immunosuppression. Among 617 subjects (mean age 53 years, 67% male), 10% developed posttransplant KC. Multivariable Cox regression analyses showed HLA-DRB1∗13 was associated with KC risk (hazard ratio, 1.84; 95% confidence interval, 1.00-3.38) and squamous cell carcinoma risk (hazard ratio, 2.24; 95% confidence interval, 1.12-4.49), whereas HLA-DRB1∗14 (hazard ratio, 2.81; 95% confidence interval, 1.14-6.91) was associated with basal cell carcinoma risk. Our findings suggest that a subset of renal transplant recipients with specific HLA polymorphisms may be at increased KC risk.


Assuntos
Carcinoma Basocelular/genética , Carcinoma de Células Escamosas/genética , Cadeias HLA-DRB1/genética , Queratinócitos/patologia , Transplante de Rim/estatística & dados numéricos , Carcinoma Basocelular/epidemiologia , Carcinoma de Células Escamosas/epidemiologia , Estudos de Coortes , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Risco
20.
Nucleic Acids Res ; 33(3): e28, 2005 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-15718294

RESUMO

We describe a physical mRNA mapping strategy employing fluorescent self-quenching reporter molecules (SQRMs) that facilitates the identification of mRNA sequence accessible for hybridization with antisense nucleic acids in vitro and in vivo, real time. SQRMs are 20-30 base oligodeoxynucleotides with 5-6 bp complementary ends to which a 5' fluorophore and 3' quenching group are attached. Alone, the SQRM complementary ends form a stem that holds the fluorophore and quencher in contact. When the SQRM forms base pairs with its target, the structure separates the fluorophore from the quencher. This event can be reported by fluorescence emission when the fluorophore is excited. The stem-loop of the SQRM suggests that SQRM be made to target natural stem-loop structures formed during mRNA synthesis. The general utility of this method is demonstrated by SQRM identification of targetable sequence within c-myb and bcl-6 mRNA. Corresponding antisense oligonucleotides reduce these gene products in cells.


Assuntos
Corantes Fluorescentes/química , Hibridização de Ácido Nucleico/métodos , Oligodesoxirribonucleotídeos Antissenso/química , RNA Mensageiro/química , Animais , Linhagem Celular , Cricetinae , Proteínas de Ligação a DNA/genética , Humanos , Biossíntese de Proteínas , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-bcl-6 , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-myb/genética , RNA Mensageiro/metabolismo , Coelhos , Fatores de Transcrição/genética , Transcrição Gênica
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