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1.
ACS Synth Biol ; 12(9): 2778-2782, 2023 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-37582217

RESUMO

Synergistic and supportive interactions among genes can be incorporated in engineering biology to enhance and stabilize the performance of biological systems, but combinatorial numerical explosion challenges the analysis of multigene interactions. The incorporation of DNA barcodes to mark genes coupled with next-generation sequencing offers a solution to this challenge. We describe improvements for a key method in this space, CombiGEM, to broaden its application to assembling typical gene-sized DNA fragments and to reduce the cost of sequencing for prevalent small-scale projects. The expanded reach of the method beyond currently targeted small RNA genes promotes the discovery and incorporation of gene synergy in natural and engineered processes such as biocontainment, the production of desired compounds, and previously uncharacterized fundamental biological mechanisms.


Assuntos
DNA , Sequenciamento de Nucleotídeos em Larga Escala , DNA/genética
2.
J Biol Chem ; 296: 100481, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33647313

RESUMO

The extracellular matrix (ECM) plays an important role in maintaining tissue homeostasis and poses a significant physical barrier to in vivo cell migration. Accordingly, as a means of enhancing tissue invasion, tumor cells use matrix metalloproteinases to degrade ECM proteins. However, the in vivo ECM is comprised not only of proteins but also of a variety of nonprotein components. Hyaluronan (HA), one of the most abundant nonprotein components of the interstitial ECM, forms a gel-like antiadhesive barrier that is impenetrable to particulate matter and cells. Mechanisms by which tumor cells penetrate the HA barrier have not been addressed. Here, we demonstrate that transmembrane protein 2 (TMEM2), the only known transmembrane hyaluronidase, is the predominant mediator of contact-dependent HA degradation and subsequent integrin-mediated cell-substrate adhesion. We show that a variety of tumor cells are able to eliminate substrate-bound HA in a tightly localized pattern corresponding to the distribution of focal adhesions (FAs) and stress fibers. This FA-targeted HA degradation is mediated by TMEM2, which itself is localized at site of FAs. TMEM2 depletion inhibits the ability of tumor cells to attach and migrate in an HA-rich environment. Importantly, TMEM2 directly binds at least two integrins via interaction between extracellular domains. Our findings demonstrate a critical role for TMEM2-mediated HA degradation in the adhesion and migration of cells on HA-rich ECM substrates and provide novel insight into the early phase of FA formation.


Assuntos
Ácido Hialurônico/metabolismo , Proteínas de Membrana/metabolismo , Animais , Adesão Celular/fisiologia , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Movimento Celular/fisiologia , Matriz Extracelular/metabolismo , Adesões Focais/metabolismo , Adesões Focais/fisiologia , Humanos , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/fisiologia , Hialuronoglucosaminidase/metabolismo , Integrinas/metabolismo , Proteínas de Membrana/fisiologia , Camundongos
3.
Matrix Biol ; 97: 40-57, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33454424

RESUMO

Little is known about extracellular matrix (ECM) contributions to formation of the earliest cell lineages in the embryo. Here, we show that the proteoglycan versican and glycosaminoglycan hyaluronan are associated with emerging Flk1+ hematoendothelial progenitors at gastrulation. The mouse versican mutant Vcanhdf lacks yolk sac vasculature, with attenuated yolk sac hematopoiesis. CRISPR/Cas9-mediated Vcan inactivation in mouse embryonic stem cells reduced vascular endothelial and hematopoietic differentiation within embryoid bodies, which generated fewer blood colonies, and had an impaired angiogenic response to VEGF165. Hyaluronan was severely depleted in Vcanhdf embryos, with corresponding upregulation of the hyaluronan-depolymerase TMEM2. Conversely, hyaluronan-deficient mouse embryos also had vasculogenic suppression but with increased versican proteolysis. VEGF165 and Indian hedgehog, crucial vasculogenic factors, utilized the versican-hyaluronan matrix, specifically versican chondroitin sulfate chains, for binding. Versican-hyaluronan ECM is thus an obligate requirement for vasculogenesis and primitive hematopoiesis, providing a vasculogenic factor-enriching microniche for Flk1+ progenitors from their origin at gastrulation.


Assuntos
Matriz Extracelular/metabolismo , Ácido Hialurônico/metabolismo , Células-Tronco Embrionárias Murinas/citologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Versicanas/genética , Animais , Sistemas CRISPR-Cas , Diferenciação Celular , Células Cultivadas , Proteínas Hedgehog/metabolismo , Hematopoese , Proteínas de Membrana/metabolismo , Camundongos , Células-Tronco Embrionárias Murinas/metabolismo , Nicho de Células-Tronco , Regulação para Cima , Versicanas/metabolismo
4.
J Clin Invest ; 128(1): 517-530, 2018 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-29227283

RESUMO

SHARPIN, an adaptor for the linear ubiquitin chain assembly complex (LUBAC), plays important roles in NF-κB signaling and inflammation. Here, we have demonstrated a LUBAC-independent role for SHARPIN in regulating melanoma growth. We observed that SHARPIN interacted with PRMT5, a type II protein arginine methyltransferase, and increased its multiprotein complex and methyltransferase activity. Activated PRMT5 controlled the expression of the transcription factors SOX10 and MITF by SHARPIN-dependent arginine dimethylation and inhibition of the transcriptional corepressor SKI. Activation of PRMT5 by SHARPIN counteracted PRMT5 inhibition by methylthioadenosine, a substrate of methylthioadenosine phosphorylase, which is codeleted with cyclin-dependent kinase inhibitor 2A (CDKN2A) in approximately 15% of human cancers. Collectively, we identified a LUBAC-independent role for SHARPIN in enhancing PRMT5 activity that contributes to melanomagenesis through the SKI/SOX10 regulatory axis.


Assuntos
Melanoma/metabolismo , Proteínas de Neoplasias/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Ubiquitinas/metabolismo , Linhagem Celular Tumoral , Células HEK293 , Humanos , Melanoma/genética , Melanoma/patologia , Proteínas de Neoplasias/genética , Proteína-Arginina N-Metiltransferases/genética , Fatores de Transcrição SOXE/genética , Fatores de Transcrição SOXE/metabolismo , Ubiquitinas/genética
5.
Sci Rep ; 6: 27806, 2016 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-27291296

RESUMO

The spiroindolones, a new class of antimalarial medicines discovered in a cellular screen, are rendered less active by mutations in a parasite P-type ATPase, PfATP4. We show here that S. cerevisiae also acquires mutations in a gene encoding a P-type ATPase (ScPMA1) after exposure to spiroindolones and that these mutations are sufficient for resistance. KAE609 resistance mutations in ScPMA1 do not confer resistance to unrelated antimicrobials, but do confer cross sensitivity to the alkyl-lysophospholipid edelfosine, which is known to displace ScPma1p from the plasma membrane. Using an in vitro cell-free assay, we demonstrate that KAE609 directly inhibits ScPma1p ATPase activity. KAE609 also increases cytoplasmic hydrogen ion concentrations in yeast cells. Computer docking into a ScPma1p homology model identifies a binding mode that supports genetic resistance determinants and in vitro experimental structure-activity relationships in both P. falciparum and S. cerevisiae. This model also suggests a shared binding site with the dihydroisoquinolones antimalarials. Our data support a model in which KAE609 exerts its antimalarial activity by directly interfering with P-type ATPase activity.


Assuntos
Antimaláricos/metabolismo , Indóis/metabolismo , ATPases do Tipo-P/metabolismo , Compostos de Espiro/metabolismo , Sequência de Aminoácidos , Antimaláricos/química , Antimaláricos/farmacologia , Sítios de Ligação , Sistemas CRISPR-Cas/genética , Citosol/química , Citosol/efeitos dos fármacos , Farmacorresistência Fúngica , Indóis/química , Indóis/farmacologia , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , ATPases do Tipo-P/antagonistas & inibidores , ATPases do Tipo-P/genética , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Estrutura Terciária de Proteína , ATPases Translocadoras de Prótons/antagonistas & inibidores , ATPases Translocadoras de Prótons/genética , ATPases Translocadoras de Prótons/metabolismo , Proteínas de Protozoários/antagonistas & inibidores , Proteínas de Protozoários/metabolismo , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/enzimologia , Proteínas de Saccharomyces cerevisiae/antagonistas & inibidores , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Alinhamento de Sequência , Análise de Sequência de DNA , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade , Sequenciamento Completo do Genoma
6.
G3 (Bethesda) ; 4(7): 1183-91, 2014 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-24776987

RESUMO

Being a simple eukaryotic organism, Saccharomyces cerevisiae provides numerous advantages for expression and functional characterization of proteins from higher eukaryotes, including humans. However, studies of complex exogenous pathways using yeast as a host have been hampered by the lack of tools to engineer strains expressing a large number of genetic components. In addition to inserting multiple genes, it is often desirable to knock out or replace multiple endogenous genes that might interfere with the processes studied. Here, we describe the "insertion Green Monster" (iGM) set of expression vectors that enable precise insertion of many heterologous genes into the yeast genome in a rapid and reproducible manner and permit simultaneous replacement of selected yeast genes. As a proof of principle, we have used the iGM method to replace components of the yeast pathway for methionine sulfoxide reduction with genes encoding the human selenoprotein biosynthesis machinery and generated a single yeast strain carrying 11 exogenous components of the selenoprotein biosynthetic pathway in precisely engineered loci.


Assuntos
Saccharomyces cerevisiae/metabolismo , Sequência de Aminoácidos , Vetores Genéticos/genética , Vetores Genéticos/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Dados de Sequência Molecular , Mutagênese Insercional , Filogenia , RNA Mensageiro/química , RNA Mensageiro/metabolismo , Proteínas Ribossômicas/química , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , Saccharomyces cerevisiae/genética , Selenoproteínas/genética , Selenoproteínas/metabolismo , Análise de Sequência de RNA
8.
Anticancer Res ; 32(3): 1081-5, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22399636

RESUMO

Wilms' tumor (WT1) protein is one of the most promising target antigens for cancer immunotherapy. In fact, clinical responses, such as growth stabilization or shrinkage of tumor with immunological responses, have been reported in patients vaccinated with WT1 peptide. Here, we performed WT1 peptide-based immunotherapy for a patient with chemotherapy-resistant salivary gland cancer, whose histologic type was carcinoma ex pleomorphic adenoma. The patient with its pulmonary metastasis, refractory to chemotherapy, was intradermally injected with 3 mg of WT1 peptide emulsified with Montanide ISA51 adjuvant at one-week intervals for 12 weeks. The considerably rapid growth of tumor was inhibited after WT1 vaccination, and stable disease, lasting three months, was achieved. Concomitantly, immunological responses, i.e. an increase in frequencies of WT1 tetramer(+) CD8(+)T cells and delayed type hypersensitivity response, were detected after the vaccination. These results indicate the potential of WT1 peptide-based immunotherapy for the treatment of chemotherapy-resistant salivery gland cancer.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias das Glândulas Salivares/tratamento farmacológico , Proteínas WT1/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas WT1/química
9.
Vaccine ; 30(4): 722-9, 2012 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-22133512

RESUMO

To induce and activate tumor-associated antigen-specific cytotoxic T lymphocytes (CTLs) for cancer immunity, it is important not only to select potent CTL epitopes but also to combine them with appropriate immunopotentiating agents. Here we investigated whether tumor immunity induced by WT1 peptide vaccination could be enhanced by IFN-ß. For the experimental group, C57BL/6 mice were twice pre-treated with WT1 peptide vaccine, implanted with WT1-expressing C1498 cells, and treated four times with WT1 peptide vaccine at one-week intervals. During the vaccination period, IFN-ß was injected three times a week. Mice in control groups were treated with WT1 peptide alone, IFN-ß alone, or PBS alone. The mice in the experimental group rejected tumor cells and survived significantly longer than mice in the control groups. The overall survival on day 75 was 40% for the mice treated with WT1 peptide+IFN-ß, while it was 7, 7, and 0% for those treated with WT1 peptide alone, IFN-ß alone or PBS alone, respectively. Induction of WT1-specific CTLs and enhancement of NK activity were detected in splenocytes from mice in the experimental group. Furthermore, administration of IFN-ß enhanced expression of MHC class I molecules on the implanted tumor cells. In conclusion, our results showed that co-administration of WT1 peptide+IFN-ß enhanced tumor immunity mainly through the induction of WT1-specific CTLs, enhancement of NK activity, and promotion of MHC class I expression on the tumor cells. WT1 peptide vaccination combined with IFN-ß administration can thus be expected to enhance the clinical efficacy of WT1 immunotherapy.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Vacinas Anticâncer/imunologia , Interferon beta/administração & dosagem , Neoplasias Renais/prevenção & controle , Proteínas WT1/imunologia , Tumor de Wilms/prevenção & controle , Animais , Vacinas Anticâncer/administração & dosagem , Neoplasias Renais/imunologia , Células Matadoras Naturais/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Baço/imunologia , Análise de Sobrevida , Linfócitos T Citotóxicos/imunologia , Proteínas WT1/administração & dosagem , Tumor de Wilms/imunologia
10.
Eur J Haematol ; 85(4): 358-60, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20633041

RESUMO

How to treat CML patients who are resistant to inhibitors of BCR-ABL tyrosine kinase such as Imatinib is a very important and urgent issue in clinical hematology. Here, we report a case of Imatinib-treated CML in which intradermally administered WT1 peptide vaccine elicited WT1-specific immune responses and the resultant reduction in the persistent residual disease in co-administration of Imatinib. BCR-ABL mRNA levels were being maintained under the detection limit for 8 months since week 77 of vaccination. No adverse effects except local erythema at the injection sites were observed. The tetramer assay revealed that the decrease in BCR-ABL mRNA levels was associated with the increase in frequency of WT1-specific cytotoxic T lymphocytes, notably effector-memory type of that, in the patient's peripheral blood. The case presented here indicates that WT1 peptide vaccine may become a safe and cure-oriented therapy for CML patients who have residual disease regardless of the treatment with Imatinib.


Assuntos
Vacinas Anticâncer/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Proteínas WT1/imunologia , Idoso , Antineoplásicos/uso terapêutico , Benzamidas , Vacinas Anticâncer/química , Vacinas Anticâncer/imunologia , Terapia Combinada , Resistencia a Medicamentos Antineoplásicos , Feminino , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Neoplasia Residual , Piperazinas/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/uso terapêutico , RNA Mensageiro , Linfócitos T Citotóxicos/imunologia , Vacinas de Subunidades Antigênicas/imunologia , Vacinas de Subunidades Antigênicas/uso terapêutico , Proteínas WT1/química
11.
Jpn J Clin Oncol ; 40(5): 395-403, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20364021

RESUMO

OBJECTIVE: Immunotherapy targeting the Wilms' tumour 1 gene product has been proven safe and effective for treating malignant glioma in a phase II clinical study. Currently, radiation/temozolomide therapy is the standard treatment with only modest benefit. Whether combining radiation/temozolomide therapy with WT1 immunotherapy will have a negating effect on immunotherapy is still controversial because of the significant lymphocytopaenia induced by the former therapy. To address this issue, we investigated the changes in frequency and number of WT1-specific T-cells in patients with malignant gliomas. METHODS: Twenty-two patients with newly diagnosed malignant glioma who received standard radiation/temozolomide therapy were recruited for the study. Blood samples were collected before treatment and on the sixth week of therapy. The frequencies and numbers of lymphocytes, CD8(+) T-cells, WT1-specific T-cells, regulatory T-cells, natural killer cells and natural killer T-cells were measured and analysed using T-tests. RESULTS: Analysis of the frequency of T lymphocytes and its subpopulation showed an increase in regulatory T-cells, but no significant change was noted in the populations of T-cells, WT1-specific T-cells, NK cells and NKT cells. Reductions in the total numbers of T-cells, WT1-specific T-cells, NK cells and NKT cells were mainly a consequence of the decrease in the total lymphocyte count. CONCLUSIONS: Radiation/temozolomide therapy did not significantly affect the frequency of WT1-specific T-cells, suggesting that the combination with WT1 immunotherapy may be possible, although further assessment in the clinical setting is warranted.


Assuntos
Neoplasias Encefálicas/terapia , Vacinas Anticâncer/administração & dosagem , Glioma/terapia , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/efeitos da radiação , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/efeitos da radiação , Proteínas WT1/imunologia , Adulto , Idoso , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Neoplasias Encefálicas/imunologia , Terapia Combinada , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Dacarbazina/análogos & derivados , Feminino , Glioma/imunologia , Humanos , Japão , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/efeitos da radiação , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Células T Matadoras Naturais/efeitos dos fármacos , Células T Matadoras Naturais/efeitos da radiação , Radioterapia Conformacional/efeitos adversos , Subpopulações de Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/efeitos da radiação , Temozolomida
12.
Cancer Sci ; 101(4): 848-54, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20136847

RESUMO

In tumor-bearing patients, tumor-associated antigen (TAA)-specific CTLs are spontaneously induced as a result of immune response to TAAs and play an important role in anti-tumor immunity. Wilms' tumor gene 1 (WT1) is overexpressed in various types of tumor and WT1 protein is a promising pan-TAA because of its high immunogenicity. In this study, to clarify the immune response to the WT1 antigen, WT1-specific CD8(+) T cells that were spontaneously induced in patients with solid tumor were comparatively analyzed in both bone marrow (BM) and peripheral blood (PB). WT1-specific CD8(+) T cells more frequently existed in BM than in PB, whereas frequencies of naïve (CCR7(+) CD45RA(+)), central memory (CCR7(+) CD45RA-), effector-memory (CCR7- CD45RA(-)), and effector (CCR7- CD45RA(+)) subsets were not significantly different between BM and PB. However, analysis of these subsets for the expression of CD57 and CD28, which were associated with differentiation, revealed that effector-memory and effector subsets of the WT1-specific CD8(+) T cells in BM had less differentiated phenotypes and more proliferative potential than those in PB. Furthermore, CD107a/b functional assay for WT1 peptide-specific cytotoxic potential and carboxyfluorescein diacetate succinimidyl ester dilution assay for WT1 peptide-specific proliferation also showed that WT1-specific CD8(+) T cells in BM were less cytotoxic and more proliferative in response to WT1 peptide than those in PB. These results implied that BM played an important role as a secondary lymphoid organ in tumor-bearing patients. Preferential residence of WT1-specific CD8(+) T cells in BM could be, at least in part, explained by higher expression of chemokine receptor CCR5, whose ligand was expressed on BM fibroblasts on the WT1-specific CD8(+) T cells in BM, compared to those in PB. These results should provide us with an insight into WT1-specific immune response in tumor-bearing patients and give us an idea of enhancement of clinical response in WT1 protein-targeted immunotherapy.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Neoplasias/imunologia , Proteínas WT1/fisiologia , Adolescente , Idoso , Medula Óssea/química , Medula Óssea/imunologia , Medula Óssea/metabolismo , Linfócitos T CD8-Positivos/patologia , Diferenciação Celular/imunologia , Proliferação de Células , Feminino , Humanos , Memória Imunológica , Antígenos Comuns de Leucócito/análise , Antígenos Comuns de Leucócito/imunologia , Contagem de Linfócitos , Subpopulações de Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade
13.
Cancer Sci ; 101(3): 594-600, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20132220

RESUMO

WT1 (Wilms' tumor gene 1) protein is a potent pan-tumor-associated antigen (TAA) and WT1-specific cytotoxic T lymphocytes (WT1 tetramer(+) CD8(+) T cells) are spontaneously induced in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). We conducted a single-cell level comparative analysis of T-cell receptor beta-chain variable region (TCR-BV) gene families of a total of 1242 spontaneously induced WT1 tetramer(+) CD8(+) T cells in HLA-A*2402(+) patients with AML or MDS and those in healthy donors (HDs). This is the first report of direct usage analysis of TCR-BV gene families of individual TAA-specific CD8(+) T cells at single-cell level. Usage analysis using single-cell RT-PCR of TCR-BV gene families of individual FACS-sorted WT1 tetramer(+) CD8(+) T cells showed for the first time (i) that BVs 5, 6, 20, and 27 were commonly biased in both HDs and patients; (ii) that BV4 was commonly biased in HDs and MDS patients; (iii) that BV19 was commonly biased in the patients; and (iv) that BVs 7 and 28, BVs 9 and 15, and BVs 12 and 29 were specifically biased in HDs, AML, and MDS patients, respectively. However, statistical analysis of similarity among HD, AML, and MDS of individual usage frequencies of 24 kinds of TCR-BV gene families indicated that the usage frequencies of TCR-BV gene families in AML and MDS patients reflect those in HDs. These findings represent a novel insight for a better understanding of WT1-specific immune response.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Genes Codificadores da Cadeia beta de Receptores de Linfócitos T , Leucemia Mieloide Aguda/imunologia , Síndromes Mielodisplásicas/imunologia , Proteínas WT1/imunologia , Adulto , Idoso , Feminino , Humanos , Antígenos Comuns de Leucócito/análise , Masculino , Pessoa de Meia-Idade , Receptores CCR7/análise
14.
Pediatr Hematol Oncol ; 26(1): 74-83, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19206012

RESUMO

Immunotherapy using a Wilms tumor (WT1) peptide has been undergoing clinical trials for adulthood leukemia and solid cancer with promising results. In this study, the authors used WT1 peptide vaccination to treat a 6-year-old girl with metastatic alveolar rhabdomyosarcoma. She received weekly intradermal injection with HLA-A*2404-restricted, 9-mer WT1 peptide against residual bone disease. After 3 months her bone disease disappeared, concurrent with an increase in the frequency of WT1-specific cytotoxic T lymphocytes (CTLs). A high proportion of WT1-specific CTLs with effector or effector memory phenotype were detected in peripheral blood of this patient. She is currently still on continued WT1 peptide immunotherapy in a disease-free condition for 22 months. WT1 peptide-based immunotherapy should be a promising option for high-risk rhabdomyosarcoma in childhood.


Assuntos
Imunoterapia/métodos , Fragmentos de Peptídeos/uso terapêutico , Rabdomiossarcoma Alveolar/tratamento farmacológico , Proteínas WT1/uso terapêutico , Doenças Ósseas/tratamento farmacológico , Criança , Intervalo Livre de Doença , Feminino , Humanos , Rabdomiossarcoma Alveolar/patologia , Linfócitos T Citotóxicos/imunologia , Vacinação
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