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1.
Med Image Anal ; 56: 122-139, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31226662

RESUMO

Breast cancer is the most common invasive cancer in women, affecting more than 10% of women worldwide. Microscopic analysis of a biopsy remains one of the most important methods to diagnose the type of breast cancer. This requires specialized analysis by pathologists, in a task that i) is highly time- and cost-consuming and ii) often leads to nonconsensual results. The relevance and potential of automatic classification algorithms using hematoxylin-eosin stained histopathological images has already been demonstrated, but the reported results are still sub-optimal for clinical use. With the goal of advancing the state-of-the-art in automatic classification, the Grand Challenge on BreAst Cancer Histology images (BACH) was organized in conjunction with the 15th International Conference on Image Analysis and Recognition (ICIAR 2018). BACH aimed at the classification and localization of clinically relevant histopathological classes in microscopy and whole-slide images from a large annotated dataset, specifically compiled and made publicly available for the challenge. Following a positive response from the scientific community, a total of 64 submissions, out of 677 registrations, effectively entered the competition. The submitted algorithms improved the state-of-the-art in automatic classification of breast cancer with microscopy images to an accuracy of 87%. Convolutional neuronal networks were the most successful methodology in the BACH challenge. Detailed analysis of the collective results allowed the identification of remaining challenges in the field and recommendations for future developments. The BACH dataset remains publicly available as to promote further improvements to the field of automatic classification in digital pathology.

2.
Anticancer Res ; 39(5): 2351-2360, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31092427

RESUMO

BACKGROUND/AIM: Hepatic hemangiomas (HH) can show an aggressive course with significant complications. Prognostic markers that identify an aggressive course are entirely absent. Since we have showed that Hedgehog signaling is overexpressed in aggressive hemangiomas of the skin. Here, we hypothesize that it is also altered in aggressive HH. MATERIALS AND METHODS: Immunohistological staining for GLUT1 and quantitative PCR was performed in seven specimens with aggressive HH. For comparison, we included specimens of kaposiform hemangioendothelioma (KHE), skin hemangioma and normal liver tissue. RESULTS: Overexpression of the Hedgehog signaling components SHH and GLI2 and its target gene FOXA2 in HH were similar to those found in aggressive skin hemangioma and KHE, their expression being significantly higher than in mild skin hemangioma. High expression levels of SHH and FOXA2 positively correlated with HH, but not with normal liver tissue. CONCLUSION: Hedgehog signaling is up-regulated in aggressive HH. This finding may lead to a biomarker allowing early intervention.


Assuntos
Proteínas Hedgehog/genética , Hemangioma/genética , Fator 3-beta Nuclear de Hepatócito/genética , Neoplasias Hepáticas/genética , Proteínas Nucleares/genética , Proteína Gli2 com Dedos de Zinco/genética , Biomarcadores Tumorais/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Transportador de Glucose Tipo 1/genética , Hemangioendotelioma/genética , Hemangioendotelioma/patologia , Hemangioma/patologia , Humanos , Lactente , Recém-Nascido , Síndrome de Kasabach-Merritt/genética , Síndrome de Kasabach-Merritt/patologia , Fígado/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Sarcoma de Kaposi/genética , Sarcoma de Kaposi/patologia , Transdução de Sinais/genética
3.
Proc Natl Acad Sci U S A ; 116(3): 970-975, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30591564

RESUMO

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a critical regulator of cell death and inflammation, but its relevance for human disease pathogenesis remains elusive. Studies of monogenic disorders might provide critical insights into disease mechanisms and therapeutic targeting of RIPK1 for common diseases. Here, we report on eight patients from six unrelated pedigrees with biallelic loss-of-function mutations in RIPK1 presenting with primary immunodeficiency and/or intestinal inflammation. Mutations in RIPK1 were associated with reduced NF-κB activity, defective differentiation of T and B cells, increased inflammasome activity, and impaired response to TNFR1-mediated cell death in intestinal epithelial cells. The characterization of RIPK1-deficient patients highlights the essential role of RIPK1 in controlling human immune and intestinal homeostasis, and might have critical implications for therapies targeting RIPK1.


Assuntos
Diferenciação Celular , Imunidade nas Mucosas/genética , Doenças Inflamatórias Intestinais , Mucosa Intestinal , Proteína Serina-Treonina Quinases de Interação com Receptores , Imunodeficiência Combinada Severa , Linfócitos B/imunologia , Linfócitos B/patologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Células Epiteliais/imunologia , Células Epiteliais/patologia , Feminino , Células HCT116 , Células HEK293 , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Masculino , Mutação , NF-kappa B/genética , NF-kappa B/imunologia , Proteína Serina-Treonina Quinases de Interação com Receptores/deficiência , Proteína Serina-Treonina Quinases de Interação com Receptores/imunologia , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/patologia , Linfócitos T/imunologia , Linfócitos T/patologia
4.
Gastroenterology ; 2018 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-30267714

RESUMO

Caspase-8 (CASP8) is a protease that initiates apoptosis and regulates inflammation and immune responses. We identified germline mutations in CASP8 in 3 unrelated patients with infant-onset inflammatory bowel disease: 2 patients were homozygous for the mutation 710A>G, p.Q237R, which resulted in reduced protein expression, and 1 patient carried the mutation 793C>T, p.R265W. We isolated peripheral blood mononuclear cells from our index patient and observed defects in T- and B-cell maturation, proliferation, and/or activation. Macrophages from 1 patient with CASP8 deficiency and monocytic BLaER1 cells with knockout of CASP8 or overexpression of CASP8 with the 710A>G mutation had altered inflammasome activity on stimulation with lipopolysaccharide. Patient-derived intestinal organoids and colon carcinoma cells with knockout of CASP8 had defects in cell death processes that involved loss of TRAIL signaling and increased necroptosis. These findings indicate that CASP8 controls inflammation, innate and adaptive immunity, and intestinal barrier integrity in humans.

5.
EMBO Mol Med ; 10(9)2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30097507

RESUMO

Patients with head-and-neck cancer can develop both lung metastasis and primary lung cancer during the course of their disease. Despite the clinical importance of discrimination, reliable diagnostic biomarkers are still lacking. Here, we have characterised a cohort of squamous cell lung (SQCLC) and head-and-neck (HNSCC) carcinomas by quantitative proteomics. In a training cohort, we quantified 4,957 proteins in 44 SQCLC and 30 HNSCC tumours. A total of 518 proteins were found to be differentially expressed between SQCLC and HNSCC, and some of these were identified as genetic dependencies in either of the two tumour types. Using supervised machine learning, we inferred a proteomic signature for the classification of squamous cell carcinomas as either SQCLC or HNSCC, with diagnostic accuracies of 90.5% and 86.8% in cross- and independent validations, respectively. Furthermore, application of this signature to a cohort of pulmonary squamous cell carcinomas of unknown origin leads to a significant prognostic separation. This study not only provides a diagnostic proteomic signature for classification of secondary lung tumours in HNSCC patients, but also represents a proteomic resource for HNSCC and SQCLC.

6.
Front Immunol ; 9: 368, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29535735

RESUMO

Epstein-Barr virus positive (EBV+) smooth muscle tumors (SMTs) constitute a very rare oncological entity. They usually develop in the context of secondary immunodeficiency caused by human immunodeficiency virus infection or immunosuppressive treatment after solid organ transplantation. However, in a small fraction of predominantly pediatric patients, EBV+ SMTs may occur in patients with primary immunodeficiency disorders (PIDs), such as GATA2 and CARMIL2 deficiency. In secondary immunodeficiencies and when the underlying condition can not be cured, the treatment of EBV+ SMTs is based on surgery in combination with antiretroviral and reduced or altered immunosuppressive pharmacotherapy, respectively. Importantly, without definitive reconstitution of cellular immunity, long-term survival is poor. This is particularly relevant for patients with EBV+ SMTs on the basis of PIDs. Recently, allogeneic hematopoietic stem cell transplantation resulted in cure of immunodeficiency and EBV+ SMTs in a GATA2-deficient patient. We propose that in the absence of secondary immunodeficiency disorders patients presenting with EBV+ SMTs should be thoroughly evaluated for PIDs. Allogeneic hematopoietic stem cell transplantation should be taken into consideration, ideally in the setting of a prospective clinical trial.

7.
Nat Genet ; 50(3): 344-348, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29483653

RESUMO

Transforming growth factor (TGF)-ß1 (encoded by TGFB1) is the prototypic member of the TGF-ß family of 33 proteins that orchestrate embryogenesis, development and tissue homeostasis1,2. Following its discovery 3 , enormous interest and numerous controversies have emerged about the role of TGF-ß in coordinating the balance of pro- and anti-oncogenic properties4,5, pro- and anti-inflammatory effects 6 , or pro- and anti-fibrinogenic characteristics 7 . Here we describe three individuals from two pedigrees with biallelic loss-of-function mutations in the TGFB1 gene who presented with severe infantile inflammatory bowel disease (IBD) and central nervous system (CNS) disease associated with epilepsy, brain atrophy and posterior leukoencephalopathy. The proteins encoded by the mutated TGFB1 alleles were characterized by impaired secretion, function or stability of the TGF-ß1-LAP complex, which is suggestive of perturbed bioavailability of TGF-ß1. Our study shows that TGF-ß1 has a critical and nonredundant role in the development and homeostasis of intestinal immunity and the CNS in humans.

8.
J Crohns Colitis ; 10(1): 112-5, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26464403

RESUMO

BACKGROUND AND AIMS: X-linked chronic granulomatous disease [X-CGD] due to hemizygous mutations in CYBB is characterised by invasive bacterial and fungal infections and granulomatous inflammation. Inflammatory bowel disease [IBD] is an additional or isolated manifestation. Allogeneic haematopoietic stem cell transplantation [alloHSCT] is the standard curative treatment. X-CGD carriers are usually healthy but those with non-random X-chromosome inactivation [XCI] may develop infectious or autoinflammatory manifestations. METHODS AND RESULTS: We report on two female patients with severe treatment-refractory Crohn-like IBD manifesting at age 23 and 8 years, respectively. NADPH-oxidase activity testing and molecular genetics proved X-CGD carrier status with non-random XCI. As in CGD, histopathology from colonic biopsies disclosed pigment-laden macrophages and reduced CD68(+) macrophages. Following submyelo-ablative conditioning, the younger patient was treated with alloHSCT at age 20 years. She came into remission within 3 months after transplantation and shows complete mucosal healing after 16 months off all medications. CONCLUSIONS: We suggest that children and young adults with refractory IBD should mandatorily be tested for CGD. AlloHSCT should be considered as curative therapy in severely diseased female carriers of X-CGD with non-random XCI.


Assuntos
Doença de Crohn/genética , Doença de Crohn/terapia , Predisposição Genética para Doença , Doença Granulomatosa Crônica/genética , Glicoproteínas de Membrana/genética , NADPH Oxidases/genética , Adulto , Aloenxertos , Biópsia por Agulha , Doença de Crohn/patologia , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas/métodos , Heterozigoto , Humanos , Imuno-Histoquímica , Mutação de Sentido Incorreto , NADPH Oxidase 2 , Medição de Risco , Amostragem , Índice de Gravidade de Doença , Resultado do Tratamento , Inativação do Cromossomo X/genética , Adulto Jovem
9.
Transplantation ; 98(8): 835-43, 2014 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-25321165

RESUMO

BACKGROUND: Graft survival is the most important factor for morbidity and mortality in cardiac transplantation. Improved immunosuppression significantly reduced early graft rejection. However, acute rejection may predispose to chronic rejection. Targeting both phases of the recipient's immune-reactivity by means of long-acting recombinant adeno-associated viral vectors (AAVs) encoding anti-inflammatory and cardioprotective factors appears to be a promising therapeutic approach. We investigate thymosin ß4 (Tß4) possessing anti-inflammatory and prosurvival abilities, as a means for pretransplant gene therapy. METHODS: Heterotopic, abdominal transplantation of cardiac allografts into landrace or into Munich mini pigs (n=5 per group) was performed. Transplants were transduced with AAV2.9 before transplantation by means of in situ perfusion of the donor organ. Vascuar endothelial growth factor and AAV2.9.Tß4 or AAV2.9.LacZ were added to the autologous blood used for perfusing the grafts for a period of 45 min. Immunosuppression was applied for 10 days after the operation. Transgene expression, capillary density, graft function, survival, and rejection were assessed. RESULTS: The AAV2.9 transduction induced robust overexpression of the transgene. In addition, Tß4 ameliorated inflammation, necrosis, vascular reaction (acute rejection) and in parallel improved capillary density. In addition, graft survival was significantly prolonged (10±3 days AAV2.9.LacZ vs. 31±4 days AAV2.9.Tß4). In the mini pig model, regional myocardial function of the grafts was improved by Tß4 transduction compared to LacZ (9.1%±0.9% subendocardial segment shortening in AAV2.9.LacZ vs. 15.8%±2.3% in AAV2.9.Tß4). CONCLUSION: In situ AAV2.9-mediated gene transfer of thymosin ß4 attenuated graft rejection in a heterotopic heart transplantation model. Perioperative cardioprotection by means of gene therapy might improve graft survival in cardiac allotransplantation.


Assuntos
Dependovirus/genética , Vetores Genéticos/genética , Rejeição de Enxerto/prevenção & controle , Transplante de Coração/efeitos adversos , Timosina/genética , Animais , Suínos , Transdução Genética
10.
FASEB J ; 28(8): 3540-51, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24760752

RESUMO

Advanced systemic mastocytosis (SM) is an aggressive hematopoietic neoplasm with poor prognosis and short survival times. So far, no curative therapy is available for affected patients. We have identified the cell surface antigen CD52 (CAMPATH-1) as a molecular target expressed abundantly on the surface of primary neoplastic mast cells (MCs) in patients with advanced SM. In contrast, neoplastic MCs of patients with indolent SM and normal MCs expressed only low levels or did not express CD52. To study the mechanisms of CD52 expression and the value of this antigen as a potential therapeutic target, we generated a human MC cell line, designated MCPV-1, by lentiviral immortalization of cord blood-derived MC progenitor cells. Functional studies revealed that activated RAS profoundly promotes surface expression of CD52. The CD52-targeting antibody alemtuzumab induced cell death in CD52(+) primary neoplastic MCs obtained from patients with SM as well as in MCPV-1 cells. NSG mice xenotransplanted with MCPV-1 cells survived significantly longer after treatment with alemtuzumab (median survival: 31 d untreated vs. 46 d treated; P=0.0012). We conclude that CD52 is a novel marker and potential therapeutic target in neoplastic MCs in patients with advanced SM.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antígenos CD/análise , Antígenos de Neoplasias/análise , Antineoplásicos/uso terapêutico , Glicoproteínas/análise , Mastocitose Sistêmica/metabolismo , Terapia de Alvo Molecular , Adulto , Idoso , Alemtuzumab , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Antígenos CD/imunologia , Antígenos de Neoplasias/imunologia , Antineoplásicos/farmacologia , Antígeno CD52 , Linhagem Celular Tumoral , Células Cultivadas , Feminino , Sangue Fetal/citologia , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/fisiologia , Genes ras , Glicoproteínas/imunologia , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Mastócitos/metabolismo , Mastocitose Sistêmica/tratamento farmacológico , Proteínas de Membrana/genética , Proteínas de Membrana/fisiologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/fisiologia , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas p21(ras) , Transdução Genética , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas ras/genética , Proteínas ras/fisiologia
11.
Gastroenterology ; 146(4): 1028-39, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24417819

RESUMO

BACKGROUND & AIMS: Very early onset inflammatory bowel diseases (VEOIBD), including infant disorders, are a diverse group of diseases found in children younger than 6 years of age. They have been associated with several gene variants. Our aim was to identify the genes that cause VEOIBD. METHODS: We performed whole exome sequencing of DNA from 1 infant with severe enterocolitis and her parents. Candidate gene mutations were validated in 40 pediatric patients and functional studies were carried out using intestinal samples and human intestinal cell lines. RESULTS: We identified compound heterozygote mutations in the Tetratricopeptide repeat domain 7 (TTC7A) gene in an infant from non-consanguineous parents with severe exfoliative apoptotic enterocolitis; we also detected TTC7A mutations in 2 unrelated families, each with 2 affected siblings. TTC7A interacts with EFR3 homolog B to regulate phosphatidylinositol 4-kinase at the plasma membrane. Functional studies demonstrated that TTC7A is expressed in human enterocytes. The mutations we identified in TTC7A result in either mislocalization or reduced expression of TTC7A. Phosphatidylinositol 4-kinase was found to co-immunoprecipitate with TTC7A; the identified TTC7A mutations reduced this binding. Knockdown of TTC7A in human intestinal-like cell lines reduced their adhesion, increased apoptosis, and decreased production of phosphatidylinositol 4-phosphate. CONCLUSIONS: In a genetic analysis, we identified loss of function mutations in TTC7A in 5 infants with VEOIBD. Functional studies demonstrated that the mutations cause defects in enterocytes and T cells that lead to severe apoptotic enterocolitis. Defects in the phosphatidylinositol 4-kinase-TTC7A-EFR3 homolog B pathway are involved in the pathogenesis of VEOIBD.


Assuntos
Doenças Inflamatórias Intestinais/genética , Mutação , Proteínas/genética , 1-Fosfatidilinositol 4-Quinase/metabolismo , Idade de Início , Apoptose , Adesão Celular , Linhagem Celular , Pré-Escolar , Análise Mutacional de DNA , Enterocolite/genética , Enterócitos/metabolismo , Enterócitos/patologia , Exoma , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Heterozigoto , Humanos , Lactente , Recém-Nascido , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Doenças Inflamatórias Intestinais/terapia , Atresia Intestinal/genética , Linfócitos/metabolismo , Linfócitos/patologia , Masculino , Linhagem , Fenótipo , Prognóstico , Ligação Proteica , Proteínas/metabolismo , Interferência de RNA , Índice de Gravidade de Doença , Transdução de Sinais , Transfecção
12.
Mod Pathol ; 27(1): 19-29, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23807778

RESUMO

Adult-onset urticaria pigmentosa/mastocytosis in the skin almost always persists throughout life. The prevalence of systemic mastocytosis in such patients is not precisely known. Bone marrow biopsies from 59 patients with mastocytosis in the skin and all available skin biopsies (n=27) were subjected to a meticulous cytological, histological, immunohistochemical, and molecular analysis for the presence of WHO-defined diagnostic criteria for systemic mastocytosis: compact mast cell infiltrates (major criterion); atypical mast cell morphology, KIT D816V, abnormal expression of CD25 by mast cells, and serum tryptase levels >20 ng/ml (minor criteria). Systemic mastocytosis is diagnosed when the major diagnostic criterion plus one minor criterion or at least three minor criteria are fulfilled. Systemic mastocytosis was confirmed in 57 patients (97%) by the diagnosis of compact mast cell infiltrates plus at least one minor diagnostic criterion (n=42, 71%) or at least three minor diagnostic criteria (n=15, 25%). In two patients, only two minor diagnostic criteria were detectable, insufficient for the diagnosis of systemic mastocytosis. By the use of highly sensitive molecular methods, including the analysis of microdissected mast cells, KIT D816V was found in all 58 bone marrow biopsies investigated for it but only in 74% (20/27) of the skin biopsies. It is important to state that even in cases with insufficient diagnostic criteria for systemic mastocytosis, KIT D816V-positive mast cells were detected in the bone marrow. This study demonstrates, for the first time, that almost all patients with adult-onset mastocytosis in the skin, in fact, have systemic mastocytosis with cutaneous involvement.


Assuntos
Mastócitos , Mastocitoma Cutâneo/diagnóstico , Mastocitose Sistêmica/diagnóstico , Pele , Adolescente , Adulto , Idade de Início , Biomarcadores/análise , Biomarcadores/sangue , Biópsia , Exame de Medula Óssea , Análise Mutacional de DNA , Feminino , Humanos , Imuno-Histoquímica , Subunidade alfa de Receptor de Interleucina-2/análise , Masculino , Mastócitos/química , Mastócitos/patologia , Mastocitoma Cutâneo/sangue , Mastocitoma Cutâneo/química , Mastocitoma Cutâneo/genética , Mastocitoma Cutâneo/patologia , Mastocitose Sistêmica/sangue , Mastocitose Sistêmica/genética , Mastocitose Sistêmica/metabolismo , Mastocitose Sistêmica/patologia , Microdissecção , Pessoa de Meia-Idade , Mutação , Valor Preditivo dos Testes , Proteínas Proto-Oncogênicas c-kit/genética , Pele/química , Pele/patologia , Triptases/sangue , Adulto Jovem
13.
Blood ; 122(14): 2460-6, 2013 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-23958953

RESUMO

To explore mechanisms contributing to the clinical heterogeneity of systemic mastocytosis (SM) and to suboptimal responses to diverse therapies, we analyzed 39 KIT D816V mutated patients with indolent SM (n = 10), smoldering SM (n = 2), SM with associated clonal hematologic nonmast cell lineage disorder (SM-AHNMD, n = 5), and aggressive SM (n = 15) or mast cell leukemia (n = 7) with (n = 18) or without (n = 4) AHNMD for additional molecular aberrations. We applied next-generation sequencing to investigate ASXL1, CBL, IDH1/2, JAK2, KRAS, MLL-PTD, NPM1, NRAS, TP53, SRSF2, SF3B1, SETBP1, U2AF1 at mutational hotspot regions, and analyzed complete coding regions of EZH2, ETV6, RUNX1, and TET2. We identified additional molecular aberrations in 24/27 (89%) patients with advanced SM (SM-AHNMD, 5/5; aggressive SM/mast cell leukemia, 19/22) whereas only 3/12 (25%) indolent SM/smoldering SM patients carried one additional mutation each (U2AF1, SETBP1, CBL) (P < .001). Most frequently affected genes were TET2, SRSF2, ASXL1, CBL, and RUNX1. In advanced SM, 21/27 patients (78%) carried ≥3 mutations, and 11/27 patients (41%) exhibited ≥5 mutations. Overall survival was significantly shorter in patients with additional aberrations as compared to those with KIT D816V only (P = .019). We conclude that biology and prognosis in SM are related to the pattern of mutated genes that are acquired during disease evolution.


Assuntos
Análise Mutacional de DNA , Mastocitose Sistêmica/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-kit/genética
14.
Blood ; 122(13): 2167-75, 2013 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-23926299

RESUMO

The transcription factor signal transducers and activators of transcription 5 (STAT5) has an important and unique role in Breakpoint Cluster Region - Abelson 1 (BCR-ABL1)-driven neoplasias. STAT5 is an essential component in the signaling network that maintains the survival and growth of chronic myeloid leukemia (CML) cells. In contrast, the function of the prototypical upstream kinase of STAT5, the Janus kinase JAK2, in CML is still under debate. Although there is widespread agreement that JAK2 is part of the signaling network downstream of BCR-ABL1, it is unclear whether and under what circumstances JAK2 inhibitors may be beneficial for CML patients. Recent studies in murine models have cast doubt on the importance of JAK2 in CML maintenance. Nevertheless, JAK2 has been proposed to have a central role in the cytokine signaling machinery that allows the survival of CML stem cells in the presence of BCR-ABL1 tyrosine kinase inhibitors. In this review, we summarize the current debate and provide an overview of the arguments on both sides of the fence. We present recent evidence showing that CML stem cells do not depend on BCR-ABL1 kinase activity but require the continuous support of the hematopoietic niche and its distinct cytokine environment and suggest that it has the potential to resolve the dispute.


Assuntos
Janus Quinase 2/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Células-Tronco Neoplásicas/metabolismo , Fator de Transcrição STAT5/metabolismo , Animais , Humanos
15.
Eur J Nucl Med Mol Imaging ; 40(11): 1701-10, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23857458

RESUMO

PURPOSE: Scintigraphy using (123)I-metaiodobenzylguanidine ((123)I-MIBG) is widely used for the detection of neuroblastic tumours. The aim of this study was to identify a possible correlation between the uptake intensity on (123)I-MIBG SPECT and histopathology of neuroblastic tumours. METHODS: (123)I-MIBG SPECT examinations were performed in 55 paediatric patients with neuroblastic tumour and compared to histopathology after surgical resection or biopsy at a mean of 2 weeks after SPECT. For each lesion International Neuroblastoma Pathology Classification System (INPC) stage, mitosis karyorrhexis index (MKI), location and a semiquantitative tumour-to-liver count-rate ratio (TLCRR) were determined. Also, the presence or absence of MYCN amplification, p1 deletion, urine catecholamine and neuron-specific enolase blood levels at the time of scanning were recorded. RESULTS: In the 55 patients, 61 lesions were evaluated with (123)I-MIBG SPECT and corresponding histopathological findings were reviewed (11 ganglioneuroma, 11 ganglioneuroblastoma and 39 neuroblastoma). TLCRR was significantly higher in the neuroblastoma group (mean TLCRR 2.7) than in the ganglioneuroblastoma group (mean TLCRR 1.0) and ganglioneuroma group (mean TLCRR 0.7) at the time of primary diagnosis (p < 0.001) and at follow-up (p = 0.039). Intense (123)I-MIBG uptake was found in tumour tissue with a high mitotic activity (MKI-high or MKI-intermediate) after treatment. Four ganglioneuromas (36 %), three ganglioneuroblastomas (27 %) and six neuroblastomas (15 %) were (123)I-MIBG-negative. CONCLUSION: In paediatric patients with peripheral neuroblastic tumours, strong (123)I-MIBG uptake indicates unfavourable histopathology. High uptake was seen in neuroblastomas and in tumours with a high mitotic activity.


Assuntos
3-Iodobenzilguanidina , Neoplasias Abdominais/diagnóstico por imagem , Neuroblastoma/diagnóstico por imagem , Compostos Radiofarmacêuticos , 3-Iodobenzilguanidina/farmacocinética , Neoplasias Abdominais/patologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Neuroblastoma/patologia , Compostos Radiofarmacêuticos/farmacocinética , Tomografia Computadorizada de Emissão de Fóton Único , Adulto Jovem
16.
Ann Hematol ; 91(9): 1477-84, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22592650

RESUMO

The clarification of enlarged lymph nodes is a common issue in clinical routine. By now, open surgery with complete lymph node extirpation, followed by histopathology, is considered as standard. We investigated the value of fine needle aspiration (FNA) and core needle biopsy (CNB) when supporting the conventional morphology by immunotyping. In total, 101 lymph nodes (reactive, n = 19; lymphoma, n = 46; metastatic, n = 36) were examined. CNB specimens were sufficient for unequivocal diagnosis by histopathology in 95 %. The FNA cytology allowed a correct diagnosis in 49 %. When supported by immunocytology, the success rate improved to 72 %. By accepting "suspicious of" as correct diagnosis, the ratio increased to 91 %. Additional use of flow cytometry in 46 samples minimized the "suspicious of" diagnoses and increased the proportion of unequivocal diagnoses in FNA specimens to 87 %. Flow cytometry allowed a correct subtyping in 20 of 21 B cell lymphoma but recognised only one of five Hodgkin lymphoma. All eight reactive samples were correctly diagnosed by flow cytometry. In summary, CNB allows a reliable clarification of an unclear lymphadenopathy. FNA is a powerful first diagnostic approach, especially if cytology is supported by immunocytology. The most substantial contribution of flow cytometry in FNA is the discrimination between reactive lymphadenopathy and B cell lymphoma.


Assuntos
Biópsia por Agulha Fina , Biópsia por Agulha , Carcinoma/secundário , Doença de Hodgkin/diagnóstico , Doenças Linfáticas/diagnóstico , Metástase Linfática/diagnóstico , Linfoma de Células B/diagnóstico , Carcinoma/diagnóstico , Carcinoma/patologia , Diagnóstico Diferencial , Citometria de Fluxo , Doença de Hodgkin/patologia , Humanos , Imunofenotipagem , Doenças Linfáticas/patologia , Metástase Linfática/patologia , Linfoma de Células B/patologia , Pseudolinfoma/diagnóstico , Pseudolinfoma/patologia , Estudos Retrospectivos
18.
Blood ; 119(15): 3550-60, 2012 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-22234689

RESUMO

STAT5 proteins are constitutively activated in malignant cells from many patients with leukemia, including the myeloproliferative neoplasms (MPNs) chronic myeloid leukemia (CML) and polycythemia vera (PV), but whether STAT5 is essential for the pathogenesis of these diseases is not known. In the present study, we used mice with a conditional null mutation in the Stat5a/b gene locus to determine the requirement for STAT5 in MPNs induced by BCR-ABL1 and JAK2(V617F) in retroviral transplantation models of CML and PV. Loss of one Stat5a/b allele resulted in a decrease in BCR-ABL1-induced CML-like MPN and the appearance of B-cell acute lymphoblastic leukemia, whereas complete deletion of Stat5a/b prevented the development of leukemia in primary recipients. However, BCR-ABL1 was expressed and active in Stat5-null leukemic stem cells, and Stat5 deletion did not prevent progression to lymphoid blast crisis or abolish established B-cell acute lymphoblastic leukemia. JAK2(V617F) failed to induce polycythemia in recipients after deletion of Stat5a/b, although the loss of STAT5 did not prevent the development of myelofibrosis. These results demonstrate that STAT5a/b is essential for the induction of CML-like leukemia by BCR-ABL1 and of polycythemia by JAK2(V617F), and validate STAT5a/b and the genes they regulate as targets for therapy in these MPNs.


Assuntos
Genes abl/fisiologia , Janus Quinase 2/fisiologia , Transtornos Mieloproliferativos/genética , Fator de Transcrição STAT5/fisiologia , Substituição de Aminoácidos , Animais , Neoplasias da Medula Óssea/genética , Neoplasias da Medula Óssea/metabolismo , Neoplasias da Medula Óssea/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Genes abl/genética , Células HEK293 , Humanos , Janus Quinase 2/genética , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Mutação de Sentido Incorreto/fisiologia , Transtornos Mieloproliferativos/metabolismo , Transtornos Mieloproliferativos/patologia , Células NIH 3T3 , Fenilalanina/genética , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Valina/genética
19.
Blood ; 118(8): 2239-42, 2011 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-21705501

RESUMO

Imatinib-resistant tyrosine kinase (TK) fusions involving FGFR1, JAK2, or FLT3 are rare but recurrent in patients with eosinophilia-associated neoplasms. We report here 2 male patients with ETV6-FLT3(+) myeloid/lymphoid neoplasms with eosinophilia who were treated with the multitargeted TK inhibitors sunitinib and sorafenib. Patient 1 achieved rapid complete hematologic response and complete cytogenetic response after 3 months of taking sunitinib. A secondary blast phase caused by clonal evolution was diagnosed after 6 months. He achieved a second complete hematologic response after taking sorafenib but relapsed 2 months later. An N841K point mutation within the TK domain of FLT3, previously reported in acute myeloid leukemia and potentially conferring resistance to sorafenib, was subsequently identified. Patient 2 was heavily pretreated according to the initial diagnosis of T-lymphoblastic lymphoma and died in sunitinib-induced pancytopenia. This report highlights the importance of a careful diagnostic workup for eosinophilia-associated neoplasms to evaluate the possibility of TK inhibitor therapy.


Assuntos
Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/genética , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/genética , Adulto , Sequência de Aminoácidos , Antineoplásicos/uso terapêutico , Sequência de Bases , Benzenossulfonatos/uso terapêutico , DNA de Neoplasias/genética , Resistencia a Medicamentos Antineoplásicos/genética , Eosinofilia/complicações , Eosinofilia/tratamento farmacológico , Eosinofilia/genética , Neoplasias Hematológicas/complicações , Humanos , Indóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Niacinamida/análogos & derivados , Fusão Oncogênica , Compostos de Fenilureia , Mutação Puntual , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Pirróis/uso terapêutico , Sorafenibe , Sunitinibe
20.
Blood ; 117(10): 2935-43, 2011 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-21224473

RESUMO

The FIP1L1-PDGFRA fusion is seen in a fraction of cases with a presumptive diagnosis of hypereosinophilic syndrome (HES). However, because most HES patients lack FIP1L1-PDGFRA, we studied whether they harbor activating mutations of the PDGFRA gene. Sequencing of 87 FIP1L1-PDGFRA-negative HES patients revealed several novel PDGFRA point mutations (R481G, L507P, I562M, H570R, H650Q, N659S, L705P, R748G, and Y849S). When cloned into 32D cells, N659S and Y849S and-on selection for high expressors-also H650Q and R748G mutants induced growth factor-independent proliferation, clonogenic growth, and constitutive phosphorylation of PDGFRA and Stat5. Imatinib antagonized Stat5 phosphorylation. Mutations involving positions 659 and 849 had been shown previously to possess transforming potential in gastrointestinal stromal tumors. Because H650Q and R748G mutants possessed only weak transforming activity, we injected 32D cells harboring these mutants or FIP1L1-PDGFRA into mice and found that they induced a leukemia-like disease. Oral imatinib treatment significantly decreased leukemic growth in vivo and prolonged survival. In conclusion, our data provide evidence that imatinib-sensitive PDGFRA point mutations play an important role in the pathogenesis of HES and we propose that more research should be performed to further define the frequency and treatment response of PDGFRA mutations in FIP1L1-PDGFRA-negative HES patients.


Assuntos
Antineoplásicos/farmacologia , Transformação Celular Neoplásica/genética , Síndrome Hipereosinofílica/genética , Leucemia/genética , Piperazinas/farmacologia , Mutação Puntual , Pirimidinas/farmacologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Animais , Benzamidas , Western Blotting , Separação Celular , Feminino , Citometria de Fluxo , Humanos , Mesilato de Imatinib , Leucemia/tratamento farmacológico , Masculino , Camundongos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ensaios Antitumorais Modelo de Xenoenxerto
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