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1.
Sci Rep ; 13(1): 1892, 2023 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-36732575

RESUMO

Peach allergy is among the most frequent food allergies in the Mediterranean area, often eliciting severe anaphylactic reactions in patients. Due to the risk of severe symptoms, studies in humans are limited, leading to a lack of therapeutic options. This study aimed to develop a peach allergy mouse model as a tool to better understand the pathomechanism and to allow preclinical investigations on the development of optimized strategies for immunotherapy. CBA/J mice were sensitized intraperitoneally with peach extract or PBS, using alum as adjuvant. Afterwards, extract was administered intragastrically to involve the intestinal tract. Allergen provocation was performed via intraperitoneal injection of extract, measuring drop of body temperature as main read out of anaphylaxis. The model induced allergy-related symptoms in mice, including decrease of body temperature. Antibody levels in serum and intestinal homogenates revealed a Th2 response with increased levels of mMCPT-1, peach- and Pru p 3-specific IgE, IgG1 and IgG2a as well as increased levels of IL-4 and IL-13. FACS analysis of small intestine lamina propria revealed increased amounts of T cells, neutrophils and DCs in peach allergic mice. These data suggest the successful establishment of a peach allergy mouse model, inducing systemic as well as local gastrointestinal reactions.


Assuntos
Anafilaxia , Hipersensibilidade Alimentar , Prunus persica , Humanos , Camundongos , Animais , Prunus persica/efeitos adversos , Antígenos de Plantas , Imunoglobulina E , Camundongos Endogâmicos CBA , Alérgenos , Imunoglobulina G , Imunidade , Extratos Vegetais/farmacologia , Proteínas de Plantas
2.
Mol Cancer ; 21(1): 172, 2022 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-36045346

RESUMO

BACKGROUND: Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin T cell lymphoma commonly driven by NPM-ALK. AP-1 transcription factors, cJUN and JUNb, act as downstream effectors of NPM-ALK and transcriptionally regulate PDGFRß. Blocking PDGFRß kinase activity with imatinib effectively reduces tumor burden and prolongs survival, although the downstream molecular mechanisms remain elusive. METHODS AND RESULTS: In a transgenic mouse model that mimics PDGFRß-driven human ALCL in vivo, we identify PDGFRß as a driver of aggressive tumor growth. Mechanistically, PDGFRß induces the pro-survival factor Bcl-xL and the growth-enhancing cytokine IL-10 via STAT5 activation. CRISPR/Cas9 deletion of both STAT5 gene products, STAT5A and STAT5B, results in the significant impairment of cell viability compared to deletion of STAT5A, STAT5B or STAT3 alone. Moreover, combined blockade of STAT3/5 activity with a selective SH2 domain inhibitor, AC-4-130, effectively obstructs tumor development in vivo. CONCLUSIONS: We therefore propose PDGFRß as a novel biomarker and introduce PDGFRß-STAT3/5 signaling as an important axis in aggressive ALCL. Furthermore, we suggest that inhibition of PDGFRß or STAT3/5 improve existing therapies for both previously untreated and relapsed/refractory ALK+ ALCL patients.


Assuntos
Linfoma Anaplásico de Células Grandes , Receptor beta de Fator de Crescimento Derivado de Plaquetas , Fator de Transcrição STAT3 , Fator de Transcrição STAT5 , Quinase do Linfoma Anaplásico , Animais , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Humanos , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/patologia , Camundongos , Fosforilação , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/farmacologia , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT5/genética , Transdução de Sinais
3.
Pathologe ; 42(Suppl 2): 122-128, 2021 Dec.
Artigo em Alemão | MEDLINE | ID: mdl-34671837

RESUMO

BACKGROUND: In situ follicular neoplasia (ISFN) is a t(14;18)(q32;q21)+ precursor lesion of follicular lymphoma (FL), which in turn can transform into diffuse large B­cell lymphoma (DLBCL). For DLBCL that arise de novo, no precursor lesion is known. Given the high frequency of the t(14;18) translocation in de novo DLBCL as well, we investigated whether they can also arise from ISFN without FL as an intermediate step. OBJECTIVES: To investigate the clonal evolution of ISFN to DLBCL - transformed from FL and de novo. MATERIALS AND METHODS: Identification of ISFN lesions in patients with DLBCL was performed by BCL2 staining of reactive lymphoid tissues. ISFN and DLBCL were subsequently analyzed by fluorescence in situ hybridization, clonality analyses, sequencing of the t(14;18) breakpoint, and targeted next-generation sequencing. RESULTS: 10 cases with paired ISFN and DLBCL samples were identified, 6 of which were de novo DLBCL and 4 transformed from FL. 3 DLBCL carried MYC-rearrangements in addition to the t(14;18) and were classified as high-grade B­cell lymphoma (HGBL). The clonal relationship of ISFN and DLBCL/HGBL was confirmed for all cases. CREBBP, KMT2D, EZH2, TNFRSF14, and BCL2 were the genes most frequently mutated, with the distribution of private and shared mutations pointing to 2 different scenarios of clonal evolution. In most cases, DLBCL/HGBL, ISFN, and, if also present, FL had evolved divergently from a common progenitor, whereas linear evolution was less frequent. CONCLUSION: We show for the first time that t(14;18)+ DLBCL/HGBL can arise directly from ISFN without FL as an intermediate step and that during this progression, divergent evolution is common.


Assuntos
Linfoma Folicular , Linfoma Difuso de Grandes Células B , Evolução Molecular , Humanos , Hibridização in Situ Fluorescente , Linfoma Folicular/genética , Linfoma Difuso de Grandes Células B/genética , Translocação Genética/genética
4.
Pathologe ; 39(Suppl 2): 247-249, 2018 Dec.
Artigo em Alemão | MEDLINE | ID: mdl-30377786

RESUMO

The identification and molecular characterisation of premalignant precursor lesions of lymphomas, such as monoclonal gammopathy of unknown significance (MGUS) and the so-called in situ lymphoproliferations, has made significant progress in the recent years. The in situ follicular neoplasia (ISFN), the best-characterised entity, is by definition not identifiable by morphology and represents a t(14;18)+ precursor lesion of follicular lymphoma with characteristic immunophenotype, low potential for progression, and already identifiable secondary genetic alterations. The use of high-throughput genetic techniques on microdissected tissues has generated novel insights into clonal evolution and biological progression of early lesions and documented that an isolated genetic analysis is insufficient to understand the complexity of proliferations.


Assuntos
Linfoma Folicular , Gamopatia Monoclonal de Significância Indeterminada , Mieloma Múltiplo , Lesões Pré-Cancerosas , Evolução Clonal , Progressão da Doença , Humanos
5.
Leukemia ; 31(12): 2853, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29130457

RESUMO

This corrects the article DOI: 10.1038/leu.2015.173.

6.
Leukemia ; 30(5): 1166-76, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26686248

RESUMO

The CALM/AF10 fusion gene is found in various hematological malignancies including acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia and malignant lymphoma. We have previously identified the leukemia stem cell (LSC) in a CALM/AF10-driven murine bone marrow transplant AML model as B220+ lymphoid cells with B-cell characteristics. To identify the target cell for leukemic transformation or 'cell of origin of leukemia' (COL) in non-disturbed steady-state hematopoiesis, we inserted the CALM/AF10 fusion gene preceded by a loxP-flanked transcriptional stop cassette into the Rosa26 locus. Vav-Cre-induced panhematopoietic expression of the CALM/AF10 fusion gene led to acute leukemia with a median latency of 12 months. Mice expressing CALM/AF10 in the B-lymphoid compartment using Mb1-Cre or CD19-Cre inducer lines did not develop leukemia. Leukemias had a predominantly myeloid phenotype but showed coexpression of the B-cell marker B220, and had clonal B-cell receptor rearrangements. Using whole-exome sequencing, we identified an average of two to three additional mutations per leukemia, including activating mutations in known oncogenes such as FLT3 and PTPN11. Our results show that the COL for CALM/AF10 leukemia is a stem or early progenitor cell and not a cell of B-cell lineage with a phenotype similar to that of the LSC in CALM/AF10+ leukemia.


Assuntos
Transformação Celular Neoplásica/patologia , Leucemia Experimental/patologia , Células-Tronco Neoplásicas/patologia , Proteínas de Fusão Oncogênica/genética , Animais , Linfócitos B/metabolismo , Exoma/genética , Engenharia Genética , Camundongos , Mutação , Análise de Sequência de DNA
8.
Leukemia ; 28(5): 1103-12, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24153014

RESUMO

Follicular lymphoma (FL) is characterized besides the t(14;18)(q32;q21), by recurrent chromosomal alterations and somatic mutations. In this study, we analyzed cases of FL in situ (FLIS) without manifest FL (mFL), partial involvement by FL (PFL) and paired cases of FLIS and mFL to detect possible early chromosomal imbalances, mutations, as well as DNA-methylation patterns of genomic regions of selected genes. We demonstrate that all paired FLIS and mFL cases were clonally related, based on IGH rearrangement patterns and BCL2 breakpoint sequences. FLIS and PFL had no or few secondary chromosomal imbalances detectable by array comparative genomic hybridization (FLIS 0.8 copy number alterations (CNA)/case; PFL 2.0 CNA/case; mFL 6.3 CNA/case) and a lower level of DNA methylation of genes recurrently de novo methylated in lymphomas, as compared with mFL. EZH2 Tyr641 mutations were detected in a subset of both FLIS (2/9) and PFL (1/3) cases. In conclusion, these findings provide evidence that FLIS represents a FL precursor lesion of long-lived clonal B cells carrying the t(14;18) with no or few secondary genetic changes. Our data suggest that there may be more than one distinct lesion driving the progression from FLIS to manifest lymphoma.


Assuntos
Cromossomos Humanos Par 14 , Cromossomos Humanos Par 18 , Epigênese Genética , Linfoma Folicular/genética , Translocação Genética , Adulto , Idoso , Hibridização Genômica Comparativa , Metilação de DNA , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade
9.
Pathologe ; 34(3): 244-53, 2013 May.
Artigo em Alemão | MEDLINE | ID: mdl-23459785

RESUMO

The increasing use of immunohistochemical and molecular investigations of lymphatic tissues results in more frequent detection of early lymphoid proliferations. These show some but not all features of malignant lymphomas without fulfilling the diagnostic criteria for the diagnosis of lymphoid malignancy. In addition to well-known premalignant B-cell proliferations, such as monoclonal gammopathy of unknown significance (MGUS) and monoclonal B-cell lymphocytosis (MBL), so-called in situ lymphomas have recently been described with minimal infiltrates of clonal B-cells in morphologically reactive lymphoid tissues which show the phenotypic and genetic features of specific B-cell lymphoma subtypes and often show a characteristic topographical distribution. This article addresses a group of clonal lymphoproliferations with usually localized disease and excellent clinical prognosis, such as pediatric follicular lymphoma and nodal marginal zone lymphoma. Another group of early lesions not addressed in this review are virally induced lymphoproliferations which represent a grey zone between purely reactive lesions and malignant lymphomas and may pose significant diagnostic as well as clinical problems. In this review diagnostic criteria for early or in situ lesions and their distinction from partial infiltration by malignant lymphoma are described.


Assuntos
Linfócitos B/patologia , Transformação Celular Neoplásica/patologia , Linfocitose/patologia , Linfoma não Hodgkin/patologia , Transtornos Linfoproliferativos/patologia , Adulto , Proliferação de Células , Criança , Diagnóstico Diferencial , Humanos , Tecido Linfoide/patologia , Linfoma Folicular/patologia , Gamopatia Monoclonal de Significância Indeterminada/patologia , Estadiamento de Neoplasias
10.
Pathologe ; 34(3): 198-209, 2013 May.
Artigo em Alemão | MEDLINE | ID: mdl-23462793

RESUMO

Plasma cell malignancies are tumors of terminally differentiated B-cells in which the neoplastic plasma cells are the dominant and proliferating tumor cell component. Plasma cell myeloma (PCM) is one of the most common hematological neoplasms and typically does not cause diagnostic problems. A morphologically and immunophenotypically detectable plasmacellular orplasmablastic differentiation is, however, commonly observed in a wide range of mature B-cell lymphomas. A confident separation of the distinct entities requires the integration of clinical and morphological findings as well as an adequate phenotyping of both the plasma cell and the B-cell component if present. Detection of lymphotropic viruses, specific translocations and novel molecular markers, such as the MYD88 L265P mutation occurring in the vast majority of lymphoplasmacytic lymphomas complement our diagnostic repertoire. In this review we describe the most commonly observed diagnostic problems in separating small B-cell lymphomas from PCM and high-grade B-cell non-Hodgkin lymphoma (B-NHL) with plasmablastic differentiation from extramedullary spread of aggressive PCM and provide helpful criteria for routine diagnostics.


Assuntos
Linfócitos B/patologia , Proliferação de Células , Transformação Celular Neoplásica/patologia , Mieloma Múltiplo/patologia , Plasmócitos/patologia , Alelos , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Transformação Celular Neoplásica/genética , Análise Mutacional de DNA , Diagnóstico Diferencial , Humanos , Linfoma de Células B/diagnóstico , Linfoma de Células B/patologia , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/genética , Gradação de Tumores , Fenótipo , Prognóstico , Translocação Genética/genética
11.
Infection ; 41(2): 565-9, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22926562

RESUMO

A 40-year-old Ghanaian woman presented with fever and exanthema. She had anemia, leukopenia, increased erythrocyte sedimentation rate (ESR), creatinin kinase, lactate dehydrogenase (LDH), and liver enzymes. She was diagnosed with schistosomiasis and was cured with praziquantel. During the following years, she developed polymyositis, chronic nephritis, and life-threatening perimyocarditis. High numbers of Epstein-Barr virus (EBV)-encoded RNA copies were demonstrated in CD8+ T-lymphocytes from endomyocardial biopsies. There was no evidence of any underlying immunosuppression or an EBV-related malignancy. Chronic active EBV infection was diagnosed, a clinical picture not described in an adult African previously. Interestingly, among all therapy attempts, only rituximab was effective at stabilizing the disease.


Assuntos
Infecções por Vírus Epstein-Barr/diagnóstico , Herpesvirus Humano 4/isolamento & purificação , RNA Viral/isolamento & purificação , Adulto , Anticorpos Monoclonais Murinos/uso terapêutico , Sedimentação Sanguínea , Linfócitos T CD8-Positivos/virologia , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Feminino , Humanos , Fígado/enzimologia , Fígado/patologia , Nefrite/patologia , Praziquantel/uso terapêutico , Rituximab , Esquistossomose/diagnóstico , Esquistossomose/tratamento farmacológico
12.
Leukemia ; 27(1): 56-65, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22828445

RESUMO

The transcriptional regulator ecotropic viral integration site-1 (EVI-1) has mainly been studied for its role in myeloid malignancies, in which high EVI-1 levels are associated with particularly aggressive disease. The role of EVI-1 in lymphoid cells, however, is largely unknown. Here we show that EVI-1 is indeed expressed in lymphoid malignancies such as acute lymphoblastic leukemia (ALL) and a subset of chronic lymphocytic leukemia. Expression data from pediatric ALL further suggest that high EVI-1 levels are associated with poor prognosis. Suppression of EVI-1 expression by RNA interference reduces cell growth and enhances apoptosis sensitivity in response to various stimuli in lymphoblastic leukemia cells. At the molecular level, EVI-1 modulates expression of several apoptosis-related genes (such as BCL2, BCL-x, XIAP, NOXA, PUMA, TRAIL-R1). Furthermore, EVI-1 knockdown strongly impairs in vivo engraftment of lymphoblastic leukemia cells upon transplantation in immune-permissive NOD/SCID/IL2Rγ(null) mice, conferring a survival benefit when compared with mice transplanted with control cells. Thus, our data show that EVI-1 is expressed not only in myeloid but also in lymphoid leukemias, and contributes to the leukemogenic potential and apoptosis resistance of ALL cells.


Assuntos
Apoptose , Proteínas de Ligação a DNA/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Leucemia Mieloide Aguda/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Fatores de Transcrição/metabolismo , Adulto , Animais , Western Blotting , Estudos de Casos e Controles , Ciclo Celular , Proliferação de Células , Criança , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/genética , Imunofluorescência , Humanos , Subunidade gama Comum de Receptores de Interleucina/fisiologia , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Proteína do Locus do Complexo MDS1 e EVI1 , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proto-Oncogenes/genética , RNA Interferente Pequeno/genética , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Células Tumorais Cultivadas
13.
Pathologe ; 33(6): 481-9, 2012 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-23085692

RESUMO

The rapid technological development in diagnostic pathology, especially of immunohistochemical and molecular techniques, also has a significant impact on diagnostic procedures for the evaluation of bone marrow trephine biopsies. The necessity for optimal morphology, combined with preservation of tissue antigens and nucleic acids on one hand and the wish for short turnaround times on the other hand require careful planning of the workflow for fixation, decalcification and embedding of trephines. Although any kind of bone marrow processing has its advantages and disadvantages, formalin fixation followed by EDTA decalcification can be considered a good compromise, which does not restrict the use of molecular techniques. Although the majority of molecular studies in haematological neoplasms are routinely performed on bone marrow aspirates or peripheral blood cells, there are certain indications, in which molecular studies such as clonality determination or detection of specific mutations need to be performed on the trephine biopsy. Especially, the determination of B- or T-cell clonality for the diagnosis of lymphoid malignancies requires stringent quality controls and knowledge of technical pitfalls. In this review, we discuss technical aspects of bone marrow biopsy processing and the application of diagnostic molecular techniques.


Assuntos
Biópsia por Agulha , Exame de Medula Óssea/métodos , Medula Óssea/patologia , Hibridização in Situ Fluorescente , Leucemia/genética , Leucemia/patologia , Linfoma/genética , Linfoma/patologia , Técnicas de Diagnóstico Molecular , Doenças Mieloproliferativas-Mielodisplásicas/genética , Doenças Mieloproliferativas-Mielodisplásicas/patologia , Biomarcadores Tumorais/genética , Aberrações Cromossômicas , Análise Mutacional de DNA , Marcadores Genéticos/genética , Imuno-Histoquímica/métodos , Prognóstico
14.
J Pathol ; 217(1): 4-13, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19016567

RESUMO

The generation of new mouse models of human disease is accelerating rapidly, due to the completion of whole-genome sequencing efforts and technological advances in the manipulation of the mouse genome. We sought to investigate manpower issues in the provision of histopathology expertise for mouse functional genomics and compared this to the perceived demand from principal investigators (PIs). Through the European Commission (EC)-funded PRIME pathology training initiative, two questionnaires were devised to collect information from pathologists and EC-funded PIs on the current provision of mouse histopathology expertise in Europe and the demands for this service. We find that pathological analysis is being performed almost exclusively by professionally qualified pathologists, generally employed in clinical diagnostic posts, where the work is undertaken as collaboration outside of their contractual commitments but without previous training in veterinary or comparative pathology. The results indicate that there is a lack of both trainees and provision of specialist training in this field. Unsurprisingly, the availability of diagnostic expertise and advice falls far short of the number of genetically engineered mice (GEM) being generated for analysis. We analyse these results with reference to previous studies and discuss solutions for the future recruitment, training and funding for pathologists in mouse functional genomics in Europe.


Assuntos
Modelos Animais de Doenças , Genômica , Patologia Veterinária , Animais , Competência Clínica , Europa (Continente) , Genômica/normas , Genômica/estatística & dados numéricos , Camundongos , Patologia Veterinária/normas , Patologia Veterinária/estatística & dados numéricos , Seleção de Pessoal/estatística & dados numéricos , Inquéritos e Questionários , Recursos Humanos , Carga de Trabalho/estatística & dados numéricos
15.
Int J Radiat Biol ; 84(11): 930-6, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19016141

RESUMO

PURPOSE: The European Radiobiology Archives (ERA), together with corresponding Japanese and American databases, hold data from nearly all experimental animal radiation biology studies carried out between 1960 and 1998, involving more than 300,000 animals. The Federal Office for Radiation Protection, together with the University of Cambridge have undertaken to transfer the existing ERA archive to a web-based database to maximize its usefulness to the scientific community and bring data coding and structure of this legacy database into congruence with currently accepted semantic standards for anatomy and pathology. METHODS: The accuracy of the primary data input was assessed and improved. The original rodent pathology nomenclature was recoded to replace the local 'DIS-ROD' (Disease Rodent) formalism with Mouse Pathology (MPATH) and Mouse Anatomy (MA) ontology terms. A pathology panel sampled histopathological slide material and compared the original diagnoses with currently accepted diagnostic criteria. RESULTS: The overall non-systematic error rate varied among the studies between 0.26% and 4.41%, the mean error being 1.71%. The errors found have been corrected and the studies thus controlled have been annotated. The majority of the original pathology terms have been successfully translated into a combination of MPATH and MA ontology terms. CONCLUSIONS: ERA has the potential of becoming a world-wide radiobiological research tool for numerous applications, such as the re-analysis of existing data with new approaches in the light of new hypotheses and techniques, and using the database as an information resource for planning future animal studies. When the database is opened for new data it may be possible to offer long-term storage of data from recent and future animal studies.


Assuntos
Bases de Dados Factuais/tendências , Radiobiologia , Animais , Arquivos , Europa (Continente) , Humanos , Internet , Sistemas de Informação em Radiologia , Terminologia como Assunto , Interface Usuário-Computador
16.
Leukemia ; 22(11): 2097-105, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18685613

RESUMO

Cyclin D1 overexpression is the hallmark of mantle cell lymphoma (MCL). However, the importance of cyclin D1 in the maintenance and progression of the disease remains to be defined. The aim of this study was to elucidate the role of cyclin D1 overexpression using an efficient cyclin D1-shRNA and a lentiviral system in well-characterized MCL cell lines. Surprisingly, the knockdown of cyclin D1 led to a moderate retardation in growth, without induction of apoptosis. The cyclin D1-shRNA-transduced MCL cells showed a 15% shift from S phase to G(1) phase of the cell cycle, a weak induction of p27(Kip1), decreased Rb (Ser807/811) phosphorylation, and a consistent upregulation of cyclin D2 mRNA and protein expression. However, double knockdown of cyclins D1 and D2 did not intensify the effects observed with cyclin D1 knockdown alone. These data suggest that the moderate effects of cyclin D1 downregulation on survival and proliferation are likely the result of compensatory cyclin-independent mechanisms governing proliferation or alternatively, secondary genetic events that make cyclin D1 dispensable. These findings have important implications for MCL therapy, as strategies targeting only cyclin D1 function might be hampered by compensatory regulatory mechanisms, resulting in a low probability of treatment response.


Assuntos
Apoptose/fisiologia , Ciclina D1/antagonistas & inibidores , Ciclinas/metabolismo , Lentivirus/genética , Linfoma de Célula do Manto/metabolismo , RNA Interferente Pequeno/farmacologia , Western Blotting , Ciclo Celular , Proliferação de Células , Ciclina D1/genética , Ciclina D1/metabolismo , Ciclina D2 , Ciclina D3 , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Ciclinas/genética , Citometria de Fluxo , Humanos , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Células Tumorais Cultivadas
17.
Neurobiol Aging ; 29(9): 1404-11, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17416441

RESUMO

The supplementation of creatine (Cr) has a marked neuroprotective effect in mouse models of neurodegenerative diseases. This has been assigned to the known bioenergetic, anti-apoptotic, anti-excitotoxic, and anti-oxidant properties of Cr. As aging and neurodegeneration share pathophysiological pathways, we investigated the effect of oral Cr supplementation on aging in 162 aged C57Bl/6J mice. Outcome variables included "healthy" life span, neurobehavioral phenotyping, as well as morphology, biochemistry, and expression profiling from brain. The median healthy life span of Cr-fed mice was 9% higher than in control mice, and they performed significantly better in neurobehavioral tests. In brains of Cr-treated mice, there was a trend towards a reduction of reactive oxygen species and significantly lower accumulation of the "aging pigment" lipofuscin. Expression profiling showed an upregulation of genes implicated in neuronal growth, neuroprotection, and learning. These data show that Cr improves health and longevity in mice. Cr may be a promising food supplement to promote healthy human aging.


Assuntos
Comportamento Animal/fisiologia , Cognição/fisiologia , Creatina/administração & dosagem , Suplementos Nutricionais , Nível de Saúde , Taxa de Sobrevida , Animais , Comportamento Animal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Sobrevida
18.
Verh Dtsch Ges Pathol ; 91: 98-103, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18314602

RESUMO

Inbred strains are the raw material for the generation of Genetically Engineered Mice (GEM) that have become indispensable tools for cancer research, and for the identification of genes involved in human diseases. The "German Mouse Clinic" was designed to provide the scientific community with a systematic, standardized and comprehensive phenotyping of mouse models on various genetic backgrounds and generated by different methods (transgenic, knockouts, ENU mutagenesis screen and gene-trap approaches). The pathology screen within the German Mouse-Clinic was conceived to ensure a complete morphologic phenotype of mouse models, to support discovery of genes functions, and to understand how these genes influence the development of human diseases. The goal is to define disease entities that can be recognized by a pathologist and relate them to human disorders when possible. Knowing the inherent morphologic phenotype of the most frequent used mouse strains is of utmost importance for the correct interpretation of mouse models. The main challenges, which pathologist are confronted to validate mouse models for human diseases include (1) knowledge of mouse biology and of histological differences between mouse strains and humans, (2) the terminology that should be used for the classification of neoplastic lesions in GEM's, (3) to asses the usefulness of a particular GEM as model for a human disease.


Assuntos
Encefalopatias/genética , Encefalopatias/patologia , Modelos Animais de Doenças , Neoplasias/genética , Neoplasias/patologia , Animais , Carcinógenos , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos , Fenótipo , Especificidade da Espécie
20.
Carcinogenesis ; 24(3): 371-6, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12663494

RESUMO

We have recently identified a locus exhibiting a high frequency of allelic imbalance (AI) in both spontaneous human (HSA 6q14.1-15) and radiogenic murine (MMU9, 42 cM) osteosarcoma. Here we describe the fine mapping of the locus in osteosarcoma arising in (BALB/cxCBA) F(1) hybrid mice. These studies have allowed us to identify Tbx18, a member of the T-box transcriptional regulator gene family, as a candidate gene. Three intragenic Tbx18 polymorphisms were used to map the region of maximum AI to within the gene itself; 16 of 17 tumours exhibited imbalances of at least one of these markers. The highest frequency was found in exon 1, where 14 of 17 tumours were affected at a single nucleotide polymorphism at 541 nt. Two polymorphic CA repeat markers in intron 2 and intron 5 demonstrated overlapping regions of imbalance in several tumours. Both markers flanking the Tbx18 gene (D9Osm48 and D9Mit269) revealed significantly lower frequencies of imbalance and confirmed the limitation of the common interval to Tbx18. Examination of both the mouse and human annotated genomic sequences indicated Tbx18 to be the only gene within the interval. Sequence analysis of the Tbx18 coding region did not reveal any evidence of mutation. Given the haploinsufficiency phenotypes reported for other T-box genes, we speculate that AI may influence the function of Tbx18 during osteosarcomagenesis.


Assuntos
Alelos , Neoplasias Ósseas/genética , Marcadores Genéticos , Osteossarcoma/genética , Fatores de Transcrição/genética , Animais , Sequência de Bases , Mapeamento Cromossômico , Primers do DNA , Feminino , Humanos , Células Híbridas/efeitos da radiação , Íntrons , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos CBA , Sitios de Sequências Rotuladas , Proteínas com Domínio T
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