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1.
Sci Rep ; 14(1): 13790, 2024 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-38877061

RESUMO

PDE1B had been found to be involved in various diseases, including tumors and non-tumors. However, little was known about the definite role of PDE1B in osteosarcoma. Therefore, we mined public data on osteosarcoma to reveal the prognostic values and immunological roles of the PDE1B gene. Three osteosarcoma-related datasets from online websites were utilized for further data analysis. R 4.3.2 software was utilized to conduct difference analysis, prognostic analysis, gene set enrichment analysis (GSEA), nomogram construction, and immunological evaluations, respectively. Experimental verification of the PDE1B gene in osteosarcoma was conducted by qRT-PCR and western blot, based on the manufacturer's instructions. The PDE1B gene was discovered to be lowly expressed in osteosarcoma, and its low expression was associated with poor OS (all P < 0.05). Experimental verifications by qRT-PCR and western blot results remained consistent (all P < 0.05). Univariate and multivariate Cox regression analyses indicated that the PDE1B gene had independent abilities in predicting OS in the TARGET osteosarcoma dataset (both P < 0.05). GSEA revealed that PDE1B was markedly linked to the calcium, cell cycle, chemokine, JAK STAT, and VEGF pathways. Moreover, PDE1B was found to be markedly associated with immunity (all P < 0.05), and the TIDE algorithm further shed light on that patients with high-PDE1B expression would have a better immune response to immunotherapies than those with low-PDE1B expression, suggesting that the PDE1B gene could prevent immune escape from osteosarcoma. The PDE1B gene was found to be a tumor suppressor gene in osteosarcoma, and its high expression was related to a better OS prognosis, suppressing immune escape from osteosarcoma.


Assuntos
Biomarcadores Tumorais , Neoplasias Ósseas , Osteossarcoma , Microambiente Tumoral , Osteossarcoma/genética , Osteossarcoma/mortalidade , Osteossarcoma/imunologia , Osteossarcoma/patologia , Humanos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Prognóstico , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Neoplasias Ósseas/genética , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Neoplasias Ósseas/imunologia , Masculino , Feminino , Regulação Neoplásica da Expressão Gênica , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/metabolismo
2.
Ann Rheum Dis ; 81(8): 1173-1178, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35428651

RESUMO

OBJECTIVES: We aim to investigate the genetic basis of a case of late-onset autoinflammatory disease characterised by arthritis, recurrent fever and skin rashes. METHODS: We performed whole-exome/genome sequencing and digital droplet PCR (ddPCR) to identify the pathogenic somatic mutation. We used single-cell RNA sequencing (scRNA-seq), intracellular cytokine staining, quantitative PCR, immunohistochemistry and western blotting to define inflammatory signatures and to explore the pathogenic mechanism. RESULTS: We identified a somatic mutation in NLRC4 (p.His443Gln) with the highest mosaicism ratio in the patient's monocytes (5.69%). The somatic mutation resulted in constitutive NLRC4 activation, spontaneous apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) aggregation, caspase-1 hyperactivation and increased production of interleukin (IL)-1ß and IL-18. Moreover, we demonstrated effective suppression of inflammatory cytokine production by targeting gasdermin D, an approach that could be considered as a novel treatment strategy for patients with NLRC4-associated autoinflammatory syndrome. CONCLUSIONS: We reported a case of a late-onset autoinflammatory disease caused by a somatic NLRC4 mutation in a small subset of leucocytes. We systemically analysed this condition at a single-cell transcriptomic level and revealed specific enhancement of inflammatory response in myeloid cells.


Assuntos
Proteínas Adaptadoras de Sinalização CARD , Doenças Hereditárias Autoinflamatórias , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas de Ligação ao Cálcio/genética , Citocinas/metabolismo , Doenças Hereditárias Autoinflamatórias/genética , Humanos , Inflamassomos/metabolismo , Mutação , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética
3.
Sci Rep ; 10(1): 10415, 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32591608

RESUMO

This paper introduces a differential vibrating beam MEMS accelerometer demonstrating excellent long-term stability for applications in gravimetry and seismology. The MEMS gravimeter module demonstrates an output Allan deviation of 9 µGal for a 1000 s integration time, a noise floor of 100 µGal/√Hz, and measurement over the full ±1 g dynamic range (1 g = 9.81 ms-2). The sensitivity of the device is demonstrated through the tracking of Earth tides and recording of ground motion corresponding to a number of teleseismic events over several months. These results demonstrate that vibrating beam MEMS accelerometers can be employed for measurements requiring high levels of stability and resolution with wider implications for precision measurement employing other resonant-output MEMS devices such as gyroscopes and magnetometers.

4.
Chemistry ; 23(24): 5824-5829, 2017 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-28295689

RESUMO

Recognition of enantiomers of chiral acids by anion-π or lone pair-π interactions has not yet been investigated but is a significant and attractive challenge. This study reports an optically active polymer-based supramolecular system with capabilities of discriminating enantiomers of various chiral acids. The polymer featuring alternate π-acidic naphthalenediimides (NDIs) and methyl l-phenylalaninates in the backbone exhibits an unprecedented slow self-assembly process that is susceptible to perturbation by various chiral acids. Thus, the combination of anion-π or lone pair-π interactions and sensitivity of the polymeric self-assembly process to external chiral species endows the system with recognition capabilities. This is the first time that anion-π or lone pair-π interactions have been applied in the recognition of enantiomers of various chiral acids with a single system. The results shed light on new strategies for material design by integrating π-acidic aromatic systems and chiral building blocks to afford relevant advanced functions.

5.
Chem Asian J ; 12(8): 841-845, 2017 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-28299911

RESUMO

Sequence-defined chiral polyimides comprising identical asymmetric diamine monomers arranged in different directions along the main chain were designed and prepared. These new sequence-defined polymers exhibit sequence-dependent self-assembly behaviors and responses to ibuprofen enantiomers, as revealed by their chiroptical spectra and gelation properties. For the first time, the self-assembly of polymers and their interactions with guest molecules have been successfully controlled by means of the directional arrangement of the monomers in their polymer backbones.

6.
ChemistryOpen ; 5(4): 386-94, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27547649

RESUMO

The motivation of foldamer chemistry is to identify novel building blocks that have the potential to imitate natural species. Peptides and peptide mimetics can form stable helical conformations and further self-assemble into diverse aggregates in water, where it is difficult to isolate a single helix. In contrast, most "abiotic" foldamers may fold into helical structures in solution, but are difficult to assemble into tertiary ones. It remains a challenge to obtain "abiotic" species similar to peptides. In this paper, a novel foldamer scaffold, in which p-phenyleneethynylene units are linked by chiral carbon atoms, was designed and prepared. In very dilute solutions, these oligomers were random coils. The hexamer and octamers could form a hexagonal lyotropic liquid crystal (LC) in CH2Cl2 when the concentrations reached the critical values. The microscopic observations indicated that they could assemble into the nanofibers in the LC. Interestingly, after some LC phases were diluted at room temperature, the nanofibers could be preserved. The good stabilities of the assemblies are possibly attributed to a more compact backbone and more rigid side chains.

7.
J Am Chem Soc ; 137(2): 632-5, 2015 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-25569141

RESUMO

We present the enantioselective synthesis of P-stereogenic phosphinamides through Pd-catalyzed desymmetric ortho C-H arylation of diarylphosphinamides with boronic esters. The method represents the first example of the synthesis of P-stereogenic phosphorus compounds via the desymmetric C-H functionalization strategy. The reaction proceeded efficiently with a wide array of reaction partners to afford the P-stereogenic phosphinamides in up to 74% yield and 98% ee. The efficiency was further demonstrated by gram scale syntheses. Moreover, the flexible conversion of the P-stereogenic phosphinamides into various types of P-stereogenic phosphorus derivatives was also elaborated. Thus, the protocol provides a novel tool for the efficient and versatile synthesis of P-stereogenic compounds.

8.
J Mass Spectrom ; 48(12): 1318-24, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24338887

RESUMO

Secondary and tertiary amines have been reported to form [M-H](+) that correspond to dehydrogenation in matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS). In this investigation, we studied the dehydrogenation of amines in MALDI-TOF MS by isotopic labeling. Aliphatic amines were labeled with deuterium on the methylene of an N-benzyl group, which resulted in the formation of [M-D](+) and [M-H](+) ions by dedeuteration and dehydrogenation, respectively. This method revealed the proton that was removed. The spectra of most tertiary amines with an N-benzyl group showed high-intensity [M-D](+) and [M-H](+) ion peaks, whereas those of secondary amines showed low-intensity ion peaks. Ratios between the peak intensities of [M-D](+) and [M-H](+) greater than 1 suggested chemoselective dehydrogenation at the N-benzyl groups. The presence of an electron donor group on the N-benzyl groups enhanced the selectivity. The dehalogenation of amines with an N-(4-halobenzyl) group was also observed alongside dehydrogenation. The amino ions from dehalogenation can undergo second dehydrogenation. These results provide the first direct evidence about the position at which dehydrogenation of an amine occurs and the first example of dehalogenation of haloaromatic compounds in MALDI-TOF MS. These results should be helpful in the structural identification and elucidation of synthetic and natural molecules.


Assuntos
Aminas/química , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Halogenação , Hidrogenação , Íons , Marcação por Isótopo , Prótons
9.
Elife ; 2: e00996, 2013 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-24381245

RESUMO

While a first pregnancy before age 22 lowers breast cancer risk, a pregnancy after age 35 significantly increases life-long breast cancer risk. Pregnancy causes several changes to the normal breast that raise barriers to transformation, but how pregnancy can also increase cancer risk remains unclear. We show in mice that pregnancy has different effects on the few early lesions that have already developed in the otherwise normal breast-it causes apoptosis evasion and accelerated progression to cancer. The apoptosis evasion is due to the normally tightly controlled STAT5 signaling going astray-these precancerous cells activate STAT5 in response to pregnancy/lactation hormones and maintain STAT5 activation even during involution, thus preventing the apoptosis normally initiated by oncoprotein and involution. Short-term anti-STAT5 treatment of lactation-completed mice bearing early lesions eliminates the increased risk after a pregnancy. This chemoprevention strategy has important implications for preventing increased human breast cancer risk caused by pregnancy. DOI: http://dx.doi.org/10.7554/eLife.00996.001.


Assuntos
Neoplasias da Mama/prevenção & controle , Modelos Animais de Doenças , Complicações Neoplásicas na Gravidez/prevenção & controle , Animais , Apoptose , Neoplasias da Mama/complicações , Neoplasias da Mama/metabolismo , Carcinogênese , Divisão Celular , Feminino , Camundongos , Mutação , Oncogenes , Gravidez , Complicações Neoplásicas na Gravidez/metabolismo , Fator de Transcrição STAT5/metabolismo
10.
Mol Cancer Res ; 10(10): 1389-99, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22878587

RESUMO

TGF-ß plays a dual role in epithelial carcinogenesis with the potential to either suppress or promote tumor progression. We found that levels of Smad3 mRNA, a critical mediator of TGF-ß signaling, are reduced by approximately 60% in human breast cancer. We therefore used conditionally immortalized mammary epithelial cells (IMEC) of differing Smad3 genotypes to quantitatively address the Smad3 requirement for different biologic responses to TGF-ß. We found that a two-fold reduction in Smad3 gene dosage led to complex effects on TGF-ß responses; the growth-inhibitory response was retained, the pro-apoptotic response was lost, the migratory response was reduced, and the invasion response was enhanced. Loss of the pro-apoptotic response in the Smad3(+/-) IMECs correlated with loss of Smad3 binding to the Bcl-2 locus, whereas retention of the growth-inhibitory response in Smad3 IMECs correlated with retention of Smad3 binding to the c-Myc locus. Addressing the integrated outcome of these changes in vivo, we showed that reduced Smad3 levels enhanced metastasis in two independent models of metastatic breast cancer. Our results suggest that different biologic responses to TGF-ß in the mammary epithelium are differentially affected by Smad3 dosage and that a mere two-fold reduction in Smad3 is sufficient to promote metastasis.


Assuntos
Neoplasias da Mama/patologia , Epitélio/metabolismo , Dosagem de Genes/efeitos dos fármacos , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Humanas/metabolismo , Proteína Smad3/genética , Fator de Crescimento Transformador beta/farmacologia , Animais , Neoplasias da Mama/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Progressão da Doença , Elementos Facilitadores Genéticos/genética , Epitélio/efeitos dos fármacos , Epitélio/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Glândulas Mamárias Animais/efeitos dos fármacos , Glândulas Mamárias Animais/patologia , Glândulas Mamárias Humanas/efeitos dos fármacos , Glândulas Mamárias Humanas/patologia , Camundongos , Metástase Neoplásica , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteína Smad3/metabolismo
11.
Development ; 138(23): 5247-56, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22069192

RESUMO

The ID family of helix-loop-helix proteins regulates cell proliferation and differentiation in many different developmental pathways, but the functions of ID4 in mammary development are unknown. We report that mouse Id4 is expressed in cap cells, basal cells and in a subset of luminal epithelial cells, and that its targeted deletion impairs ductal expansion and branching morphogenesis as well as cell proliferation induced by estrogen and/or progesterone. We discover that p38MAPK is activated in Id4-null mammary cells. p38MAPK is also activated following siRNA-mediated Id4 knockdown in transformed mammary cells. This p38MAPK activation is required for the reduced proliferation and increased apoptosis in Id4-ablated mammary glands. Therefore, ID4 promotes mammary gland development by suppressing p38MAPK activity.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Proteínas Inibidoras de Diferenciação/genética , Proteínas Inibidoras de Diferenciação/metabolismo , Glândulas Mamárias Animais/crescimento & desenvolvimento , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Apoptose/efeitos dos fármacos , Bromodesoxiuridina , Proliferação de Células/efeitos dos fármacos , Estradiol/farmacologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Immunoblotting , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Glândulas Mamárias Animais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Progesterona/farmacologia , Reação em Cadeia da Polimerase em Tempo Real
12.
Breast Cancer Res ; 12(5): R83, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20942910

RESUMO

INTRODUCTION: Molecular dissection of the signaling pathways that underlie complex biological responses in the mammary epithelium is limited by the difficulty of propagating large numbers of mouse mammary epithelial cells, and by the inability of ribonucleic acid interference (RNAi)-based knockdown approaches to fully ablate gene function. Here we describe a method for the generation of conditionally immortalized mammary epithelial cells with defined genetic defects, and we show how such cells can be used to investigate complex signal transduction processes using the transforming growth factor beta (TGFß/Smad pathway as an example. METHODS: We intercrossed the previously described H-2Kb-tsA58 transgenic mouse (Immortomouse) which expresses a temperature-sensitive mutant of the simian virus-40 large T-antigen (tsTAg), with mice of differing Smad genotypes. A panel of conditionally immortalized mammary epithelial cell (IMEC) cultures were derived from the virgin mammary glands of offspring of these crosses and used to assess the Smad dependency of different biological responses to TGFß. RESULTS: IMECs could be propagated indefinitely at permissive temperatures and had a stable epithelial phenotype, resembling primary mammary epithelial cells with respect to several criteria, including responsiveness to TGFß. Using this panel of cells, we demonstrated that Smad3, but not Smad2, is necessary for TGFß-induced apoptotic, growth inhibitory and EMT responses, whereas either Smad can support TGFß-induced invasion as long as a threshold level of total Smad is exceeded. CONCLUSIONS: This work demonstrates the practicality and utility of generating conditionally immortalized mammary epithelial cell lines from genetically modified Immortomice for detailed investigation of complex signaling pathways in the mammary epithelium.


Assuntos
Células Epiteliais/metabolismo , Glândulas Mamárias Animais/metabolismo , Transdução de Sinais , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Apoptose/genética , Diferenciação Celular , Movimento Celular , Células Cultivadas , Transição Epitelial-Mesenquimal/genética , Feminino , Técnicas de Inativação de Genes , Glândulas Mamárias Animais/citologia , Camundongos , Camundongos Transgênicos , Proteína Smad2/genética , Proteína Smad3/genética , Fator de Crescimento Transformador beta/genética
13.
Neoplasia ; 12(9): 718-26, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20824048

RESUMO

Estrogen signaling is required for the proliferation of normal breast epithelial cells. However, prophylactic inhibition of estrogen signaling fails to prevent 56% of human breast cancer cases. The underlying mechanism is not well understood. Aberrant activation of growth factor signaling is known to provide alternative proliferation pathways in breast cells that are fully transformed, but it is not known whether activation of growth factor signaling can substitute for estrogen signaling in causing aberrant proliferation in the normal breast epithelium. Here, we report that in a retrovirus-based somatic mouse model (replication-competent ALV-LTR splice acceptor/tumor virus A) that closely mimics the evolution of sporadic human breast cancers, mammary epithelial cells harboring PyMT or activated ErbB2 evolve into tumors independent of estrogen or other ovarian functions in contrast to previous observations of estrogen-dependent cancer formation in germ line mouse models of ErbB2 activation. Importantly, ErbB2 activation in normal mammary cells causes estrogen-independent proliferation in both estrogen receptor (ER)-negative cells as well as in normally quiescent ER-positive cells. Therefore, aberrant activation of growth factor signaling contributes to estrogen-independent proliferation of both preneoplastic and cancerous mammary cells, and prophylactic therapy against both growth factor signaling and estrogen signaling may need to be considered in women with increased risk of breast cancer.


Assuntos
Antígenos Virais de Tumores/genética , Carcinoma Ductal de Mama/genética , Estrogênios/farmacologia , Genes erbB-2 , Neoplasias Mamárias Experimentais/genética , Polyomavirus/genética , Animais , Antígenos Virais de Tumores/metabolismo , Antígenos Virais de Tumores/fisiologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/fisiologia , Ativação Enzimática , Feminino , Regulação Neoplásica da Expressão Gênica , Genes erbB-2/genética , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Transgênicos , Polyomavirus/imunologia , Polyomavirus/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptor ErbB-2/fisiologia , Transfecção
14.
Cancer Res ; 67(18): 8643-52, 2007 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-17875704

RESUMO

The transforming growth factor-beta (TGF-beta) pathway has tumor-suppressor activity in many epithelial tissues. Because TGF-beta is a potent inhibitor of epithelial cell proliferation, it has been widely assumed that this property underlies the tumor-suppressor effect. Here, we have used a xenograft model of breast cancer to show that endogenous TGF-beta has the potential to suppress tumorigenesis through a novel mechanism, involving effects at two distinct levels in the hierarchy of cellular progeny that make up the epithelial component of the tumor. First, TGF-beta reduces the size of the putative cancer stem or early progenitor cell population, and second it promotes differentiation of a more committed, but highly proliferative, progenitor cell population to an intrinsically less proliferative state. We further show that reduced expression of the type II TGF-beta receptor correlates with loss of luminal differentiation in a clinical breast cancer cohort, suggesting that this mechanism may be clinically relevant. At a molecular level, the induction of differentiation by TGF-beta involves down-regulation of Id1, and forced overexpression of Id1 can promote tumorigenesis despite persistence of the antiproliferative effect of TGF-beta. These data suggest new roles for the TGF-beta pathway in regulating tumor cell dynamics that are independent of direct effects on proliferation.


Assuntos
Neoplasias da Mama/patologia , Células-Tronco Neoplásicas/patologia , Fator de Crescimento Transformador beta/fisiologia , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Regulação para Baixo , Feminino , Perfilação da Expressão Gênica , Humanos , Proteína 1 Inibidora de Diferenciação/biossíntese , Proteína 1 Inibidora de Diferenciação/genética , Camundongos , Camundongos Nus , Transplante de Neoplasias , Células-Tronco Neoplásicas/metabolismo , Proteínas Serina-Treonina Quinases/biossíntese , Proteínas Serina-Treonina Quinases/deficiência , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/biossíntese , Receptores de Fatores de Crescimento Transformadores beta/deficiência , Fator de Crescimento Transformador beta/deficiência , Transplante Heterólogo
15.
Cell Cycle ; 6(7): 823-6, 2007 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-17377492

RESUMO

Mouse models of breast cancer are traditionally made by introducing genetic alterations to the entire mammary epithelium using transgenic or knockout approaches. In contrast, we have adapted the RCAS-TVA method to introduce genes into a small subset of somatic mammary cells in developmentally normal mammary glands. This new method allows the testing of the carcinogenic potential of candidate oncogenes In Vivo without the need to create individual transgenic lines. Moreover, since models created by this approach closely recapitulate evolution of human breast cancer, they may help understand human breast cancer initiation and progression, and may be useful for preclinical testing of therapeutic compounds. Finally, this approach may provide an opportunity to target oncogenes into mammary cells at different differentiation stages, providing a tool to study the relationship between cell origin and cancer phenotype.


Assuntos
Proteínas Aviárias/genética , Transformação Celular Neoplásica/genética , Técnicas de Transferência de Genes/tendências , Vetores Genéticos/genética , Neoplasias Mamárias Animais/genética , Oncogenes/genética , Receptores Virais/genética , Animais , Vírus da Leucose Aviária/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/fisiopatologia , Transformação Celular Neoplásica/metabolismo , Modelos Animais de Doenças , Feminino , Testes Genéticos/métodos , Humanos , Neoplasias Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/fisiopatologia , Camundongos
16.
Proc Natl Acad Sci U S A ; 103(46): 17396-401, 2006 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-17090666

RESUMO

We have adapted the avian leukosis virus RCAS (replication-competent avian sarcoma-leukosis virus LTR splice acceptor)-mediated somatic gene transfer technique to introduce oncogenes into mammary cells in mice transgenic for the avian subgroup A receptor gene, tva, under control of the mouse mammary tumor virus (MMTV) promoter. Intraductal instillation of an RCAS vector carrying the polyoma middle T antigen (PyMT) gene (RCAS-PyMT) induced multiple, oligoclonal tumors within 3 weeks in infected mammary glands of MMTV-tva transgenic mice. The rapid appearance of these tumors from a relatively small pool of infected cells (estimated to be approximately 2 x 10(3) cells per gland by infection with RCAS carrying a GFP gene; RCAS-GFP) was accompanied by a high fraction of cells positive for Ki67, Cyclin D1, and c-Myc, implying strong proliferation competence. Furthermore, the tumors displayed greater cellular heterogeneity than did tumors arising in MMTV-PyMT mice, suggesting that RCAS-PyMT transforms a relatively immature cell type. Infection of mice transgenic for both MMTV-Wnt-1 and MMTV-tva with RCAS virus carrying an activated Neu oncogene dramatically enhanced tumor formation over what is observed in uninfected bitransgenic animals. We conclude that infection of mammary glands with retrovirus vectors is an efficient means to screen candidate oncogenes for their capacity to initiate or promote mammary carcinogenesis in the mouse.


Assuntos
Antígenos Transformantes de Poliomavirus/metabolismo , Vírus do Sarcoma Aviário/genética , Transformação Celular Neoplásica/metabolismo , Vetores Genéticos/genética , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Animais/patologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Animais , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Ciclina D1/metabolismo , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Glândulas Mamárias Animais/virologia , Camundongos , Camundongos Transgênicos , Vírus Oncogênicos/fisiologia , Taxa de Sobrevida
17.
Philos Trans A Math Phys Eng Sci ; 364(1844): 1815-39, 2006 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-16782611

RESUMO

In this study, the flow and rheology of pre-collapse Larsen B ice shelf are investigated by using a combination of flow modelling and data assimilation. Observed shelf velocities from satellite interferometry are used to constrain an ice shelf model by using a data assimilation technique based on the control method. In particular, the ice rheology field and the velocities at the inland shelf boundary are simultaneously optimized to get a modelled flow and stress field that is consistent with the observed flow. The application to the Larsen B ice shelf shows that a strong weakening of the ice in the shear zones, mostly along the margins, is necessary to fit the observed shelf flow. This pattern of bands with weak ice is a very robust feature of the inversion, whereas the ice rheology within the main shelf body is found to be not well constrained. This suggests that these weak zones play a major role in the control of the flow of the Larsen B ice shelf and may be the key to understanding the observed pre-collapse thinning and acceleration of Larsen B. Regarding the sensitivity of the stress field to rheology, the consistency of the model with the observed flow seems crucial for any further analysis such as the application of fracture mechanics or perturbation model experiments.

18.
J Urol ; 170(5): 2000-3, 2003 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-14532841

RESUMO

PURPOSE: We investigated whether recombinant human endostatin can inhibit the growth of bladder cancer in an experimental model and its possible mechanism of action. MATERIALS AND METHODS: The recombinant human endostatin protein was induced and confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blot assays. Its biological activities and the possible mechanisms of action were studied in vitro and in vivo. RESULTS: Recombinant human endostatin inhibited the proliferation of endothelial cells (ECV304) but not bladder tumor cells (EJ). Endostatin induced the expression of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in bladder cancer cells. Endostatin slowed the growth of xenograft bladder tumors. Immunohistochemistry revealed that endostatin blocked angiogenesis by decreasing vascular endothelial growth factor expression and inducing apoptosis in bladder cancer cells. CONCLUSIONS: These findings demonstrate that endostatin can inhibit xenograft bladder cancer growth and this effect is likely to be mediated by regulating matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases and vascular endothelial growth factor expression, and by inducing apoptosis.


Assuntos
Divisão Celular/efeitos dos fármacos , Endostatinas/farmacologia , Neovascularização Patológica/patologia , Células Tumorais Cultivadas/efeitos dos fármacos , Neoplasias da Bexiga Urinária/irrigação sanguínea , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Relação Dose-Resposta a Droga , Eletroforese em Gel de Poliacrilamida , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Indução Enzimática/efeitos dos fármacos , Humanos , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Microscopia Eletrônica , Transplante de Neoplasias/patologia , Proteínas Recombinantes/farmacologia , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Células Tumorais Cultivadas/patologia , Neoplasias da Bexiga Urinária/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
19.
Chin Med J (Engl) ; 115(5): 743-5, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-12133547

RESUMO

OBJECTIVES: To detect the level of matrix metalloproteinase-2 (MMP-2) mRNA and the tissue inhibitor of metalloproteinase-2 (TIMP-2) mRNA in bladder transitional cell carcinoma (BTCC), and to estimate the prognosis for bladder tumor based on the quality and quantity of MMP-2 and TIMP-2 mRNA. METHODS: Thirty-five samples of human BTCC and 15 normal fresh bladder tissues were studied by RT-PCR analysis followed by computer-assisted image analysis. RESULTS: The level of the MMP-2 mRNA in BTCC was significantly increased compared with that in normal bladder epithelium. The positive rates of MMP-2 and TIMP-2 mRNA were 71.4% and 65.7% in BTCC, and 66.7% and 60.0% in the normal bladder wall. The expression intensity of the MMP-2 mRNA by image analysis tended to increase with tumor grading and staging, which showed statistical significance. Similarly, the MMP-2 to TIMP-2 ratio also showed statistically significant difference between normal bladder tissue and bladder carcinoma (P < 0.01). CONCLUSIONS: A high level of the MMP-2 mRNA exists in BTCC, which may function to damage collagen IV inside the basement membrane and the extracellular basement of the bladder. The level of the MMP-2 mRNA is proportional to BTCC grading and staging, which may have prognostic value. The MMP-2 to TIMP-2 ratio may play a more significant role in the determination of the aggressiveness and prognosis of bladder tumor.


Assuntos
Metaloproteinase 2 da Matriz/genética , RNA Mensageiro/metabolismo , Inibidor Tecidual de Metaloproteinase-2/genética , Neoplasias da Bexiga Urinária/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , RNA Mensageiro/genética , Bexiga Urinária/metabolismo , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/patologia
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