Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 12 de 12
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
2.
J Natl Cancer Inst ; 111(9): 933-942, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30715409

RESUMO

BACKGROUND: Oropharyngeal squamous carcinoma (OPSC) continues to increase in incidence secondary to human papillomavirus (HPV) infection. Despite the good overall prognosis for these patients, treatment with chemoradiation is associated with morbidity and treatment failure. Better predictors for disease outcome are needed to guide de-intensification regimens. We hypothesized that estrogen receptor α (ERα), a prognostic biomarker in oncology with therapeutic implications, might have similar utility in OPSC. METHODS: To investigate associations among ERα and demographics, HPV status, and survival, we analyzed ERα mRNA expression of head and neck squamous carcinomas (HNSC) from The Cancer Genome Atlas (TCGA) and immunohistochemistry (IHC) of pretreatment biopsy specimens from an independent group of 215 OPSC patients subsequently treated with primary chemoradiation (OPSC-CR). Associations among variables were evaluated with Fisher exact tests and logistic regression; associations with survival were evaluated with log-rank tests and Cox proportional hazards regression. RESULTS: Among 515 patients in TCGA, ERα mRNA expression was highest in HPV-positive OPSC. High ERα mRNA expression was associated with improved survival among those receiving chemoradiation (hazard ratio adjusted for HPV status = 0.44, 95% confidence interval = 0.21 to 0.92). In OPSC-CR, ERα was positive by IHC in 51.6% of tumors and was associated with improved overall, disease-specific, progression-free, and relapse-free survival (log-rank tests: P < .001, P < .001, P = .002, P = .003, respectively); statistically significant associations of ERα positivity with improved survival were maintained after adjusting for clinical risk factors including HPV status. CONCLUSION: In two independent cohorts, ERα is a potential biomarker for improved survival that also may represent a therapeutic target in OPSC.

6.
Endocr Pathol ; 28(2): 177-185, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28444500

RESUMO

The diagnosis of follicular-patterned carcinomas, including follicular thyroid carcinoma, oncocytic (Hürthle cell) carcinoma, and the encapsulated follicular variant of papillary thyroid carcinoma, requires evidence of capsular and/or vascular invasion. With minimally invasive carcinomas classified often within less than a millimeter of tissue segregating them from adenomas and non-invasive follicular thyroid neoplasms with papillary-like nuclear features, opinions vary internationally over how much of the capsule to submit in order to deem it well enough represented, considering that even if grossly entirely submitted in microcassettes, without leveling through each tissue block, the capsule is truly never entirely examined microscopically. Here, we retrospectively examine submission practices and outcomes at a single, high-volume institution over a 25-year period. Our results indicate that the vast majority of lesions with poor outcomes are those with wide invasion, and tumors lacking gross evidence of capsular perturbation rarely lead to recurrence or metastasis, an unsurprising result that should prompt re-evaluation of our grossing methods and approach to follicular-patterned tumors in a time of cost restraint, molecular diagnostics, and low biological potential of encapsulated, circumscribed neoplasia of the thyroid.


Assuntos
Adenocarcinoma Folicular/patologia , Adenoma Oxífilo/patologia , Carcinoma Papilar/patologia , Neoplasias da Glândula Tireoide/patologia , Humanos , Estudos Retrospectivos , Câncer Papilífero da Tireoide
7.
Circ Res ; 119(4): 519-31, 2016 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-27354212

RESUMO

RATIONALE: Endothelial Notch signaling is critical for early vascular development and survival. Yet, previously described mice lacking endothelial a disintegrin and metalloproteinase 10 (ADAM10), a key regulator of Notch signaling, survived into adulthood with organ-specific vascular defects. These findings raised questions about whether these vascular defects were related to Notch signaling or other functions of ADAM10. OBJECTIVE: The aims of the study are to determine whether compensatory or redundant functions of ADAM17 in Notch signaling can explain the survival of Adam10ΔEC mice, explore the contribution of different Tie2-Cre transgenes to the differences in survival, and establish whether the Adam10ΔEC vascular phenotypes can be recapitulated by inactivation of Notch receptors in endothelial cells. METHODS AND RESULTS: Mice lacking ADAM10 and ADAM17 in endothelial cells (Adam10/Adam17ΔEC), which survived postnatally with organ-specific vascular defects, resembled Adam10ΔEC mice. In contrast, Adam10ΔEC mice generated with the Tie2Cre transgene previously used to inactivate endothelial Notch (Adam10ΔEC(Flv)) died by E10.5. Quantitative polymerase chain reaction analysis demonstrated that Cre-mediated recombination occurs earlier in Adam10ΔEC(Flv) mice than in the previously described Adam10ΔEC mice. Finally, mice lacking endothelial Notch1 (Notch1ΔEC) share some organ-specific vascular defects with Adam10ΔEC mice, whereas Notch4(-/-) mice lacking endothelial Notch1 (Notch1ΔEC/Notch4(-/-)) had defects in all vascular beds affected in Adam10ΔEC mice. CONCLUSIONS: Our results argue against a major role for ADAM17 in endothelial Notch signaling and clarify the difference in phenotypes of previously described mice lacking ADAM10 or Notch in endothelial cells. Most notably, these findings uncover new roles for Notch signaling in the development of organ-specific vascular beds.


Assuntos
Proteína ADAM10/fisiologia , Secretases da Proteína Precursora do Amiloide/fisiologia , Circulação Sanguínea/fisiologia , Proteínas de Membrana/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Receptor Notch1/fisiologia , Receptores Notch/fisiologia , Fluxo Sanguíneo Regional/fisiologia , Transdução de Sinais/fisiologia , Proteína ADAM10/deficiência , Secretases da Proteína Precursora do Amiloide/deficiência , Animais , Células Endoteliais/fisiologia , Feminino , Proteínas de Membrana/deficiência , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Gravidez , Proteínas Proto-Oncogênicas/deficiência , Receptor Notch1/deficiência , Receptor Notch4 , Receptores Notch/deficiência
8.
J Orthop Res ; 32(2): 224-30, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24108673

RESUMO

Mice lacking ADAM10 in endothelial cells (Adam10ΔEC mice) have shorter femurs, tibiae, and humeri than controls, raising questions about how endothelial cells could control long bone growth. We performed a histopathological evaluation of the femur and tibia growth plates at different postnatal stages, and assessed the distribution of TRAP-positive osteoclasts and endothelial cells at the growth plate. The growth plates in Adam10ΔEC mice appeared normal at P7 and P14, but a thickened zone of hypertrophic chondrocytes and increased trabecular bone density were apparent by P21 and later. The number of TRAP+ cells at the COJ was normal at P7 and P14, but was strongly reduced at P21 and later. Moreover, the density of endomucin-stained endothelial cells at the COJ was increased starting at P7. The defects in long bone growth in Adam10ΔEC mice could be caused by a lack of osteoclastogenesis at the COJ. Moreover, ADAM10 appears to regulate endothelial cell organization in the developing bone vasculature, perhaps in a similar manner as in the developing retinal vascular tree, where ADAM10 is thought to control Notch-dependent endothelial cell fate decisions. This study provides evidence for the regulation of osteoclast function by endothelial cells in vivo.


Assuntos
Proteínas ADAM/deficiência , Secretases da Proteína Precursora do Amiloide/deficiência , Desenvolvimento Ósseo/fisiologia , Células Endoteliais/fisiologia , Lâmina de Crescimento/fisiologia , Proteínas de Membrana/deficiência , Osteoclastos/fisiologia , Proteína ADAM10 , Fosfatase Ácida/metabolismo , Envelhecimento , Animais , Osso e Ossos/fisiologia , Fêmur/irrigação sanguínea , Fêmur/crescimento & desenvolvimento , Isoenzimas/metabolismo , Camundongos , Fosfatase Ácida Resistente a Tartarato , Tíbia/crescimento & desenvolvimento
9.
Invest Ophthalmol Vis Sci ; 54(1): 864-70, 2013 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-23299479

RESUMO

PURPOSE: Pathological neovascularization is a crucial component of proliferative retinopathies. Previous studies showed that inactivation of A disintegrin and metalloproteinase 17 (ADAM17), a membrane-anchored metalloproteinase that regulates epidermal growth factor receptor (EGFR) signaling, reduces pathological retinal neovascularization in a mouse model of oxygen-induced retinopathy (OIR). Here, we tested how genetic inactivation of a physiological ADAM17 inhibitor, the tissue inhibitor of matrix metalloproteinases-3 (TIMP3), or intravitreal injection of TIMP3 or of the EGFR inhibitor erlotinib influenced the outcome of OIR. METHODS: Wild-type mice were subjected to OIR in a chamber with 75% oxygen for 5 days beginning at postnatal day 7 (P7). Upon removal from the oxygen chamber at P12, they received a single intravitreal injection of TIMP3, erlotinib, or control. The central avascular area and neovascular tufts were measured after 5 days in room air (21% oxygen) at P17. Moreover, OIR experiments were performed with Timp3-/- mice and littermate controls. RESULTS: Timp3-/- mice showed greater revascularization of the central avascular area and developed equal or fewer neovascular tufts compared to littermate controls, depending on the genetic background. Wild-type mice injected with TIMP3 or erlotinib developed fewer neovascular tufts when compared to untreated littermates. Moreover, vessel regrowth into the avascular area was reduced in TIMP3-injected mice, but not in erlotinib-injected mice. CONCLUSIONS: These studies demonstrate that TIMP3 and erlotinib inhibit pathological neovascularization in the mouse retina, most likely due to inactivation of ADAM17 and the EGFR, respectively. Thus, TIMP3 and erlotinib emerge as attractive candidate antiangiogenic compounds for prevention and treatment of proliferative retinopathies.


Assuntos
Receptores ErbB/antagonistas & inibidores , Neovascularização Patológica/tratamento farmacológico , Quinazolinas/farmacologia , Doenças Retinianas/tratamento farmacológico , Inibidor Tecidual de Metaloproteinase-3/farmacologia , Inibidores da Angiogênese/farmacologia , Animais , Modelos Animais de Doenças , Receptores ErbB/metabolismo , Cloridrato de Erlotinib , Feminino , Injeções Intravítreas , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neovascularização Patológica/etiologia , Neovascularização Patológica/metabolismo , Oxigênio/toxicidade , Inibidores de Proteínas Quinases/farmacologia , Doenças Retinianas/etiologia , Doenças Retinianas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Inibidor Tecidual de Metaloproteinase-3/genética
10.
Blood ; 118(4): 1163-74, 2011 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-21652679

RESUMO

During vertebrate angiogenesis, Notch regulates the cell-fate decision between vascular tip cells versus stalk cells. Canonical Notch signaling depends on sequential proteolytic events, whereby interaction of Notch with membrane-anchored ligands triggers proteolytic processing, first by Adam10 and then presenilins. This liberates the Notch intracellular domain, allowing it to enter the nucleus and activate Notch-dependent genes. Here we report that conditional inactivation of Adam10 in endothelial cells (A10ΔEC) recapitulates the increased branching and density of the retinal vasculature that is also caused by interfering with Notch signaling. Moreover, A10ΔEC mice have additional vascular abnormalities, including aberrant subcapsular hepatic veins, enlarged glomeruli, intestinal polyps containing endothelial cell masses, abnormal endochondral ossification, leading to stunted long bone growth and increased pathologic neovascularization following oxygen-induced retinopathy. Our findings support a model in which Adam10 is a crucial regulator of endothelial cell-fate decisions, most likely because of its essential role in canonical Notch signaling.


Assuntos
Proteínas ADAM/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Vasos Sanguíneos/embriologia , Vasos Sanguíneos/crescimento & desenvolvimento , Células Endoteliais/metabolismo , Proteínas de Membrana/metabolismo , Neovascularização Fisiológica/fisiologia , Transdução de Sinais/fisiologia , Proteína ADAM10 , Animais , Western Blotting , Embrião de Mamíferos , Camundongos , Camundongos Transgênicos , Receptores Notch/metabolismo , Retina/crescimento & desenvolvimento , Vasos Retinianos/crescimento & desenvolvimento
11.
Biol Bull ; 211(1): 58-65, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16946242

RESUMO

During acclimation to dilute seawater, the specific activity of Na+,K+-ATPase increases substantially in the posterior gills of the blue crab Callinectes sapidus. To determine whether this increase occurs through regulation of pre-existing enzyme or synthesis of new enzyme, mRNA and protein levels were measured over short (<24 h) and long (18 days) time courses. Na+,K+-ATPase expression, both mRNA and protein, did not change during the initial 24-h exposure to dilute seawater (10 ppt salinity). Thus, osmoregulation in C. sapidus during acute exposure to low salinity likely involves either modulation of existing enzyme or mechanisms other than an increase in the amount of Na+,K+-ATPase enzyme. However, crabs exposed to dilute seawater over 18 days showed a 300% increase in Na+,K+-ATPase specific activity as well as a 200% increase in Na+,K+-ATPase protein levels. Thus, it appears that the increase in Na+,K+-ATPase activity during chronic exposure results from the synthesis of new enzyme. The relative amounts of mRNA for the alpha-subunit increased substantially (by 150%) during the acclimation process, but once the crabs had fully acclimated to low salinity, the mRNA levels had decreased and were not different from levels in crabs fully acclimated to high salinity. Thus, there is transient induction of the Na+,K+-ATPase mRNA levels during acclimation to dilute seawater.


Assuntos
Braquiúros/enzimologia , Perfilação da Expressão Gênica , Regulação Enzimológica da Expressão Gênica , ATPase Trocadora de Sódio-Potássio/metabolismo , Estresse Fisiológico/enzimologia , Animais , Concentração Osmolar , RNA Mensageiro
12.
Artigo em Inglês | MEDLINE | ID: mdl-16352450

RESUMO

Green crabs, Carcinus maenas, exposed to dilute seawater (e.g., 5 ppt salinity, approximately 150 mOsm/kg) have hemolymph levels of methyl farnesoate (MF) that are up to 10-fold higher than animals in isosmotic seawater (27 ppt, approximately 800 mOsm/kg). In this paper, we examine aspects of osmotic and ionic stress to identify factors involved in elevating MF levels. MF levels did not rise after exposure to concentrated seawater, so only hypoosmotic stress elevates MF. MF levels rose in animals exposed to dilute seawater containing mannitol to make it isosmotic, indicating that the hypoosmotic rise in MF is due to decreased ion concentrations. Individual ions were investigated by exposing crabs either to isosmotic seawater with low concentrations of an ion or to dilute seawater with high concentrations of an ion. Ca(2+) and Mg(2+) in combination affected MF levels. Finally, we found that the increase in MF levels was accelerated when hemolymph osmolality was precociously lowered by partially replacing hemolymph with deionized water prior to transferring animals to dilute seawater. Thus, the 6-8 h delay between exposing crabs to dilute sea water and observing an increase in MF appears to reflect the time needed for specific hemolymph ions to decrease below a threshold concentration.


Assuntos
Braquiúros/metabolismo , Ácidos Graxos Insaturados/sangue , Hemolinfa/metabolismo , Água do Mar/química , Aclimatação , Animais , Braquiúros/efeitos dos fármacos , Cálcio/metabolismo , Magnésio/metabolismo , Concentração Osmolar
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA