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2.
J Thorac Oncol ; 12(7): 1098-1108, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28461256

RESUMO

INTRODUCTION: Tobacco-related NSCLC is associated with reduced survival and greater genomic instability. Veliparib, a potent poly(adenosine diphosphate-ribose) polymerase inhibitor, augments platinum-induced DNA damage. A phase 2 trial of untreated advanced NSCLC showed a trend for improved outcomes (hazard ratio [HR] = 0.80, 95% confidence interval: 0.54-1.18, p = 0.27 for overall survival and HR = 0.72, 95% CI: 0.45-1.15, p = 0.17 for progression-free survival) when veliparib was added to carboplatin/paclitaxel. Here we report an exploratory analysis by smoking history. METHODS: Patients were randomized 2:1 to receive carboplatin/paclitaxel with veliparib, 120 mg (n = 105), or placebo (n = 53). Patients were stratified by histologic subtype and smoking history (recent smokers [n = 95], former smokers [n = 42], and never-smokers [n = 21]). Plasma cotinine level was measured as a chemical index of smoking. Mutation status was assessed by whole exome sequencing (n = 38). RESULTS: Smoking history, histologic subtype, age, Eastern Cooperative Oncology Group performance status, sex, and geographic region predicted veliparib benefit in univariate analyses. In multivariate analysis, history of recent smoking was most predictive for veliparib benefit. Recent smokers treated with veliparib derived significantly greater progression-free survival and overall survival benefits (HR = 0.38 [p < 0.01] and HR = 0.43 [p < 0.01]) than former smokers (HR = 2.098 [p = 0 0208] and HR = 1.62 [p = 0.236]) and never-smokers (HR = 1.025 [p = 0.971] and HR = 1.33 [p = 0.638]). Sequencing data revealed that mutational burden was not associated with veliparib benefit. The rate of grade 3 or 4 adverse events was higher in recent smokers with veliparib treatment; all-grade and serious adverse events were similar in both treatment arms. CONCLUSIONS: Smoking history predicted for efficacy with a veliparib-chemotherapy combination; toxicity was acceptable regardless of smoking history. A prespecified analysis of recent smokers is planned for ongoing phase 3 studies of veliparib in NSCLC.


Assuntos
Benzimidazóis/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Fumar/efeitos adversos , Idoso , Benzimidazóis/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Método Duplo-Cego , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia
3.
Dev Biol ; 424(2): 236-245, 2017 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-28189604

RESUMO

Hematopoietic stem cells (HSCs) emerge during development via an endothelial-to-hematopoietic transition from hemogenic endothelium of the dorsal aorta (DA). Using in situ hybridization and analysis of a knock-in RedStar reporter, we show that the transcriptional regulator Hhex is expressed in endothelium of the dorsal aorta (DA) and in clusters of putative HSCs as they are specified during murine development. We exploited this observation, using the Hhex locus to define cis regulatory elements, enhancers and interacting transcription factors that are both necessary and sufficient to support gene expression in the emerging HSC. We identify an evolutionarily conserved non-coding region (ECR) in the Hhex locus with the capacity to bind the hematopoietic-affiliated transcriptional regulators Gata2, SCL, Fli1, Pu.1 and Ets1/2. This region is sufficient to drive the expression of a transgenic GFP reporter in the DA endothelium and intra-aortic hematopoietic clusters. GFP-positive AGM cells co-expressed HSC-associated markers c-Kit, CD34, VE-Cadherin, and CD45, and were capable of multipotential differentiation and long term engraftment when transplanted into myelo-ablated recipients. The Hhex ECR was also sufficient to drive expression at additional blood sites including the yolk sac blood islands, fetal liver, vitelline and umbilical arteries and the adult bone marrow, suggesting a common mechanism for Hhex regulation throughout ontogenesis of the blood system. To explore the physiological requirement for the Hhex ECR region during hematoendothelial development, we deleted the ECR element from the endogenous locus in the context of a targeted Hhex-RedStar reporter allele. Results indicate a specific requirement for the ECR in blood-associated Hhex expression during development and further demonstrate a requirement for this region in the adult HSC compartment. Taken together, our results identified the ECR region as an enhancer both necessary and sufficient for gene expression in HSC development and homeostasis. The Hhex ECR thus appears to be a core node for the convergence of the transcription factor network that governs the emergence of HSCs.


Assuntos
Regulação da Expressão Gênica , Hematopoese/genética , Células-Tronco Hematopoéticas/metabolismo , Proteínas de Homeodomínio/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Gênica , Animais , Compartimento Celular , Linhagem da Célula/genética , Ensaio de Unidades Formadoras de Colônias , Sequência Conservada/genética , Embrião de Mamíferos/metabolismo , Loci Gênicos , Proteínas de Fluorescência Verde/metabolismo , Células-Tronco Hematopoéticas/citologia , Proteínas de Homeodomínio/genética , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Sequências Reguladoras de Ácido Nucleico/genética , Fatores de Transcrição/genética
4.
Clin Cancer Res ; 23(8): 1937-1944, 2017 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-27803064

RESUMO

Purpose: PARP plays an important role in DNA repair. Veliparib, a PARP inhibitor, enhances the efficacy of platinum compounds and has been safely combined with carboplatin and paclitaxel. The primary endpoint of this phase II trial determined whether addition of veliparib to carboplatin and paclitaxel improved progression-free survival (PFS) in previously untreated patients with advanced/metastatic non-small cell lung cancer.Experimental Design: Patients were randomized 2:1 to carboplatin and paclitaxel with either veliparib or placebo. Veliparib (120 mg) or placebo was given on days 1 to 7 of each 3-week cycle, with carboplatin (AUC = 6 mg/mL/min) and paclitaxel (200 mg/m2) administered on day 3, for a maximum of 6 cycles.Results: Overall, 158 were included (median age, 63 years; male 68%, squamous histology 48%). Median PFS was 5.8 months in the veliparib group versus 4.2 months in the placebo group [HR, 0.72; 95% confidence interval (CI), 0.45-1.15; P = 0.17)]. Median overall survival (OS) was 11.7 and 9.1 months in the veliparib and placebo groups, respectively (HR, 0.80; 95% CI, 0.54-1.18; P = 0.27). In patients with squamous histology, median PFS (HR, 0.54; 95% CI, 0.26-1.12; P = 0.098) and OS (HR, 0.73; 95% CI, 0.43-1.24; P = 0.24) favored veliparib treatment. Objective response rate was similar between groups (veliparib: 32.4%; placebo: 32.1%), but duration of response favored veliparib treatment (HR, 0.47; 95% CI, 0.16-1.42; P = 0.18). Grade III/IV neutropenia, thrombocytopenia, and anemia were comparable between groups.Conclusions: Veliparib combination with carboplatin and paclitaxel was well-tolerated and demonstrated a favorable trend in PFS and OS versus chemotherapy alone. Patients with squamous histology had the best outcomes with veliparib combination. Clin Cancer Res; 23(8); 1937-44. ©2016 AACR.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Benzimidazóis/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Modelos de Riscos Proporcionais , Resultado do Tratamento
5.
Oncologist ; 21(7): 789-94, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27091420

RESUMO

BACKGROUND: Pegfilgrastim is widely used for the prevention of chemotherapy-induced neutropenia. In highly regulated markets, there are currently no approved biosimilars of pegfilgrastim. Pegfilgrastim Randomized Oncology (Supportive Care) Trial to Evaluate Comparative Treatment (PROTECT-2) was a confirmatory efficacy and safety study designed to compare proposed biosimilar LA-EP2006 with reference pegfilgrastim (Neulasta, Amgen) in early-stage breast cancer patients receiving adjuvant or neoadjuvant myelosuppressive chemotherapy. METHODS: A total of 308 patients were randomized to LA-EP2006 or reference pegfilgrastim. Each patient received TAC (intravenous docetaxel 75 mg/m(2), doxorubicin 50 mg/m(2), and cyclophosphamide 500 mg/m(2)) on day 1 of each cycle, for six or more cycles. Pegfilgrastim (LA-EP2006 or reference) was given subcutaneously (6 mg in 0.6 mL) on day 2 of each cycle. The primary endpoint was duration of severe neutropenia (DSN) during cycle 1 (number of consecutive days with an absolute neutrophil count <0.5 × 10(9)/L), with equivalence confirmed if 90% and 95% confidence intervals (CIs) were within a 1-day margin. RESULTS: Baseline characteristics were well balanced. DSN was equivalent between groups at mean ± SD 1.36 ± 1.13 (LA-EP2006, n = 155) and 1.19 ± 0.98 (reference, n = 153) in cycle 1. With a treatment difference (reference minus LA-EP2006) of -0.16 days (90% CI -0.36 to 0.04; 95% CI -0.40 to 0.08), LA-EP2006 was equivalent to reference pegfilgrastim. Secondary efficacy parameters were similar between groups during cycle 1 and across cycles. Safety profiles were also similar between groups. No neutralizing antibodies against pegfilgrastim, filgrastim, or polyethylene glycol were detected. CONCLUSION: LA-EP2006 and reference pegfilgrastim were therapeutically equivalent and comparable regarding efficacy and safety in the prevention of neutropenia in patients with early-stage breast cancer receiving TAC. IMPLICATIONS FOR PRACTICE: The granulocyte colony-stimulating factor pegfilgrastim is widely used for the prevention of chemotherapy-induced neutropenia. Biosimilars are biologics with similar quality, safety, and efficacy to a reference product that may increase the affordability of treatment compared with their reference compounds. There are currently no approved biosimilars of pegfilgrastim in highly regulated markets. No previous phase III studies have been performed with LA-EP2006. PROTECT-2 was conducted to confirm the similarity of the proposed biosimilar LA-EP2006 to pegfilgrastim. Biosimilar pegfilgrastim (LA-EP2006) may benefit oncology patients by offering increased access to biological treatments that may improve clinical outcomes. This means that patients could potentially be treated prophylactically with biologics rather than only after complications have occurred.


Assuntos
Medicamentos Biossimilares/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Terapia Neoadjuvante , Neutropenia/prevenção & controle , Adulto , Medula Óssea/efeitos dos fármacos , Neoplasias da Mama/patologia , Método Duplo-Cego , Feminino , Filgrastim , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Polietilenoglicóis , Estudos Prospectivos , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico
6.
Differentiation ; 89(1-2): 22-30, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25619648

RESUMO

Arkadia (also known as RING finger 111) encodes a nuclear E3 ubiquitin ligase that targets intracellular effectors and modulators of TGFß/Nodal-related signaling for polyubiquitination and proteasome-dependent degradation. In the mouse, loss of Arkadia results in early embryonic lethality, with defects attributed to compromised Nodal signaling. Here, we report the isolation of zebrafish arkadia/rnf111, which is represented by 5 transcript variants. arkadia/rnf111 is broadly expressed during the blastula and gastrula stages, with eventual enrichment in the anterior mesendoderm, including the prechordal plate. Morpholino knockdown experiments reveal an unexpected role for Arkadia/Rnf111 in both early blastula organization and epiboly progression. Using a splice junction morpholino, we present additional evidence that arkadia/rnf111 transcript variants containing a 3' alternative exon are specifically required for epiboly progression in the late gastrula. This result suggests that arkadia/rnf111 transcript variants encode functionally relevant protein isoforms that provide additional intracellular flexibility and regulation to the Nodal signaling pathway.


Assuntos
Morfogênese/genética , Isoformas de Proteínas/genética , Transcrição Gênica , Peixe-Zebra/genética , Processamento Alternativo/genética , Animais , Gástrula/crescimento & desenvolvimento , Humanos , Camundongos , Ligantes da Sinalização Nodal/genética , Isoformas de Proteínas/isolamento & purificação , Ubiquitina-Proteína Ligases/genética , Peixe-Zebra/crescimento & desenvolvimento
7.
Dev Cell ; 29(3): 277-91, 2014 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-24768165

RESUMO

Wnts are transported to the cell surface by the integral membrane protein WLS (also known as Wntless, Evi, and GPR177). Previous studies of WLS trafficking have emphasized WLS movement from the Golgi to the plasma membrane (PM) and then back to the Golgi via retromer-mediated endocytic recycling. We find that endogenous WLS binds Wnts in the endoplasmic reticulum (ER), cycles to the PM, and then returns to the ER through the Golgi. We identify an ER-targeting sequence at the carboxyl terminus of native WLS that is critical for ER retrograde recycling and contributes to Wnt secretory function. Golgi-to-ER recycling of WLS requires the COPI regulator ARF as well as ERGIC2, an ER-Golgi intermediate compartment protein that is also required for the retrograde trafficking of the KDEL receptor and certain toxins. ERGIC2 is required for efficient Wnt secretion. ER retrieval is an integral part of the WLS transport cycle.


Assuntos
Fator 1 de Ribosilação do ADP/metabolismo , Retículo Endoplasmático/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Proteína Wnt3A/metabolismo , Fator 1 de Ribosilação do ADP/genética , Fatores de Ribosilação do ADP/genética , Sequência de Aminoácidos , Animais , Transporte Biológico , Linhagem Celular , Membrana Celular/metabolismo , Complexo I de Proteína do Envoltório , Complexo de Golgi/metabolismo , Células HeLa , Humanos , Oócitos , Isoformas de Proteínas/metabolismo , Interferência de RNA , RNA Interferente Pequeno , Receptores de Peptídeos/metabolismo , Vesículas Transportadoras , Proteínas de Transporte Vesicular/genética , Xenopus laevis
8.
Stem Cells ; 31(12): 2724-36, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23939995

RESUMO

Signaling through fibroblast growth factor receptor one (FGFR1) is a known inducer of proliferation in both embryonic and human adult mesenchymal stem cells (hMSCs) and positively regulates maintenance of stem cell viability. Leveraging the mitogenic potential of FGF2/FGFR1 signaling in stem cells for therapeutic applications necessitates a mechanistic understanding of how this receptor stimulates cell cycle progression. Using small interfering RNA (siRNA) depletion, antibody-inhibition, and small molecule inhibition, we establish that FGFR1 activity is rate limiting for self-renewal of hMSCs. We show that FGFR1 promotes stem cell proliferation through multiple mechanisms that unite to antagonize cyclin-dependent kinase (CDK) inhibitors. FGFR1 not only stimulates c-Myc to suppress transcription of the CDK inhibitors p21(Waf1) and p27(Kip1), thus promoting cell cycle progression but also increases the activity of protein kinase B (AKT) and the level of S-phase kinase-associated protein 2 (Skp2), resulting in the nuclear exclusion and reduction of p21(Waf1). The in vivo importance of FGFR1 signaling for the control of proliferation in mesenchymal progenitor populations is underscored by defects in ventral mesoderm formation during development upon inhibition of its signaling. Collectively, these studies demonstrate that FGFR1 signaling mediates the continuation of MSC growth and establishes a receptor target for enhancing the expansion of mesenchymal progenitors while maintaining their multilineage potential.


Assuntos
Inibidor de Quinase Dependente de Ciclina p21/antagonistas & inibidores , Inibidor de Quinase Dependente de Ciclina p27/antagonistas & inibidores , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Animais , Ciclo Celular/fisiologia , Processos de Crescimento Celular/fisiologia , Células Cultivadas , Inibidor de Quinase Dependente de Ciclina p21/biossíntese , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/biossíntese , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Fator de Crescimento Epidérmico/metabolismo , Fase G1/fisiologia , Humanos , Proteínas Proto-Oncogênicas c-myc/biossíntese , Proteínas Proto-Oncogênicas c-myc/genética , Fase S/fisiologia , Transdução de Sinais , Xenopus laevis
9.
Phys Rev Lett ; 109(11): 113601, 2012 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-23005626

RESUMO

We analyzed the electrophysiological response of an isolated rod photoreceptor of Xenopus laevis under stimulation by coherent and pseudothermal light sources. Using the suction-electrode technique for single cell recordings and a fiber optics setup for light delivery allowed measurements of the major statistical characteristics of the rod response. The results indicate differences in average responses of rod cells to coherent and pseudothermal light of the same intensity and also differences in signal-to-noise ratios and second-order intensity correlation functions. These findings should be relevant for interdisciplinary studies seeking applications of quantum optics in biology.


Assuntos
Modelos Biológicos , Fótons , Células Fotorreceptoras Retinianas Bastonetes/fisiologia , Animais , Fenômenos Eletrofisiológicos , Tecnologia de Fibra Óptica/instrumentação , Tecnologia de Fibra Óptica/métodos , Teoria Quântica , Rodopsina/química , Rodopsina/fisiologia , Análise de Célula Única/instrumentação , Análise de Célula Única/métodos , Xenopus laevis
10.
Biomed Opt Express ; 2(11): 2926-33, 2011 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-22076256

RESUMO

A method of controllable light delivery to retinal rod cells using an optical fiber is described. Photo-induced current of the living rod cells was measured with the suction electrode technique. The approach was tested with measurements relating the spatial distribution of the light intensity to photo-induced current. In addition, the ion current responses of rod cells to polarized light at two different orientation geometries of the cells were studied.

11.
Dev Dyn ; 240(8): 1958-63, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21761481

RESUMO

Fermitin genes are highly conserved and encode cytocortex proteins that mediate integrin signalling. Fermitin 1 (Kindlin1) is implicated in Kindler syndrome, a human skin blistering disorder. We report the isolation of the three Fermitin orthologs from Xenopus laevis embryos and describe their developmental expression patterns. Fermitin 1 is expressed in the skin, otic and olfactory placodes, pharyngeal arches, pronephric duct, and heart. Fermitin 2 is restricted to the somites and neural crest. Fermitin 3 is expressed in the notochord, central nervous system, cement gland, ventral blood islands, vitelline veins, and myeloid cells. Our findings are consistent with the view that Fermitin 1 is generally expressed in the skin, Fermitin 2 in muscle, and Fermitin 3 in hematopoietic lineages. Moreover, we describe novel sites of Fermitin gene expression that extend our knowledge of this family. Our data provide a basis for further functional analysis of the Fermitin family in Xenopus laevis.


Assuntos
Embrião não Mamífero/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Membrana/metabolismo , Isoformas de Proteínas/metabolismo , Proteínas de Xenopus/metabolismo , Xenopus laevis/embriologia , Xenopus laevis/genética , Xenopus laevis/metabolismo , Animais , Embrião não Mamífero/anatomia & histologia , Humanos , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Isoformas de Proteínas/genética , Distribuição Tecidual , Proteínas de Xenopus/genética , Xenopus laevis/anatomia & histologia
12.
J Cell Sci ; 123(Pt 19): 3357-67, 2010 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-20826466

RESUMO

Wnt proteins are secreted post-translationally modified proteins that signal locally to regulate development and proliferation. The production of bioactive Wnts requires a number of dedicated factors in the secreting cell whose coordinated functions are not fully understood. A screen for small molecules identified inhibitors of vacuolar acidification as potent inhibitors of Wnt secretion. Inhibition of the V-ATPase or disruption of vacuolar pH gradients by diverse drugs potently inhibited Wnt/ß-catenin signaling both in cultured human cells and in vivo, and impaired Wnt-regulated convergent extension movements in Xenopus embryos. WNT secretion requires its binding to the carrier protein wntless (WLS); we find that WLS is ER-resident in human cells and WNT3A binding to WLS requires PORCN-dependent lipid modification of WNT3A at serine 209. Inhibition of vacuolar acidification results in accumulation of the WNT3A-WLS complex both in cells and at the plasma membrane. Modeling predictions suggest that WLS has a lipid-binding ß-barrel that is similar to the lipocalin-family fold. We propose that WLS binds Wnts in part through a lipid-binding domain, and that vacuolar acidification is required to release palmitoylated WNT3A from WLS in secretory vesicles, possibly to facilitate transfer of WNT3A to a soluble carrier protein.


Assuntos
Adenosina Trifosfatases/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Macrolídeos/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Vacúolos/metabolismo , Proteínas Wnt/metabolismo , Acilação , Animais , Embrião não Mamífero , Desenvolvimento Embrionário/efeitos dos fármacos , Células HEK293 , Humanos , Concentração de Íons de Hidrogênio , Macrolídeos/isolamento & purificação , Ligação Proteica , Serina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/isolamento & purificação , Vacúolos/química , Proteína Wnt3 , Proteína Wnt3A , Xenopus , Proteínas de Xenopus
13.
Dev Cell ; 19(3): 413-25, 2010 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-20833363

RESUMO

The segmental premature aging disease Hutchinson-Gilford Progeria (HGPS) is caused by a truncated and farnesylated form of Lamin A. In a mouse model for HGPS, a similar Lamin A variant causes the proliferative arrest and death of postnatal, but not embryonic, fibroblasts. Arrest is due to an inability to produce a functional extracellular matrix (ECM), because growth on normal ECM rescues proliferation. The defects are associated with inhibition of canonical Wnt signaling, due to reduced nuclear localization and transcriptional activity of Lef1, but not Tcf4, in both mouse and human progeric cells. Defective Wnt signaling, affecting ECM synthesis, may be critical to the etiology of HGPS because mice exhibit skeletal defects and apoptosis in major blood vessels proximal to the heart. These results establish a functional link between the nuclear envelope/lamina and the cell surface/ECM and may provide insights into the role of Wnt signaling and the ECM in aging.


Assuntos
Matriz Extracelular/metabolismo , Lâmina Nuclear/metabolismo , Progéria/metabolismo , Transdução de Sinais/fisiologia , Proteínas Wnt/metabolismo , Xenopus laevis/embriologia , Animais , Apoptose , Biomarcadores/metabolismo , Western Blotting , Proliferação de Células , Células Cultivadas , Imunoprecipitação da Cromatina , Embrião de Mamíferos/citologia , Embrião de Mamíferos/metabolismo , Ensaio de Imunoadsorção Enzimática , Fibroblastos/citologia , Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Humanos , Lamina Tipo A/fisiologia , Luciferases/metabolismo , Camundongos , Camundongos Knockout , Análise de Sequência com Séries de Oligonucleotídeos , Progéria/patologia , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Síndrome
14.
Clin Breast Cancer ; 9(2): 77-85, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19433387

RESUMO

BACKGROUND: Postmenopausal women with breast cancer receiving adjuvant aromatase inhibitors (AIs) are at risk for accelerated bone loss and subsequent fractures. The ongoing Zometa-Femara Adjuvant Synergy Trial (Z-FAST) is evaluating the efficacy and safety of zoledronic acid in preventing such bone loss. PATIENTS AND METHODS: In this multicenter study, postmenopausal women with early hormone receptor-positive breast cancer receiving adjuvant letrozole were randomized to receive up-front or delayed-start zoledronic acid (ZA; 4 mg intravenously every 6 months) for 5 years. Delayed-start ZA was administered if the lumbar spine (LS) or total hip (TH) T score fell below -2.0 or a nontraumatic fracture occurred. The primary endpoint was to compare the change from baseline in LS bone mineral density (BMD) between groups at month 12; secondary endpoints, measured at other predetermined timepoints, included comparing changes in TH BMD, LS BMD, and markers of bone turnover, fracture incidence, and time to disease recurrence. Herein, we report the results of the 36-month interim analysis. RESULTS: Overall, 301 patients were randomized to each group. At month 36, the absolute difference in mean LS and TH BMDs between the up-front and delayed groups was 6.7% and 5.2%, respectively (P < .0001 for both). Although this study was not designed to show antifracture efficacy, the incidence of fractures was slightly higher in the delayed group (up-front, 17 [5.7%] vs. delayed, 19 [6.3%]) but not statistically significant (P = .8638). Pyrexia (27 [9%] vs. 6 [2%]; P = .0002) and bone pain (39 [13%] vs. 20 [6.7%]; P = .01) were more common in up-front patients; cough (13 [4.3%] vs. 27 [9%]; P = .03) was more common in delayed patients. No severe renal dysfunction or confirmed cases of osteonecrosis of the jaw were reported. Disease recurrence was reported in 9 up-front (3.0%) and 16 delayed (5.3%) patients (Kaplan-Meier analysis, P = .127), with an absolute decrease of 2.3%. CONCLUSION: Up-front ZA more effectively prevents AI-associated bone loss in postmenopausal women with early breast cancer than delaying therapy until substantial bone loss or fracture occurs.


Assuntos
Inibidores da Aromatase/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Difosfonatos/uso terapêutico , Imidazóis/uso terapêutico , Nitrilas/efeitos adversos , Osteoporose Pós-Menopausa/tratamento farmacológico , Triazóis/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Densidade Óssea/efeitos dos fármacos , Feminino , Seguimentos , Humanos , Letrozol , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Osteoporose Pós-Menopausa/induzido quimicamente , Prognóstico , Taxa de Sobrevida , Resultado do Tratamento , Ácido Zoledrônico
15.
Neural Dev ; 3: 35, 2008 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-19077309

RESUMO

BACKGROUND: Neurogenic placodes are focal thickenings of the embryonic ectoderm that form in the vertebrate head. It is within these structures that the precursors of the majority of the sensory neurons of the cranial ganglia are specified. The trigeminal placodes, the ophthalmic and maxillomandibular, form close to the midbrain-hindbrain boundary and many lines of evidence have shown that signals emanating from this level of the neuraxis are important for the development of the ophthalmic placode. RESULTS: Here, we provide the first evidence that both the ophthalmic and maxillomandibular placodes form under the influence of isthmic Wnt and FGF signals. Activated Wnt signals direct development of the Pax3 expressing ophthalmic placodal field and induce premature differentiation of both the ophthalmic and the maxillomandibular placodes. Similarly, overexpression of Fgf8 directs premature differentiation of the trigeminal placodes. Wnt signals require FGF receptor activity to initiate Pax3 expression and, subsequently, the expression of neural markers, such as Brn3a, within the cranial ectoderm. Furthermore, fibroblast growth factor signaling via the mitogen activated protein kinase pathway is required to maintain early neuronal differentiation within the trigeminal placodes. CONCLUSION: We demonstrate the identity of inductive signals that are necessary for trigeminal ganglion formation. This is the first report that describes how isthmic derived Wnt signals act in concert with fibroblast growth factor signaling. Together, both are necessary and sufficient for the establishment and differentiation of the ophthalmic and maxillomandibular placodes and, consequently, the trigeminal ganglion.


Assuntos
Diferenciação Celular/fisiologia , Fator 8 de Crescimento de Fibroblasto/metabolismo , Tubo Neural/embriologia , Tubo Neural/metabolismo , Neurônios/metabolismo , Transdução de Sinais/fisiologia , Gânglio Trigeminal/fisiologia , Proteínas Wnt/metabolismo , Animais , Western Blotting , Embrião de Galinha , Fator 8 de Crescimento de Fibroblasto/genética , Regulação da Expressão Gênica no Desenvolvimento , Imuno-Histoquímica , Hibridização In Situ , Tubo Neural/citologia , Neurônios/citologia , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Gânglio Trigeminal/embriologia , Gânglio Trigeminal/crescimento & desenvolvimento , Gânglio Trigeminal/metabolismo , Proteínas Wnt/genética
19.
Int J Hematol ; 88(5): 489-494, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19009241

RESUMO

Polycythemia rubra vera is a chronic myeloproliferative disorder characterized by panmyelosis with the resultant potential for thrombosis, myelofibrosis, and acute leukemia. Treatment has rested on phlebotomy and hydroxyurea. In 2002, we reported two patients who were unable to tolerate hydroxyurea but responded to imatinib mesylate (Gleevec). These patients have remained in complete hematologic remission on imatinib since 1999. As a result we began a phase II, open label trial of imatinib in patients with polycythemia vera. Patients meeting the Polycythemia Vera Study group criteria for the diagnosis of polycythemia vera, either naïve or intolerant to prior treatment were allowed to enroll. Initial therapy was begun with imatinib mesylate at 400 mg a day and two dose escalations, one to 600 and second to 800 mg a day, were allowed for patients not achieving a target hematocrit of 44 or less; or a platelet count of less than 600,000/mm(3). Twenty patients were enrolled, 15 achieved complete hematologic remission within 12 weeks and ten remain on study. Six patients remain in remission on 400 mg a day and four on 500 mg a day. Gastrointestinal or cutaneous toxicities were primarily grade I or II. All patients were negative for bcr/abl. Imatinib mesylate is capable of producing hematologic remission in the majority of patients with polycythemia vera and provides another option for patient management, particularly in those intolerant to hydroxyurea.


Assuntos
Antineoplásicos/administração & dosagem , Piperazinas/administração & dosagem , Policitemia Vera/tratamento farmacológico , Pirimidinas/administração & dosagem , Adulto , Idoso , Antineoplásicos/efeitos adversos , Benzamidas , Relação Dose-Resposta a Droga , Feminino , Gastroenteropatias/sangue , Gastroenteropatias/induzido quimicamente , Hematócrito , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Piperazinas/efeitos adversos , Contagem de Plaquetas , Policitemia Vera/sangue , Pirimidinas/efeitos adversos , Indução de Remissão , Dermatopatias/sangue , Dermatopatias/induzido quimicamente
20.
Development ; 135(15): 2649-58, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18579681

RESUMO

Nodal proteins are secreted signaling factors of the transforming growth factor beta (TGFbeta) family with essential roles in embryonic development in vertebrates. Mutations affecting the Nodal factors have severe consequences in mammals and fish. Furthermore, increased Nodal levels have been associated with melanoma tumor progression. Like other TGFbeta-related proteins, Nodal factors consist of a pro-domain and a mature domain. The pro-domain of mouse Nodal protein stabilizes its precursor. However, the mechanisms by which the pro-domains exert their activities are unknown. Here, we characterize the zebrafish Nodal-related factor Cyclops (Cyc) and find unexpected functions for the pro-domain in regulating Cyc activity. We identified a lysosome-targeting region in the Cyc pro-domain that destabilizes the precursor and restricts Cyc activity, revealing the molecular basis for the short-range signaling activities of Cyc. We show that both the pro- and mature-domains of Cyc regulate its stability. We also characterize a mutation in the pro-domain of human NODAL (hNODAL) that underlies congenital heterotaxia. Heterologous expression of mutant hNODAL increases expression of Nodal-response genes. Our studies reveal unexpected roles for the pro-domain of the Nodal factors and provide a possible mechanism for familial heterotaxia.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Transdução de Sinais , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/metabolismo , Animais , Linhagem Celular , Embrião não Mamífero/embriologia , Embrião não Mamífero/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Lisossomos/genética , Lisossomos/metabolismo , Mutação/genética , Proteína Nodal , Ligantes da Sinalização Nodal , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Xenopus laevis , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
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