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1.
Am J Transl Res ; 8(2): 940-54, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27158381

RESUMO

BACKGROUND: The laminin-binding integrin (LBI) family are cell adhesion molecules that are essential for invasion and metastasis of human epithelial cancers and cell adhesion mediated drug resistance. We investigated whether copy number alteration (CNA) or mutations of a five-gene signature (ITGB4, ITGA3, LAMB3, PLEC, and SYNE3), representing essential genes for LBI adhesion, would correlate with patient outcomes within human epithelial-type tumor data sets currently available in an open access format. METHODS: We investigated the relative alteration frequency of an LBI signature panel (integrin ß4 (ITGB4), integrin α3 (ITGA3), laminin ß3 chain (LAMB3), plectin (PLEC), and nesprin 3 (SYNE3)), independent of the epithelial cancer type, within publically available and published data using cBioPortal and Oncomine software. We rank ordered the results using a 20% alteration frequency cut-off and limited the analysis to studies containing at least 100 samples. Kaplan-Meier survival curves were analyzed to determine if alterations in the LBI signature correlated with patient survival. The Oncomine data mining tool was used to compare the heat map expression of the LBI signature without SYNE3 (as this was not included in the Oncomine database) to drug resistance patterns. RESULTS: Twelve different cancer types, representing 5,647 samples, contained at least a 20% alteration frequency of the five-gene LBI signature. The frequency of alteration ranged from 38.3% to 19.8%. Within the LBI signature, PLEC was the most commonly altered followed by LAMB3, ITGB4, ITGA3, and SYNE3 across all twelve cancer types. Within cancer types, there was little overlap of the individual amplified genes from each sample, suggesting different specific amplicons may alter the LBI adhesion structures. Of the twelve cancer types, overall survival was altered by CNA presence in bladder urothelial carcinoma (p=0.0143*) and cervical squamous cell carcinoma and endocervical adenocarcinoma (p=0.0432*). Querying the in vitro drug resistance profiles with the LBI signature demonstrated a positive correlation with cells resistant to inhibitors of HDAC (Vorinostat, Panobinostat) and topoisomerase II (Irinotecan). No correlation was found with the following agents: Bleomycin, Doxorubicin, Methotrexate, Gemcitabine, Docetaxel, Bortezomib, and Shikonen. CONCLUSIONS: Our work has identified epithelial-types of human cancer that have significant CNA in our selected five-gene signature, which was based on the essential and genetically-defined functions of the protein product networks (in this case, the LBI axis). CNA of the gene signature not only predicted overall survival in bladder, cervical, and endocervical adenocarcinoma but also response to chemotherapy. This work suggests that future studies designed to optimize the gene signature are warranted. GENERAL SIGNIFICANCE: The copy number alteration of structural components of the LBI axis in epithelial-type tumors may be promising biomarkers and rational targets for personalized therapy in preventing or arresting metastatic spread.

2.
Am J Transl Res ; 7(2): 348-55, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25901201

RESUMO

Bone is a favored site for solid tumor metastasis, especially among patients with breast, lung or prostate carcinomas. Micro CT is a powerful and inexpensive tool that can be used to investigate tumor progression in xenograft models of human disease. Many previous studies have relied on terminal analysis of harvested bones to document metastatic tumor activity. The current protocol uses live animals and combines sequential micro CT evaluation of lesion development with matched histopathology at the end of the study. The approach allows for both rapid detection and evaluation of bone lesion progression in live animals. Bone resident tumors are established either by direct (intraosseous) or arterial (intracardiac) injection, and lesion development is evaluated for up to eight weeks. This protocol provides a clinically relevant method for investigating bone metastasis progression and the development of osteotropic therapeutic strategies for the treatment of bone metastases.

3.
Cancer Biol Ther ; 16(1): 43-51, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25485960

RESUMO

Gemcitabine based treatment is currently a standard first line treatment for patients with advanced pancreatic cancer, however overall survival remains poor, and few options are available for patients that fail gemcitabine based therapy. To identify potential molecular targets in gemcitabine refractory pancreatic cancer, we developed a series of gemcitabine resistant (GR) cell lines. Initial drug exposure selected for an early resistant phenotype that was independent of drug metabolic pathways. Prolonged drug selection pressure after 16 weeks, led to an induction of cytidine deaminase (CDA) and enhanced drug detoxification. Cross resistance profiles demonstrate approximately 100-fold cross resistance to the pyrimidine nucleoside cytarabine, but no resistance to the same in class agents, azacytidine and decitabine. GR cell lines demonstrated a dose dependent collateral hypersensitivity to class I and II histone deacetylase (HDAC) inhibitors and decreased expression of 3 different global heterochromatin marks, as detected by H4K20me3, H3K9me3 and H3K27me3. Cell morphology of the drug resistant cell lines demonstrated a fibroblastic type appearance with loss of cell-cell junctions and an altered microarray expression pattern, using Gene Ontology (GO) annotation, consistent with progression to an invasive phenotype. Of particular note, the gemcitabine resistant cell lines displayed up to a 15 fold increase in invasive potential that directly correlates with the level of gemcitabine resistance. These findings suggest a mechanistic relationship between chemoresistance and metastatic potential in pancreatic carcinoma and provide evidence for molecular pathways that may be exploited to develop therapeutic strategies for refractory pancreatic cancer.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos , Inibidores de Histona Desacetilases/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Cromatina/genética , Cromatina/metabolismo , Desoxicitidina/farmacologia , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Histona Desacetilases/metabolismo , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Fenótipo
4.
Mol Cancer Ther ; 13(6): 1558-66, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24739392

RESUMO

Laminin-binding integrin receptors are key mediators of epithelial cell migration and tumor metastasis. Recent studies have demonstrated a role for the α6 integrin (ITGA6/CD49f) in maintaining stem cell compartments within normal bone marrow and in residency of tumors metastatic to bone. In this study, we tested a function-blocking antibody specific for ITGA6, called J8H, to determine if preexisting cancer lesions in bone could be slowed and/or animal survival improved. Human prostate tumors were established by intracardiac injection into male SCID mice and treatment with J8H antibody was initiated after 1 week. Tumor progression was monitored by micro-computed tomography (CT) imaging of skeletal lesions. Animals that received weekly injections of the anti-ITGA6 antibody showed radiographic progression in only 40% of osseous tumors (femur or tibia), compared with control animals, where 80% of the lesions (femur or tibia) showed progression at 5 weeks. Kaplan-Meier survival analysis demonstrated a significant survival advantage for J8H-treated animals. Unexpectedly, CT image analysis revealed an increased proportion of bone lesions displaying a sclerotic rim of new bone formation, encapsulating the arrested lytic lesions in animals that received the anti-ITGA6 antibody treatment. Histopathology of the sclerotic lesions demonstrated well-circumscribed tumor within bone, surrounded by fibrosis. These data suggest that systemic targeting of the ITGA6-dependent function of established tumors in bone may offer a noncytotoxic approach to arrest the osteolytic progression of metastatic prostate cancer, thereby providing a new therapeutic strategy for advanced disease.


Assuntos
Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos/administração & dosagem , Neoplasias Ósseas/tratamento farmacológico , Integrina alfa6/metabolismo , Terapia de Alvo Molecular , Neoplasias da Próstata/tratamento farmacológico , Animais , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Linhagem Celular Tumoral , Humanos , Integrina alfa6/efeitos dos fármacos , Masculino , Camundongos , Osteoblastos/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
5.
J Immigr Minor Health ; 15(2): 234-43, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22618357

RESUMO

Obesity at diagnosis of breast cancer is associated with higher all-cause mortality and treatment-associated toxicities. We evaluated the association between parity and obesity in the Ella study, a population of Mexican and Mexican-American breast cancer patients with high parity. Obesity outcomes included body mass index (BMI) ≥30 kg/m(2), waist circumference (WC) ≥35 in (88 cm), and waist-to-hip-ratio (WHR) ≥0.85. Prevalence of obesity ([BMI] ≥ 30 kg/m(2)) was 38.9 %. For WC, the multivariate odds ratio (OR) (95 % confidence interval [CI]) for having WC ≥ 35 inches in women with ≥4 pregnancies relative to those with 1-2 pregnancies was 1.59 (1.01-2.47). Higher parity (≥4 pregnancies) was non-significantly associated with high BMI (OR = 1.10; 95 % CI 0.73-1.67). No positive association was observed for WHR. Our results suggest WC is independently associated with high parity in Hispanic women and may be an optimal target for post-partum weight loss interventions.


Assuntos
Americanos Mexicanos , Obesidade/etnologia , Paridade , Feminino , Humanos , México , Pessoa de Meia-Idade , Gravidez , Estados Unidos , Circunferência da Cintura
6.
J Surg Oncol ; 105(1): 48-54, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21882193

RESUMO

BACKGROUND: The purpose of this study was to evaluate the effect of a video on patient understanding of basic breast cancer concepts. METHODS: An 11 item tool of breast cancer concepts was devised. A previous study obtained baseline information on patient knowledge. Subsequently an 8 min video was designed to facilitate the understanding of these concepts. The next 40 consecutive patients who saw the video were then administered the same 11 item questionnaire. RESULTS: Eighty-one women agreed to participate in the study, 41 before and 40 after the implementation of the video. Fifty-one percent had less than a high school education. The group who saw the video had a higher mean number of questions correct (6.7 vs. 8.9, P = 0.0007). Interestingly 90% of all respondents correctly answered the question on the value of screening mammography, however, only 37% of these patients underwent screening mammograms. A multiple linear regression model adjusting for years of education, language, and seeing the video, revealed that having seen the video (P = 0.0029) and years of education (P = 0.0002) remained significantly associated with higher score. CONCLUSIONS: Implementation of an educational video significantly improved understanding of breast cancer concepts in an undereducated population.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/prevenção & controle , Conhecimentos, Atitudes e Prática em Saúde , Hospitais de Condado , Mamografia/estatística & dados numéricos , Educação de Pacientes como Assunto , Gravação de Videoteipe , Adulto , Idoso , Arizona/epidemiologia , Neoplasias da Mama/diagnóstico por imagem , Carcinoma Ductal de Mama/diagnóstico por imagem , Carcinoma Ductal de Mama/epidemiologia , Carcinoma Ductal de Mama/prevenção & controle , Carcinoma Lobular/diagnóstico por imagem , Carcinoma Lobular/epidemiologia , Carcinoma Lobular/prevenção & controle , Compreensão , Feminino , Humanos , Programas de Rastreamento , Pessoa de Meia-Idade , Prognóstico , Inquéritos e Questionários
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