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1.
Vaccine ; 32(37): 4708-12, 2014 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-24768580

RESUMO

Vaccines are among the most cost-effective interventions against infectious diseases. Many candidate vaccines targeting neglected diseases in low- and middle-income countries are now progressing to large-scale clinical testing. However, controversy surrounds the appropriate design of vaccine trials and, in particular, the use of unvaccinated controls (with or without placebo) when an efficacious vaccine already exists. This paper specifies four situations in which placebo use may be acceptable, provided that the study question cannot be answered in an active-controlled trial design; the risks of delaying or foregoing an efficacious vaccine are mitigated; the risks of using a placebo control are justified by the social and public health value of the research; and the research is responsive to local health needs. The four situations are: (1) developing a locally affordable vaccine, (2) evaluating the local safety and efficacy of an existing vaccine, (3) testing a new vaccine when an existing vaccine is considered inappropriate for local use (e.g. based on epidemiologic or demographic factors), and (4) determining the local burden of disease.


Assuntos
Placebos , Ensaios Clínicos Controlados Aleatórios como Assunto/ética , Projetos de Pesquisa , Vacinas , Guias como Assunto , Organização Mundial da Saúde
5.
Virtual Mentor ; 11(9): 714-20, 2009 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-23199469
10.
Mol Cancer Ther ; 4(10): 1484-94, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16227397

RESUMO

Similar to other anticancer agents, intrinsic or acquired resistance to DNA-damaging chemotherapeutics is a major obstacle for cancer therapy. Current strategies aimed at overcoming this problem are mostly based on the premise that tumor cells acquire heritable genetic mutations that contribute to drug resistance. Here, we present evidence for an epigenetic, tumor cell adhesion-mediated, and reversible form of drug resistance that is associated with a reduction of DNA mismatch repair proteins PMS2 and/or MLH1 as well as other members of this DNA repair process. Growth of human breast cancer, human melanoma, and murine EMT-6 breast cancer cell lines as multicellular spheroids in vitro, which is associated with increased resistance to many chemotherapeutic drugs, including alkylating agents, is shown to lead to a reproducible down-regulation of PMS2, MLH1, or, in some cases, both as well as MHS6, MSH3, and MSH2. The observed down-regulation is in part reversible by treatment of tumor spheroids with the DNA-demethylating agent, 5-azacytidine. Thus, treatment of EMT-6 mouse mammary carcinoma spheroids with 5-azacytidine resulted in reduced and/or disrupted cell-cell adhesion, which in turn sensitized tumor spheroids to cisplatin-mediated killing in vitro. Our results suggest that antiadhesive agents might sensitize tumor spheroids to alkylating agents in part by reversing or preventing reduced DNA mismatch repair activity and that the chemosensitization properties of 5-azacytidine may conceivably reflect its role as a potential antiadhesive agent as well as reversal agent for MLH1 gene silencing in human tumors.


Assuntos
Adenosina Trifosfatases/metabolismo , Antineoplásicos Alquilantes/farmacologia , Proteínas de Transporte/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Reparo do DNA , Proteínas de Ligação a DNA/metabolismo , Neoplasias Mamárias Experimentais/tratamento farmacológico , Proteínas Nucleares/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Azacitidina/farmacologia , Pareamento Incorreto de Bases , Western Blotting , Linhagem Celular Tumoral , Cisplatino/farmacologia , Metilação de DNA , Resistencia a Medicamentos Antineoplásicos , Humanos , Ácidos Hidroxâmicos/farmacologia , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/metabolismo , Camundongos , Endonuclease PMS2 de Reparo de Erro de Pareamento , Proteína 1 Homóloga a MutL , Regiões Promotoras Genéticas , Esferoides Celulares , Células Tumorais Cultivadas
13.
Biosecur Bioterror ; 3(2): 128-37, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16000044

RESUMO

The threat of bioterrorism has prompted the U.S. to undertake a vast biodefense initiative, including funding biodefense-related scientific research at unprecedented levels. Unfortunately, the many ethical, economic, environmental, legal, and social implications (E(3)LSI) of biodefense research and activities are not yet receiving the attention they warrant. Previously, in laudable demonstrations of foresight and responsibility, the federal government has funded research into the E(3)LSI of other recent scientific endeavors--namely, the Human Genome Project and the nanotechnology research program--through directed appropriations from their respective research budgets. This article advocates and proposes a model for a portion of biodefense funding to be similarly set aside for an E(3)LSI research program to complement biodefense research, to ensure that bioterror preparedness does not give rise to harmful or otherwise undesirable unintended consequences.


Assuntos
Bioterrorismo , Defesa Civil , Defesa Civil/economia , Defesa Civil/ética , Defesa Civil/legislação & jurisprudência , Defesa Civil/organização & administração , Planejamento em Desastres , Humanos , Pesquisa/organização & administração , Estados Unidos
14.
Cancer Res ; 64(18): 6616-25, 2004 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-15374976

RESUMO

A major obstacle compromising the successful application of many of the new targeted anticancer drugs, including angiogenesis inhibitors, is the empiricism associated with determining an effective biological/therapeutic dose because many of these drugs express optimum therapeutic activity below the maximum tolerated dose, if such a dose can be defined. Hence, surrogate markers are needed to help determine optimal dosing. Here we describe such a molecular marker, increased plasma levels of vascular endothelial growth factor (VEGF), in normal or tumor-bearing mice that received injections of an anti-VEGF receptor (VEGFR)-2 monoclonal antibody, such as DC101. Rapid increases of mouse VEGF (e.g., within 24 hours) up to 1 order of magnitude were observed after single injections of DC101 in non-tumor-bearing severe combined immunodeficient or nude mice; similar increases in human plasma VEGF were detected in human tumor-bearing mice. RAFL-1, another anti-VEGFR-2 antibody, also caused a significant increase in plasma VEGF. In contrast, increases in mouse VEGF levels were not seen when small molecule VEGFR-2 inhibitors were tested in normal mice. Most importantly, the increases in plasma VEGF were induced in a dose-dependent manner, with the maximum values peaking when doses previously determined to be optimally therapeutic were used. Plasma VEGF should be considered as a possible surrogate pharmacodynamic marker for determining the optimal biological dose of antibody drugs that block VEGFR-2 (KDR) activity in a clinical setting.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Neoplasias Colorretais/sangue , Neoplasias Colorretais/terapia , Neoplasias da Próstata/sangue , Neoplasias da Próstata/terapia , Fator A de Crescimento do Endotélio Vascular/sangue , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/imunologia , Adenocarcinoma/sangue , Adenocarcinoma/irrigação sanguínea , Adenocarcinoma/terapia , Animais , Anticorpos Monoclonais/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biomarcadores Tumorais/sangue , Plaquetas/metabolismo , Linhagem Celular Tumoral , Neoplasias Colorretais/irrigação sanguínea , Terapia Combinada , Esquema de Medicação , Humanos , Masculino , Camundongos , Camundongos Nus , Camundongos SCID , Neovascularização Patológica/sangue , Neovascularização Patológica/terapia , Neoplasias da Próstata/irrigação sanguínea , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Fator A de Crescimento do Endotélio Vascular/biossíntese , Fator A de Crescimento do Endotélio Vascular/genética
16.
Mol Cancer Ther ; 3(2): 149-59, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14985455

RESUMO

Multicellular resistance, a subtype of therapeutic resistance manifested in cancer cells grown as three-dimensional multicellular masses, such as spheroids in vitro and solid tumors in vivo, occurs with respect to a variety of anticancer treatment strategies including chemotherapy, ionizing radiation, and even host-mediated antibody-dependent cellular cytotoxicity. Previous studies from our laboratory have shown that multicellular resistance to chemotherapy demonstrated by aggregates of EMT-6 murine mammary carcinoma cells can be overcome by using hyaluronidase to disrupt intercellular adhesive interactions and associated patterns of protein expression. In this proof of principle study, we explored the concept of antiadhesive chemosensitization in the context of human cancer cells by using a monoclonal antibody to disrupt E-cadherin-mediated cell-cell interactions in multicellular spheroids of HT29 human colorectal adenocarcinoma. In so doing, we found that disruption of E-cadherin-mediated adhesion sensitizes multicellular spheroids of HT29 in vitro to treatment with 5-fluorouracil, paclitaxel, vinblastine, and etoposide but not cisplatin. Furthermore, we have found that antibody-mediated blockage of E-cadherin function leads to decreased expression and activity of protein kinase C alpha and beta1, both of which have previously been implicated in chemoresistance exhibited by HT29 cells; however, we have found that the chemosensitization effects of the anti-E-cadherin antibody are independent of its influence on protein kinase C beta1.


Assuntos
Anticorpos/imunologia , Anticorpos/uso terapêutico , Caderinas/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Animais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Resistência a Medicamentos/efeitos dos fármacos , Etoposídeo/farmacologia , Fluoruracila/farmacologia , Humanos , Camundongos , Paclitaxel/farmacologia , Proteína Quinase C/metabolismo , Proteína Quinase C beta , Esferoides Celulares , Vimblastina/farmacologia
17.
18.
Virtual Mentor ; 6(5)2004 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-23260588
20.
Virtual Mentor ; 6(8)2004 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-23260789
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