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1.
Cancers (Basel) ; 10(6)2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29914097

RESUMO

As the current efficacy of oncolytic viruses (OVs) as monotherapy is limited, exploration of OVs as part of a broader immunotherapeutic treatment strategy for cancer is necessary. Here, we investigated the ability for immune checkpoint blockade to enhance the efficacy of oncolytic reovirus (RV) for the treatment of breast cancer (BrCa). In vitro, oncolysis and cytokine production were assessed in human and murine BrCa cell lines following RV exposure. Furthermore, RV-induced upregulation of tumor cell PD-L1 was evaluated. In vivo, the immunocompetent, syngeneic EMT6 murine model of BrCa was employed to determine therapeutic and tumor-specific immune responses following treatment with RV, anti-PD-1 antibodies or in combination. RV-mediated oncolysis and cytokine production were observed following BrCa cell infection and RV upregulated tumor cell expression of PD-L1. In vivo, RV monotherapy significantly reduced disease burden and enhanced survival in treated mice, and was further enhanced by PD-1 blockade. RV therapy increased the number of intratumoral regulatory T cells, which was reversed by the addition of PD-1 blockade. Finally, dual treatment led to the generation of a systemic adaptive anti-tumor immune response evidenced by an increase in tumor-specific IFN-γ producing CD8⁺ T cells, and immunity from tumor re-challenge. The combination of PD-1 blockade and RV appears to be an efficacious immunotherapeutic strategy for the treatment of BrCa, and warrants further investigation in early-phase clinical trials.

2.
Blood Cancer J ; 7(12): 640, 2017 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-29208938

RESUMO

Multiple Myeloma (MM), a clonal malignancy of antibody-producing plasma cells, is the second most common hematologic malignancy and results in significant patient morbidity and mortality. The high degree of immune dysregulation in MM, including T cell imbalances and up-regulation of immunosuppressive checkpoint proteins and myeloid derived suppressor cells, allows this malignancy to escape from host immune control. Despite advances in the therapeutic landscape of MM over the last decade, including the introduction of immunomodulatory drugs, the prognosis for this disease is poor, with less than 50% of patients surviving 5 years. Thus, novel treatment strategies are required. Oncolytic viruses (OV) are a promising new class of therapeutics that rely on tumour specific oncolysis and the generation of a potent adaptive anti-tumour immune response for efficacy. To date, a number of OV have shown efficacy in pre-clinical studies of MM with three reaching early phase clinical trials. OVs represent a rational therapeutic strategy for MM based on (1) their tumour tropism, (2) their ability to potentiate anti-tumour immunity and (3) their ability to be rationally combined with other immunotherapeutic agents to achieve a more robust clinical response.


Assuntos
Antineoplásicos/uso terapêutico , Imunoterapia/métodos , Mieloma Múltiplo/terapia , Terapia Viral Oncolítica/métodos , Humanos
3.
Front Oncol ; 7: 114, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28634571

RESUMO

Oncolytic viruses (OV) represent a promising strategy to augment the spectrum of cancer therapeutics. For efficacy, they rely on two general mechanisms: tumor-specific infection/cell-killing, followed by subsequent activation of the host's adaptive immune response. Numerous OV genera have been utilized in clinical trials, ultimately culminating in the 2015 Food and Drug Administration approval of a genetically engineered herpes virus, Talminogene laherparepvec (T-VEC). It is generally accepted that OV as monotherapy have only modest clinical efficacy. However, due to their ability to elicit specific antitumor immune responses, they are prime candidates to be paired with other immune-modulating strategies in order to optimize therapeutic efficacy. Synergistic strategies to enhance the efficacy of OV include augmenting the host antitumor response through the insertion of therapeutic transgenes such as GM-CSF, utilization of the prime-boost strategy, and combining OV with immune-modulatory drugs such as cyclophosphamide, sunitinib, and immune checkpoint inhibitors. This review provides an overview of these immune-based strategies to improve the clinical efficacy of oncolytic virotherapy.

4.
BMJ Case Rep ; 20172017 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-28193644

RESUMO

Tumour thrombus is seen in renal cell and hepatocellular carcinoma, but is rarely reported in colorectal cancer. A woman aged 46 years, with metastatic colonic adenocarcinoma, was found to have a large mass in the inferior vena cava (IVC) extending into the right atrium. Although this lesion was initially thought to be bland thrombus, imaging with contrast-enhanced CT scan and contrast-enhanced ultrasound supported the diagnosis of tumour thrombus. Despite the large size of the lesion, the patient was asymptomatic. Her lack of symptoms, and poor overall prognosis from her cancer led to the decision to avoid aggressive surgical or radiological interventions. Several months later, the patient passed away. At autopsy, there was no evidence of fatal embolisation from the pre-existing thrombus. Diagnosis of tumour thrombus in the IVC is difficult and management can be challenging due to the significant risks associated with treatment options.


Assuntos
Adenocarcinoma/secundário , Neoplasias do Colo/patologia , Átrios do Coração/diagnóstico por imagem , Células Neoplásicas Circulantes , Veia Cava Inferior/diagnóstico por imagem , Evolução Fatal , Feminino , Humanos , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X , Ultrassonografia
5.
ACS Med Chem Lett ; 7(6): 590-4, 2016 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-27326332

RESUMO

BMS-711939 (3) is a potent and selective peroxisome proliferator-activated receptor (PPAR) α agonist, with an EC50 of 4 nM for human PPARα and >1000-fold selectivity vs human PPARγ (EC50 = 4.5 µM) and PPARδ (EC50 > 100 µM) in PPAR-GAL4 transactivation assays. Compound 3 also demonstrated excellent in vivo efficacy and safety profiles in preclinical studies and thus was chosen for further preclinical evaluation. The synthesis, structure-activity relationship (SAR) studies, and in vivo pharmacology of 3 in preclinical animal models as well as its ADME profile are described.

6.
J Pharmacol Exp Ther ; 350(2): 412-24, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24917546

RESUMO

Proprotein convertase subtilisin kexin-9 (PCSK9) is an important pharmacological target for decreasing low-density lipoprotein (LDL) in cardiovascular disease, although seemingly inaccessible to small molecule approaches. Compared with therapeutic IgG antibodies currently in development, targeting circulating PCSK9 with smaller molecular scaffolds could offer different profiles and reduced dose burdens. This inspired genesis of PCSK9-binding Adnectins, a protein family derived from human fibronectin-10th-type III-domain and engineered for high-affinity target binding. BMS-962476, an ∼11-kDa polypeptide conjugated to polyethylene glycol to enhance pharmacokinetics, binds with subnanomolar affinity to human. The X-ray cocrystal structure of PCSK9 with a progenitor Adnectin shows ∼910 Å(2) of PCSK9 surface covered next to the LDL receptor binding site, largely by residues of a single loop of the Adnectin. In hypercholesterolemic, overexpressing human PCSK9 transgenic mice, BMS-962476 rapidly lowered cholesterol and free PCSK9 levels. In genomic transgenic mice, BMS-962476 potently reduced free human PCSK9 (ED50 ∼0.01 mg/kg) followed by ∼2-fold increases in total PCSK9 before return to baseline. Treatment of cynomolgus monkeys with BMS-962476 rapidly suppressed free PCSK9 >99% and LDL-cholesterol ∼55% with subsequent 6-fold increase in total PCSK9, suggesting reduced clearance of circulating complex. Liver sterol response genes were consequently downregulated, following which LDL and total PCSK9 returned to baseline. These studies highlight the rapid dynamics of PCSK9 control over LDL and liver cholesterol metabolism and characterize BMS-962476 as a potent and efficacious PCSK9 inhibitor.


Assuntos
Anticolesterolemiantes/farmacologia , Lipoproteínas LDL/sangue , Polietilenoglicóis/farmacologia , Pró-Proteína Convertases/antagonistas & inibidores , Proteínas/farmacologia , Sequência de Aminoácidos , Animais , HDL-Colesterol/sangue , Cristalização , Feminino , Humanos , Macaca fascicularis , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Dados de Sequência Molecular , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/química , Pró-Proteína Convertases/metabolismo , Ratos , Receptores de LDL/antagonistas & inibidores , Serina Endopeptidases/química , Serina Endopeptidases/metabolismo , Especificidade da Espécie
7.
Ortho Sci., Orthod. sci. pract ; 4(16): 888-898, 2011. ilus
Artigo em Português | LILACS, BBO - Odontologia | ID: lil-642602

RESUMO

Na edição de 22 de maio de 2000 da revista americana Time, a Ortodontia foi listada como uma das 10 carreiras que desapareceriam no novo milênio. Naquela época, a previsão parecia ridícula e era sequer passível de análise. Porém, no início da segunda década deste terceiro milênio, existem evidências que nos fazem pensar se a especialidade como a conhecemos não está realmente ameaçada. A Ortodontia passa por um momento divisor de águas em vários sentidos. Novas tecnologias e filosofias de tratamento estão sendo desenvolvidas e incorporadas rapidamente à prática clínica, além de despertarem grande interesse científico. Nesse universo de inovações tecnológicas e conceitos emergentes, percebe-se uma prática clínica dividida, em que um segmento da Odontologia segue preocupado somente com aspectos comerciais, realizando alinhamentos dentários sem maiores critérios de diagnóstico e planejamento e aumentando a cada dia sua cota de mercado, enquanto a verdadeira especialidade busca desesperadamente por um novo caminho. A utilização dessas inovações tecnológicas em conjunto com os conceitos contemporâneos de tratamento ortodôntico, como prática clínica baseada em evidências científicas, procedimentos minimamente invasivos, engenharia tecidual e medicina oral sistêmica, definem uma inovadora abordagem para a especialidade, focada em promoção de saúde e qualidade de vida em oposição ao tradicional “paradigma de Angle”.


In the Time Magazine issued on May 22, 2000, orthodontics was listed as one of the 10 careers that would disappear in the “new millennium.” At that time, this prediction seemed ridiculous, not even worthy of consideration. Now, as we approach the end of this millennium’s first decade, there is evidence that might lead one to believe that this profession might be at risk after all. Orthodontics is going through a watershed moment in many ways. New technologies and emerging concepts of dental care are being rapidly developed and incorporated into clinical practice, and getting scientific interest around the world. In this world of innovative technologies, we realize that we have a shared clinical practice, where a segment of Dentistry is concerned uniquely with commercial aspects, performing dental alignments without major criteria for diagnosis and treatment planning and increasing its market share daily, while the real specialty desperately looks for a new path to follow. The use of these innovative Technologies allied with the contemporary concepts of orthodontic treatment as clinical practice based on scientific evidence, minimally invasive procedures, tissue engineering and oral systemic medicine, to define an innovative approach to the specialty focuses on a systemic approach to promoting health and life quality, as opposed to the traditional “Angle’s paradigm”.


Assuntos
Biotecnologia , Ortodontia
8.
Bioorg Med Chem Lett ; 20(9): 2933-7, 2010 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-20356736

RESUMO

The synthesis and follow-up SAR studies of our development candidate 1 by incorporating 2-aryl-4-oxazolylmethoxy and 2-aryl-4-thiazolylmethoxy moieties into the oxybenzylglycine framework of the PPARalpha/gamma dual agonist muraglitazar is described. SAR studies indicate that different substituents on the aryloxazole/thiazole moieties as well as the choice of carbamate substituent on the glycine moiety can significantly modulate the selectivity of PPARalpha versus PPARgamma. Potent, highly selective PPARalpha activators 2a and 2l, as well as PPARalpha activators with significant PPARgamma activity, such as 2s, were identified. The in vivo pharmacology of these compounds in preclinical animal models as well as their ADME profiles are discussed.


Assuntos
Anti-Inflamatórios/síntese química , Glicina/análogos & derivados , PPAR alfa/agonistas , PPAR gama/agonistas , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacocinética , Sítios de Ligação , Cricetinae , Cristalografia por Raios X , Glicina/síntese química , Glicina/farmacocinética , Humanos , Masculino , PPAR alfa/metabolismo , PPAR gama/metabolismo , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
9.
J Med Chem ; 53(7): 2854-64, 2010 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-20218621

RESUMO

An 1,3-oxybenzylglycine based compound 2 (BMS-687453) was discovered to be a potent and selective peroxisome proliferator activated receptor (PPAR) alpha agonist, with an EC(50) of 10 nM for human PPARalpha and approximately 410-fold selectivity vs human PPARgamma in PPAR-GAL4 transactivation assays. Similar potencies and selectivity were also observed in the full length receptor co-transfection assays. Compound 2 has negligible cross-reactivity against a panel of human nuclear hormone receptors including PPARdelta. Compound 2 demonstrated an excellent pharmacological and safety profile in preclinical studies and thus was chosen as a development candidate for the treatment of atherosclerosis and dyslipidemia. The X-ray cocrystal structures of the early lead compound 12 and compound 2 in complex with PPARalpha ligand binding domain (LBD) were determined. The role of the crystal structure of compound 12 with PPARalpha in the development of the SAR that ultimately resulted in the discovery of compound 2 is discussed.


Assuntos
Descoberta de Drogas , Glicina/análogos & derivados , Oxazóis/química , Oxazóis/farmacologia , PPAR alfa/agonistas , Animais , Linhagem Celular , Cricetinae , Cristalografia por Raios X , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Glicina/síntese química , Glicina/química , Glicina/farmacologia , Glicina/toxicidade , Humanos , Masculino , Camundongos , Modelos Moleculares , Oxazóis/síntese química , Oxazóis/toxicidade , PPAR alfa/química , PPAR alfa/genética , Estrutura Terciária de Proteína , Especificidade por Substrato , Ativação Transcricional/efeitos dos fármacos
10.
J Pharmacol Exp Ther ; 327(3): 716-26, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18799592

RESUMO

The first generation peroxisome proliferator-activated receptor (PPAR) alpha agonist gemfibrozil reduces the risk of major cardiovascular events; therefore, more potent PPARalpha agonists for the treatment of cardiovascular diseases have been actively sought. We describe two novel, potent oxybenzylglycine PPARalpha-selective agonists, BMS-687453 [N-[[3-[[2-(4-chlorophenyl)-5-methyl-4-oxazolyl]methoxy]phenyl]methyl]-N-(methoxycarbonyl)-glycine] and BMS-711939 N-[[5-[[2-(4-chlorophenyl)-5-methyl-4-oxazolyl]methoxy]-2-fluorophenyl]methyl]-N-(methoxycarbonyl)-glycine], that robustly increase apolipoprotein (Apo) A1 and high-density lipoprotein cholesterol in human ApoA1 transgenic mice and lower low-density lipoprotein-cholesterol and triglycerides in fat-fed hamsters. These compounds have much lower potency against mouse PPARalpha than human PPARalpha; therefore, they were tested in PPARalpha-humanized mice that do not express murine PPARalpha but express human PPARalpha selectively in the liver. We developed hepatic gene induction as a novel biomarker for efficacy and demonstrate hepatic gene induction at very low doses of these compounds. BMS-711939 induces fecal cholesterol excretion, which is further increased upon cotreatment with a liver X receptor (LXR) agonist. It is surprising that this synergistic increase upon coadministration is also observed in mice that express PPARalpha in the liver only. BMS-711939 also prevented the LXR agonist-induced elevation of serum triglycerides. Such PPARalpha agonists could be attractive candidates to explore for the treatment of cardiovascular diseases, especially in combination with a suitable LXR agonist.


Assuntos
Colesterol/metabolismo , Proteínas de Ligação a DNA/agonistas , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , PPAR alfa/agonistas , Receptores Citoplasmáticos e Nucleares/agonistas , Triglicerídeos/sangue , Animais , Sinergismo Farmacológico , Humanos , Fígado/metabolismo , Receptores X do Fígado , Camundongos , Camundongos Transgênicos , Receptores Nucleares Órfãos , Ativação Transcricional/efeitos dos fármacos
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