RESUMO
The Surveillance, Epidemiology, and End Results (SEER) Program established in 1973 was the first laboratory for experimenting with new methods for cancer data collection and translating the data into population-based cancer statistics. The SEER Program staff have been instrumental in the development of the International Classification of Disease-Oncology and successfully implemented the routine collection of anatomic and prognostic cancer stage at diagnosis. Currently the program consists of 21 central registries that generate cancer statistics covering more than 48% of the US population and an additional 10 research support registries contributing to certain research projects, such as the National Childhood Cancer Registry. In parallel with the geographical expansion, the program built an architecture of methods and tools for population-based cancer statistics, with SEER*Explorer as the most recent online tool for descriptive statistics. In addition, SEER releases annual updates for a comprehensive data product line, which includes SEER*Stat databases with an annual caseload of more than 800â000 incident cases. Furthermore, the program developed a full suite of analytical applications for population-based cancer statistics that include Joinpoint (regression-based trend analysis), DevCan (risk of diagnosis and death), CanSurv (survival models), and ComPrev and PrejPrev (cancer prevalence), among others. The future of the SEER Program is closely aligned to the overall goals of the "war on cancer." The program aims to release longitudinal treatment data coupled with a comprehensive genomic characterization of cancers with a declared goal of decreasing the cancer burden and disparities across a wide spectrum of diseases and communities.
Assuntos
Neoplasias , Programa de SEER , Humanos , Programa de SEER/estatística & dados numéricos , Neoplasias/epidemiologia , Neoplasias/diagnóstico , Estados Unidos/epidemiologia , História do Século XX , História do Século XXI , Sistema de Registros/estatística & dados numéricosRESUMO
11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) has been identified as the primary enzyme responsible for the activation of hepatic cortisone to cortisol in specific peripheral tissues, resulting in the concomitant antagonism of insulin action within these tissues. Dysregulation of 11ß-HSD1, particularly in adipose tissues, has been associated with a variety of ailments including metabolic syndrome and type 2 diabetes mellitus. Therefore, inhibition of 11ß-HSD1 with a small nonsteroidal molecule is therapeutically desirable. Implementation of a scaffold-hopping approach revealed a 3-point pharmacophore for 11ß-HSD1 that was utilized to design a 2-spiroproline derivative as a steroid mimetic scaffold. Reiterative optimization provided valuable insight into the bioactive conformation of our novel scaffold and led to the discovery of several leads, such as compounds 39 and 51. Importantly, deleterious hERG inhibition and pregnane X receptor induction were mitigated by the introduction of a 4-hydroxyl group to the proline ring system.
Assuntos
Diabetes Mellitus Tipo 2 , Síndrome Metabólica , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Hidrocortisona/metabolismoRESUMO
11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) has been identified as the primary enzyme responsible for the activation of hepatic cortisone to cortisol in specific peripheral tissues resulting in the concomitant antagonism of insulin action within these tissues. Dysregulation of 11ß-HSD1, particularly in adipose tissues, has been associated with metabolic syndrome and type 2 diabetes mellitus. Therefore, inhibition of 11ß-HSD1 with a small nonsteroidal molecule is therapeutically desirable. Implementation of a scaffold-hopping approach revealed a three-point pharmacophore for 11ß-HSD1 that was utilized to design a steroid mimetic scaffold. Reiterative optimization provided valuable insight into the bioactive conformation of our novel scaffold and led to the discovery of INCB13739. Clinical evaluation of INCB13739 confirmed for the first time that tissue-specific inhibition of 11ß-HSD1 in patients with type 2 diabetes mellitus was efficacious in controlling glucose levels and reducing cardiovascular risk factors.
Assuntos
Diabetes Mellitus Tipo 2 , Síndrome Metabólica , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Hidrocortisona/metabolismo , Síndrome Metabólica/metabolismoRESUMO
C-C chemokine receptor 5 (CCR5) is a clinically proven target for inhibition of HIV-1 infection and a potential target for various inflammatory diseases. In this article, we describe 5-[(4-{(3S)-4-[(1R,2R)-2-ethoxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl)carbonyl]-4,6-dimethylpyrimidine dihydrochloride (INCB9471), a potent and specific inhibitor of human CCR5 that has been proven to be safe and efficacious in viral load reduction in phase I and II human clinical trails. INCB9471 was identified using a primary human monocyte-based radioligand competition binding assay. It potently inhibited macrophage inflammatory protein-1ß-induced monocyte migration and infection of peripheral blood mononuclear cells by a panel of R5-HIV-1 strains. The results from binding and signaling studies using incremental amounts of INCB9471 demonstrated INCB9471 as a noncompetitive CCR5 inhibitor. The CCR5 residues that are essential for interaction with INCB9471 were identified by site-specific mutagenesis studies. INCB9471 rapidly associates with but slowly dissociates from CCR5. When INCB9471 was compared with three CCR5 antagonists that had been tested in clinical trials, the potency of INCB9471 in blocking CCR5 ligand binding was similar to those of 4,6-dimethyl-5-{[4-methyl-4-((3S)-3-methyl-4-{(1R0-2-(methyloxy)-1-[4-(trifluoromethyl) phenyl]ethyl}-1-piperazingyl)-1-piperidinyl]carbonyl}pyrimidine (SCH-D; vicriviroc), 4-{[4-({(3R)-1-butyl-3-[(R)-cyclohexyl(hydroxyl)methyl]-2, 5-dioxo-1,4,9-triazaspiro[5.5]undec-9-yl}methyl)phenyl]oxy}benzoic acid hydrochloride (873140; aplaviroc), and 4,4-difluoro-N-((1S)-3-{(3-endo)-3-[3-methyl-5-(1-methylethyl)-4H-1,2,4-triazol-4-yl]-8-azabicyclo[3.2.1]oct-8-yl}-1-phenylpropyl)cyclohexanecarboxamide (UK427857; maraviroc). Its inhibitory activity against CCR5-mediated Ca(2+) mobilization was also similar to those of SCH-D and 873140. Further analysis suggested that INCB9471 and UK427857 may have different binding sites on CCR5. The significance of two CCR5 antagonists with different binding sites is discussed in the context of potentially overcoming drug-resistant HIV-1 strains.
Assuntos
Fármacos Anti-HIV/farmacologia , Antagonistas dos Receptores CCR5 , Movimento Celular/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Sítio Alostérico/fisiologia , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/uso terapêutico , Movimento Celular/fisiologia , Células Cultivadas , Relação Dose-Resposta a Droga , Células HEK293 , Infecções por HIV/imunologia , Infecções por HIV/patologia , Humanos , Macaca fascicularis , Monócitos/patologia , Piperazinas/química , Ligação Proteica/fisiologia , Pirimidinas/química , Receptores CCR5/fisiologiaRESUMO
A novel series of carbamates was discovered as potent and selective HER-2 sheddase inhibitors. Significant enhancement in potency and selectivity was achieved through attenuating the P1 moiety, which was conventionally believed to be exposed to solvent.
Assuntos
Carbamatos/química , Inibidores de Proteínas Quinases/química , Receptor ErbB-2/antagonistas & inibidores , Carbamatos/síntese química , Carbamatos/farmacologia , Colagenases/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Receptor ErbB-2/metabolismo , Relação Estrutura-AtividadeRESUMO
A serendipitous discovery that the metalloprotease binding profile of a novel class of 2-carboxamide-3-hydroxamic acid piperidines could be significantly attenuated by the modification of the unexplored P1 substituent enabled the design and synthesis of a novel 2-carboxamide-1-hydroxamic acid cyclohexyl scaffold core that exhibited excellent HER-2 potency and unprecedented MMP-selectivity that we believe would not have been possible via conventional P1' perturbations.
Assuntos
Proteínas ADAM/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Antineoplásicos/síntese química , Ácidos Hidroxâmicos/síntese química , Proteínas de Membrana/metabolismo , Receptor ErbB-2/metabolismo , Proteína ADAM10 , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Metaloproteinase 2 da Matriz/metabolismo , Ligação Proteica , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
Little information is currently available concerning the effects of suicide awareness and prevention campaigns. This brief report provides preliminary information about the influence of such a media campaign on the number of suicide-related telephone calls to an emergency mental health service in Cuyahoga County, Ohio. Examination of the pattern of calls before, during, and between phases of the campaign suggests that the media campaign significantly increased telephone calls to the emergency service. We provide this information to catalyze similar sharing of data and experiences among those organizations and agencies working to prevent suicide.
Assuntos
Atitude Frente a Saúde , Educação em Saúde/métodos , Meios de Comunicação de Massa/estatística & dados numéricos , Prevenção do Suicídio , Suicídio/psicologia , Adulto , Publicidade/estatística & dados numéricos , Distribuição por Idade , Idoso , Conscientização , Feminino , Educação em Saúde/organização & administração , Promoção da Saúde/métodos , Promoção da Saúde/organização & administração , Linhas Diretas/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Ohio/epidemiologia , Suicídio/estatística & dados numéricos , Tentativa de Suicídio/psicologia , Tentativa de Suicídio/estatística & dados numéricos , Sobreviventes/psicologia , Sobreviventes/estatística & dados numéricosRESUMO
Unlike previous investigations of shelter-based samples, our study examined whether profiles of adjustment problems occurred in a community-program-based sample of 175 school-aged children exposed to domestic violence. Cluster analysis revealed three stable profiles/clusters. The largest cluster (69%) consisted of children below clinical thresholds for any internalizing or externalizing problem. Children in the next largest cluster (18%) were characterized as having externalizing problems with or without internalizing problems. The smallest cluster (13%) consisted of children with internalizing problems only. Comparison across demographic and violence characteristics revealed that the profiles differed by child gender, mother's education, child's lifetime exposure to violence, and aspects of the event precipitating contact with the community program. Clinical and future research implications of study findings are discussed.
Assuntos
Transtornos do Comportamento Infantil/diagnóstico , Comportamento Infantil/psicologia , Desenvolvimento Infantil , Vítimas de Crime/estatística & dados numéricos , Violência Doméstica/estatística & dados numéricos , Relações Pais-Filho , Sintomas Afetivos/diagnóstico , Criança , Transtornos do Comportamento Infantil/epidemiologia , Análise por Conglomerados , Vítimas de Crime/psicologia , Feminino , Humanos , Masculino , Fatores de Risco , Estados Unidos/epidemiologiaRESUMO
In an effort to obtain a MMP selective and potent inhibitor of HER-2 sheddase (ADAM-10), the P1' group of a novel class of (6S,7S)-7-[(hydroxyamino)carbonyl]-6-carboxamide-5-azaspiro[2.5]octane-5-carboxylates was attenuated and the structure-activity relationships (SAR) will be discussed. In addition, it was discovered that unconventional perturbation of the P2' moiety could confer MMP selectivity, which was hypothesized to be a manifestation of the P2' group effecting global conformational changes.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácidos Hidroxâmicos/química , Proteínas de Membrana/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Receptor ErbB-2/antagonistas & inibidores , Proteínas ADAM/metabolismo , Proteína ADAM10 , Amidas/síntese química , Amidas/química , Amidas/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Compostos Aza/síntese química , Compostos Aza/química , Compostos Aza/farmacologia , Desenho de Fármacos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/farmacologia , Proteínas de Membrana/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Estrutura Terciária de Proteína , Receptor ErbB-2/metabolismo , Compostos de Espiro/síntese química , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
A series of beta-sulfonamide piperidine hydroxamates were prepared and shown to be potent inhibitors of the human epidermal growth factor receptor-2 (HER-2) sheddase with excellent selectivity against MMP-1, -2, -3, and -9. This was achieved by exploiting subtle differences within the otherwise highly conserved S(1)(') binding pocket of the active sites within the metalloprotease family. In addition, it was discovered that the introduction of polarity to the P(1) and P(1)(') groups reduced the projected human clearance.
Assuntos
Inibidores Enzimáticos/farmacologia , Metaloproteinases da Matriz/metabolismo , Piperidinas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Sítios de Ligação , Humanos , Metaloproteinases da Matriz/química , Piperidinas/química , Piperidinas/metabolismo , Receptor ErbB-2/químicaRESUMO
This report describes the characterization of INCB3344, a novel, potent and selective small molecule antagonist of the mouse CCR2 receptor. The lack of rodent cross-reactivity inherent in the small molecule CCR2 antagonists discovered to date has precluded pharmacological studies of antagonists of this receptor and its therapeutic relevance. In vitro, INCB3344 inhibits the binding of CCL2 to mouse monocytes with nanomolar potency (IC(50) = 10 nM) and displays dose-dependent inhibition of CCL2-mediated functional responses such as ERK phosphorylation and chemotaxis with similar potency. Against a panel of G protein-coupled receptors that includes other CC chemokine receptors, INCB3344 is at least 100-fold selective for CCR2. INCB3344 possesses good oral bioavailability and systemic exposure in rodents that allows in vivo pharmacological studies. INCB3344 treatment results in a dose-dependent inhibition of macrophage influx in a mouse model of delayed-type hypersensitivity. The histopathological analysis of tissues from the delayed-type hypersensitivity model demonstrates that inhibition of CCR2 leads to a substantial reduction in tissue inflammation, suggesting that macrophages play an orchestrating role in immune-based inflammatory reactions. These results led to the investigation of INCB3344 in inflammatory disease models. We demonstrate that therapeutic dosing of INCB3344 significantly reduces disease in mice subjected to experimental autoimmune encephalomyelitis, a model of multiple sclerosis, as well as a rat model of inflammatory arthritis. In summary, we present the first report on the pharmacological characterization of a selective, potent and rodent-active small molecule CCR2 antagonist. These data support targeting this receptor for the treatment of chronic inflammatory diseases.
Assuntos
Pirrolidinas/farmacologia , Receptores de Quimiocinas/antagonistas & inibidores , Animais , Artrite Experimental/tratamento farmacológico , Linhagem Celular , Quimiotaxia de Leucócito/efeitos dos fármacos , Quimiotaxia de Leucócito/imunologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/prevenção & controle , Feminino , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/imunologia , Pirrolidinas/farmacocinética , Ratos , Ratos Endogâmicos Lew , Receptores CCR2 , Receptores de Quimiocinas/deficiência , Receptores de Quimiocinas/genética , Relação Estrutura-AtividadeRESUMO
This study determined psychometric properties of the Pediatric Emotional Distress Scale (PEDS) with an ethnically diverse sample of 383 children 2 to 7 years of age exposed to interpersonal violence and participating in a community-based intervention. Means and alpha coefficients for the total scale and 3 subscales fell within previously reported parameters. Separate exploratory factor analysis and confirmatory factor analysis using structural equation modeling revealed that compared to the PEDS's 3-factor structure (Anxious/Withdrawn, Fearful, Act Out), a modified PEDS model with 2 latent factors (Act Out and Internalize) better fit the data and also held for both African American and White subsamples. Different correlations between the two factors and the Revised Behavior Problem Checklist further suggested that the factors represented unique latent constructs and gave evidence of construct validity. The modified PEDS could potentially be used for screening children exposed to violence.
Assuntos
Sintomas Afetivos/diagnóstico , Sintomas Afetivos/psicologia , Escalas de Graduação Psiquiátrica , Violência/psicologia , Sintomas Afetivos/etiologia , População Negra/psicologia , Criança , Pré-Escolar , Análise Fatorial , Feminino , Humanos , Masculino , Psicometria , Sensibilidade e Especificidade , População Branca/psicologiaRESUMO
A disintegrin and metalloproteases (ADAMs) are zinc-dependent trans-membrane metalloproteases that shed the extracellular domains of membrane-bound growth factors, cytokines and receptors. Key functions of ADAMs have emerged in ErbB signalling pathways as being sheddases for multiple ErbB ligands. As the ErbB pathway is a validated target for anti-cancer drugs, the upstream activators of ErbB ligands, their sheddases, now enter the spotlight as new drug targets in the ErbB pathway. ADAMs are involved not only in tumour cell proliferation but also in angiogenesis and metastasis. Therefore, strategies targeting ADAMs might be an important complement to existing anti-ErbB approaches.