RESUMEN
BACKGROUND: Despite aggressive multimodal therapy, locally advanced and/or metastatic penile squamous cell carcinoma (SqCC) is associated with significant morbidity and mortality, indicating a need for new therapeutic options. Given the emerging clinical utility of immunotherapeutics, we sought to assess the incidence and potential clinical significance of PD-L1 expression in penile SqCC. PATIENTS AND METHODS: Using an anti-PD-L1 primary antibody (clone 5H1), immunohistochemistry was carried out on whole tumor sections from 37 patients with penile SqCC treated at our institution between 2005 and 2013. PD-L1-positive tumors were defined as those with membranous staining in ≥5% of tumor cells. Association between PD-L1 expression and clinicopathologic parameters was examined using Fisher's exact test. Correlation between PD-L1 expression in primary tumors and matched metastases was assessed using the Spearman rank correlation coefficient (ρ). The difference in cancer-specific mortality between PD-L1-positive and -negative groups was examined using the log-rank test. RESULTS: Twenty-three (62.2%) of 37 primary tumors were positive for PD-L1 expression, and there was strong positive correlation of PD-L1 expression in primary and metastatic samples (ρ = 0.72; 0.032 < P < 0.036). Primary tumor PD-L1 expression was significantly associated with usual type histology (P = 0.040) and regional lymph node metastasis (P = 0.024), as well as decreased cancer-specific survival (P = 0.011). CONCLUSIONS: The majority of primary penile SqCC tumors express PD-L1, which is associated with high-risk clinicopathologic features and poor clinical outcome. These data provide a rational basis for further investigation of anti-PD-1 and anti-PD-L1 immunotherapeutics in patients with advanced penile SqCC.
Asunto(s)
Antígeno B7-H1/genética , Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/genética , Neoplasias del Pene/genética , Anciano , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/terapia , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Inmunoterapia , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Masculino , Persona de Mediana Edad , Neoplasias del Pene/inmunología , Neoplasias del Pene/patología , Neoplasias del Pene/terapia , Factores de RiesgoRESUMEN
Protein kinases are intensely studied mediators of cellular signaling. While traditional biochemical screens are capable of identifying compounds that modulate kinase activity, these assays are limited in their capability of predicting compound behavior in a cellular environment. Here, we aim to bridge target engagement and compound-cellular phenotypic behavior by utilizing a bioluminescence resonance energy transfer (BRET) assay to characterize target occupancy within living cells for Bruton's tyrosine kinase (BTK). Using a diverse chemical set of BTK inhibitors, we determine intracellular engagement affinity profiles and successfully correlate these measurements with BTK cellular functional readouts. In addition, we leveraged the kinetic capability of this technology to gain insight into in-cell target residence time and the duration of target engagement, and to explore a structural hypothesis.
Asunto(s)
Agammaglobulinemia Tirosina Quinasa/aislamiento & purificación , Transferencia Resonante de Energía de Fluorescencia/métodos , Ensayos Analíticos de Alto Rendimiento/métodos , Inhibidores de Proteínas Quinasas/farmacología , Agammaglobulinemia Tirosina Quinasa/química , Agammaglobulinemia Tirosina Quinasa/genética , Humanos , Cinética , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/químicaRESUMEN
This study examined levels, timing, and patterns of posttreatment alcohol and drug use in adolescents (n = 113) during the 12 months following completion of primary treatment. Data were collected from clinical records, random urine screens, and interviews with the adolescents and their parents. In all, 61.1% relapsed to pretreatment levels of use during the 12 months after treatment, 79.6% of the males and 59.3% of the females. Of those with alcohol as the drug of dependence, 45.9% relapsed to pretreatment levels of use in 12 months. Likewise, 75.0% marijuana users, 70.6% combined alcohol and marijuana users, and 50.2% other drug users relapsed to pretreatment levels of use in the 12 months. Relapse curves are presented to demonstrate the specific timing and patterns of relapse. Implications for primary treatment and aftercare are discussed.
Asunto(s)
Alcoholismo/rehabilitación , Trastornos Relacionados con Sustancias/rehabilitación , Adolescente , Femenino , Estudios de Seguimiento , Humanos , Masculino , Abuso de Marihuana/rehabilitación , Recurrencia , Detección de Abuso de Sustancias , Centros de Tratamiento de Abuso de SustanciasRESUMEN
Potent and selective bicyclic heteroaryl hydroxamic acid MMP and TACE inhibitors were synthesized by a novel convergent route. Selectivity and efficacy versus MMPs and TACE could be controlled by appropriate substitution on the scaffolds and by variation of the P1' group. Select compounds were found to be effective in in vivo models of arthritis.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Inhibidores de la Metaloproteinasa de la Matriz , Metaloendopeptidasas/antagonistas & inhibidores , Proteínas ADAM , Proteína ADAM17 , Animales , Artritis/tratamiento farmacológico , Artritis/patología , Disponibilidad Biológica , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Cartílago/efectos de los fármacos , Cartílago/patología , Bovinos , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/síntesis química , Ácidos Hidroxámicos/síntesis química , Ratones , Ratas , Relación Estructura-ActividadRESUMEN
Anthranilic acid derivatives bearing basic amines were prepared and evaluated in vitro and in vivo as inhibitors of MMP-1, MMP-9, MMP-13, and TACE. Piperazine 4u has been identified as a potent, selective, orally active inhibitor of MMP-9 and MMP-13.
Asunto(s)
Aminas/química , Inhibidores Enzimáticos/farmacología , Inhibidores de la Metaloproteinasa de la Matriz , ortoaminobenzoatos/farmacología , Proteínas ADAM , Proteína ADAM17 , Animales , Sitios de Unión , Colagenasas/metabolismo , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Ácidos Hidroxámicos/química , Interleucina-1 , Interleucina-1beta , Espectroscopía de Resonancia Magnética , Metaloproteinasa 1 de la Matriz/metabolismo , Metaloproteinasa 13 de la Matriz , Metaloproteinasa 9 de la Matriz/metabolismo , Metaloendopeptidasas , Ratones , Modelos Moleculares , Osteoartritis/tratamiento farmacológico , Ratas , Relación Estructura-Actividad , ortoaminobenzoatos/síntesis química , ortoaminobenzoatos/químicaRESUMEN
The SAR of a series of potent sulfonamide hydroxamate TACE inhibitors bearing novel acetylenic P1' groups was explored. In particular, compound 4t bearing a butynyloxy P1' moiety has excellent in vitro potency against isolated TACE enzyme and in cells, good selectivity over MMP-1 and oral activity in an in vivo model of TNF-alpha production.
Asunto(s)
Acetileno/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Metaloendopeptidasas/antagonistas & inhibidores , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , ortoaminobenzoatos/química , ortoaminobenzoatos/farmacología , Proteínas ADAM , Proteína ADAM17 , Relación Estructura-ActividadRESUMEN
A novel series of anthranilic acid-based inhibitors of MMP-1, MMP-9, MMP-13, and TACE was prepared and evaluated. Selective inhibitors of MMP-9, MMP-13, and TACE were identified, including the potent, orally active MMP-13 inhibitor 4p.