RESUMEN
OBJECTIVE: To determine the in vitro effects of the proteasome inhibitor bortezomib in feline injection site sarcoma (FISS) cell lines. SAMPLE: In vitro cultures of the FISS cell lines Ela-1, Hamilton, and Kaiser. PROCEDURES: Cells were treated with increasing doses of bortezomib or vehicle alone (dimethyl sulfoxide) and evaluated for cell viability via an adenosine triphosphate concentration assay, proteasome activity via a commercially available proteasome assay, accumulation of ubiquitinated proteins via Western blot, and apoptosis via flow cytometry. RESULTS: All 3 cell lines were sensitive to bortezomib with a 50% inhibitory concentration after 48 hours of treatment at 17.46 nM (95% CI, 15.47 to 19.72 nM) for Ela-1, 19.48 nM (95% CI, 16.52 to 23.00 nM) for Hamilton, and 21.38 nM (95% CI, 19.24 to 23.78 nM) for Kaiser. In the Ela-1 cell line, 20 nM bortezomib inhibited 20S proteasome activity by 90.9% compared with the vehicle-only control. In the Kaiser cell line, 20 nM bortezomib decreased 20S proteasome activity by 70%, compared with the untreated vehicle-only control. Last, treatment with bortezomib (25 and 40 nM) resulted in statistically significant decreases in viable cells accompanied by a statistically significant increase in apoptotic cells. CLINICAL RELEVANCE: Treatment options for FISS, especially nonresectable FISS, are currently very limited. These results support further investigation of bortezomib either alone or in combination with other treatments in such cases.
Asunto(s)
Antineoplásicos , Enfermedades de los Gatos , Sarcoma , Animales , Antineoplásicos/farmacología , Apoptosis , Ácidos Borónicos/farmacología , Bortezomib/farmacología , Gatos , Línea Celular Tumoral , Complejo de la Endopetidasa Proteasomal/farmacología , Pirazinas/farmacología , Sarcoma/veterinariaRESUMEN
The stage classification for canine primary pulmonary carcinomas (PPC) was last updated in 1980. In people, the human lung cancer stage classification (HLCSC) (currently in its eighth edition) plays an integral role in diagnostic and therapeutic decision-making and is prognostic despite a heterogeneous population of tumours. The objective of this retrospective case study was to evaluate the prognostic significance of a canine lung carcinoma stage classification (CLCSC) adapted from the HLCSC by removal of substage for ease of application to canine PPC. A secondary objective was to evaluate the effect of adjuvant chemotherapy. Medical records of 71 dogs with histologically confirmed PPC were reviewed. All dogs underwent surgical excision of the primary lung tumour. Primary tumour features (referring to T1-T4 stages) and TNM stages (1-4) were assigned using the CLCSC. Canine lung carcinoma stage was I (n = 7), II (n = 32), III (n = 24) and IV (n = 8). Median survival time was 952, 658, 158 and 52 days for stages I-IV, respectively. Primary tumour features (T1-T4), incomplete surgical excision, presence of lymph node metastasis and tumour grade were independent prognostic indicators for overall survival. Twenty-six dogs received adjuvant chemotherapy; however, no statistically significant benefit was found. The CLCSC primary tumour features and stage classification were highly prognostic for survival in dogs with PPC. We propose further application and evaluation of this update to canine PPC stage classification. Given the poor prognosis of advanced stage canine PPC, novel treatments are needed.
Asunto(s)
Carcinoma/veterinaria , Enfermedades de los Perros/clasificación , Enfermedades de los Perros/patología , Neoplasias Pulmonares/veterinaria , Estadificación de Neoplasias/métodos , Estadificación de Neoplasias/veterinaria , Animales , Antineoplásicos/uso terapéutico , Carcinoma/clasificación , Carcinoma/patología , Carcinoma/cirugía , Quimioradioterapia Adyuvante/métodos , Quimioradioterapia Adyuvante/veterinaria , Enfermedades de los Perros/mortalidad , Enfermedades de los Perros/cirugía , Perros , Femenino , Georgia/epidemiología , Humanos , Neoplasias Pulmonares/clasificación , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Metástasis Linfática , Masculino , Pronóstico , Estudios RetrospectivosRESUMEN
OBJECTIVE: To describe a case of documented serum sickness in a dog following administration of a single dose of a novel antivenin crotalidae polyvalent. CASE SUMMARY: A 4-year-old female neutered mixed breed dog developed recurrent signs of hypersensitivity (swelling, edema, urticaria/hives, gastrointestinal signs, vasculitis) at 1 and 2 weeks following administration of a single unit of a novel antivenin crotalidae polyvalent plasma product. Both episodes were treated with antihistamines and glucocorticoids and signs improved rapidly, with a prolonged course of glucocorticoids and antihistamines administered following the second occurrence. Diagnosis of serum sickness was based on clinical appearance of delayed hypersensitivity following exposure to novel biologic product, absence of other inciting cause of hypersensitivity, complement testing, and skin biopsies confirming vasculitis. NEW OR UNIQUE INFORMATION PROVIDED: This case documents the first report of delayed hypersensitivity with a novel antivenin plasma product. This is the only case report of serum sickness to a single unit of antivenin. Additionally, the dog developed recurrence of hypersensitivity following the initial episode at 1 week; appropriate identification and prolonged treatment could have prevented recurrence and additional hospitalization. Cost and benefit analysis should be considered with antivenin administration.
Asunto(s)
Antivenenos/efectos adversos , Venenos de Crotálidos , Crotalinae , Enfermedades de los Perros/diagnóstico , Enfermedad del Suero/veterinaria , Animales , Diagnóstico Diferencial , Perros , Femenino , Enfermedad del Suero/diagnóstico , Mordeduras de Serpientes/terapia , Mordeduras de Serpientes/veterinariaRESUMEN
CHD4, the core subunit of the Nucleosome Remodelling and Deacetylase (NuRD) complex, is a chromatin remodelling ATPase that, in addition to a helicase domain, harbors tandem plant homeo finger and chromo domains. By using a panel of domain constructs we dissect their roles and demonstrate that DNA binding, histone binding and ATPase activities are allosterically regulated. Molecular shape reconstruction from small-angle X-ray scattering reveals extensive domain-domain interactions, which provide a structural explanation for the regulation of CHD4 activities by intramolecular domain communication. Our results demonstrate functional interdependency between domains within a chromatin remodeller.
Asunto(s)
Adenosina Trifosfatasas/química , Autoantígenos/química , Ensamble y Desensamble de Cromatina , Cromatina/química , Regulación de la Expresión Génica , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/química , Sitio Alostérico , ADN/química , ADN Helicasas/química , Escherichia coli/metabolismo , Histonas/química , Humanos , Cinética , Nucleosomas/química , Unión Proteica , Estructura Terciaria de Proteína , Dispersión de Radiación , Resonancia por Plasmón de SuperficieRESUMEN
The combination of chromatin immunoprecipitation (ChIP) with microarray analysis (ChIP-chip) or high-throughput sequencing (ChIP-seq and ChIP-SAGE) has provided maps of a wide variety of site-specific histone modifications across mammalian genomes in various cell types. Although distinct genomic regions and functional elements have been strongly associated with specific histone modifications, an overwhelming number of combinatorial patterns have also been observed across the genome. While peaks of enrichment in ChIP-chip and ChIP-seq data may suggest stable and predictive 'landmarks' across the genomic landscape, studies from transcribed genes indicate a more dynamic model of how these data may be interpreted. In light of such studies, which show highly dynamic methylation, acetylation and phosphorylation of histone H3 during gene transcription, we consider the extent to which genome-wide maps of chromatin state could be interpreted as 'snapshots' of heterogeneous profiles deriving from dynamic modification processes. Rather than acting as static 'epigenetic' landmarks, histone modifications may function as dynamic and transient operational marks supporting specific steps in diverse processes throughout the mammalian genome.