RESUMEN
The tumor antigen (TA)-targeted monoclonal antibodies (mAb) cetuximab and panitumumab target the human epidermal growth factor receptor and have been integrated into treatment regimens for advanced squamous cell carcinoma of the head and neck (SCCHN). The therapeutic efficacy of these mAbs has been found to be enhanced when combined with radiotherapy and chemotherapy. However, clinical trials indicate that these findings are limited to fewer than 20% of treated patients. Therefore, identifying patients who are likely to benefit from these agents is crucial to improving therapeutic strategies. Interestingly, it has been noted that TA-targeted mAbs mediate their effects by contributing to cell-mediated cytotoxicity in addition to inhibition of downstream signaling pathways. Here, we describe the potential immunogenic mechanisms underlying these clinical findings, their role in the varied clinical response and identify the putative biomarkers of antitumor activity. We review potential immunological biomarkers that affect mAb therapy in SCCHN patients, the implications of these findings and how they translate to the clinical scenario, which are critical to improving patient selection and ultimately outcomes for patients undergoing therapy.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Receptores ErbB/antagonistas & inhibidores , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Antígenos de Neoplasias/inmunología , Biomarcadores , Carcinoma de Células Escamosas/radioterapia , Cetuximab , Terapia Combinada , Receptores ErbB/inmunología , Neoplasias de Cabeza y Cuello/radioterapia , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Macrófagos/inmunología , Panitumumab , Infecciones por Papillomavirus , Receptores de IgG/genética , Factor de Transcripción STAT3/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello , Linfocitos T Reguladores/inmunología , Escape del Tumor/inmunologíaRESUMEN
BACKGROUND: Although regulatory T cells (Treg) are highly enriched in human tumours compared with peripheral blood, expression of the immune-checkpoint receptors, immunosuppressive molecules and function of Treg in these two sites remains undefined. METHODS: Tumour-infiltrating lymphocytes and peripheral blood lymphocytes were isolated from a cohort of head and neck squamous cell carcinoma (HNSCC) patients. The immunosuppressive phenotypes and function of intratumoral Treg were compared with those of peripheral blood Treg. RESULTS: The frequency of immune-checkpoint receptor-positive cells was higher on intratumoral FOXP3(+)CD25(hi) Treg compared with circulating Treg (CTLA-4, P=0.002; TIM-3, P=0.002 and PD-1, P=0.002). Immunosuppressive effector molecules, LAP and ectonucleotidase CD39 were also upregulated on intratumoral FOXP3(+) Treg (P=0.002 and P=0.004, respectively). CTLA-4 and CD39 were co-expressed on the majority of intratumoral FOXP3(+)CD4(+) Treg, suggesting that these molecules have a key role in regulatory functions of these cells in situ. Notably, intratumoral Treg exhibited more potently immunosuppressive activity than circulating Treg. CONCLUSION: These results indicate that intratumoral Treg are more immunosuppressive than circulating Treg and CTLA-4 and CD39 expressed can be potential target molecules to inhibit suppressive activities of intratumoral Treg in situ.
Asunto(s)
Carcinoma de Células Escamosas/inmunología , Neoplasias de Cabeza y Cuello/inmunología , Inmunosupresores/metabolismo , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos T Reguladores/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD/metabolismo , Apirasa/metabolismo , Antígeno CTLA-4/metabolismo , Carcinoma de Células Escamosas/sangre , Carcinoma de Células Escamosas/metabolismo , Citocinas/metabolismo , Femenino , Neoplasias de Cabeza y Cuello/sangre , Neoplasias de Cabeza y Cuello/metabolismo , Humanos , Tolerancia Inmunológica/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Masculino , Persona de Mediana Edad , Carcinoma de Células Escamosas de Cabeza y Cuello , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismoRESUMEN
Evaluation of a wide range of avermectin derivatives for flea activity in an in vitro feeding screen using the cat flea, Ctenocephalides felis, revealed a narrow structure-activity relationship (SAR) with activity surprisingly associated with monosaccharides and especially their C-5-oximes. We discovered commercially exploitable flea activity in a single compound, selamectin 33, which also possessed the necessary antiparasitic spectrum and margin of safety for development as a broad-spectrum companion animal endectocide.
Asunto(s)
Insecticidas/química , Insecticidas/farmacología , Ivermectina/análogos & derivados , Ivermectina/química , Ivermectina/farmacología , Siphonaptera , Animales , Gatos , Perros , Femenino , Insecticidas/síntesis química , Ivermectina/síntesis química , Espectroscopía de Resonancia Magnética , Masculino , Estructura Molecular , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-ActividadRESUMEN
Selamectin, 25-cyclohexyl-25-de(1-methylpropyl)-5-deoxy-22, 23-dihydro-5-(hydroxyimino)-avermectin B1 monosaccharide, is a novel endectocide with a unique combination of efficacy and safety in dogs and cats following both oral and topical administration. The compound is active against fleas and ticks, intestinal hookworms and ascarids, and immature heartworms. Also it is well tolerated at higher dosages than 22,23-dihydroavermectin B1a (DHAVM) or milbemycin oxime in Collies, which is a breed known to exhibit idiosyncratic sensitivity to avermectins.
Asunto(s)
Antiparasitarios/administración & dosificación , Antiparasitarios/uso terapéutico , Enfermedades de los Gatos/tratamiento farmacológico , Enfermedades de los Perros/tratamiento farmacológico , Infestaciones Ectoparasitarias/veterinaria , Ivermectina/análogos & derivados , Siphonaptera/efectos de los fármacos , Administración Tópica , Animales , Gatos , Perros , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Infestaciones Ectoparasitarias/tratamiento farmacológico , Femenino , Ivermectina/uso terapéutico , MasculinoRESUMEN
Several observations suggest that inherited factors are influential in the development of nephropathy in patients with insulin-dependent diabetes mellitus (IDDM). Genetic components of the renin angiotensin system are possible candidate genes. The aim of this study was to determine the role of the hypertension associated angiotensin II type 1 receptor (AT1R) gene A1166C polymorphism in susceptibility to nephropathy in IDDM. We examined 264 Caucasoid patients with IDDM and overt nephropathy (as defined by persistent proteinuria in the absence of other causes, hypertension and retinopathy), 136 IDDM patients with long duration of diabetes and no nephropathy (LDNN group), 200 recently diagnosed IDDM patients (Sporadic Diabetic group), and 212 non-diabetic subjects. The AT1R gene polymorphism was assessed using the polymerase chain reaction and restriction isotyping. Genotype frequencies did not differ significantly between the sporadic diabetic group and the nephropathy group (p = 0.245), nor between the long duration non-nephropathy group and the nephropathy group (p = 0.250). Allele frequencies were not significantly different between the three groups (p = 0.753). We conclude that there is no significant association between the hypertension associated AT1R gene polymorphism and diabetic nephropathy in patients with IDDM in the UK.
Asunto(s)
Diabetes Mellitus Tipo 1/genética , Nefropatías Diabéticas/genética , Polimorfismo Genético , Receptores de Angiotensina/genética , Adolescente , Adulto , Alelos , Sustitución de Aminoácidos , Femenino , Genotipo , Humanos , Hipertensión/genética , Masculino , Receptor de Angiotensina Tipo 1 , Receptor de Angiotensina Tipo 2RESUMEN
Premature cardiovascular disease is common in insulin-dependent diabetic (IDDM) patients who develop diabetic nephropathy. Genetic polymorphism within the renin-angiotensin system has been implicated in the aetiology of a number of cardiovascular disorders; these loci are therefore candidate genes for susceptibility to diabetic renal disease. We have examined the angiotensin converting enzyme insertion/deletion polymorphism and angiotensinogen methionine 235 threonine polymorphism in a large cohort of Caucasian patients with IDDM and diabetic nephropathy. Patients were classified as having nephropathy by the presence of persistent dipstick positive proteinuria (in the absence of other causes), retinopathy and hypertension (n = 242). Three groups were examined for comparison: ethnically matched non-diabetic subjects (n = 187); a geographically defined cohort of newly diagnosed diabetic patients (n = 341); and IDDM patients with long duration of disease (> 15 years) and no evidence of overt nephropathy (n = 166). No significant difference was seen in distribution of angiotensin converting enzyme or angiotensinogen genotypes between IDDM patients with nephropathy and recently diagnosed diabetic subjects (p = 0.282 and 0.584, respectively), nor the long-duration non-nephropathy diabetic subjects (p = 0.701 and 0.190, respectively). We conclude that these genetic loci are unlikely to influence susceptibility to diabetic nephropathy in IDDM in the United Kingdom.
Asunto(s)
Angiotensinógeno/genética , Diabetes Mellitus Tipo 1/genética , Nefropatías Diabéticas/genética , Peptidil-Dipeptidasa A/genética , Polimorfismo Genético , Sistema Renina-Angiotensina/genética , Adulto , Edad de Inicio , Alelos , Estudios de Cohortes , Diabetes Mellitus Tipo 1/fisiopatología , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , ProbabilidadRESUMEN
The pharmacokinetics of doramectin, a novel avermectin, were evaluated following parenteral administration in a range of oil-based formulations in an attempt to optimise the formulation. Therapeutic and persistent efficacies against Cooperia oncophora were also evaluated. This approach led to the identification of formulations based upon sesame oil and ethyl oleate which gave more prolonged doramectin plasma concentrations with no loss in therapeutic efficacy and improved persistent efficacy following subcutaneous administration to cattle at a dosage of 200 micrograms kg-1. The importance of using both pharmacokinetic and efficacy end points to distinguish between formulations is discussed. All formulations were well tolerated as evidenced by the absence of any reaction to injection either in the form of behavioural responses, injection site swelling or postmortem lesions. Sesame oil with ethyl oleate was the best parenteral vehicle tested for doramectin, allowing the expression of a high level of therapeutic and persistent efficacy and offering the benefit of excellent injection site toleration.
Asunto(s)
Antihelmínticos/farmacocinética , Enfermedades de los Bovinos/tratamiento farmacológico , Ivermectina/análogos & derivados , Infecciones por Nematodos/veterinaria , Análisis de Varianza , Animales , Antihelmínticos/administración & dosificación , Antihelmínticos/uso terapéutico , Disponibilidad Biológica , Bovinos , Química Farmacéutica , Diglicéridos , Portadores de Fármacos , Evaluación de Medicamentos , Heces/parasitología , Inyecciones Subcutáneas , Ivermectina/administración & dosificación , Ivermectina/farmacocinética , Ivermectina/uso terapéutico , Modelos Lineales , Micelas , Infecciones por Nematodos/tratamiento farmacológico , Ácidos Oléicos , Aceite de SésamoRESUMEN
Doramectin, 25-cyclohexyl-5-O-demethyl-25-de(l-methylpropyl)avermectin A1a, was selected as the best of a series of novel avermectins prepared by mutational biosynthesis. The primary evaluation of its in vivo antiparasitic activity was carried out using a rat Trichostrongylus colubriformis model and a rabbit Psoroptes cuniculi model. In each case the new avermectin performed favourably relative to dihydroavermectin B1a (DHAVM), the major component of ivermectin. Doramectin was extensively evaluated in cattle using an experimental micelle formulation, proving highly effective in cattle infected with Ostertagia ostertagi, Cooperia oncophora and Dictyocaulus viviparus when administered subcutaneously at 200 micrograms kg-1. The plasma pharmacokinetic characteristics of doramectin in cattle following intravenous administration revealed a plasma half-life of approximately 89 h. In the micelle formulation, doramectin administered subcutaneously at 400 micrograms kg-1 provided persistent activity against infection of cattle with C. oncophora and O. ostertagi for at least 8 and 12 days respectively.
Asunto(s)
Antihelmínticos/uso terapéutico , Enfermedades de los Bovinos/tratamiento farmacológico , Insecticidas/uso terapéutico , Ivermectina/análogos & derivados , Infestaciones por Ácaros/veterinaria , Infecciones por Nematodos/veterinaria , Administración Oral , Animales , Antihelmínticos/administración & dosificación , Antihelmínticos/farmacocinética , Bovinos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación de Medicamentos , Femenino , Inyecciones Subcutáneas/veterinaria , Insecticidas/administración & dosificación , Insecticidas/farmacocinética , Parasitosis Intestinales/tratamiento farmacológico , Parasitosis Intestinales/veterinaria , Ivermectina/administración & dosificación , Ivermectina/farmacocinética , Ivermectina/uso terapéutico , Masculino , Micelas , Infestaciones por Ácaros/tratamiento farmacológico , Ácaros , Infecciones por Nematodos/tratamiento farmacológico , Conejos , Distribución Aleatoria , Ratas , Ratas Wistar , Tricostrongiliasis/tratamiento farmacológico , Tricostrongiliasis/veterinariaRESUMEN
We audited our practice of bronchoscoping patients admitted with community acquired pneumonia to detect latent underlying abnormalities. Fifty-five bronchoscopies were performed immediately after clinical recovery in 64 sequential patients without obvious underlying carcinoma. Five (9.1%) showed abnormalities (four carcinomas and one mild tracheal stenosis). The detection rate of abnormalities and the number of unnecessary bronchoscopies would be improved if only those patients aged 50 years or over who were current or ex-smokers were bronchoscoped. In this group 13.9% (5/36) had an underlying abnormality. The cost implications of such a policy of early bronchoscopy are discussed and compared with traditional follow-up.
Asunto(s)
Broncoscopía , Tecnología de Fibra Óptica , Auditoría Médica , Neumonía/etiología , Adolescente , Adulto , Factores de Edad , Anciano , Carcinoma Broncogénico/diagnóstico por imagen , Femenino , Humanos , Pulmón/diagnóstico por imagen , Enfermedades Pulmonares/diagnóstico , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Neumonía/diagnóstico por imagen , Estudios Prospectivos , Radiografía , Fumar/efectos adversosAsunto(s)
Ciprofloxacina/administración & dosificación , Diálisis Peritoneal Ambulatoria Continua , Peritonitis/tratamiento farmacológico , Vancomicina/administración & dosificación , Administración Oral , Ciprofloxacina/farmacología , Quimioterapia Combinada/uso terapéutico , Humanos , Pruebas de Sensibilidad Microbiana , Diálisis Peritoneal Ambulatoria Continua/efectos adversos , Peritonitis/etiología , Peritonitis/microbiología , Vancomicina/farmacologíaRESUMEN
The results of a 2-year prospective study of primary and secondary vascular access surgery for haemodialysis have been compared with a retrospective study of central venous access via a flexible silicone catheter (Permcath). Cumulative patency for 61 primary fistulae in 57 patients was 64.8% at 1 year and 57.7% at 2 years. The patency of 55 secondary procedures in 43 patients was 48.1% at 1 and 2 years. Cumulative survival of 64 Permcaths inserted into 51 patients was 74% at 1 year and 43% at 2 years. Surgical complications included explorations for bleeding (2), haematomas (4), swollen arms (4), and inadequately dilated veins (4). Permcath complications included explorations for bleeding (3) and a temporary recurrent laryngeal nerve palsy (1). Exit site infection and septicaemia rates were 4.95 and 3.36 per 1000 catheter days respectively, but 20.6% of septicaemic episodes occurred in a patient who refused catheter removal. For haemodialysis, the Permcath is comparable with secondary vascular access. The Permcath may have a primary access role in patients with limited life expectancy.
Asunto(s)
Cateterismo Venoso Central , Catéteres de Permanencia , Diálisis Renal , Análisis Actuarial , Adolescente , Adulto , Anciano , Cateterismo Venoso Central/efectos adversos , Cateterismo Venoso Central/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Avermectins with a wide range of novel C-25 substituents have been prepared by feeding carboxylic acids or their biosynthetic precursors to a Streptomyces avermitilis mutant strain ATCC 53568. This organism lacks the ability to form isobutyric and S-2-methylbutyric acids from their 2-oxo acid precursors and thus is unable to produce natural avermectins unless supplied with these acids. The novel avermectins produced by mutational biosynthesis possess broad-spectrum antiparasitic activity.
Asunto(s)
Antihelmínticos/metabolismo , Ivermectina/análogos & derivados , Streptomyces/metabolismo , Animales , Antihelmínticos/química , Antihelmínticos/farmacología , Caenorhabditis/efectos de los fármacos , Ácidos Carboxílicos/metabolismo , Cromatografía Líquida de Alta Presión , Dípteros , Fermentación , Ivermectina/química , Ivermectina/metabolismo , Ivermectina/farmacología , Estructura Molecular , Mutación , Streptomyces/genéticaAsunto(s)
Catéteres de Permanencia , Diálisis Renal/efectos adversos , Estreptoquinasa/uso terapéutico , Tromboflebitis/tratamiento farmacológico , Adulto , Derivación Arteriovenosa Quirúrgica , Nefropatías Diabéticas/complicaciones , Nefropatías Diabéticas/terapia , Retinopatía Diabética/complicaciones , Femenino , Humanos , Radiografía , Tromboflebitis/diagnóstico por imagen , Tromboflebitis/etiologíaRESUMEN
Over a five-year period 64 Quinton Permcaths were inserted into 51 dialysis patients (age range 17-72 years, mean 52.1 SD 12.83). The duration of catheter use ranged from 5 to 1479 days, mean 315.7 SD 337. The actuarial catheter survival rate at 1 year was 74%, at 2 years 43%, at 3 years 25% and at 4 years 12%. The indications for use were: exhausted peripheral access; CAPD contraindicated; abrupt failure or lack of an arteriovenous fistula; acute renal failure; limited life expectancy; patient insistence; conventional access contraindicated. Only minor complications occurred during insertion: haemorrhage requiring exploration in three patients and a temporary left recurrent laryngeal nerve palsy in one patient. The exit site infection and septicaemia rates were 4.95 and 3.36 per 1000 catheter days respectively. Eighteen catheters failed due to infection (range of use 72-1479 days, mean 559 SD 388). Inadequate initial blood flow (less than 150 ml/min) occurred in 10% of dialyses but only six catheters failed due to intractable flow difficulties (range of use 5-49 days, mean 22 SD 17.5). Catheter sepsis was implicated in the death of two patients. One subclavan/innominate vein thrombosis occurred. The Quinton Permcath represents a significant advance providing immediate, durable, and relatively safe access in a variety of difficult circumstances.
Asunto(s)
Catéteres de Permanencia , Adolescente , Adulto , Anciano , Velocidad del Flujo Sanguíneo , Estudios de Evaluación como Asunto , Femenino , Humanos , Infecciones/etiología , Masculino , Persona de Mediana Edad , Diálisis Renal , Sepsis/etiología , Factores de TiempoRESUMEN
The development of a new polarographic sensor for measuring simultaneously both N2O and O2, in either gas or blood, is described. The cathode is made of silver, and it is shown that silver deposition on normal platinum or gold cathode electrodes can result in an enhancement of a PO2 signal, when measured in the presence of nitrous oxide. Silver can be deposited on the cathode by means of Ag+ ions diffusing through the electrolyte from an Ag/AgCl reference electrode. The use of an Ag cathode enables both O2 and N2O signals to be measured.