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1.
Ann Vasc Surg ; 93: 428-436, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-36708765

RESUMEN

BACKGROUND: Through-knee amputation (TKA) carries potential biomechanical advantages over above knee amputation (AKA) in patients unsuitable for a below-knee amputation. However, concerns regarding prosthetic fit, cosmesis and wound healing have tempered enthusiasm for the operation. Furthermore, there are many described surgical techniques for performing a TKA. This frustrates attempts to compare past and future comparative data, limiting the opportunity to identify which procedure is associated with the best patient centered outcomes. The aim of this systematic review is to identify all the recognized operative TKA techniques described in the literature and to develop a clear descriptive system to support future research in this area. METHODS: A systematic review was performed, searching the OVID, PubMed, and Cochrane Library databases, according to Cochrane and PRISMA guidelines. Papers of any design were included if they described an operative technique for a TKA. Key operative descriptions were captured and used to design a classification system for surgical techniques. RESULTS: A total of 906 papers were identified, of which 28 are included. The most important distinctions in operative technique were the level of division of the femur (disarticulation without bone division, transcondylar amputation, with or without shaving of the medial, lateral, and posterior condyles and supracondylar amputation), management of the patella (kept whole, partially preserved, completely removed), use of a muscular gastrocnaemius flap, and skin incisions. A 4-component classification system was developed to be able to describe TKA operative techniques. A suggested shorthand nomenclature uses the first letter of each component (FPMS; Femur, Patella, Muscular flap, Skin incision), followed by a number, to describe the operation. Patient outcomes were poorly reported, and therefore outcomes for different types of TKA are not addressed in this review. CONCLUSIONS: A novel descriptive system for describing different techniques for performing a TKA has been developed. This classification system will help in reporting, comparing, and interpreting past and future studies of patients undergoing TKA.


Asunto(s)
Amputación Quirúrgica , Desarticulación , Humanos , Desarticulación/métodos , Resultado del Tratamiento , Extremidad Inferior/cirugía , Reoperación , Articulación de la Rodilla/cirugía
2.
Int J Dent Hyg ; 14(4): 255-260, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-27457776

RESUMEN

OBJECTIVES: Effective dietary counselling in a dental setting can significantly reduce the risk of oral disease. However, studies suggest that dental professionals are not instigating dietary advice on a regular basis, and there is a lack of current information of the barriers experienced that limit the delivery of dietary advice. The aim of this study was to investigate the current attitudes and practice behaviours of dental hygienists and oral health therapists in NSW, Australia, regarding dietary advice, and identify the barriers that limit its delivery. METHODS: A convenience sample of dental hygienists and oral health therapists were surveyed using a mail-out questionnaire. The questionnaire investigated the demographic data of participants, the attitudes and practice behaviours of participants, the perceived barriers and current dietary resources accessed by participants. RESULTS: Of 987 dental hygienists and oral health therapists, 426 participants responded. The study results suggest that many dental hygienists and oral health therapists have positive beliefs regarding the importance of dietary counselling. However, there are a multitude of barriers preventing the delivery of dietary advice; these include time, patient compliance, patient knowledge of nutrition topics, personal counselling skills and practitioners' knowledge of nutrition. CONCLUSION: Whilst dental hygienists and oral health therapists recognize the importance of diet and have positive attitudes towards providing dietary advice to patients, this study identified many barriers preventing implementation in practice. This information may be used to develop targeted strategies aimed at overcoming these barriers and improving behaviours.


Asunto(s)
Actitud del Personal de Salud , Asistentes Dentales/psicología , Higienistas Dentales/psicología , Dieta/psicología , Adulto , Consejo , Estudios Transversales , Femenino , Humanos , Masculino , Encuestas y Cuestionarios
3.
J Infect ; 88(5): 106145, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38552719

RESUMEN

OBJECTIVES: The aims of this study were to assess aetiology and clinical characteristics in childhood meningitis, and develop clinical decision rules to distinguish bacterial meningitis from other similar clinical syndromes. METHODS: Children aged <16 years hospitalised with suspected meningitis/encephalitis were included, and prospectively recruited at 31 UK hospitals. Meningitis was defined as identification of bacteria/viruses from cerebrospinal fluid (CSF) and/or a raised CSF white blood cell count. New clinical decision rules were developed to distinguish bacterial from viral meningitis and those of alternative aetiology. RESULTS: The cohort included 3002 children (median age 2·4 months); 1101/3002 (36·7%) had meningitis, including 180 bacterial, 423 viral and 280 with no pathogen identified. Enterovirus was the most common pathogen in those aged <6 months and 10-16 years, with Neisseria meningitidis and/or Streptococcus pneumoniae commonest at age 6 months to 9 years. The Bacterial Meningitis Score had a negative predictive value of 95·3%. We developed two clinical decision rules, that could be used either before (sensitivity 82%, specificity 71%) or after lumbar puncture (sensitivity 84%, specificity 93%), to determine risk of bacterial meningitis. CONCLUSIONS: Bacterial meningitis comprised 6% of children with suspected meningitis/encephalitis. Our clinical decision rules provide potential novel approaches to assist with identifying children with bacterial meningitis. FUNDING: This study was funded by the Meningitis Research Foundation, Pfizer and the NIHR Programme Grants for Applied Research.


Asunto(s)
Meningitis Bacterianas , Meningitis Viral , Vacunas Conjugadas , Humanos , Niño , Lactante , Meningitis Bacterianas/diagnóstico , Meningitis Bacterianas/líquido cefalorraquídeo , Meningitis Bacterianas/microbiología , Preescolar , Adolescente , Femenino , Masculino , Estudios Prospectivos , Meningitis Viral/diagnóstico , Meningitis Viral/líquido cefalorraquídeo , Reglas de Decisión Clínica , Reino Unido/epidemiología , Neisseria meningitidis/aislamiento & purificación , Streptococcus pneumoniae/aislamiento & purificación , Técnicas de Apoyo para la Decisión
4.
Ann R Coll Surg Engl ; 105(1): 43-51, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34941458

RESUMEN

INTRODUCTION: The impact of the COVID-19 pandemic on healthcare professionals has been significant. The aim of this study was to explore the mental state and wellbeing of UK junior doctors at different phases of the initial outbreak. METHODS: This is a cross-sectional study of UK-based junior doctors' perceptions of threat and support during and after the first wave of the COVID-19 pandemic. Levels of anxiety, depression, post-traumatic stress disorder symptoms and use of coping mechanisms were explored through a Google questionnaire. RESULTS: 196 participants were included in this study (93 in period A and 103 in period B). Junior doctors reported feeling increased risk (p=0.001) and increased fear of contracting the virus (p<0.001) during period A. Increased levels of severe anxiety (Generalized Anxiety Disorder-7 score >15) along with increased cases level of depression (Patient Health Questionnaire-9 score >10) were reported for both periods. Junior doctors described suffering more frequently with flashbacks (p=0.006) and nightmares (p=0.024) in comparison with senior colleagues during period A. During period A, 21.4% of participants felt isolated at work (p<0.001), whereas 13% reported being easily annoyed on a daily basis, 11.7% reported very low morale (p<0.001) and 66% were not aware of any psychological support being available. The use of exercise, peer support and mindfulness apps increased during period B (p=0.023). CONCLUSIONS: Healthcare systems need to urgently establish robust psychological support mechanisms and infrastructure to protect junior doctors and provide institutional resilience against the adverse consequences of the long physical and mental battle with COVID-19.


Asunto(s)
COVID-19 , Humanos , COVID-19/epidemiología , Pandemias , Estudios Transversales , Adaptación Psicológica , Ansiedad/epidemiología , Ansiedad/etiología
5.
J Endocrinol Invest ; 35(2): 181-90, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21422803

RESUMEN

BACKGROUND: Medullary thyroid cancer (MTC) is frequently associated with mutations in the tyrosine kinase Ret and with increased expression of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2). Motesanib is an investigational, orally administered small molecule antagonist of VEGFR1, 2, and 3; platelet-derived growth factor receptor (PDGFR); Kit; and possibly Ret. AIM: The aim of this study was to investigate the effects of motesanib on wildtype and mutant Ret activity in vitro and on tumor xenograft growth in a mouse model of MTC. METHODS/RESULTS: In cellular phosphorylation assays, motesanib inhibited the activity of wild-type Ret (IC(50)=66 nM), while it had limited activity against mutant Ret C634W (IC(50)=1100 nM) or Ret M918T (IC(50)>2500 nM). In vivo, motesanib significantly inhibited the growth of TT tumor cell xenografts (expressing Ret C634W) and significantly reduced tumor blood vessel area and tumor cell proliferation, compared with control. Treatment with motesanib resulted in substantial inhibition of Ret tyrosine phosphorylation in TT xenografts and, at comparable doses, in equivalent inhibition of VEGFR2 phosphorylation in both TT xenografts and in mouse lung tissue. CONCLUSIONS: The results of this study demonstrate that motesanib inhibited thyroid tumor xenograft growth predominantly through inhibition of angiogenesis and possibly via a direct inhibition of VEGFR2 and Ret expressed on tumor cells. These data suggest that targeting angiogenesis pathways and specifically the VEGF pathway may represent a novel therapeutic approach in the treatment of MTC.


Asunto(s)
Indoles/farmacología , Indoles/uso terapéutico , Niacinamida/análogos & derivados , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/patología , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Carcinoma Neuroendocrino , Línea Celular Tumoral , Células Cultivadas , Femenino , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ratones , Ratones Desnudos , Niacinamida/farmacología , Niacinamida/uso terapéutico , Oligonucleótidos , Polimorfismo de Nucleótido Simple/fisiología , Proteínas Proto-Oncogénicas c-ret/genética , Neoplasias de la Tiroides/genética , Transfección , Ensayos Antitumor por Modelo de Xenoinjerto
6.
J Exp Med ; 190(7): 923-34, 1999 Oct 04.
Artículo en Inglés | MEDLINE | ID: mdl-10510082

RESUMEN

The activation of endothelium is important in recruiting neutrophils to sites of inflammation and in modulating their function. We demonstrate that conditioned medium from cultured, activated endothelial cells acts to significantly delay the constitutive apoptosis of neutrophils, resulting in their enhanced survival and increased phagocytic function. The antiapoptotic activity is, in part, attributable to granulocyte/macrophage colony-stimulating factor (GM-CSF) secreted by activated endothelial cells. The in vivo relevance of these findings was investigated in a cytokine-induced model of acute meningitis in mice. Peripheral blood neutrophils (PBNs) from mice with meningitis exhibited a delay in apoptosis compared with untreated mice. Furthermore, neutrophils recovered from the inflamed cerebrospinal fluid (CSF) exhibited enhanced survival compared with neutrophils isolated from the peripheral blood of the same animals. In unchallenged GM-CSF-deficient mice, the apoptosis of circulating PBNs was similar to wild-type animals; however, after cytokine-induced meningitis, the delay in neutrophil apoptosis typically observed in wild-type mice was attenuated. In contrast, the apoptosis of neutrophils recovered from the CSF of mice of both genotypes was comparable. Taken together, these studies suggest that neutrophil apoptosis is regulated during an inflammatory response, in both intravascular and extravascular compartments. GM-CSF released by activated endothelium can act to increase neutrophil survival and function in the peripheral blood, whereas other factor(s) appear to perform this function in the extravascular space.


Asunto(s)
Apoptosis/fisiología , Antígenos CD18/fisiología , Citocinas/fisiología , Citocinas/toxicidad , Endotelio Vascular/fisiopatología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/fisiología , Antígeno de Macrófago-1/fisiología , Meningitis/fisiopatología , Neutrófilos/citología , Neutrófilos/fisiología , Animales , Antígenos CD18/genética , Células Cultivadas , Quimiotaxis de Leucocito , Endotelio Vascular/fisiología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/líquido cefalorraquídeo , Humanos , Interleucina-1/toxicidad , Antígeno de Macrófago-1/genética , Masculino , Meningitis/líquido cefalorraquídeo , Meningitis/patología , Ratones , Ratones Noqueados , Factor de Necrosis Tumoral alfa/toxicidad , Venas Umbilicales
7.
BJS Open ; 4(3): 416-423, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32232963

RESUMEN

BACKGROUND: Inflammation has an important role in cancer survival, yet whether serum markers of inflammation predict response to potentially curative neoadjuvant chemotherapy (NAC) in oesophageal adenocarcinoma (OAC) is controversial. This study aimed to determine whether the systemic inflammatory response (SIR) is associated with response to NAC and survival. METHODS: Consecutive patients with OAC planned for surgery with curative intent received blood neutrophil and lymphocyte measurements at diagnosis to calculate the neutrophil to lymphocyte ratio (NLR). Pathological variables including pTNM stage, differentiation, vascular invasion and Mandard tumour regression grade (TRG) were recorded. TRGs 1 and 2 were taken to represent a good response, and the primary outcome was overall survival. RESULTS: During follow-up of 136 patients, 36 patients (26·5 per cent) had recurrence and 69 (50·7 per cent) died. Receiver operating characteristic (ROC) curve analysis of NLR before NAC predicted poor TRG (area under the ROC curve 0·71, 95 per cent c.i. 0·58 to 0·83; P = 0·002). In univariable analysis, pT category (P < 0·001), pN category (P < 0·001), poor differentiation (P = 0·006), margin positivity (P = 0·001), poor TRG (P = 0·014) and NLR (dichotomized at 2·25; P = 0·017) were associated with poor overall survival, and NLR retained independent significance in multivariable analysis (hazard ratio 2·26, 95 per cent c.i. 1·03 to 4·93; P = 0·042). CONCLUSION: The pretreatment NLR was associated with a pathological response to NAC and overall survival in patients with OAC. ANTECEDENTES: La inflamación juega un importante papel en la supervivencia por cáncer, aunque aún no se sabe si los marcadores séricos de inflamación predicen la respuesta a la quimioterapia neoadyuvante (neoadjuvant chemotherapy, NAC) potencialmente curativa en el adenocarcinoma de esófago (oesophageal adenocarcinoma, OAC). Este estudio se propuso determinar si la respuesta inflamatoria sistémica (systemic inflammatory response, SIR) estaba asociada con la respuesta a la NAC y a la supervivencia. MÉTODOS: A pacientes consecutivos con OAC en los que se planificó cirugía con intención curativa se les determinó neutrófilos y linfocitos en sangre en el momento del diagnóstico para calcular la tasa neutrófilo-linfocito (neutrophil-lymphocyte ratio, NLR). Se registraron variables patológicas que incluían el estadio pTNM, diferenciación tumoral, invasión vascular y grado de regresión tumoral (tumour regression grade, TRG) de Mandard. Los grados TRG 1 y 2 fueron considerados como una buena respuesta y el resultado primario fue la supervivencia global (overall survival, OS). RESULTADOS: Durante el seguimiento de 136 pacientes, 36 pacientes (26,5%) presentaron recidiva y 69 pacientes (50,7%) fallecieron. El análisis de las características operativas del receptor (receiver-operator-characteristic, ROC) de NLR antes de la NAC predijo una pobre TRG (área bajo la curva ROC, AUC 0,71, i.c. del 95% 0,58-0,83, P = 0,002). En el análisis univariable, el estadio pT (P < 0,001), el estadio pN (P < 0,001), una pobre diferenciación tumoral (P = 0,006), un margen positivo (P = 0,001), una pobre TRG (P = 0,014) y la NLR (dicotomizada a 2,25, P = 0,017) se asociaron con una pobre OS, pero solamente la NLR (cociente de riesgos instantáneos, hazard ratio, HR 2,28, i.c. del 95% 1,03-4,93, P = 0,042) conservó la significación estadística como variable independiente en el análisis multivariable. CONCLUSIÓN: La NLR antes del tratamiento se asoció con respuesta patológica del OAC a la NAC y OS.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Neoplasias Esofágicas/tratamiento farmacológico , Linfocitos/patología , Terapia Neoadyuvante , Neutrófilos/patología , Adenocarcinoma/sangre , Adenocarcinoma/mortalidad , Anciano , Estudios de Cohortes , Neoplasias Esofágicas/sangre , Neoplasias Esofágicas/mortalidad , Femenino , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Pronóstico , Índice de Severidad de la Enfermedad , Análisis de Supervivencia
8.
BJS Open ; 4(5): 840-846, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32749071

RESUMEN

BACKGROUND: The extent to which physiological factors influence outcome following oesophageal cancer surgery is poorly understood. This study aimed to evaluate the extent to which cardiorespiratory fitness and selected metabolic factors predicted complications after surgery for carcinoma. METHODS: Two hundred and twenty-five consecutive patients underwent preoperative cardiopulmonary exercise testing to determine peak oxygen uptake ( V ˙ o2peak ), anaerobic threshold and the ventilatory equivalent for carbon dioxide ( V ˙ e/ V ˙ co2 ). Cephalic venous blood was assayed for serum C-reactive protein (CRP) and albumin levels, and a full blood count was done. The primary outcome measure was the Morbidity Severity Score (MSS). RESULTS: One hundred and ninety-eight patients had anatomical resection. A high MSS (Clavien-Dindo grade III or above) was found in 48 patients (24·2 per cent) and was related to an increased CRP concentration (area under the receiver operating characteristic (ROC) curve (AUC) 0·62, P = 0·001) and lower V ˙ o2peak (AUC 0·36, P = 0·003). Dichotomization of CRP levels (above 10 mg/l) and V ˙ o2peak (below 18·6 ml per kg per min) yielded adjusted odds ratios (ORs) for a high MSS of 2·86 (P = 0·025) and 2·92 (P = 0·002) respectively. Compared with a cohort with a low Combined Inflammatory and Physiology Score (CIPS), the OR was 1·70 (95 per cent c.i. 0·85 to 3·39) for intermediate and 27·47 (3·12 to 241·69) for high CIPS (P < 0·001). CONCLUSION: CRP and V ˙ o2peak were independently associated with major complications after potentially curative oesophagectomy for cancer. A composite risk score identified a group of patients with a high risk of developing complications.


ANTECEDENTES: El grado en el que los factores fisiológicos influyen en el resultado tras la cirugía del cáncer de esófago no se conoce bien. Este estudio tuvo como objetivo evaluar en qué medida el estado cardiorrespiratorio y los factores metabólicos seleccionados predecían complicaciones después de cirugía por cáncer. MÉTODOS: Pacientes consecutivos fueron sometidos a una prueba de ejercicio cardiopulmonar preoperatoria para determinar el consumo pico de oxígeno (peak oxygen uptake, V ̇ O2Peak ), el umbral anaeróbico (anaerobic threshold, AT) y el equivalente ventilatorio de dióxido de carbono (ventilatory equivalent for carbon dioxide, V ̇ E / V ̇ CO2 ). Se extrajo sangre de la vena cefálica para analizar la proteína C reactiva (C-reactive protein, CRP) sérica, albumina y hemograma completo. La medida de resultado primario fue la puntuación de la gravedad de la morbilidad (Morbidity Severity Score, MSS). RESULTADOS: Se observó MSS (Clavien-Dindo > 2) en 33 (17,7%) pacientes, relacionándose con CRP elevada (AUC 0,69, P = 0,001) y V ̇O2Peak baja (AUC 0,33, P = 0,003). La dicotomización de la CRP (por encima de 10 mg/L) y V ̇O2Peak (por debajo de 18,6 mL/kg/min) se asociada a una razón de oportunidades (odds ratio, OR) de 4,01 (P = 0,002) y 3,74 (P = 0,002) para MSS y CD > 2, respectivamente. En comparación con la cohorte con una puntuación combinada inflamatoria y fisiológica (Combined Inflammatory and Physiology Score, CIPS) baja, el OR fue de 1,70 (i.c. del 95% 0,85-3,39) para una CIPS intermedia y de 27,47 (3,12-241,69, P < 0,001) para CIPS elevada. CONCLUSIÓN: CRP y V ̇O2Peak se asociaron de forma independiente con complicaciones mayores tras esofaguectomía potencialmente curativa por cáncer. Una puntuación combinada de riesgo identificó a un grupo de pacientes con un riesgo elevado de desarrollar complicaciones.


Asunto(s)
Proteína C-Reactiva/análisis , Capacidad Cardiovascular , Neoplasias Esofágicas/cirugía , Esofagectomía/efectos adversos , Complicaciones Posoperatorias/epidemiología , Anciano , Umbral Anaerobio , Biomarcadores/sangre , Prueba de Esfuerzo , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Morbilidad , Consumo de Oxígeno , Curva ROC , Medición de Riesgo/métodos
9.
Oncogene ; 25(45): 6128-32, 2006 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-16652146

RESUMEN

Mucoepidermoid (MEC) salivary gland tumors arise from a t(11;19) rearrangement which generates a fusion oncogene, Mect1-Maml2, that functions to activate CREB-responsive target genes. To determine if sustained expression of Mect1-Maml2 is required for tumor cell growth, we first showed that ectopic expression of Mect1-Maml2 in rat epithelial RK3E cells is tumorigenic in vivo in nude mice and that excised xenografts continue to express the fusion oncogene. We then generated a hairpin RNAi vector that selectively suppressed the fusion peptide and showed that ectopic expression in either parotid or pulmonary MEC tumor cell lines containing the t(11;19) rearrangement resulted in at least 90% colony growth inhibition. In contrast, single nucleotide changes within this RNAi sequence abolished the ability to suppress Mect1-Maml2 protein and abolished all growth inhibition of these MEC tumor lines. In addition, the RNAi-specific vector had no effect on colony growth of non-MEC tumors including a lung tumor or two other salivary gland cell lines that do not express Mect1-Maml2. We also generated a mutant Mect1-Maml2 expression plasmid that carried silent nucleotide changes within the RNAi target sequence and observed that co-transfection of this mutant, but not wild-type Mect1-Maml2, could partially rescue RNAi growth inhibition in the MEC tumor line. The recent detection of acquired fusion oncogenes in epithelial solid tumors has suggested new possibilities for the diagnosis and therapy of these cancers. Our data show that the 'gain-of-function' activity from aberrant Mect1-Maml2 expression is a candidate therapeutic target for this group of malignant salivary gland tumors.


Asunto(s)
División Celular/genética , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 19 , Proteínas de Fusión Oncogénica/fisiología , Neoplasias de las Glándulas Salivales/patología , Translocación Genética , Secuencia de Bases , ADN de Neoplasias , Humanos , Proteínas de Fusión Oncogénica/genética , Interferencia de ARN , Neoplasias de las Glándulas Salivales/genética
10.
Mol Cell Biol ; 14(11): 7256-64, 1994 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-7935440

RESUMEN

The growth suppressor activities of the RB and p107 products are believed to be mediated by the reversible binding of a heterogeneous family of cellular proteins to a conserved T/E1A pocket domain that is present within both proteins. To study the functional role of these interactions, we examined the properties of cellular retinoblastoma binding protein 2 (RBP2) binding to RB, p107, and the related TATA-binding protein (TBP) product. We observed that although RBP2 bound exclusively to the T/E1A pocket of p107, it could interact with RB through independent T/E1A and non-T/E1A domains and with TBP only through the non-T/E1A domain. Consistent with this observation, we found that a mutation within the Leu-X-Cys-X-Glu motif of RBP2 resulted in loss of ability to precipitate p107, while RB- and TBP-binding activities were retained. We located the non-T/E1A binding site of RBP2 on a 15-kDa fragment that is independent from the Leu-X-Cys-X-Glu motif and encodes binding activity for RB and TBP but does not interact with p107. Despite the presence of a non-T/E1A binding site, however, recombinant RBP2 retained the ability to preferentially precipitate active hypophosphorylated RB from whole-cell lysates. In addition, we found that cotransfection of RBP2 can reverse in vivo RB-mediated suppression of E2F activity. These findings confirm the differential binding specificities of the related RB, p107, and TBP proteins and support the presence of multifunctional domains on the nuclear RBP2 product which may allow complex interactions with the cellular transcription machinery.


Asunto(s)
Proteínas Portadoras/metabolismo , Proteínas de Ciclo Celular , Proteínas de Unión al ADN/metabolismo , Péptidos y Proteínas de Señalización Intracelular , Proteínas Nucleares , Proteínas/metabolismo , Proteína de Retinoblastoma/metabolismo , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor , Secuencia de Aminoácidos , Proteínas Portadoras/genética , Factores de Transcripción E2F , Genes de Retinoblastoma , Humanos , Modelos Biológicos , Datos de Secuencia Molecular , Mutación , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Unión Proteica , Proteínas Recombinantes de Fusión/metabolismo , Proteína 1 de Unión a Retinoblastoma , Proteína 2 de Unión a Retinoblastoma , Proteína p107 Similar a la del Retinoblastoma , Proteína de Unión a TATA-Box , Factor de Transcripción DP1 , Células Tumorales Cultivadas/metabolismo
11.
Sleep Med ; 7(3): 269-80, 2006 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-16567127

RESUMEN

STUDY OBJECTIVES: Complex relationships exist between pediatric sleep disorders and daytime behavior. Using a multidimensional scaling model, we investigated these relationships in 126 children with sleep breathing disorders (SBD). METHOD: Validated questionnaires on nighttime behavior, daytime behavior, and respiratory health were administered to a large number of school children in Belgium. Children who met the criterion of having at least one sleep-related breathing problem (three or more times per week during the past six months) were selected for further analyses. A total of 26 indicators were defined and modeled, including sleep problems, sleep efficiency, sleep environment, sleep enuresis, internalised and externalised behavioral problems, respiratory health of the child and relatives, smoking exposure, and caffeine consumption. RESULTS: From 3,045 questionnaire responses 4.1% of the children were reported to have a SBD symptom. SBD children differed on sleep and health domains from non-SBD children. Furthermore, through scaling of the (dis)similarities among the 26 indicators the SBD child was able to be modeled. By way of an internal analysis of the data-matrix the following indicators were eliminated: sleep correlates, health of the family, and behavior rated by teachers, followed by caffeine intake, drugs, and behavior rated by the parents. This revealed a two-dimensional model, consisting of primary SBD and secondary SBD. CONCLUSION: Children with SBD differ on many domains from children without such disorders and an underlying two-fold SBD concept was found. Firstly, the SBD-indicator positioned in between investigated correlates with disorders of initiating and maintaining sleep and sleep hyperhydrosis on one hand and with respiratory-related illnesses on the other; this was labeled primary SBD. Secondly, the SDB-indicator not closely associated with any of the investigated correlates can be interpreted as secondary SBD.


Asunto(s)
Síndromes de la Apnea del Sueño/epidemiología , Niño , Trastornos de la Conducta Infantil/epidemiología , Enuresis/epidemiología , Femenino , Estado de Salud , Humanos , Hiperhidrosis/epidemiología , Masculino , Prevalencia , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios , Contaminación por Humo de Tabaco/estadística & datos numéricos
12.
Oncogene ; 14(10): 1243-8, 1997 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-9121775

RESUMEN

Dephosphorylation of the RB protein has been reported to be associated with apoptosis. In contrast, we show that treatment of HL60 cells with etoposide or cytosine arabinoside or treatment of breast epithelial cells with alpha-FAS is associated with the cleavage of a 5 kDa fragment from the C-terminus of RB, resulting in a truncated product that we have designated as p100cl. This cleavage event coincides with the activation of cysteine proteases at the onset of apoptosis, is blocked by the addition of iodoacetamide to cells prior to the onset of apoptosis, and results in the expression of faster migrating protein species which can mimic dephosphorylated RB. The free 5 kDa fragment is detected only during apoptosis, predicts a cleavage site that we have mapped to a unique CPP32-like recognition sequence which is present at the C-terminus of all reported RB homologues, and results in a truncated RB protein with enhanced E2F binding affinity. While the causality for this cleavage event in the apoptotic process is still under investigation, our findings suggest distinct post-translational pathways for the RB product between cells examined during growth arrest (p105 hypophosphorylated RB) or apoptosis (p100cl).


Asunto(s)
Apoptosis/fisiología , Proteínas Portadoras , Proteínas de Ciclo Celular , Proteínas de Unión al ADN , Fragmentos de Péptidos/metabolismo , Proteína de Retinoblastoma/metabolismo , Factores de Transcripción/metabolismo , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Cisteína Endopeptidasas/metabolismo , Citarabina/farmacología , Factores de Transcripción E2F , Etopósido/farmacología , Femenino , Células HL-60/efectos de los fármacos , Células HL-60/metabolismo , Humanos , Fosforilación , Proteína 1 de Unión a Retinoblastoma , Factor de Transcripción DP1 , Receptor fas/fisiología
13.
Oncogene ; 17(12): 1625-8, 1998 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-9794240

RESUMEN

Mice bred to carry germline Rb and p53 null alleles are associated with a tumor spectrum that overlaps with the inherited multiple endocrine neoplasia-1 (MEN1) and MEN2 syndromes in humans, including medullary thyroid cancer (MTC). To study the genetic basis for these tumors, we microdissected MTC specimens or obtained fresh MTC tissue from nine independent Rb(+/-) p53(+/-) mice, amplified the region of the Ret gene known to be mutated in human MTC, and detected acquired missense Ret mutations in four different mice. These mutations were localized to a group of tandem cysteines which are analogous to activating germline mutations observed in human MEN2A and familial MTC (FMTC). To determine whether the remaining wild type Rb allele was inactivated in these murine MTC samples, we subjected tumor tissue to immunohistochemical staining with an Rb antibody, and demonstrated the absence of RB staining in murine MTC, while normal tissue retained RB nuclear staining. These findings demonstrate the ability of the gene knockout model to recapitulate somatic multi-step tumorigenesis and suggest that the development of a murine neuroendocrine tumor requires mutational dysregulation within both receptor tyrosine kinase and nuclear tumor suppressor gene pathways.


Asunto(s)
Proteínas de Drosophila , Proteínas Proto-Oncogénicas/genética , Proteínas Tirosina Quinasas Receptoras/genética , Proteína de Retinoblastoma/genética , Neoplasias de la Tiroides/genética , Proteína p53 Supresora de Tumor/genética , Animales , Modelos Animales de Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Ratones , Neoplasia Endocrina Múltiple Tipo 1/genética , Mutación , Proteínas Proto-Oncogénicas/fisiología , Proteínas Proto-Oncogénicas c-ret , Proteínas Tirosina Quinasas Receptoras/fisiología , Proteína de Retinoblastoma/análisis , Neoplasias de la Tiroides/patología , Proteína p53 Supresora de Tumor/análisis
14.
Oncogene ; 11(6): 1211-6, 1995 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-7566983

RESUMEN

Absent expression of the cyclin dependent kinase-inhibitor, p16INK4, is observed in a wide range of primary human cancers. Although homozygous deletions and point mutations have been reported in a subset of these tumors, the molecular basis for absent p16INK4 in other samples is unknown. We have examined 33 tumor cell lines and have shown that hypermethylation of a G:C-rich region within exon 1 of the CDKN2 gene was present in 100% of samples with wildtype RB expression and no detectable CDKN2 mutations. Treatment for at least 4 hours with the demethylating agent 5-aza 2'deoxycytidine, but not 5-azacytidine or 6-azacytidine, induces the prolonged expression of p16INK4 protein in each of these samples following a discrete 24-48 hour lag period. Consistent with the hypothesis that hypermethylation of the CDKN2 gene is a tumor-specific mechanism for gene inactivation, we observed hypomethylation at the exon 1 site exclusively in tumor lines that expressed p16INK4 or that had sustained inactivating point mutations within the CDKN2 open reading frame. These findings demonstrate a link between DNA methylation and the p16INK4:RB tumor suppressor pathway.


Asunto(s)
Azacitidina/análogos & derivados , Proteínas Portadoras/biosíntesis , Proteínas Portadoras/genética , Metilasas de Modificación del ADN/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Neoplasias Pulmonares/genética , Inhibidores de Proteínas Quinasas , Azacitidina/farmacología , Azacitidina/uso terapéutico , Secuencia de Bases , Inhibidor p16 de la Quinasa Dependiente de Ciclina , ADN/metabolismo , Decitabina , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Metilación , Datos de Secuencia Molecular , Células Tumorales Cultivadas
15.
Oncogene ; 19(40): 4632-9, 2000 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-11030152

RESUMEN

Mutational inactivation of the RB-related gene RBL2/p130 has been reported as a common and important prognostic factor in human lung cancer. To examine the role of the RB-related gene family in lung cancer we analysed the protein expression of the RB gene in cell lines obtained from 83 patients with small cell lung cancer (SCLC) and 114 patients with non-SCLC that included 21 novel lung tumor samples. While we detected five new SCLC with mutant RB expression (RB inactivation in 75/83; 90.4%), we did not detect any RB mutations in the new non-SCLC cell lines (RB inactivation in 13/114 non-SCLC and mesothelioma; 11.4%). In addition, we detected expression of a full-length RBL1/p107 and RBL2/p130 species in every sample tested (RBL1 or RBL2 inactivation in 0/69) and confirmed that both RB-related gene products retain functional binding activity to the E1A viral oncoprotein. Since expression of SV40 Large T antigen (Tag) has been reported in a subset of human lung tumors where it may inactivate RBL1 and RBL2, we also examined mesothelioma and non-mesothelioma lung tumors for Tag expression. Although we detected a faint 85 kDa protein species using specific anti-Tag antibodies, this signal migrated slightly faster than Tag extracted from Cos7 cells and did not exhibit binding activity to the RB or RBL1 proteins. Finally, we subjected 11 lung cancer cell lines to nucleotide sequencing and did not detect mutations within the C-terminal RBL2 exons 19-22 as recently reported. While the RB/p16 tumor suppressor pathway is targeted for mutations in 100% of lung cancers, mutational inactivation of the related RBL1 and RBL2 genes is a rare event.


Asunto(s)
Antígenos Transformadores de Poliomavirus/biosíntesis , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Células Pequeñas/genética , Regulación Neoplásica de la Expresión Génica , Genes de Retinoblastoma , Neoplasias Pulmonares/genética , Mesotelioma/genética , Proteínas de Neoplasias/biosíntesis , Fosfoproteínas/biosíntesis , Neoplasias Pleurales/genética , Proteínas , Proteína de Retinoblastoma/biosíntesis , Virus 40 de los Simios/genética , Proteínas E1A de Adenovirus/metabolismo , Animales , Antígenos Transformadores de Poliomavirus/genética , Células COS , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Pequeñas/metabolismo , Carcinoma de Células Pequeñas/patología , Chlorocebus aethiops , Análisis Mutacional de ADN , ADN de Neoplasias/genética , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Mesotelioma/metabolismo , Mesotelioma/patología , Mutación , Proteínas de Neoplasias/genética , Fosfoproteínas/genética , Neoplasias Pleurales/metabolismo , Neoplasias Pleurales/patología , Unión Proteica , Proteínas Recombinantes de Fusión/metabolismo , Proteína p130 Similar a la del Retinoblastoma , Transfección , Células Tumorales Cultivadas/metabolismo
16.
Oncogene ; 9(11): 3375-8, 1994 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-7936665

RESUMEN

Cell cycle dependent phosphorylation of the RB tumor suppressor protein is mediated by a family of G1 cyclin dependent kinases (cdks) and cyclins including the activated cdk4:cyclin D complex. The identification of a cdk4 inhibitor, p16INK4, as a target for mutations in cultured tumor lines and primary tumors suggested that RB activity may be affected in these cells. We have examined 88 lung cancer lines for p16INK4 protein expression and have observed a striking inverse correlation between the presence of p16INK4 and wildtype RB. We demonstrated that only 6/55 (11%) of small cell lung cancer (SCLC) samples had absent p16INK4 protein, and all 6 belonged to the rare subset of SCLC with wildtype RB expression. Conversely of 48 SCLC samples with absent or mutant RB, all showed detectable levels of p16INK4 protein. In contrast, we observed that 23/33 (70%) of non-SCLC samples had loss of p16INK4. Twenty-two of 26 non-SCLC lines with wildtype RB had absent p16INK4 while 6 of 7 non-SCLC lines with absent or mutant RB had detectable p16INK4. The inverse correlation of RB and p16INK4 expression and the absence of p16INK4 inactivation in RB (-/-) SCLC lines (0/48) confirms a common p16INK4/RB growth suppressor pathway in human cancers and provides evidence that p16INK4, and not an adjacent gene on chromosome 9p, is a specific target for mutational events.


Asunto(s)
Proteínas Portadoras/metabolismo , Genes de Retinoblastoma , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteínas de Neoplasias/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Pequeñas/metabolismo , Carcinoma de Células Pequeñas/patología , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Humanos , Neoplasias Pulmonares/patología , Células Tumorales Cultivadas
17.
Oncogene ; 9(9): 2441-8, 1994 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-8058306

RESUMEN

We have studied RB protein expression in 171 cell lines derived from patients with small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), pulmonary carcinoid, mesothelioma, and extrapulmonary small cell cancer (EPSC) and have correlated this data with clinical outcome. We detected absent or aberrant RB protein expression in 66/75 SCLC, 12/80 NSCLC, 1/6 carcinoid, 0/5 mesothelioma, and 4/5 EPSC samples. In addition, we observed integration of human papilloma virus (HPV) DNA in the single EPSC cell line that retained wildtype RB protein. We did not detect integration of HPV, SV40 or adenoviral DNA in other tumor samples with wildtype RB status. We also noted a stable, hypophosphorylated mutant RB in 12 SCLC and 3 NSCLC samples which might have been falsely interpreted as wildtype by current immunohistochemical techniques. Analysis of the matched clinical data showed no associations between RB status and age, sex, extent of disease, performance status, smoking history, and previous treatment. In addition, retrospective analyses showed no consistent correlation of RB protein expression with either best clinical response, overall survival, or in vitro chemotherapeutic drug sensitivity. The stable expression of RB after gene transfection into RB(-) SCLC cells, however, resulted in a trend toward increased in vitro resistance to etoposide, cisplatin and doxorubicin.


Asunto(s)
Carcinoma de Células Pequeñas/química , Neoplasias Pulmonares/química , Mesotelioma/química , Proteína de Retinoblastoma/análisis , Adulto , Anciano , Carcinoma de Pulmón de Células no Pequeñas/química , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Células Pequeñas/mortalidad , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Masculino , Mesotelioma/mortalidad , Persona de Mediana Edad , Tasa de Supervivencia , Células Tumorales Cultivadas
18.
Oncogene ; 9(5): 1321-6, 1994 May.
Artículo en Inglés | MEDLINE | ID: mdl-8152792

RESUMEN

While familial retinoblastoma has served as the paradigm for the two-hit theory of tumorigenesis and for the concept of the tumor suppressor gene, the etiology of incomplete penetrance of familial retinoblastoma is poorly understood. To address the molecular basis for this phenotype we have studied the functional properties of a mutant Rb gene identified in a kindred with incomplete penetrance of familial retinoblastoma and evidence for regressed retinal lesions (retinomas). In contrast to all previously isolated RB mutant proteins, we demonstrated that the mutant product from this kindred retained the wildtype properties of nuclear localization, the ability to undergo hyperphosphorylation in vivo, and the capacity to suppress growth of RB(-) cells. Protein binding ('pocket') activity, however, was defective defining a new class of RB mutant with partial inactivation. The presence of this unique RB mutant in the germline of obligate carriers with incomplete penetrance and regressed retinal lesions suggests a molecular basis for this phenotype and supports the hypothesis that a minimum 'RB threshold' level of protein binding activity is required to suppress tumorigenesis.


Asunto(s)
Neoplasias del Ojo/genética , Genes de Retinoblastoma/genética , Proteína de Retinoblastoma/genética , Retinoblastoma/genética , Alelos , Secuencia de Bases , Familia , Humanos , Datos de Secuencia Molecular , Fenotipo , Fosforilación , Mutación Puntual/genética , Proteína de Retinoblastoma/metabolismo , Células Tumorales Cultivadas
19.
Chem Biol ; 2(3): 119-21, 1995 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-9383412

RESUMEN

An intrinsically fluorescent protein from a Pacific jellyfish promises to become an important power tool in experimental biology. Mutant forms of this green fluorescent protein with altered spectral characteristics have recently been constructed. It is now possible to envision a range of derivatives optimized for specific applications.


Asunto(s)
Proteínas Luminiscentes/química , Escifozoos/metabolismo , Aequorina/química , Aequorina/metabolismo , Animales , Fluorescencia , Proteínas Fluorescentes Verdes , Proteínas Luminiscentes/genética
20.
AIDS ; 5(6): 723-8, 1991 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-1883544

RESUMEN

This paper argues that the notion of sexual partners per se is insufficient for estimating levels of HIV risk behaviour or changes in HIV risk over time, even though it is a crucial element of most epidemiological models of HIV. The concept of a penetrative sexual partner (PSP) is introduced as a considerably more accurate measure of HIV risk. Using data from a longitudinal study of 930 homosexually active men in England and Wales, this paper demonstrates that variation in numbers of PSPs (and thus HIV risk) is not related to variation in the gross numbers of sexual partners.


Asunto(s)
Infecciones por VIH/epidemiología , Homosexualidad , Conducta Sexual , Parejas Sexuales , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Inglaterra/epidemiología , Infecciones por VIH/etiología , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Factores de Riesgo , Gales/epidemiología
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