RESUMEN
11q13 amplification is a frequent event in human cancer and in particular in squamous cell carcinomas (SCC). Despite almost invariably spanning 10 genes, it is unclear which genetic components of the amplicon are the key driver events in SCC. A combination of computational, in vitro, ex vivo, and in vivo models leveraging efficient primary human keratinocyte genome editing by Cas9-RNP electroporation, identified ORAOV1, CCND1, and MIR548K as the critical drivers of the amplicon in head and neck SCC. CCND1 amplification drives the cell cycle in a CDK4/6/RB1-independent fashion and may confer a novel dependency on RRM2. MIR548K contributes to epithelial-mesenchymal transition. Finally, we identify ORAOV1 as an oncogene that acts likely via its ability to modulate reactive oxygen species. Thus, the 11q13 amplicon drives SCC through at least three independent genetic elements and suggests therapeutic targets for this morbid and lethal disease. IMPLICATIONS: This work demonstrates novel mechanisms and ways to target these mechanisms underlying the most common amplification in squamous cell carcinoma, one of the most prevalent and deadly forms of human cancer.
Asunto(s)
Carcinoma de Células Escamosas , Humanos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Ciclo Celular , Línea Celular Tumoral , Ciclina D1/genética , Amplificación de Genes , Oncogenes/genéticaRESUMEN
In humans, epidermal melanocytes are responsible for skin pigmentation, defence against ultraviolet radiation and the deadliest common skin cancer, melanoma. Although there is substantial overlap in melanocyte development pathways between different model organisms, species-dependent differences are frequent and the conservation of these processes in human skin remains unresolved. Here, we used a single-cell enrichment and RNA-sequencing pipeline to study human epidermal melanocytes directly from the skin, capturing transcriptomes across different anatomical sites, developmental age, sexes and multiple skin tones. We uncovered subpopulations of melanocytes that exhibit anatomical site-specific enrichment that occurs during gestation and persists through adulthood. The transcriptional signature of the volar-enriched subpopulation is retained in acral melanomas. Furthermore, we identified human melanocyte differentiation transcriptional programs that are distinct from gene signatures generated from model systems. Finally, we used these programs to define patterns of dedifferentiation that are predictive of melanoma prognosis and response to immune checkpoint inhibitor therapy.
Asunto(s)
Epidermis/metabolismo , Melanocitos/metabolismo , Melanoma/metabolismo , Neoplasias Cutáneas/metabolismo , Diferenciación Celular/fisiología , Humanos , Piel/metabolismo , Neoplasias Cutáneas/genética , Rayos Ultravioleta , Melanoma Cutáneo MalignoRESUMEN
BACKGROUND: Cancer/testis (CT) genes have expression normally restricted to the testis, but become activated during oncogenesis, so they have excellent potential as cancer-specific biomarkers. Evidence is starting to emerge to indicate that they also provide function(s) in the oncogenic programme. Human TEX19 is a recently identified CT gene, but a functional role for TEX19 in cancer has not yet been defined. METHODS: siRNA was used to deplete TEX19 levels in various cancer cell lines. This was extended using shRNA to deplete TEX19 in vivo. Western blotting, fluorescence activated cell sorting and immunofluorescence were used to study the effect of TEX19 depletion in cancer cells and to localize TEX19 in normal testis and cancer cells/tissues. RT-qPCR and RNA sequencing were employed to determine the changes to the transcriptome of cancer cells depleted for TEX19 and Kaplan-Meier plots were generated to explore the relationship between TEX19 expression and prognosis for a range of cancer types. RESULTS: Depletion of TEX19 levels in a range of cancer cell lines in vitro and in vivo restricts cellular proliferation/self-renewal/reduces tumour volume, indicating TEX19 is required for cancer cell proliferative/self-renewal potential. Analysis of cells depleted for TEX19 indicates they enter a quiescent-like state and have subtle defects in S-phase progression. TEX19 is present in both the nucleus and cytoplasm in both cancerous cells and normal testis. In cancer cells, localization switches in a context-dependent fashion. Transcriptome analysis of TEX19 depleted cells reveals altered transcript levels of a number of cancer-/proliferation-associated genes, suggesting that TEX19 could control oncogenic proliferation via a transcript/transcription regulation pathway. Finally, overall survival analysis of high verses low TEX19 expressing tumours indicates that TEX19 expression is linked to prognostic outcomes in different tumour types. CONCLUSIONS: TEX19 is required to drive cell proliferation in a range of cancer cell types, possibly mediated via an oncogenic transcript regulation mechanism. TEX19 expression is linked to a poor prognosis for some cancers and collectively these findings indicate that not only can TEX19 expression serve as a novel cancer biomarker, but may also offer a cancer-specific therapeutic target with broad spectrum potential.
Asunto(s)
Biomarcadores de Tumor/genética , Células Germinativas/metabolismo , Neoplasias/genética , Proteínas Nucleares/genética , Testículo/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular/genética , Supervivencia sin Enfermedad , Regulación Neoplásica de la Expresión Génica/genética , Células Germinativas/patología , Humanos , Estimación de Kaplan-Meier , Masculino , Ratones , Neoplasias/patología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Pronóstico , Proteínas de Unión al ARN , Testículo/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Translin and Trax proteins are highly conserved nucleic acid binding proteins that have been implicated in RNA regulation in a range of biological processes including tRNA processing, RNA interference, microRNA degradation during oncogenesis, spermatogenesis and neuronal regulation. Here, we explore the function of this paralogue pair of proteins in the fission yeast. Using transcript analysis we demonstrate a reciprocal mechanism for control of telomere-associated transcripts. Mutation of tfx1+ (Trax) elevates transcript levels from silenced sub-telomeric regions of the genome, but not other silenced regions, such as the peri-centromeric heterochromatin. In the case of some sub-telomeric transcripts, but not all, this elevation is dependent on the Trax paralogue, Tsn1 (Translin). In a reciprocal fashion, Tsn1 (Translin) serves to repress levels of transcripts (TERRAs) from the telomeric repeats, whereas Tfx1 serves to maintain these elevated levels. This reveals a novel mechanism for the regulation of telomeric transcripts. We extend this to demonstrate that human Translin and Trax also control telomere-associated transcript levels in human cells in a telomere-specific fashion.
Asunto(s)
Proteínas Portadoras/metabolismo , Proteínas de Unión al ADN/metabolismo , Neoplasias/metabolismo , ARN de Hongos/metabolismo , ARN Largo no Codificante/metabolismo , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/metabolismo , Proteínas de Schizosaccharomyces pombe/metabolismo , Schizosaccharomyces/metabolismo , Homeostasis del Telómero , Telómero/metabolismo , Proteínas Argonautas/genética , Proteínas Argonautas/metabolismo , Proteínas Portadoras/genética , Línea Celular Tumoral , Proteínas de Unión al ADN/genética , Regulación Fúngica de la Expresión Génica , Humanos , Mutación , Neoplasias/genética , Interferencia de ARN , ARN de Hongos/genética , ARN Largo no Codificante/genética , ARN Mensajero/genética , Proteínas de Unión al ARN/genética , Schizosaccharomyces/genética , Proteínas de Schizosaccharomyces pombe/genética , Telómero/genética , Transcriptoma , TransfecciónRESUMEN
BACKGROUND: Primary care interventions that promote cessation of benzodiazepine (BZD) use in long-term users are effective at 1 year, but their efficacy at 3 years is uncertain. AIM: To assess the 3-year efficacy of two primary care interventions delivered by GPs on cessation of BZD use in long-term users. DESIGN AND SETTING: Multicentre, three-arm, cluster randomised, controlled trial, with random allocation at the GP level. METHOD: Seventy-five GPs and 532 patients were randomly allocated to three groups: usual care (control), structured intervention with stepped-dose reduction and follow-up visits (SIF), or structured intervention with written stepped-dose reduction (SIW). The primary outcome was BZD use at 36 months. RESULTS: At 36 months, 66/168 patients (39.2%) in the SIW group, 79/191 patients (41.3%) in the SIF group, and 45/173 patients (26.0%) in the control group had discontinued BZD use. The relative risks (RR) adjusted by cluster were 1.51 (95% CI = 1.10 to 2.05; P = 0.009) in the SIW group and 1.59 (95% CI = 1.15 to 2.19; P = 0.005) in the SIF group. A total of 131/188 patients (69.7%) who successfully discontinued BZD use at 12 months remained abstinent at 36 months. The groups showed no significant differences in anxiety, depression, or sleep dissatisfaction at 36 months. CONCLUSION: The interventions were effective on cessation of BZD use; most patients who discontinued at 12 months remained abstinent at 3 years. Discontinuation of BZD use did not have a significant effect on anxiety, depression, or sleep quality.
Asunto(s)
Trastornos de Ansiedad/tratamiento farmacológico , Benzodiazepinas/administración & dosificación , Trastorno Depresivo/tratamiento farmacológico , Manejo de la Enfermedad , Atención Primaria de Salud/métodos , Calidad de Vida , Síndrome de Abstinencia a Sustancias/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Educación del Paciente como Asunto , Estudios Retrospectivos , Síndrome de Abstinencia a Sustancias/etiología , Factores de Tiempo , Privación de Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Emotional disorders (depression and anxiety disorders) are highly prevalent mental health problems. Although evidence showing the effectiveness of disorder-specific treatments exists, high comorbidity rates among emotional disorders limit the utility of these protocols. This has led some researchers to focus their interest on transdiagnostic interventions, a treatment perspective that might be more widely effective across these disorders. Also, the current way of delivering treatments makes it difficult provide assistance to all of the population in need. The use of the Internet in the delivery of evidence-based treatments may help to disseminate treatments among the population. In this study, we aim to test the effectiveness of EmotionRegulation, a new transdiagnostic Internet-based protocol for unipolar mood disorders, five anxiety disorders (panic disorder, agoraphobia, social anxiety disorder, generalized anxiety disorder and anxiety disorder not otherwise specified), and obsessive-compulsive disorder in comparison to treatment as usual as provided in Spanish public specialized mental health care. We will also study its potential impact on basic temperament dimensions (neuroticism/behavioral inhibition and extraversion/behavioral activation). Expectations and opinions of patients about this protocol will also be studied. METHODS/DESIGN: The study is a randomized controlled trial. 200 participants recruited in specialized care will be allocated to one of two treatment conditions: a) EmotionRegulation or b) treatment as usual. Primary outcome measures will be the BAI and the BDI-II. Secondary outcomes will include a specific measure of the principal disorder, and measures of neuroticism/behavioral inhibition and extraversion/behavioral activation. Patients will be assessed at baseline, post-treatment, and 3- and 12-month follow-ups. Intention to treat and per protocol analyses will be performed. DISCUSSION: Although the effectiveness of face-to-face transdiagnostic protocols has been investigated in previous studies, the number of published transdiagnostic Internet-based programs is still quite low. To our knowledge, this is the first randomized controlled trial studying the effectiveness of a transdiagnostic Internet-based treatment for several emotional disorders in public specialized care. Combining both a transdiagnostic approach with an Internet-based therapy format may help to decrease the burden of mental disorders, reducing the difficulties associated with disorder-specific treatments and facilitating access to people in need of treatment. Strengths and limitations are discussed. TRIAL REGISTRATION: ClinicalTrials.gov NCT02345668 . Registered 27 July 2015.
Asunto(s)
Trastornos de Ansiedad/terapia , Atención a la Salud , Trastorno Depresivo/terapia , Emociones , Internet , Psicoterapia/métodos , Terapia Asistida por Computador/métodos , Trastornos de Ansiedad/diagnóstico , Trastornos de Ansiedad/psicología , Protocolos Clínicos , Trastorno Depresivo/diagnóstico , Trastorno Depresivo/psicología , Femenino , Humanos , Análisis de Intención de Tratar , Masculino , Satisfacción del Paciente , Escalas de Valoración Psiquiátrica , Calidad de Vida , Proyectos de Investigación , España , Encuestas y Cuestionarios , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Although benzodiazepines are effective, long-term use is not recommended because of potential adverse effects; the risks of tolerance and dependence; and an increased risk of hip fractures, motor vehicle accidents, and memory impairment. The estimated prevalence of long-term benzodiazepine use in the general population is about 2,2 to 2,6%, is higher in women and increases steadily with age. Interventions performed by General Practitioners may help patients to discontinue long-term benzodiazepine use. We have designed a trial to evaluate the effectiveness and safety of two brief general practitioner-provided interventions, based on gradual dose reduction, and will compare the effectiveness of these interventions with that of routine clinical practice. METHODS/DESIGN: In a three-arm cluster randomized controlled trial, general practitioners will be randomly allocated to: a) a group in which the first patient visit will feature a structured interview, followed by visits every 2-3 weeks to the end of dose reduction; b) a group in which the first patient visit will feature a structured interview plus delivery of written instructions to self-reduce benzodiazepine dose, or c) routine care. Using a computerized pharmaceutical prescription database, 495 patients, aged 18-80 years, taking benzodiazepine for at least 6 months, will be recruited in primary care health districts of three regions of Spain (the Balearic Islands, Catalonia, and Valencia). The primary outcome will be benzodiazepine use at 12 months. The secondary outcomes will include measurements of anxiety and depression symptoms, benzodiazepine dependence, quality of sleep, and alcohol consumption. DISCUSSION: Although some interventions have been shown to be effective in reducing benzodiazepine consumption by long-term users, the clinical relevance of such interventions is limited by their complexity. This randomized trial will compare the effectiveness and safety of two complex stepped care interventions with that of routine care in a study with sufficient statistical power to detect clinically relevant differences. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN13024375.
Asunto(s)
Benzodiazepinas/efectos adversos , Educación del Paciente como Asunto , Atención Primaria de Salud/métodos , Síndrome de Abstinencia a Sustancias/prevención & control , Trastornos Relacionados con Sustancias/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Ansiedad/epidemiología , Depresión/epidemiología , Humanos , Entrevistas como Asunto , Persona de Mediana Edad , Proyectos de Investigación , Método Simple Ciego , Adulto JovenRESUMEN
OBJECTIVE: To analyze whether for an equal health problem there are gender differences in the drugs used in an adult population attended in the Health Care Centers of the Valencian Community (Spain). METHODS: A cross-sectional analytical study was carried out between February-August 1997. The independent variables were: socio-economic parameters, frequency of visits, and self-perceived or diagnosed health problems, and the dependent one the number of drugs consumed. RESULTS: Of the 812 patients considered, 801 consumed medication. Eighty percent of the health problems for which drugs were used involved 5 apparatuses and systems (mean: 3.3 health problems/patient). The 5 most consumed therapeutic groups accounted for 81% of the total (mean: 4.5 drugs/patient). Significant differences were recorded, with greater female consumption in the central nervous system and genitourinary tract therapeutic groups, and with greater male consumption in relation to the respiratory system and systemic anti-infectious therapy. Drug use increased with age, lowest educational level, lowest professional categories, and with the highest frequency of visits to the physician. Significant differences were also recorded in drug use by occupational status, marital status and family structure. The multivariate analysis showed the number of health problems and the frequency of visits accounted for 82.2% of the variability of the variable <
Asunto(s)
Utilización de Medicamentos/estadística & datos numéricos , Atención Primaria de Salud/estadística & datos numéricos , Factores Sexuales , Adolescente , Adulto , Anciano , Estudios Transversales , Educación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Distribución por Sexo , Factores Socioeconómicos , España , Encuestas y CuestionariosRESUMEN
Objective: To analyze whether for an equal health problem there are gender differences in the drugs used in an adult population attended in the Health Care Centers of the Valencian Community (Spain). Methods: A cross-sectional analytical study was carried out between February-August 1997. The independent variables were: socio-economic parameters, frequency of visits, and self-perceived or diagnosed health problems, and the dependent one the number of drugs consumed. Results: Of the 812 patients considered, 801 consumed medication. Eighty percent of the health problems for which drugs were used involved 5 apparatuses and systems (mean: 3.3 health problems/patient). The 5 most consumed therapeutic groups accounted for 81% of the total (mean: 4.5 drugs/patient). Significant differences were recorded, with greater female consumption in the central nervous system and genitourinary tract therapeutic groups, and with greater male consumption in relation to the respiratory system and systemic anti-infectious therapy. Drug use increased with age, lowest educational level, lowest professional categories, and with the highest frequency of visits to the physician. Significant differences were also recorded in drug use by occupational status, marital status and family structure. The multivariate analysis showed the number of health problems and the frequency of visits accounted for 82.2% of the variability of the variable «number of drugs consumed». The variability accounted for by gender was explained by the variable health problems, the main factor underlying drug consumption among women and men. Conclusion: The main finding is probably that women do not use larger numbers of drugs than men if health problems and frequency of visits are controlled (AU)
Objetivo: Analizar si para el mismo problema de salud hay diferencias de género en los medicamentos utilizados en una población adulta atendida en centros de salud de la Comunidad Valenciana. Métodos: Estudio observacional transversal analítico realizado entre febrero y agosto de 1997. Variables independientes: parámetros socioeconómicos, frecuentación de los servicios de salud y problemas de salud autopercibidos o diagnosticados. Variable independiente: número de medicamentos consumidos. Resultados: De los 812 pacientes, 801 tomaban medicamentos. El 80% de los problemas de salud por los que se medicaban pertenece a 5 aparatos y sistemas (media: 3,3 problemas de salud por paciente). Los 5 grupos terapéuticos más consumidos suponen el 81% del total (media: 4,5 medicamentos por paciente). Se evidenció un mayor consumo significativo por la mujer de medicamentos de los grupos terapéuticos del sistema nervioso central e infecciones genitourinarias, y mayor consumo por los varones de medicamentos de los grupos terapéuticos del sistema respiratorio y terapia antiinfecciosa sistémica. El uso de los medicamentos incrementó con la edad, el menor nivel educativo, menor categoría profesional y con la mayor frecuencia de visitas. También se encontraron diferencias significativas en el uso de medicamentos según la situación laboral, estado marital y la estructura familiar. El análisis multivariante mostró que el número de problemas de salud y la frecuencia de visitas explicaban el 82,2% de la variabilidad de la variable «número de medicamentos consumidos». La variabilidad representada por el género se explicó por la variable de problemas de salud, el principal factor subyacente del consumo de medicamentos entre mujeres y hombres. Conclusiones: El hallazgo principal es, probablemente, que las mujeres no utilizan mayor número de medicamentos que los hombres al ajustar por problemas de salud y la frecuencia de las visitas (AU)
Asunto(s)
Humanos , Masculino , Femenino , Atención Primaria de Salud/estadística & datos numéricos , Utilización de Medicamentos/estadística & datos numéricos , Distribución por Sexo , Encuestas Epidemiológicas , Distribución por Edad , Grupos Diagnósticos Relacionados/estadística & datos numéricosRESUMEN
BACKGROUND: Indication-based, in comparison to diagnoses-based, drug utilization studies in children are scarce in the literature. AIM: To determine the adequacy of the prescriber's indications for specific drug treatments compared to the current literature in five different European countries; and to show the possibilities of performing indication-based drug utilization studies. DESIGN: a descriptive, cross-sectional, international study. PATIENTS AND METHODS: Randomly selected sample of 12,264 paediatric outpatients seen in consultation rooms attended by paediatricians or general practitioners. Data on patient demographics, diagnoses, and pharmacological treatment, with therapeutic indications for each drug, were collected in pre-designed forms. Diagnoses and indications were coded using the ICD-9 and drugs according to the ATC classifications. RESULTS: Indications were registered for every drug prescribed in all locations. Antibiotic indications considered incorrect (common cold, upper respiratory tract infections, viral infections, general symptoms or "not specified") accounted from 24.1% of the total antibiotics prescribed in Tenerife to 67.4% in Slovakia. Incorrect indication of first-choice antibiotics prescribed in acute otitis media and tonsillitis ranged from 28.9% of total antibiotics use in Russia to 75.4% in Tenerife. Correct antibiotic indications ranged from 23.4% of total antibiotics used in Slovakia to 65.7% in Tenerife. Aspirin use in febrile viral conditions was detected mainly in Toulouse and Russia. CONCLUSION: The main areas for improvement detected were high use of mucolytics, prescription of aspirin in potential or established viral infections, overuse of antibiotics and identification of specific patterns of incorrect antibiotic prescription and clinical entities associated with each location.