Evaluation of Risk Models and Biomarkers for the Optimization of Lung Cancer Screening

More deaths can be attributed to lung cancer, than to any other cancer type. Evidence collected over the last 10 years, from randomized trials in the USA and Europe, indicates that screening by means of low-dose computed tomography (LDCT) could reduce the number of lung cancer (LC) deaths by about 20%-24%. While these findings have led to the implementation of screening programs in the USA, South Korea and Poland, discussions on their optimal design and execution are still ongoing in various countries, including Germany. Optimizing screening means finding the right balance between mortality reduction and risks, harms, and monetary costs. LDCT-scans are expensive, expose participants to radiation and put them at risk for overdiagnosis, as well as at risk for unnecessary invasive and expensive confirmatory procedures triggered by false positive (FP) results. Minimizing the number of unnecessary screening and confirmatory examinations should be prioritized. While risk-based eligibility has been shown to best target candidates, questions regarding optimal screening frequency, accurate nodule evaluation, stop-screening criteria to reduce overdiagnosis, and the use of complementary non-invasive diagnostic methods, remain open. Statistical models and biomarkers have been developed to help answer these questions. However, there is limited evidence of their validity in data from screening contexts and populations other than those in which they were developed. The analyses presented in this thesis are based on data collected as part of the German Lung Cancer Screening Intervention (LUSI) trial in order to validate models that address the questions: 1) can candidates for biennial vs annual screening be identified on the basis of their LC risk? 2) can the number of FP test results be reduced by accurately estimating the malignancy of LDCT-detected nodules? 3) What was the extent of overdiagnosis in the LUSI trial and how does overdiagnosis risk relate to the age and remaining lifetime of participants? Additionally, blood samples from participants of the LUSI were measured to evaluate: 4) whether the well-validated diagnostic biomarker test EarlyCDT®-Lung is sensitive enough to detect tumors seen in LDCT images. The LCRAT+CT and Polynomial models predict LC risk based on subject characteristics and LDCT imaging findings. Results of this first external validation confirmed their ability to identify participants with LC detected within 1-2 years after first screening. Discrimination was higher compared to a criterion based on nodule size and, to a lesser degree, compared to a model based on smoking and subject characteristics (LCRAT). This suggested that while LDCT findings can enhance models, most of their performance can could be attributed to information on smoking. Skipping 50% of annual LDCT examinations (i.e., for participants with estimated risks <5th decile) would have caused <10% delayed diagnoses, indicating that candidates for biennial screening could be identified based on their predicted LC risks without compromising on early detection. Absolute risk estimates were, on average, below the observed LC rates, indicating poor calibration. Models developed using data from the Canadian screening study PanCan showed excellent ability to differentiate between tumors and non-malignant nodules seen on LDCT scans taken at first screening participation and to accurately predict absolute malignancy risk. However, they showed lower performance when applied on data of nodules detected in later rounds. In contrast, a model developed on data from the UKLS trial and models developed on data from clinical settings did not perform as well in any screening round. Excess incidence of screen-detected lung tumors, an estimator of overdiagnosis, was within the range of values reported by other trials after similar post-screening follow-up (ca. 5-6 years). Estimates of mean pre-clinical sojourn time (MPST) and LDCT detection sensitivity were obtained via mathematical modeling. The highest excess incidence and longest MPST estimates were found among adenocarcinomas. The proportion of tumors with long lead times predicted based on MPST estimates (e.g., 23% with lead times ≥8 years) suggested a substantial overdiagnosis risk for individuals with residual life expectancies shorter than these hypothetical lead times, for example for heavy smokers over the age of 75. The tumor autoantibody panel measured by EarlyCDT®-Lung, a test widely validated as a diagnostic tool in clinical settings and recently tested as a pre-screening tool in a large randomized Scottish trial (ECLS), was found to have insufficient sensitivity for the identification of lung tumors detected via LDCT and of participants with screen-detected pulmonary nodules for whom more invasive diagnostic procedures should be recommended. Overall, the findings presented in this thesis indicate that risk prediction models can help optimize LC screening by assigning participants to appropriate screening intervals, and by increasing the accuracy of nodule evaluation. However, there is a need for further external model validation and re-calibration. Additionally, while excess incidence can provide estimates of overdiagnosis risk at a population-level, a better approach would be to obtain model-based personalized estimates of tumor lead and residual lifetime. Better individualized decisions about whether to start or stop screening could be taken on the basis of the relationship between these estimates and the risk of overdiagnosis. Finally, although there is evidence for the potential of biomarkers to complement LC screening, the so far most promising candidate (EarlyCDT®-Lung) cannot be recommended as a pre-screening tool given its poor sensitivity for the identification of lung tumors detected via LDCT. In conclusion, while steps have been taken in the right direction, more research is required in order to answer all open questions regarding the optimal design of lung cancer screening programs

Implicaciones del trabajo remunerado en mujeres pobres: tensiones y posibilidades.

The participation of women in the productive area, carrying out work of extradomestic work (García, de Oliveira, 1994) has been increasing rapidly in the last decades, due to different factors, from changes in lifestyles, in The aspirations of women, to a greater demand of women workers in some economic sectors (Razavi, 2008). This access to the world of work has not been a harmonious or conciliatory process of traditional activities: motherhood, care and domestic work. On the other hand, tensions are often experienced as a result of the hierarchy of gender roles, resulting in a patriarchal differential (Moreno, 2008), reflected in a deficit of women compared to men who also participate in the labor market. Assuming that every family model is based on different models of production under a certain conception of development, on which depends the distribution of labor in the labor market, the role played by the state and the obligations assigned to the unit (Esping-Andersen 2000), it is possible to see that safe, stable jobs coexist with precarious, flexible jobs. Finally, we incorporate poverty into the analysis; Poor women have seen their opportunities for development reduced, as well as the employment options they encounter tend to be more rigid in terms of organization (Moreno, 2008), thus increasing the tension between domestic and extradition.In the present work, we first present a sociodemographic view of a polygon of poverty in Leon, Guanajuato, and deepen the analysis with testimoniesof a group of women who work in the toilet in an institution of Private Higher Education, who live in that area analyzing the tensions between the Domestic and extradition areas, as well as the impact that the paid activity has had on them.La participación de las mujeres en el ámbito productivo, realizando labores de trabajo extradoméstico (Garcí­a, de Oliveira, 1994) ha ido en acelerado aumento en las últimas décadas, lo cual obedece a distintos factores, desde los cambios en los estilos de vida, en las aspiraciones de las mujeres, hasta una mayor demanda de trabajadoras en algunos sectores económicos (Razavi, 2008). Este acceso al mundo laboral no ha sido un proceso armónico ni conciliatorio de las actividades tradicionales: la maternidad, el cuidado y el trabajo doméstico. Por el contrario, suelen experimentarse tensiones derivadas de la jerarquización de los roles de género, resultando en un diferencial patriarcal (Moreno, 2008) que se refleja en un déficit de las mujeres frente a los hombres que también participan en el mercado laboral. Asumiendo que todo modelo de familia, se asienta en distintos modelos de producción bajo una determinada concepción de desarrollo, de la cual depende la distribución del trabajo en el mercado laboral, el papel que juega el estado y las obligaciones que se le asignan a la unidad familiar (Esping-Andersen 2000), es posible ver que coexisten trabajos seguros, estables con trabajos precarios, flexibles. Finalmente, incorporamos al análisis la pobreza; las mujeres pobres han visto reducidas sus oportunidades de desarrollo, además de que las opciones laborales que encuentran suelen ser más rí­gidas en cuanto a la organización, (Moreno, 2008) incrementando así­ la tensión entre lo doméstico y extradoméstico. En el presente trabajo presentamos primero una mirada sociodemográfica de un polí­gono de pobreza en León, Guanajuato y profundizamos el análisis con testimonios de un conjunto de mujeres trabajadoras del aseo en una institución de Educación Superior privada, que viven en dicha zona analizando las tensiones entre los ámbitos doméstico y extradoméstico, así­ como el impacto que la actividad remunerada ha tenido en ellas

Enfermedad de von Willebrand, biología molecular y diagnóstico

ResumenAntecedentesLa enfermedad de von Willebrand es el trastorno hereditario más frecuente de las proteínas de la coagulación en los seres humanos. Existen 3 tipos: 1, 2A, 2B, 2N, 2M, y 3. Está asociada a mutaciones en el cromosoma 12, en la región p13.2, que codifica para el factor de von Willebrand (VWF), el cual se sintetiza en las células endoteliales y megacariocitos.DiscusiónLa biología molecular ha permitido la caracterización del gen del VWF, adquiriendo un papel importante en el diagnóstico la enfermedad de von Willebrand así como en la investigación de alteraciones en otros genes, que pueden estar involucrados en la regulación de la síntesis, procesamiento y secreción del VWF. Sin embargo, aún no se han integrado las estrategias de biología molecular entre las pruebas de diagnóstico disponibles.El análisis de los multímeros del VWF es una metodología que cumple con las características para el diagnóstico, pero no es fácil de estandarizar. Tomando en consideración que aún en los centros de tercer nivel en nuestro país los enfermos de von Willebrand no cuentan con un diagnóstico definitivo, es necesario implementar estas metodologías para su estudio y mejorar su diagnóstico.ConclusionesLa enfermedad de von Willebrand es heterogénea debido a los mecanismos moleculares que producen los distintos fenotipos clínicos y de laboratorio. En México existen pocos trabajos relacionados con esta enfermedad, por ello es fundamental realizar un estudio integral que incluya aspectos clínicos, pruebas de laboratorio básicas y especiales, para establecer el diagnóstico correcto, desarrollar nuevos enfoques terapéuticos, y así ofrecer atención médica y asesoramiento genético adecuados.AbstractBackgroundVon Willebrand disease is the most common inherited disorder of the coagulation proteins in humans. There are three types: 1, 2A, 2B, 2N, 2M and 3. It is associated with mutations on chromosome 12 in the region p13.2, encoding the von Willebrand factor (VWF), which is synthesized in endothelial cells and megakaryocytes.DiscussionThe VWF gene has been characterised using molecular biology techniques, which have acquired an important role in diagnosis von Willebrand disease, as well as in the investigation of alterations in other genes, which may be involved in regulating the synthesis, processing, and secretion of VWF. However, there are still no strategies to integrate the molecular biology diagnostic tests available.Analysis of VWF multimers is a methodology that meets the characteristics for diagnosis, but it is not easy to standardise. Considering that even in tertiary centres in our country, von Willebrand patients do not have a definitive diagnosis, it is necessary to implement these methodologies to study and improve diagnosis.ConclusionsVon Willebrand disease is highly heterogeneous due to the molecular mechanisms that produce the various clinical and laboratory phenotypes. In Mexico there are few studies related to this disease; therefore it is essential to conduct a comprehensive study including clinical, basic, and special testing laboratory tests, in order to establish a correct diagnosis, develop new therapeutic approaches, and offer the appropriate medical care and genetic counselling

También las publicaciones deben comprometerse con el impacto social

Recientemente el gobierno español ha modifi-cado los criterios de evaluación del profesorado universitario, introduciendo el valor cualitativo a la hora de determinar el peso de las publicaciones. Hasta ahora y desde hace más de una década se venía haciendo exclusivamente a través de un indicador indirecto: el Factor de Impacto que reciben las revistas científicas. Aunque tímidamente, el nue-vo criterio supone una ruptura al menos conceptual: al exigir a los académicos que muestren la repercu-sión bibliométrica de algunas de sus publicaciones, se está lanzando el mensaje de que lo importante es el impacto social del conocimiento,2 más que la producción acumulada del mismo. De alguna ma-nera se pone de manifiesto la preocupación que nuestras autoridades tienen sobre la escasa capaci-dad competitiva de nuestra actividad investigadora

Epithelial–Mesenchymal Transition Associated with Head and Neck Squamous Cell Carcinomas: A Review

Head and neck squamous cell carcinomas (HNSCCs) are aggressive, recurrent, and metastatic neoplasms with a high occurrence around the world and can lead to death when not treated appropriately. Several molecules and signaling pathways are involved in the malignant conversion process. Epithelial–mesenchymal transition (EMT) has been described in HNSCCs, a major type of aggressive carcinoma. EMT describes the development of epithelial cells into mesenchymal cells, which depends on several molecular interactions and signaling pathways that facilitate mesenchymal conversion. This is related to interactions with the microenvironment of the tumor, hypoxia, growth factors, matrix metalloproteinases, and the presence of viral infections. In this review, we focus on the main molecules related to EMT, their interactions with the tumor microenvironment, plasticity phenomena, epigenetic regulation, hypoxia, inflammation, their relationship with immune cells, and the inhibition of EMT in the context of HNSCC

Estrategias de intervención pedagógica que movilizan los procesos iniciales de lectura y escritura en los alumnos de preescolar

El trabajo busca generar nuevas didácticas en los procesos de adquisición de la lengua escrita en el preescolar y desarrollar estrategias pedagógicas que permitan adquirir los procesos iniciales de lectura y escritura, estas estrategias podrán ser retomadas por maestros para hacer más eficaz el aprendizaje de la lengua escrita en los alumnos

Adaptation of the classical end-point ITS-PCR for the diagnosis of avian trichomonosis to a real-time PCR reveals Bonelli’s eagle as a new host for Trichomonas gypaetinii

Avian trichomonosis is a parasitic disease caused mainly by Trichomonas gallinae and other Trichomonas species. It can be asymptomatic, or it can produce a necrotic lesion in the upper digestive tract and spread to other organs, causing the death of the infected birds. In this study, we aimed to evaluate an adapted real-time PCR method for the diagnosis of different genotypes and species of avian oropharyngeal trichomonads. Fifty-six samples from the oropharynx of Bonelli’s eagles (Aquila fasciata) obtained between 2018 and 2019 were analyzed using the real-time PCR and the end-point PCR, both targeting trichomonads ITS, and the results were compared by a coefficient of agreement. All positive samples were sequenced. The analysis showed a higher percentage of detection of real-time PCR ITS compared with end-point PCR ITS (64.3 vs 55.4%), and good agreement value (Kappa = 0.816). Melting temperature value for resulting amplicons of real-time PCR for avian trichomonads was 83.45 ± 0.72 °C. Genotypes A, D, and III were found among the sequences. Moreover, Trichomonas gypaetinii, a common species in scavenger birds, is reported for the first time in Bonelli’s eagles

Using participatory action research to reimagine community mental health services in Colombia: a mixed-method study protocol

Introduction Mental healthcare systems are challenged by how they hear and respond to what marginalised communities experience as drivers of mental distress. In Colombia, this challenge intersects with wider challenges facing post-conflict reconstruction. Our pilot study will explore the feasibility and acceptability of a participatory approach to developing community-led participatory interventions for community mental health systems strengthening and mental health improvement, in two sites in Caquetá, Colombia. Methods and analysis The project is divided into three distinct phases aligned with community participatory action research cycles: diagnostic, intervention and evaluation. This allows us to use a participatory approach to design a community-led, bottom-up intervention for mental health systems strengthening and the promotion of mental health and well-being. The diagnostic phase explores local understandings of mental health, mental distress and access to mental health services from community members and health providers. The intervention stage will be guided by a participatory Theory of Change process. Community priorities will inform the development of a participatory, learning and action (PLA) informed group intervention, with a community linkage forum. The pilot of the PLA intervention will be evaluated using MRC process evaluation guidelines. Ethics and dissemination This project has received ethical approval from two sources. Universidad de Los Andes (2021-1393) and the University College London (16127/005). Dissemination of findings will include academic publications, community forums, policy briefs and visual media (cartoons, pod casts and short films)

Endothelin-1 as a Mediator of Heme Oxygenase-1-Induced Stemness in Colorectal Cancer: Influence of p53

Heme oxygenase-1 (HO-1) is an antioxidant protein implicated in tumor progression, metastasis, and resistance to therapy. Elevated HO-1 expression is associated with stemness in several types of cancer, although this aspect has not yet been studied in colorectal cancer (CRC). Using an in vitro model, we demonstrated that HO-1 overexpression regulates stemness and resistance to 5-FU treatment, regardless of p53. In samples from CRC patients, HO-1 and endothelin converting enzyme-1 (ECE-1) expression correlated significantly, and p53 had no influence on this result. Carbon monoxide (CO) activated the ECE-1/endothelin-1 (ET-1) pathway, which could account for the protumoral effects of HO-1 in p53 wild-type cells, as demonstrated after treatment with bosentan (an antagonist of both ETRA and ETRB endothelin-1 receptors). Surprisingly, in cells with a non-active p53 or a mutated p53 with gain-of-function, ECE-1-produced ET-1 acted as a protective molecule, since treatment with bosentan led to increased efficiency for spheres formation and percentage of cancer stem cells (CSCs) markers. In these cells, HO-1 could activate or inactivate certain unknown routes that could induce these contrary responses after treatment with bosentan in our cell model. However more research is warranted to confirm these results. Patients carrying tumors with a high expression of both HO-1 and ECE-1 and a non-wild-type p53 should be considered for HO-1 based-therapies instead of ET-1 antagonists-based ones.Instituto de Salud Carlos IIIFEDER (PI18/01947)MINECO grant (DPI2017-84439-R)Nicolás Monardes Program from the Andalusian Health Service (C-0033-2015)FPU2019 fellowship (FPU19/02269) from the Ministerio de Ciencia, Innovación y Universidades (Spain