Background
Hepatocellular carcinoma is the third leading cause of cancer death. Single or multiple mutations in genes related to growth control, apoptosis, invasion and metastasis have been ...determined; so a better understanding of the molecular genetic basis of malignant transformation, tumor progression and host interaction has led to significant progress in the development of new therapeutic agents. The ability of adenovirus vectors to deliver and express genes at high yields in HCC treatment has been demonstrated and well documented over the last few years.
Objective
To overview and provide an update of what has been accomplished in the field of adenoviral gene therapy and its application in hepatocellular carcinoma treatment.
Methods
Original articles were searched using Pubmed and other medical databases to get the most representative and actual information to establish the current state of the investigation of Ad vectors in HCC.
Results
Good results have been accomplished in preclinical models using new Ad vectors and especially AAV vectors, it is important to motivate further clinical trials to corroborate all the experience obtained.
Conclusions
Ad and AAV must be considered as an opportunity to improve the quality of life and survival of HCC patients.
Earlywood vessel lumen areas were measured in 72 consecutive tree rings in wood cores from oak (Quercus robur L.) trees in a maritime woodland. This anatomical time series was statistically ...correlated with climate data for the same time span. There was a strong dependence of earlywood vessel lumen area on rainfall between February and April, which reflects the role of water availability in vessel ontogeny. By inversion, earlywood vessel lumen areas can be used as a proxy to reconstruct spring precipitation beyond the archived weather records. Such information may be of value in the context of climate change.
El presente trabajo propone una revisión completa de la potestad de recalificación de los convenios de colaboración para la gestión y prestación de servicios entre Comunidades Autónomas que el ...artículo 145.2 de nuestra Constitución reconoce a las Cortes Generales. En concreto, se expone aquí una novedosa interpretación de la reserva estatutaria del carácter y efectos de la comunicación de ese tipo de pactos interautonómicos al Parlamento nacional, y las importantes consecuencias jurídicas que de ello se derivan. The immediate paper proposes a full review of the Parliament's authority to re-evaluate the power of the Co-operation Agreements to the management and provision of services between Comunidades Autónomas granted to the Parliament by articule 145.2 CE. Specifically, we will view an innovative interpretation of the statutory holding of effects and character of the communication of these Agreements by the Parliament, as well as the relevant legal consequences.
Background Existing criteria for predicting patient survival from immunotherapy are primarily centered on the PD-L1 status of patients. We tested the hypothesis that noninvasively captured baseline ...whole-lung radiomics features from CT images, baseline clinical parameters, combined with advanced machine learning approaches, can help to build models of patient survival that compare favorably with PD-L1 status for predicting ‘less-than-median-survival risk’ in the metastatic NSCLC setting for patients on durvalumab. With a total of 1062 patients, inclusive of model training and validation, this is the largest such study yet. Methods To ensure a sufficient sample size, we combined data from treatment arms of three metastatic NSCLC studies. About 80% of this data was used for model training, and the remainder was held-out for validation. We first trained two independent models; Model-C trained to predict survival using clinical data; and Model-R trained to predict survival using whole-lung radiomics features. Finally, we created Model-C+R which leveraged both clinical and radiomics features. Results The classification accuracy (for median survival) of Model-C, Model-R, and Model-C+R was 63%, 55%, and 68% respectively. Sensitivity analysis of survival prediction across different training and validation cohorts showed concordance indices (95 percentile) of 0.64 (0.63, 0.65), 0.60 (0.59, 0.60), and 0.66 (0.65,0.67), respectively. We additionally evaluated generalization of these models on a comparable cohort of 144 patients from an independent study, demonstrating classification accuracies of 65%, 62%, and 72% respectively. Conclusion Machine Learning models combining baseline whole-lung CT radiomic and clinical features may be a useful tool for patient selection in immunotherapy. Further validation through prospective studies is needed.
En las últimas dos décadas la controversia sobre una eventual integración de Navarra en la Comunidad Autónoma del País Vasco ha recobrado actualidad en el debate político. Tanto los actores ...principales del sistema como la inmensa mayoría de la doctrina constitucionalista presumen todavía vigente y aplicable lo dispuesto a tal efecto en la disposición transitoria cuarta de la Constitución. En este trabajo se intenta justificar por qué esa norma, como otras también relativas al proceso de creación autonómica, agotó sus efectos en el momento en que Navarra accedió a la autonomía por una vía distinta (disposición adicional primera de la Constitución) y es, por tanto, desde entonces inaplicable.
The safety and preliminary efficacy of MEDI1873, an agonistic IgG1 fusion protein targeting glucocorticoid-induced TNF receptor-related protein (GITR), were evaluated in an open-label, ...first-in-human, phase I, dose escalation study in previously treated patients with advanced solid tumors.
Two single-patient cohorts at 1.5 and 3 mg i.v. were followed by 3+3 dose escalation in six cohorts at 7.5, 25, 75, 250, 500, and 750 mg, all every 2 weeks, for up to 52 weeks. Primary endpoints were safety and tolerability, dose-limiting toxicities (DLT), and MTD. Secondary endpoints included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics.
Forty patients received MEDI1873. Three experienced DLTs: grade 3 worsening tumor pain (250 mg); grade 3 nausea, vomiting, and headache (500 mg); and grade 3 non-ST segment elevation myocardial infarction (750 mg). An MTD was not reached and treatment was well tolerated up to 500 mg. Most common treatment-related adverse events were headache (25%), infusion-related reaction (17.5%), and decreased appetite (17.5%). MEDI1873 exposure was dose proportional. Antidrug-antibody incidence was low. MEDI1873 increased peripheral CD4
effector memory T-cell proliferation as well as cytokines associated with effector T-cell activation at dose levels ≥75 mg. The best response was stable disease (SD) in 17 patients (42.5%), including 1 unconfirmed partial response. Eight patients (20.0%) had SD ≥24 weeks.
MEDI1873 showed acceptable safety up to 500 mg i.v. every 2 weeks with pharmacodynamics activity, and prolonged SD in some patients. However, further development is not planned because of lack of demonstrated tumor response.
In this paper, we propose a methodology combining Bayesian and big data tools designed to optimize the investigation of fraud in the most important taxes that affect companies, VAT, corporate tax and ...customs duties. This methodology is called Bayesian dialysis. We address three issues: (a) Is it possible to capitalize on the evidence provided by data indicating fraud without a parametric model and using an interpretable approach? (b) If so, would it be the best solution in any case? (c) What is the effect size of the different strategies that proposed? We have proved the viability of a new method using as an exemplary case the selection for VAT control in the Spanish Tax Agency (Agencia Estatal de Administración Tributaria—AEAT) and verified the approach using microdata of customs taxes. The new method improves fraudster detection precision in VAT by 13.82%, which is increased from an average of 82.28 to 96.10%. In the case of customs, we have built an alternative that increases precision from current 3.63 to 23.8% and obtained an alternative solution using ML with an impressive ROC of 0.98 that let obtain a precision of 53.63%. We discuss the benefits of this approach versus machine learning techniques. Finally, based on the concept of tetrads, we propose a method to quantify the effect of unknown latent variables on model analysis.
Resumen:En el actual contexto de profunda crisis del modelo territorial diseñado por la Constitución Española de 1978, son muchos los autores que han abogado por una reforma del Estado de las ...Autonomías en clave federal. Bien para transformarlo plenamente en un Estado federal, bien para corregir en un sentido más federal algunos de sus instrumentos disfuncionales. Uno de ellos es, sin duda, la colaboración entre Comunidades Autónomas y, en particular, los convenios de cooperación interautonómicos.La doctrina ha venido manifestando que el muy escaso número de convenios celebrados entre Comunidades Autónomas trae causa de la rigidez de su régimen jurídico, recogido en el artículo 145 CE y en los correspondientes Estatutos de Autonomía. En consecuencia, se ha venido proponiendo, de manera mayoritaria y reiterada, la reforma del citado artículo 145 CE en la dirección de eliminar el control que las Cortes Generales ejercen sobre la celebración de estospactos interautonómicos, en el entendido de que, además, así se le daría a este precepto constitucional una configuración más cercana a la que tendría en un verdadero Estado federal. En este trabajo se intenta justificar, sin embargo, que el régimen jurídico del artículo 145 CE no es la causa del deficiente funcionamiento de la colaboración horizontal en nuestro sistema, que el alcance de la potestad de control de las Cortes sobre estos convenios es muy distinto al descrito por la doctrina y que, además, la formulación actual del artículo 145 CE es plenamente compatible con la reconsideración en clave federal del resto del modelo territorial. Por todo ello, se defiende finalmente la improcedencia de lareforma constitucional propuesta.SummaryI. The failure of our model of territorial power distribution and the discussion on its alternatives. II. The federal «solution»: its political and technical legal dimension. 2.1. The federalism as an exit to the crisis of the model. 2.2. The technical aspects of an eventual federal or federalizing reform. III. Federal amendment of Article 145 of Spanish Constitution: the scholar diagnosis to the problem and the proposals of review. IV. Diagnostic errors and unsuitability of the proposed reform. 4.1. The «rigidity» of Article 145 of Spanish Constitution neither is a cause nor a concurring cause. 4.2. The federal nature of this constitutional provision. 4.3. The real extent of Article 145 of Spanish Constitution and the authorizing control of the Cortes Generales. 4.4. The intervention of the parliament of the State as an act reviewable by the Constitutional Court. V. Concluding remarks. VI. References. Abstract:In the current context of serious crisis of the territorial pattern envisaged by the 1978 Spanish Constitution, many authors have advocated for a reform of the State of the Autonomies in federal terms, either for transforming it fully into a Federal State, or for correcting some of its most dysfunctional instruments towards a more federal orientation. One of them is certainly the cooperation between Autonomous Communities and, in particular, agreements on inter-autonomic cooperation. The scholars have pointed out that the cause of the low number of agreements between Autonomous Communities is the rigidity of theirlegal regime, contained in Article 145 of the Spanish Constitution and the corresponding Statutes of Autonomy. Consequently, it has been repeatedly and mostly proposed to amend the mentioned Article 145 in the sense of removing the control of the Cortes Generales over the establishment of these autonomic agreements, on the understanding that, moreover, this constitutional provision would receive a configuration closer to a real federal state. Notwithstanding, this paper attempts to justify that the legal regime of Article 145 of the Spanish Constitution is not the cause of the insufficient functioning of the horizontal cooperation in our system; that the scope of the powers of control of the Cortes on these agreements is very different to the described one by the authors; and, moreover, that the current wording of Article 145 is fully compatible with the review in federal terms of the rest of the territorial pattern. Thus, it is finally defended the unsuitability of the proposed constitutional reform.
In the current context of serious crisis of the territorial pattern envisaged by the 1978 Spanish Constitution, many authors have advocated for a reform of the State of the Autonomies in federal ...terms, either for transforming it fully into a Federal State, or for correcting some of its most dysfunctional instruments towards a more federal orientation. One of them is certainly the cooperation between Autonomous Communities and, in particular, agreements on inter-autonomic cooperation. The scholars have pointed out that the cause of the low number of agreements between Autonomous Communities is the rigidity of their legal regime, contained in Article 145 of the Spanish Constitution and the corresponding Statutes of Autonomy. Consequently, it has been repeatedly and mostly proposed to amend the mentioned Article 145 in the sense of removing the control of the Cortes Generales over the establishment of these autonomic agreements, on the understanding that, moreover, this constitutional provision would receive a configuration closer to a real federal state. Notwithstanding, this paper attempts to justify that the legal regime of Article 145 of the Spanish Constitution is not the cause of the insufficient functioning of the horizontal cooperation in our system; that the scope of the powers of control of the Cortes on these agreements is very different to the described one by the authors; and, moreover, that the current wording of Article 145 is fully compatible with the review in federal terms of the rest of the territorial pattern. Thus, it is finally defended the unsuitability of the proposed constitutional reform.
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