Estudios acerca de una axiologia formal y fenomenológica

Fil: Jesinghaus, Carlos

Genetische Analyse der Hämoxygenase-1 bei verschiedenen Formen der Pankreatitis

Die Hämoxygenase-1 (HO-1) ist das geschwindigkeitsbestimmende Enzym des Hämabbaus und ist wichtiger Regulator inflammatorischer Prozesse. Der Verlauf einer experimentellen akuten Pankreatitis (AP) konnte im Tiermodell durch HO-1 Induktion abgemildert werden. Die Aktivierung und Proliferation pankreatischer Stellatum Zellen (PSC) wird durch eine experimentelle HO-1 Induktion inhibiert und kann so möglicherweise vor der Fibrosierung des Pankreasparenchyms bei chronischer Pankreatitis (CP) schützen. Die Transkription der HO-1 wird durch einen GT-Repeat beeinflusst, der im Promoter lokalisiert ist. Diese Arbeit untersuchte, ob Varianten des GT-Repeat oder weitere genetische Varianten der HO-1 mit verschiedenen Pankreatitisformen assoziiert sind. Der GT-Repeat und der SNP rs2071746 wurden mit fluoreszensmarkierten Primern bzw. mit Schmelzkurvenanalyse bei 285 Patienten mit AP, bei 208 Patienten mit alkoholischer CP (ACP), bei 207 mit idiopathischer/hereditärer CP (ICP/HCP), 147 Patienten mit Alkoholischer Leberzirrhose (ALZ) und bei 289 Kontrollen untersucht. Bei den ACP Patienten wurde die GT-Repeat Analyse auf insgesamt 446 Patienten erhöht. Zusätzlich wurden die kodierenden HO-1 Abschnitte mittels DNA-Sequenzierung bei 145 Patienten mit ACP, 138 Patienten mit ICP/HCP, 147 Patienten mit ALZ und bei 151 Kontrollen analysiert. Das Exon 3 wurde darüber hinaus bei zusätzlichen ICP/HP Patienten und Kontrollen untersucht. Die Längenverteilungen des GT-Repeat, die Allelverteilung des SNP rs2071746 und die Verteilung der bei der DNA-Sequenzierung gefundenen synonymen und nicht synonymen Varianten waren bei allen untersuchten Gruppen nicht signifikant unterschiedlich. Obwohl die funktionellen Daten einen Einfluss von HO-1 Varianten auf die Pathogenese der verschiedenen Pankreatitis-Formen nahelegen, konnte unsere umfangreiche genetische Analyse keine Assoziation nachweisen. Genetische Varianten der HO-1 haben keinen Einfluss auf die Entwicklung einer AP, ACP, ICP/HCP und ALZ.:Inhaltsverzeichnis Vorbemerkung ..................................................................................................... 3 Bibliographische Beschreibung.......................................................................... 4 Abkürzungen/Abbildungen ................................................................................ 6 1. Einleitung........................................................................................................9 1.1 Akute Pankreatitis ......................................................................................................................... 9 1.2 Chronische Pankreatitis ............................................................................................................... 11 1.3 Genetische Aspekte der Chronischen Pankreatitis ...................................................................... 12 1.3.1 Kationisches Trypsinogen (PRSS1) ...................................................................................... 12 1.3.2 Anionisches Trypsinogen (PRSS2) ....................................................................................... 14 1.3.3 Serinproteaseinhibitor, Kazal Typ1 (SPINK1)..................................................................... 14 1.3.4 Chymotrypsin C (CTRC) ...................................................................................................... 15 1.3.5 CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) ...................................... 15 1.4 Hämoxygenase-1 ......................................................................................................................... 16 1.4.1 Physiologische Bedeutung der Hämoxygenase-1 (HO-1) .................................................... 16 1.4.2 Genetische Varianten der Hämoxygenase-1 ........................................................................ 18 1.4.3 Hämoxygenase-1 und Pankreatitis....................................................................................... 20 1.5 Hypothese/Fragestellung ............................................................................................................. 21 2. Publikation ..................................................................................................... 22 3. Zusammenfassung der Arbeit ...................................................................... 23 4. Literaturverzeichnis...................................................................................... 28 5. Danksagung.................................................................................................... 35 6. Erklärung über die eigenständige Abfassung der Arbeit .......................... 36 7. Lebenslauf ...................................................................................................... 3

El sistema de los problemas psicológicos

El pensar científico tiene como fin la comprensión de la experiencia a base de una reconstrucción ideal por medio de los conceptos. La complejidad de los objetos de la investigación es ahora, por lo general, tan grande, que la observación y el análisis no llegan a su fin sino paso a paso, fijándose en determinados factores que resaltan y se separan en nuestra reflexión a base de los puntos de vista aplicados en cada caso. Si los grandes grupos fundamentales de las ciencias y las letras son el producto de diferencias radicadas en los mismos objetos empíricos, las partes de una ciencia determinada, que se ocupa de una clase definida de hechos, se derivan más bien de la necesidad de que el pensar debe estudiarlos sucesivamente bajo los distintos aspectos posibles.Facultad de Humanidades y Ciencias de la Educació

Indicators to Assess Sustainability of Transport Activities - Part 2: Measurement and Evaluation of Transport Sustainability Performance in the EU27

Inspired by the growing interest of academic and policy environments in the field of transport sustainability, this work focuses on the measurement and assessment of transport activities in the European Union (EU) with the use of transport sustainability indicators. On the basis of major international transport related indicator initiatives a set of 55 transport sustainability indicators has been developed (as defined in the first part of the report by Dobranskyte-Niskota et al., 2007) where due to lack of data 32 indicators have been assessed in quantitative terms and the JRC SusTrans Index has been developed. The Joint Research Centre software tool entitled ¿the Dashboard of Sustainability¿ based on a simple graphic interface has been applied to the JRC SusTrans Index in the assessment of transport sustainability performance in the EU Member States. The Dashboard tool has compared indicator groups using the EWA method and communicated a quick impression by pointing to areas where transport indicators showed particular success or problems. Additionally, the Dashboard tool has been also applied to the Transport and Environment Reporting Mechanism (TERM) indicator set developed by the European Environmental Agency and the TERM Index has been calculated. The TERM Index has been used as a reference point to benchmark transport sustainability performance results of the EU Member States obtained by the SusTrans Index. The outcomes of the two indices (the SusTrans and the TERM) have revealed the highest rank of transport sustainability performance in Germany and Netherlands while the lowest performance ranks - in Greece and Bulgaria. The results of the two indices have revealed many similarities, while some differences in the outcomes observed are due to the variations in the structures of the indices. This in-depth analysis of EU 27 transport activities by the selected sustainability indicators using adequate modelling tools serves as valuable guidelines for forming transport policy strategies and scenarios. These policies aim to reduce negative impacts of transport activities with the final goal of achieving a sustainable transportation system in the European Union.JRC.H.4-Transport and air qualit

Indicators for Lisbon post-2010 - business as usual?

This paper looks at the ongoing debate within the European Commission on the EU 2020 strategy and in particular to the potential role of statistics-based knowledge in the strategy , and takes partly inspiration from a reflection on the Lisbon strategy for growth and jobs EU 2020 in the framework of the implementation of the European economic recovery plan. We highlight three shortcomings in the present (pre-EU 2020) use of statistical indicators which the present debate does not seem to address and which hence risk being perpetuated in their EU 2020 formulation: - The paradox of the coexistence within the same European Commission of two holistic frameworks: the Structural Indicators and the Sustainable Development Indicators. One does not understand which of these two systems is taken to measure the overall policy performance of the Commission. The resulting dualism ¿ in the opinion of the authors - does not help the communication policy of the European Commission. - A communication issue whereby the Lisbon strategy and its offspring EU 2020 are not communicated (Lisbon is to the average citizen the capital of Portugal) and are especially not communicated in relation to existing statistical indicators of good quality, against the opinion of academicians that transparency and accountability based on sound statistics favour democracy and participation and may be useful against citizens¿ and voters¿ apathy. - The paradox that EU policy and its communication is mostly economic -- the financial crisis (the ¿crunch¿) and its management in relation to the health of public finances, and environmental (global change, carbon emission, post Copenhagen), and less to an EU social agenda. There is little emphasis in EU policy and communication on the challenge of inequality which might impact adversely on democratic participation and values. We illustrate the reasons that lead us to see these points as problematic and offer suggestions on how these should be tackled. Without a change of course on these three challenges the debate on the selection of new indicators will very much risk being and internal European Commission business as usual.JRC.DG.G.9-Econometrics and applied statistic

Sustainability Indicators Past and Present: What Next?

This paper discusses the current state of thought amongst the Sustainability Indicator (SI) community, what has been achieved and where we are succeeding and failing. Recent years have witnessed the rise of “alternative facts” and “fake news” and this paper discusses how SIs fit into this maelstrom, especially as they are themselves designed to encapsulate complexity into condensed signals and it has long been known that SIs can be selectively used to support polarized sides of a debate. This paper draws from chapters in a new edited volume, the “Routledge Handbook of Sustainability Indicators and Indices”, edited by the authors. The book has 34 chapters written by a total of 59 SI experts from a wide range of backgrounds, and attempts to provide a picture of the past and present, strengths and weaknesses of SI development today. This paper is an “analysis of those analyses”—a mindful reflection on reflection, and an assessment of the malign and benign forces at work in 2018 within the SI arena. Finally, we seek to identify where SIs may be going over the coming, unpredictable years

Predictive value of clinical and 18F-FDG-PET/CT derived imaging parameters in patients undergoing neoadjuvant chemoradiation for esophageal squamous cell carcinoma.

Aim of this study was to validate the prognostic impact of clinical parameters and baseline 18F-FDG-PET/CT derived textural features to predict histopathologic response and survival in patients with esophageal squamous cell carcinoma undergoing neoadjuvant chemoradiation (nCRT) and surgery. Between 2005 and 2014, 38 ESCC were treated with nCRT and surgery. For all patients, the 18F-FDG-PET-derived parameters metabolic tumor volume (MTV), SUVmax, contrast and busyness were calculated for the primary tumor using a SUV-threshold of 3. The parameter uniformity was calculated using contrast-enhanced computed tomography. Based on histopathological response to nCRT, patients were classified as good responders (< 10% residual tumor) (R) or non-responders (≥ 10% residual tumor) (NR). Regression analyses were used to analyse the association of clinical parameters and imaging parameters with treatment response and overall survival (OS). Good response to nCRT was seen in 27 patients (71.1%) and non-response was seen in 11 patients (28.9%). Grading was the only parameter predicting response to nCRT (Odds Ratio (OR) = 0.188, 95% CI: 0.040-0.883; p = 0.034). No association with histopathologic treatment response was seen for any of the evaluated imaging parameters including SUVmax, MTV, busyness, contrast and uniformity. Using multivariate Cox-regression analysis, the heterogeneity parameters busyness (Hazard Ratio (HR) = 1.424, 95% CI: 1.044-1.943; p = 0.026) and contrast (HR = 6.678, 95% CI: 1.969-22.643; p = 0.002) were independently associated with OS, while no independent association with OS was seen for SUVmax and MTV. In patients with ESCC undergoing nCRT and surgery, baseline 18F-FDG-PET/CT derived parameters could not predict histopathologic response to nCRT. However, the PET/CT derived features busyness and contrast were independently associated with OS and should be further investigated

Pharmacoproteomic characterisation of human colon and rectal cancer

Most molecular cancer therapies act on protein targets but data on the proteome status of patients and cellular models for proteome-guided pre-clinical drug sensitivity studies are only beginning to emerge. Here, we profiled the proteomes of 65 colorectal cancer (CRC) cell lines to a depth of > 10,000 proteins using mass spectrometry. Integration with proteomes of 90 CRC patients and matched transcriptomics data defined integrated CRC subtypes, highlighting cell lines representative of each tumour subtype. Modelling the responses of 52 CRC cell lines to 577 drugs as a function of proteome profiles enabled predicting drug sensitivity for cell lines and patients. Among many novel associations, MERTK was identified as a predictive marker for resistance towards MEK1/2 inhibitors and immunohistochemistry of 1,074 CRC tumours confirmed MERTK as a prognostic survival marker. We provide the proteomic and pharmacological data as a resource to the community to, for example, facilitate the design of innovative prospective clinical trials. © 2017 The Authors. Published under the terms of the CC BY 4.0 licens

Investigation of Colonic Regeneration via Precise Damage Application Using Femtosecond Laser-Based Nanosurgery

Organoids represent the cellular composition of natural tissue. So called colonoids, organoids derived from colon tissue, are a good model for understanding regeneration. However, next to the cellular composition, the surrounding matrix, the cell–cell interactions, and environmental factors have to be considered. This requires new approaches for the manipulation of a colonoid. Of key interest is the precise application of localized damage and the following cellular reaction. We have established multiphoton imaging in combination with femtosecond laser-based cellular nanosurgery in colonoids to ablate single cells in the colonoids’ crypts, the proliferative zones, and the differentiated zones. We observed that half of the colonoids recovered within six hours after manipulation. An invagination of the damaged cell and closing of the structure was observed. In about a third of the cases of targeted crypt damage, it caused a stop in crypt proliferation. In the majority of colonoids ablated in the crypt, the damage led to an increase in Wnt signalling, indicated via a fluorescent lentiviral biosensor. qRT-PCR analysis showed increased expression of various proliferation and Wnt-associated genes in response to damage. Our new model of probing colonoid regeneration paves the way to better understand organoid dynamics on a single cell level. © 2022 by the authors. Licensee MDPI, Basel, Switzerland

Impact of tumor localization and molecular subtypes on the prognostic and predictive significance of p53 expression in gastric cancer

We investigated the prognostic and predictive impact of p53 expression for gastric cancer (GC) patients treated without or with preoperative chemotherapy (CTx) and its relationship with specific molecular GC subtypes. Specimens from 694 GC patients (562 surgical resection specimens without or after CTx, 132 biopsies before CTx) were analyzed by p53 immunohistochemistry. High (H) and low (L) microsatellite instability (MSI) and Epstein&ndash;Barr virus positivity were determined previously. Our results show that aberrant p53 expression was a negative prognostic factor in uni- and multivariable analysis in the resection specimens cohort (each p &lt; 0.01). Subgroup analysis showed the strongest prognostic effect for patients with distally located tumors or no CTx treatment. In the biopsy cohort before CTx, p53 did not predict response or survival. p53 expression was significantly different among the molecular subtypes in surgical resection and bioptic specimens with strong association of altered p53 with MSI-L. Patients with MSI-H and aberrant p53 showed the worst survival in the biopsy cohort. In conclusion, the prognostic impact of p53 in GC differs according to tumor localization and CTx. Altered p53 is characteristic for MSI-L, and the p53 status in biopsies before CTx delineates MSI-H subtypes with inverse prognostic impact