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High Response Rate to Second-Line Combination Antiangiogenic Chemotherapy in Patients with Metastatic Melanoma

Journal of Cancer Therapy 2016年第12期7卷 908-918页

作者： Ozan Haase Ozan Angün Ewan A. Langan Franziska Hübner Florian M. Vogt Christoph Thorns detlef zillikens Patrick Terheyden Department of Dermatology University of Lübeck Lübeck Germany Department of Radiology University of Lübeck Lübeck Germany Institute of Pathology Section for Hematopathology and Endocrine Pathology University of Lübeck Lübeck Germany

Objectives: Despite the array of new treatment strategies for the management of metastatic melanoma, the prognosis remains poor when immune checkpoint inhibition and targeted therapy options are exhausted. The antiangiogenic monoclonal antibody bevacizumab has documented its efficacy in the treatment of several solid tumors, when used in combination with standard chemotherapy. Phase II studies and case series have led to the speculation that it may also improve the prognosis when used in stage IV melanoma. Therefore, we investigated the influence of bevacizumab, combined with a platinum-based chemotherapy, in the treatment of melanoma and sought to identify prognostic factors affecting the response. Methods: Eight patients with metastatic melanoma, with documented progress after at least one previous therapy, received bevacizumab (5 mg/kg intravenously every two weeks) in combination with cisplatin (100 mg/m2 every four weeks) and carboplatin (200 mg/m2 every four weeks). The therapy was continued until renewed disease progression occurred. The response rate, progression-free and overall survival, and toxicity were evaluated. Results: We observed complete remission in two patients (25%) and partial response in an additional four patients. In one patient, the disease remained stable (total disease control rate of 87.5%). Only one patient (12.5%) had progressive disease. The median progression-free survival was 6 months (range 3 - 37 months). The median overall survival time was 15.5 months (range 6 - 77 months). Every patient experienced at least one adverse event of grade 3 - 4, most commonly bleeding associated with severe thrombocytopenia. Conclusion: Our observations indicate that bevacizumab, in combination with cisplatin and carboplatin, may represent an effective treatment option for patients with metastatic melanoma and disease progression.

关键词： Melanoma Cisplatin Carboplatin Bevacizumab Response Angiogenesis

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Leveraging machine learning to generate a unified and complete building height dataset for Germany

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Energy and AI 2024年第3期17卷 327-341页

作者： Kristina Dabrock Noah Pflugradt Jann Michael Weinand detlef Stolten Forschungszentrum Jülich GmbH Institute of Climate and Energy SystemsJülich Systems Analysis52425 JülichGermany RWTH Aachen University Chair for Fuel CellsFaculty of Mechanical Engineering52062 AachenGermany

Building geometry data is crucial for detailed, spatially-explicit analyses of the building stock in energy systems analysis and beyond. Despite the existence of diverse datasets and methods, a standardized and validated approach for creating a nation-wide unified and complete dataset of German building heights is not yet available. This study develops and validates such a methodology, combining different data sources for building footprints and heights and filling gaps in height data using an XGBoost machine learning algorithm. The XGBoost model achieves a mean absolute error of 1.78 m at the national level and between 1.52 m and 3.47 m at the federal state level. The goal is proving the applicability of the methodology at a large scale and creating a useful dataset. The resulting dataset is thoroughly evaluated on a building-by-building level and spatially resolved statistics on the quality of the dataset are reported. This detailed validation found that the building number and footprint area of German building stock is 90.31 % and 94.84 % correct, respectively, and the building height accuracy is 0.59 m at the national level. However, errors are not homogeneous across Germany and further research is needed into the impact of including additional datasets, especially for regions and building types with lower accuracies. This study proves that the chosen methodology is useful for generating a building height dataset and the workflow, with some modifications for regional data availability, can be transferred to other countries. The generated building dataset for Germany constitutes a valuable data basis for the research community in fields such as energy research, urban planning and building decarbonization policy development.

关键词： Machine learning XGBoost Building height Building footprint 3-D building data Geodata Spatial analysis

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Opportunities for large language models and discourse in engineering

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Energy and AI 2024年第3期17卷 136-142页

作者： Jan Göpfert Jann M.Weinand Patrick Kuckertz detlef Stolten Institute of Energy and Climate Research–Techno-economic Systems Analysis(IEK-3) Forschungszentrum Jülich GmbHJülich52425Germany Chair for Fuel Cells RWTH Aachen UniversityFaculty of Mechanical EngineeringAachen52062Germany

In recent years, large language models have achieved breakthroughs on a wide range of benchmarks in natural language processing and continue to increase in performance. Recently, the advances of large language models have raised interest outside the natural language processing community and could have a large impact on daily life. In this paper, we pose the question: How will large language models and other foundation models shape the future product development process? We provide the reader with an overview of the subject by summarizing both recent advances in natural language processing and the use of information technology in the engineering design process. We argue that discourse should be regarded as the core of engineering design processes, and therefore should be represented in a digital artifact. On this basis, we describe how foundation models such as large language models could contribute to the design discourse by automating parts thereof that involve creativity and reasoning, and were previously reserved for humans. We describe how simulations, experiments, topology optimizations, and other process steps can be integrated into a machine-actionable, discourse-centric design process. As an example, we present a design discourse on the optimization of wind turbine blades. Finally, we outline the future research that will be necessary for the implementation of the conceptualized framework.

关键词： Product development process Conceptual design Design methodology Design generation Natural language processing Foundation models Multi-modal models

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A systematic review of spatial disaggregation methods for climate action planning

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Energy and AI 2024年第3期17卷 458-469页

作者： Shruthi Patil Noah Pflugradt Jann M.Weinand detlef Stolten Jürgen Kropp Institute of Energy and Climate Research Techno-economic Systems Analysis(IEK-3)Forschungszentrum JülichWilhelm-Johnen-StraßeJülich52425NRWGermany University of Potsdam Institute for Environmental Science and GeographyKarl-Liebknecht-Str.24-25Potsdam-Golm14476BrandenburgGermany Chair for Fuel Cells RWTH Aachen Universityc/o IEK-3Forschungszentrum JülichJülich52425NRWGermany Potsdam Institute for Climate Impact Research(PIK) Member of the Leibniz AssociationP.O.Box 601203PotsdamD-14412BrandenburgGermany

National-level climate action plans are often formulated broadly. Spatially disaggregating these plans to individual municipalities can offer substantial benefits, such as enabling regional climate action strategies and for assessing the feasibility of national objectives. Numerous spatial disaggregation approaches can be found in the literature. This study reviews and categorizes these. The review is followed by a discussion of the relevant methods for the disaggregation of climate action plans. It is seen that methods employing proxy data, machine learning models, and geostatistical ones are the most relevant methods for the spatial disaggregation of national energy and climate plans. The analysis offers guidance for selecting appropriate methods based on factors such as data availability at the municipal level and the presence of spatial autocorrelation in the *** the urgency of addressing climate change escalates, understanding the spatial aspects of national energy and climate strategies becomes increasingly important. This review will serve as a valuable guide for researchers and practitioners applying spatial disaggregation in this crucial field.

关键词： Spatial downscaling Proxy data Mass-preserving Climate action plans Spatial autocorrelation Machine learning Geostatistical models

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Ethyl-iophenoxic acid as a quantitative bait marker for small mammals

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Integrative Zoology 2022年第6期17卷 981-990页

作者： Kyra JACOBLINNERT Christian IMHOLT detlef SCHENKE Jens JACOB Julius Kühn Institute(JKI) Federal Research Centre for Cultivated PlantsInstitute for Plant Protection in Horticulture and ForestsVertebrate ResearchMünsterGermany Department of Behavioral Biology University of OsnabrückOsnabrückGermany Julius Kühn Institute(JKI) Federal Research Centre for Cultivated PlantsInstitute for Ecological ChemistryPlant Analysis and Stored Product ProtectionBerlinGermany

Bait markers are indispensable for ecological research but in small mammals,most markers are invasive,expensive and do not enable quantitative analyses of ***-iophenoxic acid(Et-IPA)is a non-toxic,quantitative bait marker,which has been used for studying bait uptake in several carnivores and *** developed a bait with Et-IPA,assessed its palatability to common voles(Microtus arvalis),and determined the dose-residue-relation for this important agricultural pest rodent ***-IPA concentrations of 40 to 1280μg Et-IPA per g bait were applied to wheat using sunﬂower oil or polyethylene glycol 300 as potential *** a laboratory study,common voles were offered the bait and blood samples were collected 1,7,and 14 days after *** samples were analyzed with LC-ESI-MS/MS for blood residues of ***ﬂower-oil was the most suitable bait ***-IPA seemed to be palatable to common voles at all test ***-dependent residues could be detected in blood samples in a dose-dependent manner and up to 14 days after uptake enabling generation of a calibration curve of the dose-residue ***-IPA was present in common vole blood for at least 14 days,but there was dissipation by 33–37%depending on ***-IPA meets many criteria for an“ideal”quantitative bait marker for use in futureﬁeld studies on common voles and possibly other small mammal species.

关键词： baiting biomarker Microtus arvalis quantitative bait marker small mammals

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THERMOCHROMIC EFFECTS OF LEUCO DYES STUDIED IN POLYPROPYLENE

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Chinese Journal of Polymer Science 2006年第4期24卷 363-368页

作者： Arno Seeboth detlef L(o|¨)tzsch Elvira Potechius Renate Vetter Fraunhofer Institute for Applied Polymer Research

A series of thermochromic polypropylene foils were prepared by embedding various leuco dye-developer-solvent systems in the polymer matrix. Bisphenol A, laurylgallate, ethylgallate and p-hydroxybenzoic acid methyl ester were used as developers, crystal violet lactone and 3,3-bis-（1-n-butyl-2-methyl-3-indolyl）-phthalide as dyes and l-octanoic acid methyl ester as solvent. The molar ratio between the three components of the investigated leuco dye-developer-solvent systems was kept constant. All obtained polypropylene foils exhibit an excellent thermochromic behavior. The foils, prepared by extrusion technology, switch from color to colorless with increasing temperature. The influence of molecular structure of the developer on the intensity of the colored state and the influence of a developer-surfactant complex on the resulting thermochromic properties were investigated. The results are presented and discussed in detail according to a molecular model suggesting that the ring-opening process of the leuco dye is triggered by the formation of dye-developer complexes via H-bondings.

关键词： Thermochromism Dyes Extrusion UV-Vis spectroscopy.

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Growth factor receptors and related signalling pathways as targets for novel treatment strategies of hepatocellular cancer

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World Journal of Gastroenterology 2008年第1期14卷 1-14页

作者： Michael Hpfner detlef Schuppan Hans Scherübl Institute of Physiology Charité-Universittsmedizin Berlin Campus Benjamin Franklin Berlin 12200 Germany Beth Israel Deaconess Medical Center Harvard Medical School Boston MA 02215 United States Klinik für Innere Medizin Gastroenterologie und Gastrointestinale Onkologie Klinikum am Urban Vivantes Netzwerk für Gesundheit Berlin 10967 Germany

Growth factors and their corresponding receptors are commonly overexpressed and/or dysregulated in many cancers including hepatocellular cancer （HCC）. Clinical trials indicate that growth factor receptors and their related signalling pathways play important roles in HCC cancer etiology and progression, thus providing rational targets for innovative cancer therapies. A number of strategies including monoclonal antibodies, tyrosine kinase inhibitors （＂small molecule inhibitors＂） and antisense oligonucleotides have already been evaluated for their potency to inhibit the activity and downstream signalling cascades of these receptors in HCC. First clinical trials have also shown that multi-kinase inhibition is an effective novel treatment strategy in HCC. In this respect sorafenib, an inhibitor of Raf-, VEGF- and PDGF-signalling, is the first multi-kinase inhibitor that has been approved by the FDA for the treatment of advanced HCC. Moreover, the serine-threonine kinase of mammalian target of rapamycin （mTOR） upon which the signalling of several growth factor receptors converge plays a central role in cancer cell proliferation, roTOR inhibition of HCC is currently also being studied in preclinical trials. As HCCs represent hypervascularized neoplasms, inhibition of tumour vessel formation via interfering with the VEGF/VEGFR system is another promising approach in HCC treatment. This review will summarize the current status of the various growth factor receptor-based treatment strategies and in view of the multitude of novel targeted approaches, the rationale for combination therapies for advanced HCC treatment will also be taken into account.

关键词： Growth factor receptor Hepatocellular cancer Small molecule inhibitor Monoclonal antibody Innovative cancer treatment Sorafenib Bevacizumab Erlotinib

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Role of the receptor for advanced glycation end products in hepatic fibrosis

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World Journal of Gastroenterology 2009年第46期15卷 5789-5798页

作者： Christina Lohwasser Daniel Neureiter Yury Popov Michael Bauer detlef Schuppan Department of Medicine Ⅰ University of Erlangen-NurembergErlangen-Nürnberg Institute of Pathology Paracelsus Private Medicine UniversitySalzburg Division of Gastroenterology Beth Israel Deaconess Medical CenterHarvard Medical SchoolBoston

AIM： To study the role of advanced glycation end products （AGE） and their specific receptor （RAGE） in the pathogenesis of liver fibrogenesis. METHODS： In vitro RAGE expression and extracellular matrix-related gene expression in both rat and human hepatic stellate cells （HSC） were measured after stimulation with the two RAGE ligands, advanced glycation end product-bovine serum albumin （AGE- BSA） and N＇-（carboxymethyl） lysine （CML）-BSA, or with tumor necrosis factor-α （TNF-α）. In vivo RAGE expression was examined in models of hepatic fibrosis induced by bile duct ligation or thioacetamide. The effects of AGE-BSA and CML-BSA on HSC proliferation, signal transduction and profibrogenic gene expression were studied in vitro. RESULTS： In hepatic fibrosis, RAGE expression was enhanced in activated HSC, and also in endothelial cells, inflammatory cells and activated bile duct epithelia. HSC expressed RAGE which was upregulated after stimulation with AGE-BSA, CML-BSA, and TNF-α.RAGE stimulation with AGE-BSA and CML-BSA did not alter HSC proliferation, apoptosis, fibrogenic signal transduction and fibrosis- or fibrolysis-related gene expression, except for marginal upregulation of procollagen α1（ I ） mRNA by AGE-BSA. CONCLUSION： Despite upregulation of RAGE in activated HSC, RAGE stimulation by AGE does not alter their fibrogenic activation. Therefore, RAGE does not contribute directly to hepatic fibrogenesis.

关键词： Advanced glycation end product Extracellularmatrix Hepatic stellate cell Matrix metalloproteinase Myofibroblast Receptor for advanced glycation endproducts Transforming growth factor β Tissue inhibitorof metalloproteinase Tumor necrosis factor α

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Treatment of gastrointestinal neuroendocrine tumors with inhibitors of growth factor receptors and their signaling pathways: Recent advances and future perspectives

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World Journal of Gastroenterology 2008年第16期14卷 2461-2473页

作者： Michael Hpfner detlef Schuppan Hans Scherübl Institute of Physiology Charité-Universitts-medizin Berlin Campus Benjamin Franklin Beth Israel Deaconess Medical Center and Harvard Medical School Klinik für Innere Medizin Gastroenterologie und Gastrointestinale Onkologie Klinikum am Urban Vivantes Netzwerk für Gesundheit

The limited efficacy of conventional cytotoxic treatment regimes for advanced gastrointestinal neuroendocrine cancers emphasizes the need for novel and more effective medical treatment options. Recent findings on the specific biological features of this family of neoplasms has led to the development of new targeted therapies, which take into account the high vascularization and abundant expression of specific growth factors and cognate tyrosine kinase receptors. This review will briefly summarize the status and future perspectives of antiangiogenic, mTOR- or growth factor receptor-based pharmacological approaches for the innovative treatment of gastrointestinal neuroendocrine tumors. In view of the multitude of novel targeted approaches, the rationale for innovative combination therapies, i.e. combining growth factor (receptor)-targeting agents with chemo- or biotherapeutics or with other novel anticancer drugs such as HDAC or proteasome inhibitors will be taken into account.

关键词： Growth factor receptor Neuroendocrinegastrointestinal tumor Small molecule inhibitor lonoclonal antibody Multi kinase inhibition

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Targeted medical therapy of biliary tract cancer:Recent advances and future perspectives

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World Journal of Gastroenterology 2008年第46期14卷 7021-7032页

作者： Michael Hpfner detlef Schuppan Hans Scherübl Institute of Physiology Charité-Universittsmedizin BerlinCampus Benjamin Franklin Beth Israel Deaconess Medical Center and Harvard Medical School Klinik für Innere Medizin Gastroenterologieund Gastrointestinale OnkologieKlinikum am Urban Vivantes Netzwerk für Gesundheit10967 BerlinGermany

The limited efficacy of cytotoxic therapy for advanced biliary tract and gallbladder cancers emphasizes the need for novel and more effective medical treatment options. A better understanding of the specific biological features of these neoplasms led to the development of new targeted therapies, which take the abundant expression of several growth factors and cognate tyrosine kinase receptors into account. This review will briefly summarize the status and future perspectives of antiangiogenic and growth factor receptor-based pharmacological approaches for the treatment of biliary tract and gallbladder cancers. In view of multiple novel targeted approaches, the rationale for innovative therapies, such as combinations of growth factor (receptor)-targeting agents with cytotoxic drugs or with other novel anticancer drugs will be highlighted.

关键词： Growth factor receptor Biliary tract cancer Small molecule inhibitor lonoclonal antibody Innovative cancer treatment Sorafenib Bevacizumab Erlotinib

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