Compartmental modeling for the volatile organic compound isoprene in human breath

Der menschliche Atemluft enthält hunderte von flüchtigen Spurenelementen, die entweder im Organismus als Folge von biochemischen und metabolischen Prozessen entstehen, oder von der Umwelt absorbiert werden. Der Quantifizierung von flüchtigen organischen Spurenelementen (VOCs) im menschlichen Atem wird ein diagnostisches Potential zugeschrieben. Atemgasanalyse ist die wissenschaftliche Untersuchung der Atemluft und ihre Hauptmotivation ist die Suche nach Marker-Substanzen, die als Indikatoren von pathophysiologischen Erkrankungen dienen können. Aufgrund ihrer nicht-invasiven Natur haben atemgasanalytische Untersuchungen in den letzten Jahren enorm an Interesse gewonnen. Allerdings ist der nicht-invasive Test noch in Entwicklung und hat in der klinischen Routine noch nicht Eingang gefunden. Neben Problemen bezüglich der Standardisierung der Atemluftabnahme und der Analysemethoden, verhindert das unzureichende Wissen über die Herkunft und die biochemischen Prozesse dieser Substanzen die Anwendung der Atemtests. Die physiologisch basierte mathematische Modellierung spielt bei der quantitativen Analyse der experimentellen Daten eine entscheidende Rolle. Ihre Aufgabe ist es, eine mechanische Beschreibung der zugrundeliegenden physiologischen Phänomene unter Berücksichtigung aller relevanten experimentellen Daten zu liefern. Somit ermöglicht die mathematische Modellierung einerseits ein detailliertes Verständnis der physiologischen Vorgänge und kann andererseits aufgrund dessen bei der Standardisierung und Entwicklung der Atemluftentnahmemethoden eine wichtige Rolle spielen. Die Arbeit konzentriert sich auf Isopren, welches eine der wichtigsten organischen Substanzen in der menschlichen Atemluft ist. Das Ziel der vorliegenden Arbeit war, den quantitativen Zusammenhang zwischen den Atemluftkonzentration und der zugrundeliegenden endogenen Blut/und Gewebekonzentrationen von Isopren zu beschreiben. Um die Kurzzeiteffekte der relevanten physiologischen Faktoren (sowie Blutfluss und Atemfluss) zu bestimmen, wurden Echtzeitmessungen unter Ergometerbelastung durchgeführt. Die herkömmlichen Modelle, die sich hauptsächlich auf die funktionellen Änderungen der Lunge konzentrieren, sind nicht in der Lage, eine physiologisch relevante Beschreibung der experimentellen Daten zu liefern. Im Gegensatz dazu wurde ein neues Modell auf Basis einer peripheren Herkunft von Isopren von unserer Arbeitsgruppe entwickelt. Die neue Hypothese wurde in der vorliegenden Arbeit durch weitere Experimente bekräftigt und das zugrundeliegende Modell verfeinert, was uns zu der Schlussfolgerung führte, dass die Skelettmuskeln eine wichtige Rolle bei der Isoprenformation spielen. Diese Hypothese wirft ein neues Licht auf die bisherigen Untersuchungen und eröffnet neue Diskussions- und Interpretationsmöglichkeiten über die Herkunft von Isopren.The interest in the diagnostic potential of volatile organic compounds (VOCs) in breath increases as a result of constantly improving modern analyzing techniques. Unfortunately, physicians have paid little attention to a causal mathematical description of the underlying physiological processes yet. Even if mathematical models are idealized representations of the reality, their impact on combining all the information and in prediction is undisputable. The emphasis of this work was to derive a mechanical description of the physiological processes governing the gas exchange dynamics of isoprene under physical exercise. Isoprene has been classified in the group of biomarkers and can be seen as a prototypic example of low-soluble substances concerning its gas exchange mechanisms. Modern mass spectrometric techniques allow its online quantification in exhaled breath in real time. Describing short-term effects is crucial to get a deeper understanding of the determining factors of the underlying mechanisms. Changes in physiology occurring during physical exercise, such as increased ventilation and increased cardiac output, offer an opportunity to examine and understand the exchange processes that determine absorption, desorption, and distribution of this important volatile organic compound. Thus, for the present work cycling exercises on a medical ergometer were carried out and an experimental setup allowing parallel and real-time measurements of exhaled isoprene time-courses in conjunction with physiological parameters was used to collect relevant information for modeling purposes. Isoprene concentrations show a distinct peak shaped response to exercise, which has been recognized before by several investigators. The existing model describing exhaled dynamics of isoprene in response to exercise is able to explain its dynamics only on the basis of physiological assumptions, which contradict physiological facts and real-time measurements. As conventional knowledge suggests isoprene is expected to be sensitive to the regional inhomogeneities in the lung due to its low solubility in blood. For this reason, we focused our attention onto various existing lung models first, which take into account regional inhomogeneities of the lung. However, such representations also fail to describe the observed data. On the contrary, experimental evidence suggests a relationship between muscle compartment activity and isoprene excretion. The first known physio\-logical model developed for isoprene exposure studies assumes a production of isoprene in the liver as the solely source of isoprene in the human body and fails to describe its exchange dynamics under physical exercise. Based on this model, we derived a compartment model, which suggests a metabolic activity of the skeletal muscles. The new model is capable to explain the observed isoprene profiles within a range of acceptable parameter sets. Even if further investigations are necessary to consolidate this hypothesis, several findings about isoprene, such as the linkage of its output to age and statin therapy, and the effect of bilateral deficit when switching from two-legged to one-legged exercise appear to fit into this hypothesis

Interleukin‐6 initiates muscle‐ and adipose tissue wasting in a novel C57BL/6 model of cancer‐associated cachexia

BACKGROUND: Cancer‐associated cachexia (CAC) is a wasting syndrome drastically reducing efficacy of chemotherapy and life expectancy of patients. CAC affects up to 80% of cancer patients, yet the mechanisms underlying the disease are not well understood and no approved disease‐specific medication exists. As a multiorgan disorder, CAC can only be studied on an organismal level. To cover the diverse aetiologies of CAC, researchers rely on the availability of a multifaceted pool of cancer models with varying degrees of cachexia symptoms. So far, no tumour model syngeneic to C57BL/6 mice exists that allows direct comparison between cachexigenic‐ and non‐cachexigenic tumours. METHODS: MCA207 and CHX207 fibrosarcoma cells were intramuscularly implanted into male or female, 10–11‐week‐old C57BL/6J mice. Tumour tissues were subjected to magnetic resonance imaging, immunohistochemical‐, and transcriptomic analysis. Mice were analysed for tumour growth, body weight and ‐composition, food‐ and water intake, locomotor activity, O(2) consumption, CO(2) production, circulating blood cells, metabolites, and tumourkines. Mice were sacrificed with same tumour weights in all groups. Adipose tissues were examined using high‐resolution respirometry, lipolysis measurements in vitro and ex vivo, and radioactive tracer studies in vivo. Gene expression was determined in adipose‐ and muscle tissues by quantitative PCR and Western blotting analyses. Muscles and cultured myotubes were analysed histologically and by immunofluorescence microscopy for myofibre cross sectional area and myofibre diameter, respectively. Interleukin‐6 (Il‐6) was deleted from cancer cells using CRISPR/Cas9 mediated gene editing. RESULTS: CHX207, but not MCA207‐tumour‐bearing mice exhibited major clinical features of CAC, including systemic inflammation, increased plasma IL‐6 concentrations (190 pg/mL, P ≤ 0.0001), increased energy expenditure (+28%, P ≤ 0.01), adipose tissue loss (−47%, P ≤ 0.0001), skeletal muscle wasting (−18%, P ≤ 0.001), and body weight reduction (−13%, P ≤ 0.01) 13 days after cancer cell inoculation. Adipose tissue loss resulted from reduced lipid uptake and ‐synthesis combined with increased lipolysis but was not associated with elevated beta‐adrenergic signalling or adipose tissue browning. Muscle atrophy was evident by reduced myofibre cross sectional area (−21.8%, P ≤ 0.001), increased catabolic‐ and reduced anabolic signalling. Deletion of IL‐6 from CHX207 cancer cells completely protected CHX207(IL6KO)‐tumour‐bearing mice from CAC. CONCLUSIONS: In this study, we present CHX207 fibrosarcoma cells as a novel tool to investigate the mediators and metabolic consequences of CAC in C57BL/6 mice in comparison to non‐cachectic MCA207‐tumour‐bearing mice. IL‐6 represents an essential trigger for CAC development in CHX207‐tumour‐bearing mice

Quiescence, Stemness and Adipogenic Differentiation Capacity in Human DLK1−/CD34+/CD24+ Adipose Stem/Progenitor Cells

We explore the status of quiescence, stemness and adipogenic differentiation capacity in adipose stem/progenitor cells (ASCs) ex vivo, immediately after isolation from human subcutaneous white adipose tissue, by sorting the stromal vascular fraction into cell-surface DLK1+/CD34−, DLK1+/CD34dim and DLK1−/CD34+ cells. We demonstrate that DLK1−/CD34+ cells, the only population exhibiting proliferative and adipogenic capacity, express ex vivo the bonafide quiescence markers p21Cip1, p27Kip1 and p57Kip2 but neither proliferation markers nor the senescence marker p16Ink4a. The pluripotency markers NANOG, SOX2 and OCT4 are barely detectable in ex vivo ASCs while the somatic stemness factors, c-MYC and KLF4 and the early adipogenic factor C/EBPβ are highly expressed. Further sorting of ASCs into DLK1−/CD34+/CD24− and DLK1−/CD34+/CD24+ fractions shows that KLF4 and c-MYC are higher expressed in DLK1−/CD34+/CD24+ cells correlating with higher colony formation capacity and considerably lower adipogenic activity. Proliferation capacity is similar in both populations. Next, we show that ASCs routinely isolated by plastic-adherence are DLK1−/CD34+/CD24+. Intriguingly, CD24 knock-down in these cells reduces proliferation and adipogenesis. In conclusion, DLK1−/CD34+ ASCs in human sWAT exist in a quiescent state, express high levels of somatic stemness factors and the early adipogenic transcription factor C/EBPβ but senescence and pluripotency markers are barely detectable. Moreover, our data indicate that CD24 is necessary for adequate ASC proliferation and adipogenesis and that stemness is higher and adipogenic capacity lower in DLK1−/CD34+/CD24+ relative to DLK1−/CD34+/CD24− subpopulations

Prospective Observational Study of Pazopanib in Patients with Advanced Renal Cell Carcinoma (PRINCIPAL Study)

Background: Real-world data are essential to accurately assessing efficacy and toxicity of approved agents in everyday practice. PRINCIPAL, a prospective, observational study, was designed to confirm the real-world safety and efficacy of pazopanib in patients with advanced renal cell carcinoma (RCC). Subjects, Materials, and Methods: Patients with clear cell advanced/metastatic RCC and a clinical decision to initiate pazopanib treatment within 30 days of enrollment were eligible. Primary objectives included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), relative dose intensity (RDI) and its effect on treatment outcomes, change in health-related quality of life (HRQoL), and safety. We also compared characteristics and outcomes of clinical-trial-eligible (CTE) patients, defined using COMPARZ trial eligibility criteria, with those of non-clinical-trial-eligible (NCTE) patients. Secondary study objectives were to evaluate clinical efficacy, safety, and RDI in patient subgroups. Results: Six hundred fifty-seven patients were enrolled and received ≥1 dose of pazopanib. Median PFS and OS were 10.3 months (95% confidence interval [CI], 9.2–12.0) and 29.9 months (95% CI, 24.7 to not reached), respectively, and the ORR was 30.3%. HRQoL showed no or little deterioration over time. Treatment-related serious adverse events (AEs) and AEs of special interest occurred in 64 (9.7%), and 399 (60.7%) patients, respectively. More patients were classified NCTE than CTE (85.2% vs. 14.8%). Efficacy of pazopanib was similar between the two groups. Conclusion: PRINCIPAL confirms the efficacy and safety of pazopanib in patients with advanced/metastatic RCC in a real-world clinical setting. Implications for Practice: PRINCIPAL is the largest (n = 657) prospective, observational study of pazopanib in patients with advanced/metastatic renal cell carcinoma, to the authors’ knowledge. Consistent with clinical trial results that often contain specific patient types, the PRINCIPAL study demonstrated that the effectiveness and safety of pazopanib is similarly safe and effective in patients with advanced kidney cancer in a real-world clinical setting. The PRINCIPAL study showed that patients with advanced kidney cancer who are treated with first-line pazopanib generally do not show disease progression for approximately 10 months and generally survive for nearly 30 months

Summer thermal insulation in building construction

Der sommerliche Wärmeschutz im Hochbau ist ein wesentliches Thema, welches immer mehr an Bedeutung gewinnt. Die Klimaerwärmung sowie der steigende Energieverbrauch für Klimatisierung machen es notwendig, Gebäude so zu planen und zu gestalten, dass ein angenehmes Raumklima geschaffen wird. Im Sommer kann es zur Überwärmung von Gebäuden kommen, welches neben einer Schädigung der Bausubstanz auch zu einem unangenehmen Raumklima führen kann. Aus diesem Grund ist es wichtig, verschiedene Maßnahmen des sommerlichen Wärmeschutzes zu berücksichtigen. Dazu gehören unter anderem der Einsatz von Sonnenschutzsystemen wie Jalousien, Rollläden, Markisen oder Sonnenschutzfolien an Fenstern und Türen, um den Eintrag von direktem Sonnenlicht ins Gebäude zu minimieren. Auch eine natürliche Belüftung durch gezielte Raumgestaltung und Fensterpositionierung kann dazu beitragen, die Temperatur im Gebäude zu senken. Des Weiteren sollte bei der Planung eines Gebäudes auch die Gebäudeorientierung und -positionierung berücksichtigt werden, um den Eintrag von Sonnenenergie zu minimieren. Eine sorgfältige Planung und Umsetzung des sommerlichen Wärmeschutzes kann dazu beitragen, den Energieverbrauch zu reduzieren und ein angenehmes Raumklima zu schaffen, was zu einem höheren Komfort der Nutzer und einer verbesserten Energieeffizienz des Gebäudes beiträgt.Summer thermal insulation in building construction is an important topic that is becoming increasingly significant. Global warming and increasing energy consumption for air conditioning make it necessary to plan and design buildings in such a way as to create a comfortable indoor climate while minimizing energy consumption. In summer, buildings can become overheated, which can lead to an unpleasant indoor climate. For this reason, it is important to consider various measures of summer thermal protection. These include the use of sun protection systems such as blinds, shutters, awnings or sun protection films on windows and doors to minimize the entry of direct sunlight into the building. Natural ventilation through targeted room design and window positioning can also help to reduce the temperature in the building. Furthermore, building orientation and positioning should also be considered in the design of the building to minimize the entry of solar energy. Careful planning and implementation of summer thermal protection can help reducing energy consumption and create a comfortable indoor environment, contributing to increased occupant comfort and improved energy efficiency of the building.vorgelegt von: Michael RauchenwaldAbweichender Titel laut Übersetzung von der:dem Verfasser:inMasterarbeit FH JOANNEUM 202

On the Physics and ageing of medium voltage-cables in an Austrian distribution grid

Mittelspannungskabel stellen einen wesentlichen Bestandteil der Stromnetze dar, gleichzeitig sind viele Kabel bereits seit 30 Jahren oder länger in Betrieb und ihr Zustand ist nur schwer festzustellen. Reparaturen und der Austausch von Erdkabeln sind einerseits mit hohem Arbeitsaufwand, Behördenverfahren und Kosten verbunden. Schäden können andererseits zu Stromausfällen und Beeinträchtigungen der Versorgungssicherheit führen. In vorliegender Arbeit wird ein Überblick über die physikalischen Vorgänge und Alterung von Erdkabeln und den aktuellen Stand der Wissenschaft zu diesem Thema gegeben. Das praktische Hauptproblem hierbei ist die Beschaffung von Daten über den aktuellen Kabelzustand, da für die Alterung relevante Parameter der Kabel im Betrieb in der Regel nicht ohne Weiteres festgestellt werden können. Eine Möglichkeit zur Informationsbeschaffung über den tatsächlichen Zustand der Kabel stellen die Verfahren der technischen Diagnostik dar. Die am weitesten verbreiteten Verfahren, Messung von Teilentladungen und des Verlustfaktors tan wurden vorgestellt und anhand von praktischen Messungen bei Kärnten Netz erläutert. Abschließend wurde der aktuelle Forschungsstand zu einer Methode zur Nutzung von Power Line Communication (PLC) Signalen zur Zustandsbewertung in Netzen vorgestellt, analysiert und mit den etablierten Methoden verglichen.Medium Voltage power cables are essential components of electricity grids, at the same time many cables have yet been more than 30 years in service and their condition can hardly be evaluated. Repairs and exchange of underground cables on the one hand always lead to high work effort, official procedures and costs. On the other hand, cable failures can lead to power outages and difficulties in security of supply. In the present thesis, an overview of the physics and ageing of cables and the current state of research to this topic is given. The practical main problem here is the gathering of data about the current cable condition, because relevant cableparameters can usually not be determined while in operation. Possibilities for an assessment of the actual cable condition are technical diagnostic techniques. The most widely used ones, measurements of partial discharges and the dissipation factor tan are explained with practical examples of measurements from the grid of Kärnten Netz GmbH. Finally, the current state of research of a promising method for using power line communication (PLC) signals for an online condition monitoring of cable grids is shown, analyzed and compared to the current methods.11