199 research outputs found
Untersuchungen zum EinfluĂ extrazellulĂ€rer Matrixkomponenten auf das Differenzierungsverhalten humaner Hepatozyten unter BerĂŒcksichtigung der VerĂ€nderungen von Zytoskelett-Proteinen und OberflĂ€chenantigenen
1. Zielsetzung Die menschliche Leber erfĂŒllt im Körper eine Vielzahl von Funktionen. Diese reichen von der Produktion von Blutgerinnugsfaktoren ĂŒber die Speicherung von Glykogen bis zum Metabolismus von Fremstoffen. Pro Jahr ereignen sich jedoch mehrere tausend FĂ€lle eines akuten oder chronischen Leberversagens, die hĂ€ufig nicht anders als durch eine Lebertransplantation beherrschbar sind und hĂ€ufig im âTod auf der Wartelisteâ enden. Eine adjuvante MaĂnahme zur Lebertranplantation stellt die ĂberbrĂŒckung der Wartezeit mit Bioreaktoren oder Hepatozytentransplantationen dar, beide jedoch benötigen groĂe Menge an differenzierten Hepatozyten. Hepatozyten dedifferenzieren jedoch schnell in Zellkulturen, so daĂ zuverlĂ€ssige Marker zur Bestimmung des Differenzierungsgrades vonnöten sind. 2. Material und Methode Hepatozyten, die aus menschlichen Gewebeproben isoliert worden waren, wurden verschiedenen Komponenten der extrazellulĂ€ren Matrix ausgesetzt, um zu ĂŒberprĂŒfen, ob sich ein spezifischer EinfluĂ einer oder mehrerer Komponenten belegen lieĂe. Als Marker dienten die zytoskelettalen Marker der Zytokeratine sowie die OberflĂ€chenmarker der Integrine, MHC-I und II sowie ICAM-I, da von diesen Markern VerĂ€nderungen im Rahmen entzĂŒndlicher, neoplastischer und metabolischer Erkrankungen bekannt sind und weiterhin ein unterschiedliches Expressionsverhalten in embryonalen und adulten Geweben bekannt ist. Integrine, MHC-I und II sowie ICAM-I wurden stimuliert, um die ReaktionsfĂ€higkeit im Laufe der Zellkultur zu erfassen. Untersucht wurden diese Marker mittels DurchfluĂzytometrie, Western Blot und konfokaler Laserscanmikroskopie. 3. Ergebnisse In allen Zellkulturen kam es zu Dedifferenzierungserscheinungen mit dem Auftreten unphysiologischer Zytokeratine und unphysiologischer Integrine. Hierbei war das AusmaĂ der Dedifferenzierungserscheinungen eher von der Struktur der extrazellulĂ€ren Matrix als ihrer Zusammensetzung abhĂ€ngig, so daĂ unter dreidimensionalen Kulturbedingungen eine bessere Differenzierung als unter zweidimensionalen Bedingungen erzielt wurde. 4. SchluĂfolgerung Humane Hepatozyten dedifferenzieren in Zellkulturen nach Aussaat in verschiedene extra zellulĂ€re Matrices. Dabei ist das AusmaĂ an Dedifferenzierung weniger abhĂ€ngig von der Zusammensetzung der Matrix als mehr von der zwei- respektive DreidimensionalitĂ€t. Integrine stellen einen interessanten frĂŒhen Marker zur Beurteilung der Differenzierung dar und sollten in ergĂ€nzenden Experimenten, z. B. Kokultivierung mit nichtparenchymalen Zellen, weiter evaluirt werden
Rosiglitazone Affects Nitric Oxide Synthases and Improves Renal Outcome in a Rat Model of Severe Ischemia/Reperfusion Injury
Background. Nitric oxide (NO)-signal transduction plays an important role in renal ischemia/reperfusion (I/R) injury. NO produced by endothelial NO-synthase (eNOS) has protective functions whereas NO from inducible NO-synthase (iNOS) induces impairment. Rosiglitazone (RGZ), a peroxisome proliferator-activated receptor (PPAR)-Îł agonist exerted beneficial effects after renal I/R injury, so we investigated whether this might be causally linked with NOS imbalance. Methods. RGZ (5âmg/kg) was administered i.p. to SD-rats (f) subjected to bilateral renal ischemia (60âmin). Following 24âh of reperfusion, inulin- and PAH-clearance as well as PAH-net secretion were determined. Morphological alterations were graded by histopathological scoring. Plasma NOx-production was measured. eNOS and iNOS expression was analyzed by qPCR. Cleaved caspase 3 (CC3) was determined as an apoptosis indicator and ED1 as a marker of macrophage infiltration in renal tissue. Results. RGZ improves renal function after renal I/R injury (PAH-/inulin-clearance, PAH-net secretion) and reduces histomorphological injury. Additionally, RGZ reduces NOx plasma levels, ED-1 positive cell infiltration and CC3 expression. iNOS-mRNA is reduced whereas eNOS-mRNA is increased by RGZ. Conclusion. RGZ has protective properties after severe renal I/R injury. Alterations of the NO pathway regarding eNOS and iNOS could be an explanation of the underlying mechanism of RGZ protection in renal I/R injury
Hyperhidrosis: a central nervous dysfunction of sweat secretion
Hyperhidrosis (HH) is a central nervous dysfunction characterized by abnormally increased sweating due to a central dysregulation of sweat secretion. HH significantly affects the quality of life of patients in their private, social and professional environments. Physiologically, sweating is a mechanism that regulates body temperature, but it may also be triggered by emotional or gustatory stimuli. There are two main types of sweat glands: eccrine and apocrine glands. The central nervous system controls sweat secretion through the release of neurotransmitters into the autonomous nervous system (ANS) that activate the sweat glands. The hypothalamus has two separate neuronal pathways, one for thermoregulation and one for emotions. HH may thus be due to either a neuronal dysfunction of ANS regulation leading to a hyperactivity of the sympathetic nervous system, or to abnormal central processing of emotions. Crucially, there is no dysfunction of the sweat glands themselves. Various pathogenic mechanisms have been proposed to be involved in pathological sweat secretion in HH, ranging from structural changes within the ANS to increased expression of aquaporin 5 and upregulation of activin A receptor type 1 in eccrine sweat glands. Although a genetic predisposition has been demonstrated, it remains unclear exactly which genes are involved. To identify new, potential therapeutic targets and to improve treatment options, a good understanding of the signaling pathways involved, the underlying mechanisms, and the genetic components is essential. In this review we discuss the various aspects of sweat physiology and function that are necessary to explain pathological sweating. Our aim is to raise awareness of the complexity of HH to promote a better understanding of the disorder
Cold-crystallization of poly(butylene 2,6-naphthalate) following Ostwald's rule of stages
Melt-crystallization of poly (butylene 2,6-naphthalate) (PBN) at temperatures lower than about 160 \ub0C follows Ostwald's rule of stages, leading first to formation of a transient smectic liquid crystalline phase (LC) which then may convert in a second step into crystals, controlled by kinetics. In the present work, the PBN melt was cooled at different rates in a fast scanning chip calorimeter to below the glass transition temperature, to obtain different structural states before analysis of the cold-crystallization behavior on heating. It was found that heating of fully amorphous PBN at 1000 K/s leads to a similar two-step crystallization process as on cooling the quiescent melt, with LC-formation occurring slightly above Tg and their transformation into crystals at their stability limit close to 200 \ub0C. In-situ polarized-light optical microscopy provided information that the transition of the LC-phase into crystals on slow heating is not connected with a change of the micrometer-scale superstructure, as the recently found Schlieren texture remains unchanged
The melting properties of D-α-glucose, D-ÎČ-fructose, D-sucrose, D-α-galactose, and D-α-xylose and their solubility in water: a revision
Saccharides are still commonly isolated from biological feedstock by crystallization from aqueous solutions. Precise thermodynamic data on solubility are essential to optimize the downstream crystallization process. Solubility modeling, in turn, requires knowledge of melting properties. In the first part of this work, following our previous work on amino acids and peptides, D-α-glucose, D-ÎČ-fructose, D-sucrose, D-α-galactose, and D-α-xylose were investigated with Fast Scanning Calorimetry (FSC) in a wide scanning rate range (2000 K·sâ1 to 10000 K·sâ1). Using the experimental melting properties of saccharides from FSC allowed successfully modeling aqueous solubility for D-sucrose and D-α-galactose with the equation of state PC-SAFT. This provides cross-validation of the measurement methods to determine accurate experimental melting properties with FSC. Unexpectedly, the experimental FSC melting temperatures, extrapolated to zero scanning rates for thermal lag correction, were higher than results determined with DSC and available literature data. To clarify this inconsistency, FSC measurements towards low scanning rates from 10000 K·sâ1 to 1 K·sâ1 (D-α-glucose, D-ÎČ-fructose, D-sucrose) overlapping with the scanning rates of DSC and literature data were combined. At scanning rates below 1000 K·sâ1, the melting properties followed a consistent non-linear trend, observed in both the FSC and the literature data. In order to understand the non-linear decrease of apparent melting temperatures with decreasing heating rate, the endothermic peaks were investigated in terms of isoconversional kinetics. The activation energies in the non-linear dependency region are in the range of 300<EA<600kJâmolâ1. These values are higher than the enthalpy of sublimation for D-α-glucose, indicating that the non-linear behavior does not have a physical nature but attributes to chemical processes corresponding to the decomposition of molecular compounds within the crystal lattice before melting. The melting properties reported in the literature, commonly determined with conventional methods such as DSC, lead to inaccurate results due to the decomposition of these biomolecules at low heating rates. In addition, the FSC results at lower scanning rates coincide with results from DSC and literature in the overlapping scanning rate range, further validating the accuracy of FSC measurements to determine reliable melting properties of thermally labile biomolecules. The experimental FSC melting properties determined at higher scanning rates are considered as the correct equilibrium melting properties, which are not influenced by any chemical processes. The combination of FSC and PC-SAFT opens the door to model solubility of solid compounds that commonly decompose before melting
Arbeitszeitbedarf in der ökologischen Legehennenhaltung
Der Arbeitszeitbedarf fĂŒr Legehennen in Bodenhaltung unterscheidet sich kaum von dem in der Volierenhaltung: Gesamtarbeitszeitbedarf und Verteilung auf die einzelnen ArbeitsgĂ€nge sind annĂ€hernd gleich. Der gröĂte Arbeitszeitbedarf liegt mit einem Anteil von 53 % bei der Produktgewinnung. Die BetriebsfĂŒhrung macht einen Anteil von 17% am Gesamtarbeitszeitbedarf aus. Bei beiden Arbeiten handelt es sich um tĂ€gliche, meist mit hohem manuellem Aufwand verbundene TĂ€tigkeiten. Produktgewinnung, BetriebsfĂŒhrung, FĂŒtterung und Auslaufbewirtschaftung summieren sich auf 92 % des Arbeitszeitbedarfs. Einfluss auf den Arbeitszeitbedarf haben vor allem die BestandsgröĂe und der Anteil an manuellen TĂ€tigkeiten
New experimental melting properties as access for predicting amino-acid solubility
The properties of melting are required for the prediction of solubility of solid compounds. Unfortunately, direct determination of the enthalpy of fusion and melting temperature by using conventional DSC or adiabatic calorimetry is often not possible for biological compounds due to decomposition during the measurement. To overcome this, fast scanning calorimetry (FSC) with scanning rates up to 2 Ă 104 K sâ1 was used in this work to measure the melting parameters for L-alanine and glycine. The enthalpy of fusion and melting temperature (extrapolated to zero heating rate) were ÎfusH = (22 ± 5) kJ molâ1 and Tfus = (608 ± 9) K for L-alanine, and ÎfusH = (21 ± 4) kJ molâ1 and Tfus = (569 ± 7) K for glycine. These melting properties were used in the modeling framework PC-SAFT to predict amino-acid solubility in water. The pure-component PC-SAFT parameters and one binary parameter were taken from literature, in which these parameters were fitted to solubility-independent thermodynamic properties such as osmotic coefficients or mixture densities. It was shown that this allowed accurately predicting amino-acid solubility in water over a broad temperature range. The combined methodology of PC-SAFT and FSC proposed in this work opens the door for predicting solubility of molecules that decompose before melting
Effect of Backbone Rigidity on the Glass Transition of Polymers of Intrinsic Microporosity Probed by Fast Scanning Calorimetry
Study protocol of the FIRE-8 (AIO-KRK/YMO-0519) trial: a prospective, randomized, open-label, multicenter phase II trial investigating the efficacy of trifluridine/tipiracil plus panitumumab versus trifluridine/tipiracil plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer
Background: Initial systemic therapy for patients with metastatic colorectal cancer (mCRC) is usually based on two- or three-drug chemotherapy regimens with fluoropyrimidine (5-fluorouracil (5-FU) or capecitabine), oxaliplatin and/or irinotecan, combined with either anti-VEGF (bevacizumab) or, for RAS wild-type (WT) tumors, anti-EGFR antibodies (panitumumab or cetuximab). Recommendations for patients who are not eligible for intensive combination therapies are limited and include fluoropyrimidine plus bevacizumab or single agent anti-EGFR antibody treatment. The use of a monochemotherapy concept of trifluridine/ tipiracil in combination with monoclonal antibodies is not approved for first-line therapy, yet. Results from the phase II TASCO trial evaluating trifluridine/tipiracil plus bevacicumab in first-line treatment of mCRC patients and from the phase I/II APOLLON trial investigating trifluridine/tipiracil plus panitumumab in pre-treated mCRC patients suggest favourable activity and tolerability of these new therapeutic approaches.
Methods: FIRE-8 (NCT05007132) is a prospective, randomized, open-label, multicenter phase II study which aims to evaluate the efficacy of first-line treatment with trifluridine/tipiracil (35 mg/m(2) body surface area (BSA), orally twice daily on days 1-5 and 8-12, q28 days) plus either the anti-EGFR antibody panitumumab (6 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm A] or (as control arm) the anti-VEGF antibody bevacizumab (5 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm B] in RAS WT mCRC patients. The primary objective is to demonstrate an improved objective response rate (ORR) according to RECIST 1.1 from 30% (control arm) to 55% with panitumumab. With a power of 80% and a two-sided significance level of 0.05, 138 evaluable patients are needed. Given an estimated drop-out rate of 10%, 153 patients will be enrolled.
Discussion: To the best of our knowledge, this is the first phase II trial to evaluate the efficacy of trifluridine/tipiracil plus panitumumab in first-line treatment of RAS WT mCRC patients. The administration of anti-EGFR antibodies rather than anti-VEGF antibodies in combination with trifluridine/tipiracil may result in an increased initial efficacy
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