an essential signaling element in the liver and can regulate hepatic glucose, lipid and energy homeostasis through activation of G-protein coupled receptor (GPCR) signaling (Chiang, 2013). Bile secretion involves multiple complex mechanisms which start with the formation in hepatocytes followed by modification in the bile ducts before delivery into the intestine where it can further be modified by resident microbial flora .Bile acids, the main component of bile, are synthesized from cholesterol in a multistep process. The synthesis occurs in hepatocytes and the resulting bile acids are secreted into the network of bile canaliculi. Structurally, hepatocytes are polarized epithelial cells with both apical and basolateral membranes residing on opposite sides of the cell. In hepatocytes the basolateral area encompasses the majority of the plasma membrane and lies adjacent to the sinusoidal space. Conversely, the apical membrane only takes up a small area and lies between two hepatocytes forming the bile canaliculi. The bile canaliculi are joined to the small bile ductules through the canals of hering. Bile is subsequently transported from these small ductules to the large ductules and finally to the common hepatic duct, which is connected to the gall bladder were bile acids are deposited and stored (Boyer, 2013). The biliary tree is composed of small and large ductules. These luminal tubules are constructed from cholangiocytes, which are epithelial cells derived from hepatoblasts, or specialized pluripotent stem cells residing in the portal tract (Boyer, 2013; Huch et al., 2013). Cholangiocytes also function to modify bile acids and alter the constituents of bile. There are two known types of cholangiocytes. The large cholangiocytes which compose the large bile ducts and have a primary secretary function in response to hormones, whereas the small cholangiocytes inhabit the small bile ducts and proliferative rapidly in reaction to toxic changes in bile acid composition (Lazaridis et al., 2004).
Mammary gland branching occurs at the terminal end buds (TEBs) and within the mammary gland two types of branching patterns can be distinguished. The dichotomous branching occurs with an angle of 60 degree, which is also called primary branching. Dichotomous branching occurs through ductal elongation filling first the entire fat pat before secondary branching occurs. Secondary branches develop from already pre-existing branches by side branching of 90 degree (164). Several studies support the importance of the GH/IGF- I axis and respective receptors in mammary gland branching. Full differentiation and development of the mammary gland depends on a combination of hormones including the pituitary hormones (growthhormone and prolactin), the ovarian hormones (estrogen and progesterone) and glucocorticoids (165, 166). Growthhormone mediates via growthhormonereceptor the local production of IGF-I which stimulates duct formation (167). IGF-I causes outgrowth of primary branches during development. In addition, evidence also indicates that the transmembrane tyrosine kinase and potential EGFR partner ErbB2 influences ductal morphogenesis (56). Moreover, genetic studies have shown that gene targeted deletion of IGF-I, IGF-IR, or growthhormonereceptor, have retarded ductal development (55). Finally, any effect on normal development would likely alter subsequent tumorigenesis, thus we felt it important to first examine the normal mammary gland.
An active lifestyle is generally recommended for hypertensive patients to pre- vent subsequent end-organ damage. However, experimental data on long-term effects of exercise on hypertension are insufficient and underlying mechanisms are not well understood. This study was aimed to investigate the effect of exercise on renal expression of parathyroid hormone-related protein (PTHrP) and parathyroid hormonereceptor type 1 (PTHR1) in spontaneously hyper- tensive rats (SHR). Twenty-four rats started free running wheel exercise at the age of 1.5 months (pre-hypertensive state) and proceeded for 1.5, 3.0, 6.0, and 10.0 months. Thirty rats kept under standard housing conditions were used as sedentary controls. Kidney function was assessed by measuring plasma crea- tinine levels and urine albumin-to-creatinine ratios. Renal expression of PTHrP and PTHR1 was analyzed by qRT-PCR and western blot. Renal expression of PTHR1 was markedly increased between the 6th and 10th months in sedentary rats and this increase was significantly lower in SHRs with high physical activity on mRNA ( 30%) and protein level ( 27%). At the same time, urine albumin-to-creatinine ratio increased (from 65 to 231 mg/g) but somehow lower in exercise performing SHRs (48–196 mg/g). Our data suggest that enhanced exercise, stimulated by allocation of a free running wheel, is associated with lower PTHR1 expression in SHRs and this may contribute to preserved kidney function.
For the diagnosis of GH disorders, it is suggested to gather biochemical evidence by performing at least one laboratory test [ 15 ]. Such provocative tests are time-consuming and include complex and partially hazardous procedures [ 16 ]. Additionally, they are considered unreliable, variable and do lack reproducibility [ 17 ]. Therefore, IGF-1 is used to complement the diagnostics but also to monitor treatment. However, IGF-1 is said to be not useful for screening and can give conflicting results, as its regulation is dependent on factors such as age, gender or nutritional status [ 18 – 20 ]. For patients with a GHD this is especially problematic, as there are considerable overlaps with the normal range that further increase with age [ 21 ]. Of major concern is the lack of standardization of IGF-1 assays and the variability of applied clinical reference ranges. Laboratories use different methods for IGF-1 detection, which results in the limits of applied reference ranges varying by more than twofold [ 22 , 23 ]. For the screening of a GHD, the additional measurement of insulin-like growth factor binding protein-3 (IGFBP-3) can be useful. Its use, however, is equally controversial. While some studies showed that due to its low sensitivity the use of IGFBP-3 does not provide an advantage over the measurement of IGF-1 alone [ 24 , 25 ], others highlight the significantly higher specificity of IGFBP-3 [ 18 , 26 ].
5.3. Der Kapitän
Die Hypophyse ist zwar die „Königin“ der Hormondrüse, aber sie ist keine unabhän- gig regierende Monarchin. Sie ist selbst eingebunden ein Kommunikationssystem, das die beiden großen Steuerungssysteme unseres Körpers, Nerven- und Hormon- system, miteinander verbindet und ihre Tätigkeiten koordiniert. Das Bindeglied zum übrigen Gehirn ist ein Teil des Zwischenhirns, der Hypothalamus. Er ist selbst eine Art Zwitter, da er einerseits selbst aus Nervengewebe besteht und damit zellulär ein Gehirnteil ist, er aber andererseits auch Hormone oder hormonähnliche Stoffe aus- scheidet. Dazu zählt das für unser Problem wichtige TRH (Thyreoliberin, auch Thy-
The heterodimerization is influenced by the bivalency of ErbB ligands, the varying binding affinities of ligands as well as the pH stability of the ligand-receptor complex (Beerli et al., 1996; French et al., 1995), making the dimerization a process depending on various parameters, not only being influenced by the microenvironment of the cell, but also by the various stimulating ligands. Therefore, there is considerable variability in the pairing of receptors during dimerization, and taking into account that the EGFR can be activated via various ligands, the signal inputs to the receptor system are of a great diversity (Olayioye et al., 2000). As a consequence of the diverse activation patterns of EGFR, there are a variety of downstream pathways that can be activated (Lemmon et al., 1994; Yarden et al., 2001), leading to a very complex pattern of cascade activations with partly crossing pathways, making the EGFR signal transduction a very complex and interconnected signaling network.
Das HCC entwickelt sich im Laufe von vielen Jahren aus dysplastischen Knoten bei chroni- schem Leberschaden. Neben Ätiologie-spezifischen molekularen Mechanismen kommt es in der entzündeten oder bereits fibrotischen/zirrhotischen Leber zur Überexpression von Zytoki- nen wie Tumornekrosefaktor (TNF)-α und Interferon (INF)-γ, zu einem Nitritoxid (NO)-An- stieg und dadurch zu DNA-Schädigung sowie zu Inaktivierung von Tumorsuppressorgenen und Aktivierung von Protoonkogenen (9). Aus einem dysplastischen Fokus mit zunehmend entdif- ferenzierten und funktionslosen Hepatozyten und Regenerationsarealen entsteht ein dysplasti- scher Knoten und anschließend ein frühes differenziertes Karzinom, welches sich zu einem fortgeschrittenen, wenig differenzierten Karzinom mit Tendenz zu weiterem Wachstum, Meta- stasierung und Invasion entwickelt (10). Die Dysregulierung von Wachstumsfaktor-Signalwe- gen wie insuline-linke growth factor (IGF), epidermal growth factor (EGF), vascular endothe- lial growth factor (VEGF) und fibroblast growth factor (FGF) und das komplexe Zusammen- spiel der Tumorzellen mit dem umliegenden Gewebe spielen dabei eine große Rolle. Das HCC kann anhand der betroffenen Signalwege und Gendysregulationen in viele verschiedene, hete- rogene Subklassen eingeteilt werden (11). Auf die spezifische Rolle des VEGF-Signalweges und der Angiogenese wird in Kapitel 5.1.3 näher eingegangen.
capecitabine. HR+ was defined as ≥ 10% of tumor cells
with estrogen receptor and/or progesterone receptor expression, as defined in the study protocol. HER2 posi- tivity was determined by immunohistochemistry (HER2 score 3+) and in situ hybridization where appropriate (HER2/CEP17 ratio > 2.2). Endocrine treatment for 5 years was planned for patients with HR+ disease but was not part of the protocol. HER2 therapy was not available at that time. We used all samples with available material in the central biobank. Additional file 3 : Table S1 lists the pathological and clinical characteristics of the pa- tients. The extend of tumor-infiltrating lymphocytes (TILs) was estimated on H&E-stained whole tissue slides as the area of tumor cells (for intratumoral TILs) or the stromal area (for stromal TILs) that is covered by lymphocytes [ 3 ].
Even though bone metastases in prostate cancer display a predominantly osteoblastic appearance, osteolytic changes usually precede bone formation, and elevated bone breakdown remains a dominant feature of metastatic prostate cancer . Inhibition of bone degradation with anti-resorptive medications has been shown to significantly delay skeletal-related events in patients with advanced prostate cancer, emphasizing the fundamental role of bone resorption in the growth even of osteoblastic metastases . Therefore, findings from a predominantly osteolytic cancer cell line such as PC3 are of clinical relevance for the treatment of osteoblastic tumors . According to the literature, it is important to get at least a 50 % inhibition in tumor growth in mouse models in order to predict clinical responses in patients . The presented thesis fulfills this demand, yet, the neutralizing antibody did not stop the osteolytic process. This is not unexpected. Other factors in addition to IL-6 are also involved in bone resorption and in fact, IL-6 maintains many reciprocal interrelations with other pro- resorptive cytokines, forming a whole network in which they often act in synergism .
3.4. Functional effects of growth factors on primary human pituitary cells 63 3.4.1. Effect of serum deprivation on apoptosis in PP 63 3.4.2. Effect of growth factors on apoptosis in PP 64 3.4.3. Effect of neutralizing growth factor antibodies on apoptosis in PP 65
Obwohl sich ein Reihe von Arbeitsgruppen mit Messungen zum Vorkommen von Arzneimit- telwirkstoffen in der Umwelt beschäftigen und eine Vielzahl von Einzeldaten bereits vor- liegen, standen systematische und abgestimmte Untersuchungen lange Zeit aus. Auf der 51. Umweltministerkonferenz (UMK) am 19./20.11.1998 wurde deshalb beschlossen, ein koordi- niertes Untersuchungsprogramm der Länder zu planen und durchzuführen, in das insbeson- dere Untersuchungen auf Arzneistoffe in Wasser, Boden und maßgeblichen Eintragspfaden aufgenommen werden sollten. Der Bund/Länderausschuss für Chemikaliensicherheit (BLAC) hat zu diesem Ziel den Arbeitskreis „Arzneimittel in der Umwelt – Untersuchungsprogramm“ gegründet, der zur 53. UMK am 27./28. Oktober 1999 einen Bericht erarbeitet hat, der Vor- schläge für ein Untersuchungsprogramm mit einer Charakterisierung der zu beprobenden Messstellen sowie einer Übersicht über den zu untersuchenden maximalen Parameterum- fang enthält . Das Forschungsvorhaben „Vorkommen von Pharmaka und Hormonen in Grund-, Oberflächengewässern und Böden in Baden-Württemberg“ war Teil des vom Mini- sterium für Umwelt und Verkehr Baden-Württemberg geförderten Projekts „Pharmaka und Hormone in der aquatischen Umwelt“. Ziel des Gesamtprojekts war es, umfassende und aussagekräftige Daten zum Vorkommen und Umweltverhalten von Arzneimittelwirkstoffen und hormonell wirksamen Verbindungen in Grundwässern, Oberflächengewässern, Abwässern und Deponiesickerwässern sowie in Böden und Klärschlamm in Baden- Württemberg zu gewinnen.
The plasminogen system is harnessed in a wide variety of physiological processes, such as fibri- nolysis, cell migration, or efferocytosis; and accordingly, it is essential upon inflammation, tissue remodeling, wound healing, and for homeostatic maintenance in general. Previously, we identi- fied a plasminogen receptor in the mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R, CD222). Here, we demonstrate by means of genetic knockdown, knockout, and res- cue approaches combined with functional studies that M6P/IGF2R is up-regulated on the surface of macrophages, recognizes plasminogen exposed on the surface of apoptotic cells, and mediates plasminogen-induced efferocytosis. The level of uptake of plasminogen-coated apoptotic cells inversely correlates with the TNF- 𝛼 production by phagocytes indicating tissue clearance with- out inflammation by this mechanism. Our results reveal an up-to-now undetermined function of M6P/IGF2R in clearance of apoptotic cells, which is crucial for tissue homeostasis.
Axons are equipped with an exploratory tip, the growth cone, to navigate and sense the cues presented by the surrounding environment. Several families of ligands are present along the axonal pathways, while their receptors are expressed on the growth cone and allow different axons to follow a great variety of trajectories. However, the number of molecules involved could be considered relatively small if compared to the diversity of trajectories, speed of growth and arborization patterns present in developed organisms. The fine tuning and the integration of different guidance cues represent good mechanisms to amplify and diversify the outputs of a relatively small number of ligand/receptor systems. The molecular players taking part in the modulation and integration of different signaling are not yet fully elucidated. In this study I focused on three intrinsic mechanisms to modulate receptor tyrosine kinase signaling: dephosphorylation by receptor protein tyrosine phosphatases (RPTPs), receptor cleavage and receptor cross-talk.
BDNF is a neurotrophic factor involved in neuronal survival and differentiation as well as axonal growth (Chao 2003). Oligodendrocytes produce BDNF that promote the survival of neurons, advancing oligodendrocyte differentiation and myelination, especially during CNS myelin lesion and repair (Bankston et al. 2013). However, how BDNF expression is regulated in oligodendrocyte is much less understood. It has been proven that BDNF is a suppressing factor for macrophage migration and infiltration and may play a detrimental role after spinal cord injury (Wong et al. 2010) and intracerebroventricular administration of BDNF has been reported to significantly reduce blood brain barrier breakdown. In multiple sclerosis immune cells are a major source of BDNF (Kerschensteiner et al. 1999). More BDNF (+) cells are found in active demyelinating lesions compared with inactive lesions (Stadelmann et al. 2002). Furthermore, neurons around active lesions and reactive astrocytes within lesions express high levels of its high affinity receptor gp145trkB (Stadelmann et al. 2002).