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The hypoxia-inducible transcription factors (HIFs) are central components in the cellular responses to a lack of O2, i.e. hypoxia. Homologs of the HIF system (HIF-1, -2 and -3) are detectable in all nucleated cells of multicellular organisms. Active HIFs are heterodimers (HIF-α/β). In hypoxia the O2-labile α-subunit is translocated to the nucleus where it binds HIF-β. Over 100 HIF target genes have already been identified. The translational products of these genes increase O2 delivery to hypoxic tissues, such as erythropoietin which stimulates the production of red blood cells, and they adapt cellular metabolism to hypoxia, such as glycolytic enzymes. HIFs are inactive in normoxia because of O2-dependent enzymatic hydroxylation and subsequent degradation of their α-subunit. Three HIF-α prolyl hydroxylases (PHD1, 2 and 3) initiate proteasomal degradation while an asparaginyl hydroxylase (factor inhibiting HIF-1, FIH-1) inhibits the function of the C-terminal transactivation domain of HIF-α. In addition to O2 and 2-oxoglutarate, the HIF-α hydroxylases require Fe2+ and ascorbate as co-factors. Products of glycolysis can act as endogenous inhibitors of HIF hydroxylases which may lead to sustained activation of HIFs in cancer cells. The cofactor requirements define the routes to inhibition of the enzymes when HIF activation is desirable. In particular, 2- oxoglutarate analogues have emerged as promising tools for stimulation of erythropoiesis and angiogenesis (\"HIF-stabilizers\"). However, as the HIF system promotes the transcription of many genes, and other 2-oxoglutarate dependent dioxygenases are likely to be inhibited by the same analogues, careful evaluation of the inhibitors seems mandatory prior to their clinical use.

Purpose: Tumour hypoxia activates hypoxia-inducible factor-1 (HIF-1) and indluences angiogenesis, cell survival and invasion. Prolyl hydroxylase-3 (PHD3) regulates degradation of HIF-1 α . The effects of PHD3 in tumour growth are largely unknown. Experimental design: PHD3 expression was analysed in human pancreatic cancer tissues and cancer cell lines by real-time quantitative PCR and immunohistochemistry. PHD3 overexpression was established by stable transfection and downregulation by short interfering RNA technology. VEGF was quantified by enzyme-linked immunosorbent assay. Matrigel invasion assays were performed to examine tumour cell invasion. Apoptosis was measured by annexin-V staining and caspase-3 assays. The effect of PHD3 on tumour growth in vivo was evaluated in an established orthotopic murine model. Results: PHD3 was upregulated in well-differentiated human tumours and cell lines, and regulated hypoxic VEGF secretion. PHD3 overexpression mediated tumour cell growth and invasion by induction of apoptosis in a nerve growth factor-dependent manner by the activation of caspase-3 and phosphorylation of focal adhesion kinase HIF-1 independently. In vivo , PHD3 inhibited tumour growth by abrogation of tumour angiogenesis. Conclusion: Our results indicate essential functions of PHD3 in tumour growth, apoptosis and angiogenesis and through HIF-1-dependent and HIF-1-independent pathways.

Hypoxia-inducible factor-1 (HIF-1) is a dimeric transcriptional complex that has been recognized primarily for its role in the maintenance of oxygen and energy homoeostasis. The HIF-1 alpha subunit is O sub(2) labile and is degraded by the proteasome following prolyl-hydroxylation and ubiquitination in normoxic cells. The present review summarizes evidence that HIF-1 is also involved in immune reactions. Immunomodulatory peptides, including interleukin-1 (IL-1) and tumor necrosis factor- alpha (TNF- alpha ), stimulate HIF-1 dependent gene expression even in normoxic cells. Both the hypoxic and the cytokine-induced activation of HIF-1 involve the phosphatidylinositol-3-kinase (PI3K) and the mitogen-activated protein kinase (MAPK) signaling pathways. In addition, heat shock proteins (HSP) and other cofactors interact with HIF-1 subunits. HIF-1 increases the transcription of several genes for proteins that promote blood flow and inflammation, including vascular endothelial growth factor (VEGF), heme oxygenase-1, endothelial and inducible nitric oxide synthase (NOS) and cyclooxygenase-2 (COX-2). The pharmacologic activation of the HIF-1 complex can be desirable in ischemic and inflammatory disorders. In contrast, HIF-1 blockade may be beneficial to prevent tumor angiogenesis and tumor growth.

Hintergrund: Patient:innen mit somatoformer Schmerzstörung (SFS) zeigen bestimmte Merkmale einer veränderten emotionalen Wahrnehmungsfähigkeit und Ausdrucksweise von Gefühlen. Sie haben Schwierigkeiten, eigene Gefühle als solche zu erkennen und/oder diese zu beschreiben (Alexithymie). Zudem haben sie Probleme, Emotionen von körperlichen Beschwerden abzugrenzen. Ziel dieser Studie war es, die Emotionsverarbeitung bei Patient:innen mit SFS im Vergleich zu Proband:innen zu charakterisieren. Zusätzlich wurde in Anbetracht der Covid-19 Pandemie erstmalig der Einfluss von Masken auf die faziale Affektverarbeitung in diesem Patientenkollektiv untersucht. Methoden: Bei 20 Patient:innen (16 weiblich, 4 männlich) mit SFS und einem Durchschnittsalter von 50,25 ± 10,96 Jahren sowie 20 nach Alter und Geschlecht gematchten Proband:innen wurden zunächst psychometrische Fragebögen (SOMS-7T, TAS-20, PHQ-D, PTSS-10) erhoben. Anschließend wurde den Studienteilnehmer:innen affektives Stimulusmaterial (Freude, Trauer, Wut) mit und ohne Maske präsentiert und die elektrophysiologische Aktivität mittels EEG aufgezeichnet. Die ereigniskorrelierten Potenziale P1, N170 und P2 wurden hinsichtlich der Amplitude und der Latenz vergleichend analysiert. Ergebnisse: Die mixed ANOVA von P2 in den Elektroden C3, C4 und Cz zeigte signifikante Ergebnisse (F = 3,48; p = 0,037) bei der Interaktion Gruppe x Emotion. Patient:innen zeigten im Mittel eine niedrigere P2 Amplitude nach wütenden Gesichtern (2,82 ± 1,85) im Vergleich zur Kontrollgruppe (3,55 ± 1,36). Des Weiteren zeigte sich in der mixed ANOVA bei der Interaktion Gruppe x Maske eine signifikant niedrigere P2 Amplitude (F = 5,35; p = 0,026) in der Kontrollgruppe nach Stimuluspräsentation mit (2,73 ± 1,27) versus ohne (3,55 ± 1,519) Maske. Im Gegensatz dazu führte die Stimuluspräsentation bei den Patient:innen zu keinen signifikanten Unterschieden im Vergleich mit (2,78 ± 1,92) versus ohne Maske (2,96 ± 1,74). P1 und N170 sowie die Latenzanalysen zeigten keine signifikanten Gruppenunterschiede. Schlussfolgerung: Zusammenfassend deuten die ERP-Analysen darauf hin, dass Patient:innen mit SFS die Emotion Wut schwächer verarbeiten. Im gesunden Kollektiv zeigen Masken einen deutlich dämpfenden Einfluss auf die Verarbeitung von Emotionen. Demgegenüber fällt dieser dämpfende Effekt von Masken bei den Patient:innen mit SFS wesentlich geringer aus.

The hypoxia-inducible transcription factors (HIFs) are central components in the cellular responses to a lack of O(2), i.e. hypoxia. Homologs of the HIF system (HIF-1, -2 and -3) are detectable in all nucleated cells of multicellular organisms. Active HIFs are heterodimers (HIF-alpha/ beta). In hypoxia the O(2)-labile alpha-subunit is translocated to the nucleus where it binds HIF-beta. Over 100 HIF target genes have already been identified. The translational products of these genes increase O(2) delivery to hypoxic tissues, such as erythropoietin which stimulates the production of red blood cells, and they adapt cellular metabolism to hypoxia, such as glycolytic enzymes. HIFs are inactive in normoxia because of O(2)-dependent enzymatic hydroxylation and subsequent degradation of their alpha-subunit. Three HIF-alpha prolyl hydroxylases (PHD1, 2 and 3) initiate proteasomal degradation while an asparaginyl hydroxylase (factor inhibiting HIF-1, FIH-1) inhibits the function of the C-terminal transactivation domain of HIF-alpha. In addition to O(2) and 2-oxoglutarate, the HIF-alpha hydroxylases require Fe(2+) and ascorbate as co-factors. Products of glycolysis can act as endogenous inhibitors of HIF hydroxylases which may lead to sustained activation of HIFs in cancer cells. The cofactor requirements define the routes to inhibition of the enzymes when HIF activation is desirable. In particular, 2-oxoglutarate analogues have emerged as promising tools for stimulation of erythropoiesis and angiogenesis (\"HIF-stabilizers\"). However, as the HIF system promotes the transcription of many genes, and other 2-oxoglutarate dependent dioxygenases are likely to be inhibited by the same analogues, careful evaluation of the inhibitors seems mandatory prior to their clinical use.

Hypoxia and interleukin-1β stimulate vascular endothelial growth factor production in human proximal tubular cells. Vascular endothelial growth factor (VEGF) promotes angiogenesis and inflammatory reactions. VEGF mRNA is detectable in the proximal tubules of inflamed kidneys but not in normals. In other organs VEGF gene expression is induced by hypoxia and cytokines such as interleukin 1 (IL-1). To identify the cellular mechanisms in control of tubular VEGF production, we studied effects of hypoxia and IL-1β in VEGF mRNA levels, VEGF secretion, and activity of the hypoxia-inducible dimeric transcription factor 1 (HIF-1α/β) in human proximal tubular epithelial cells (PTECs) in primary culture. PTECs were grown in monolayers from human kidneys. Hypoxia was induced by incubation at 3% O2. VEGF mRNA was quantitated by competitive polymerase chain reaction following reverse transcription. VEGF was measured by enzyme-linked immunoassay. HIF-1α was demonstrated by Western blot analysis and HIF-1 DNA binding by gel shift assay. Significant amounts of VEGF mRNA and VEGF protein were measured in PTEC extracts and culture media, respectively. Stimulation of VEGF synthesis at low O2 tension and following IL-1β treatment was detectable at the protein level only. Nuclear HIF-1α protein levels and HIF-1 binding to DNA were also increased under these conditions. PTECs in culture produce VEGF. One mechanism of induction appears to be increased DNA binding of HIF-1 to hypoxia-responsive elements in the VEGF gene promoter. In inflammatory diseases of the kidney, tubular cell-derived VEGF may contribute to microvascular leakage and monocyte extravasation.

Vascular endothelial growth factor (VEGF) promotes angiogenesis and inflammatory reactions. VEGF mRNA is detectable in the proximal tubules of inflamed kidneys but not in normals. In other organs VEGF gene expression is induced by hypoxia and cytokines such as interleukin 1 (IL-1). To identify the cellular mechanisms in control of tubular VEGF production, we studied effects of hypoxia and IL-1beta in VEGF mRNA levels, VEGF secretion, and activity of the hypoxia-inducible dimeric transcription factor 1 (HIF-1alpha/beta) in human proximal tubular epithelial cells (PTECs) in primary culture. PTECs were grown in monolayers from human kidneys. Hypoxia was induced by incubation at 3% O2. VEGF mRNA was quantitated by competitive polymerase chain reaction following reverse transcription. VEGF was measured by enzyme-linked immunoassay. HIF-1alpha was demonstrated by Western blot analysis and HIF-1 DNA binding by gel shift assay. Significant amounts of VEGF mRNA and VEGF protein were measured in PTEC extracts and culture media, respectively. Stimulation of VEGF synthesis at low O2 tension and following IL-1beta treatment was detectable at the protein level only. Nuclear HIF-1alpha protein levels and HIF-1 binding to DNA were also increased under these conditions. PTECs in culture produce VEGF. One mechanism of induction appears to be increased DNA binding of HIF-1 to hypoxia-responsive elements in the VEGF gene promoter. In inflammatory diseases of the kidney, tubular cell-derived VEGF may contribute to microvascular leakage and monocyte extravasation.

Anämie ist ein wichtiger und unabhängiger Prognosefaktor bei Patienten mit Plattenepithelkarzinomen im Kopf-Hals-Bereich, insbesondere bei definitiver Strahlentherapie. Dies beruht wahrscheinlich auf verschiedenen Ursachen, von denen die Verstärkung einer Tumorhypoxie durch Anämie ein wichtiger Faktor ist. Im Tiermodell kann man durch Anämiekorrektur mittels Erythropoetinen die Strahlenempfindlichkeit verbessern. Der Einsatz von Erythropoetin bei Kopf-Hals-Tumoren ist deshalb logisch und konsequent. Allerdings zeigen die bisherigen klinischen Ergebnisse keine Vorteile hinsichtlich des Überlebens.

A claim adjudicated in small claims court is substantively not resolved until the judgement rendered has been received by the winning plaintiff. Using data from the Boone County, Missouri, Small Claims Court, this study found that one‐half of the winning claims were collected in full. Differences in collection success were more closely related to the judgment amount and characteristics of the defendant than to characteristics of the plaintiff.

The purpose of this study is to ascertain the extent of individual plaintiff success in the trial stage of the small claims process and the impact of selected factors upon these favorable outcomes. Results of this study provide a basis for litigants and potential litigants to predict the outcome of the small claims trial. Of particular interest is the finding that litigant use of legal advice and representation in court is not a major factor in the outcome of a small claims court case. The results of this examination of the small claims court as it functions in Boone County, Missouri, suggest that, with the possible exception of plaintiff's gender, “justice is blind.”