Untersuchungen zum stromalen Laminin-Matrix-Remodelling in der Invasionsfront humaner oraler Karzinome

Das orale Plattenepithelkarzinom (OSCC) ist der häufigste maligne Tumor der Mundhöhle. Die aktuell zur Verfügung stehenden Therapieoptionen zeigen nur unzureichende Erfolge, so dass die Suche nach neuen therapeutischen Ansätzen von hohem klinischem Interesse ist. Die im Rahmen der Tumorinvasion stattfindende Reorganisation der extrazellulären Matrix (stromales Remodelling) ist mit einer Reexpression onkofetaler Matrixproteinvarianten verbunden. Laminine als bedeutende Gruppe nichtkollagener Glykoproteine der extrazellulären Matrix (ECM) existieren in 16 verschiedenen Isoformen, welche durch alternativen Zusammenbau der unterschiedlichen α, β und γ – Ketten entstehen. Im OSCC kommt es zu deutlichen Veränderungen in der Expression der Lamininisoformen verglichen mit normaler Mundschleimhaut insbesondere in epithelialen Tumorzellen und in Basalmembranstrukturen. Hierbei besteht eine klare Assoziation zum malignen Potential des Tumors. Die Bedeutung der Expression und extrazellulären Deposition einzelner Lamininketten für die stromale Reorganisation im Bereich der Tumorinvasionszone und Prozesse der Angiogenese ist aktuell nicht hinreichend verstanden. Ziel der vorliegenden Arbeit war deshalb eine detaillierte qualitative und semiquantitative Analyse der Expression und extrazellulären Deposition der funktionell bedeutsamen Lamininketten α2, α3, α4, α5, β2, β3 und γ2 im Stroma und in der Umgebung neu gebildeter Tumorgefäße der Invasionsfront des OSCC im Vergleich zu normaler und hyperplastischer Mundschleimhaut. Es erfolgten semiquantitative immunhistochemische Analysen der Lamininketten sowie von α–glattmuskulärem Aktin (αSMA). Die Ergebnisse wurden auf ihre Beziehungen zu Malignitätsgrad und Ausmaß der αSMA–Positivität überprüft. Die Detektion der Gefäßpositivität für die Lamininketten α3, α4, α5 und β2 erfolgte durch Immunfluoreszenzdoppelmarkierung mit dem Endothelzellmarker CD 31

EPA Program Review: Consequences of Global Climate Change: Water Quality Impacts, Ecological Impacts & Nonlinear Responses

A presentation that overviews existing modeling frameworks to analyze water system sensitivity to climate change and other stress factors

Transdermal fentanyl for the treatment of pain caused by osteoarthritis of the knee or hip: an open, multicentre study

BACKGROUND: This study was designed to evaluate the utility of transdermal fentanyl (TDF, Durogesic(®)) for the treatment of pain due to osteoarthritis (OA) of the knee or hip, which was not adequately controlled by non-opioid analgesics or weak opioids. The second part of the trial, investigating TDF in patients with rheumatoid arthritis (RA) is reported separately. METHODS: Current analgesia was optimised during a 1-week run-in. Patients then received 28 days treatment with TDF starting at 25 μg/hr, with the option to increase the dose until adequate pain control was achieved. Metoclopramide was taken during the first week and then as needed. RESULTS: Of the 159 patients recruited, 75 with OA knee and 44 with OA hip completed the treatment phase, 30 knee and 18 hip patients entered the one-week taper-off phase. The most frequently used maximum dose of TDF was 25 μg/hr. The number of patients with adequate pain control increased during the run-in period from 4% to 27%, and further increased during TDF treatment to 88% on day 28. From baseline to endpoint, there were significant reductions in pain (p < 0.001) and improvements in functioning (p < 0.001) and physical (p < 0.001) and mental (p < 0.05) health. Scores for 'pain right now' decreased significantly within 24 hours of starting TDF treatment. TDF was assessed favourably and 84% of patients would recommend it for OA-related pain. Nausea and vomiting were the most common adverse events (reported by 32% and 26% of patients respectively), despite prophylaxis with metoclopramide, which showed limited efficacy in this setting. CONCLUSION: TDF significantly increased pain control, and improved functioning and quality of life. Metoclopramide appeared to be of limited value in preventing nausea and vomiting; more effective anti-emetic treatment may enable more people to benefit from strong opioids such as TDF. This study suggests that four weeks is a reasonable period to test the benefit of adding TDF to improve pain control in OA patients and that discontinuing therapy in cases of limited benefit creates no major obstacles

Loss of ZnT8 function protects against diabetes by enhanced insulin secretion.

A rare loss-of-function allele p.Arg138* in SLC30A8 encoding the zinc transporter 8 (ZnT8), which is enriched in Western Finland, protects against type 2 diabetes (T2D). We recruited relatives of the identified carriers and showed that protection was associated with better insulin secretion due to enhanced glucose responsiveness and proinsulin conversion, particularly when compared with individuals matched for the genotype of a common T2D-risk allele in SLC30A8, p.Arg325. In genome-edited human induced pluripotent stem cell (iPSC)-derived β-like cells, we establish that the p.Arg138* allele results in reduced SLC30A8 expression due to haploinsufficiency. In human β cells, loss of SLC30A8 leads to increased glucose responsiveness and reduced KATP channel function similar to isolated islets from carriers of the T2D-protective allele p.Trp325. These data position ZnT8 as an appealing target for treatment aimed at maintaining insulin secretion capacity in T2D

Закономерности формирования угольных бассейнов Южно-Гобийской провинции Монголии и содержание в них редких элементов

Background— Ion channels are key determinants for the function of excitable cells, but little is known about their role and involvement during cardiac development. Earlier work identified Ca 2+ -activated potassium channels of small and intermediate conductance (SKCas) as important regulators of neural stem cell fate. Here we have investigated their impact on the differentiation of pluripotent cells toward the cardiac lineage. Methods and Results— We have applied the SKCa activator 1-ethyl-2-benzimidazolinone on embryonic stem cells and identified this particular ion channel family as a new critical target involved in the generation of cardiac pacemaker-like cells: SKCa activation led to rapid remodeling of the actin cytoskeleton, inhibition of proliferation, induction of differentiation, and diminished teratoma formation. Time-restricted SKCa activation induced cardiac mesoderm and commitment to the cardiac lineage as shown by gene regulation, protein, and functional electrophysiological studies. In addition, the differentiation into cardiomyocytes was modulated in a qualitative fashion, resulting in a strong enrichment of pacemaker-like cells. This was accompanied by induction of the sino-atrial gene program and in parallel by a loss of the chamber-specific myocardium. In addition, SKCa activity induced activation of the Ras-Mek-Erk signaling cascade, a signaling pathway involved in the 1-ethyl-2-benzimidazolinone–induced effects. Conclusions— SKCa activation drives the fate of pluripotent cells toward mesoderm commitment and cardiomyocyte specification, preferentially into nodal-like cardiomyocytes. This provides a novel strategy for the enrichment of cardiomyocytes and in particular, the generation of a specific subtype of cardiomyocytes, pacemaker-like cells, without genetic modification. </jats:sec