Stefan Eder

Clinical significance of epithelial-mesenchymal transition

The concept of epithelial-mesenchymal transition (EMT), a process where cells change their epithelial towards a mesenchymal phenotype, has gained overwhelming attention especially in the cancer research community. Thousands of scientific reports investigated changes in gene, mRNA and protein expression compatible with EMT and their possible correlation with tumor invasion, metastatic spread or patient prognosis; however, up to now, a proof of clinical significance of the concept is still missing. This review, with a main focus on the role of EMT in tumors, will summarize the basic molecular events underlying EMT including the signaling pathways capable of its induction as well as changes in EMT-associated protein expression and will very briefly touch the role of microRNAs in EMT. We then outline protein markers that are used most frequently for the assessment of EMT in research and diagnostic evaluation of tumor specimens and depict the link between EMT, a cancer stem cell (CSC) phenotype and resistance to conventional antineoplastic therapies. Furthermore, we evaluate a possible correlation between EMT marker expression and patient prognosis as well as current therapeutic concepts targeting the EMT process to slow down or prevent metastatic spread of malignant tumors.

Late structural alterations of cerebral white matter in long-term survivors of childhood leukemia.

To look for the presence and age‐dependence of late structural alterations of otherwise normal‐appearing cerebral gray and white matter after radiation and chemotherapy in adult survivors of acute lymphoblastic leukemia (ALL) during childhood.

Mehrfachbindungen zwischen Hauptgruppenelementen und Übergangsmetallen: XCIV. Pyridin-Komplexe organischer Osmiumoxide: Synthese, Spektren und Kristallstrukturen der Stoffklassen R2OsO2·(L) und R2OsO2·(L)2☆☆☆

Abstract Alkylosmium(VI) complexes of compositions R2OsO2·(L) and R2OsO2·(L)2 are accessible from glycolate osmium(VI) complexes (R = CH3, CH2Si(CH3)3; L = pyridine). The equilibrium R2OsO2·(L)2 ⇌ R2OsO2·(L)+L is adjustable by vacuum (right) and pyridine (left). The dimethyl complex (CH3)2OsO2·C5H5N, albeit monomeric in solution, has a trinuclear structure (Os3O3 core geometry) in the crystal, while the formally analogous derivative [(CH3)3SiCH2]2OsO2·C5H5N is monomeric, displaying a strongly distorted trigonal-bipyramidal geometry (O-Os-O′ angle 141.3(4)°/141.7(4)°). All four complexes R2OsO2·(C5H5N)2 (R = CH3, 3a; CH2Si(CH3)3, 3b and R2OsO2·(C5H5N) (R = CH3, 4a; CH2Si(CH3)3, 4b) were characterized by means of single-crystal X-ray diffraction techniques.

Mehrfachbindungen zwischen Hauptgruppenelementen und Übergangsmetallen: XCIX. Synthese, Struktur und Eigenschaften von Bis(pentafluorphenyl)dioxobis(pyridin)osmium(VI), (C6F5)2OsO2·(py)2☆

Abstract The reaction of the glycolate complex O2 Os(OCH 2 CH 2 O )·(py)2 (1) with (C6F5)2Zn·(py)2 (2) afforded the first perfluorophenyl compound of osmium. The octahedral geometry of the title compound (η1-C6F5)2OsO2·(py)2 (3), containing a linear osmyl group {OsO2}2+, was determined by single crystal X-ray diffraction methods. The strikingly high stability of the bis(pyridine) complex, which sublimes at 230°C without decomposition, is due to the presence of the strongly electron withdrawing, σ-bonded perfluorophenyl groups.

Mehrfachbindungen zwischen hauptgruppenelementen und übergangsmetallen: CIII. cis-Dimethylbis(2,2-dimethylpropyl)-oxoosmium(VI): Röntgenstrukturanalyse eines gemischtalkylierten Osmiumoxids☆☆☆

Abstract Mixed-alkyl osmium oxides of formula (R 1 ) 2 (R 2 ) 2 OsO accessible along two different synthetic approaches, exhibit cis configuration owing to the stereochemistry of the precursor complexes. This geometry has now been shown for the crystalline state by means of an X-ray diffraction study of cis -dimethylbis(2,2-dimethylpropyl)oxoosmium(VI) ( 4 ): monoclinic space group P 2 1 / n ; a 565.9(2), b 2650.1(5), and c 962.1(5) pm; β 99.05(2)°; R = 0.027, R w = 0.017. The title compound ( 4 ) is a mixed-alkyl derivative of tetraalkyloxoosmium(VI) complexes and displays a slightly-distorted square pyramidal structure. The oxo ligand is in the apical position ( d (OsO) 166.9(3) pm), while the cis -oriented alkyl groups are found in the basal positions ( d (OsC) 208.3(4) to 212.6(3) pm).

Mehrfachbindungen zwischen Hauptgruppenelementen und Übergangsmetallen: CI. Stereoselektive synthese gemischtalkylierter osmiumoxide

Abstract Two-step alkylation of osmium(VI) glycolate complexes yields mixed-alkyl oxoosmium complexes of formula (R 1 ) 2 (R 2 ) 2 OsO along two different routes. Due to the chelate ligands present in the starting compounds, square-pyramidal alkyl complexes of cis -geometry (R 1 /R 1 and R 2 /R 2 respectively) are obtained in stereoselective reactions. The crystal and molecular structure of dimethyl(2,3-dimethylbutane-2,3-diolato)oxoosmium(VI) ( 4a ) has been determined by X-ray diffraction, again revealing a square-pyramidal core geometry with the oxo ligand at the apex position [ d (OsO) = 162.1(4) pm].

Mehrfachbindungen zwischen hauptgruppenelementen und übergangsmetallen: CXVI. Tetrakis(2-methylpropyl)oxoosmium(VI), ein thermisch stabiles, sterisch überladenes d2-alkylmetalloxid mit β-ständigem wasserstoff☆

Abstract Treatment of (py)2OsO2(O2C2H4) 1 with the Grignard reagent (CH3)2CHCH2MgCl gives the d2-osmium(VI) complex

Personalized therapy: CNS HGNET-BCOR responsiveness to arsenic trioxide combined with radiotherapy

High-grade neuroepithelial tumor of the central nervous system with BCOR alteration (HGNET-BCOR) is a rare, highly malignant tumor. At the time of this publication, no standard protocol exists to treat this tumor entity. In this work, we tested the responsiveness of the primary culture PhKh1 derived from tumor tissue from a pediatric HGNET-BCOR patient (P1) to inhibitors of the Sonic hedgehog pathway combined with radiation. The SMO inhibitors vismodegib and itraconazole had low effect on the proliferation of the PhKh1 cells. However, the GLI inhibitor arsenic trioxide reduced the expression of GLI target genes in the PhKh1 cells and in combination with radiotherapy significantly decreased their clonogenic potential. PhKh1 cells resistant to arsenic trioxide were characterized by the overexpression of molecular chaperones. We combined arsenic trioxide and radiation in the relapse therapy protocol of P1, achieving complete remission after seven weeks. Clinical remission lasted for six months, when P1 developed systemic metastases. Meanwhile, an increase in the concentration of circulating tumor DNA carrying a BCOR internal tandem duplication was observed. Molecular characterization of a second patient (P2) was also performed. In P2, we detected a larger tandem duplication and greater activation of the Sonic hedgehog pathway than in P1. These findings suggest that combining arsenic trioxide with radiotherapy may represent a new therapeutic approach. Moreover, peripheral blood analysis for circulating tumor DNA could help in the early detection of systemic metastases.

Anaplastic lymphoma kinase (ALK) gene rearrangements in radiation-related human papillary thyroid carcinoma after the Chernobyl accident: ALK rearrangements in post-Chernobyl PTC samples

Childhood radiation exposure has been associated with increased papillary thyroid carcinoma (PTC) risk. The role of anaplastic lymphoma kinase (ALK) gene rearrangements in radiation‐related PTC remains unclear, but STRN‐ALK fusions have recently been detected in PTCs from radiation exposed persons after Chernobyl using targeted next‐generation sequencing and RNA‐seq. We investigated ALK and RET gene rearrangements as well as known driver point mutations in PTC tumours from 77 radiation‐exposed patients (mean age at surgery 22.4 years) and PTC tumours from 19 non‐exposed individuals after the Chernobyl accident. ALK rearrangements were detected by fluorescence in situ hybridisation (FISH) and confirmed with immunohistochemistry (IHC); point mutations in the BRAF and RAS genes were detected by DNA pyrosequencing. Among the 77 tumours from exposed persons, we identified 7 ALK rearrangements and none in the unexposed group. When combining ALK and RET rearrangements, we found 24 in the exposed (31.2%) compared to two (10.5%) in the unexposed group. Odds ratios increased significantly in a dose‐dependent manner up to 6.2 (95%CI: 1.1, 34.7; p = 0.039) at Iodine‐131 thyroid doses >500 mGy. In total, 27 cases carried point mutations of BRAF or RAS genes, yet logistic regression analysis failed to identify significant dose association. To our knowledge we are the first to describe ALK rearrangements in post‐Chernobyl PTC samples using routine methods such as FISH and IHC. Our findings further support the hypothesis that gene rearrangements, but not oncogenic driver mutations, are associated with ionising radiation‐related tumour risk. IHC may represent an effective method for ALK‐screening in PTCs with known radiation aetiology, which is of clinical value since oncogenic ALK activation might represent a valuable target for small molecule inhibitors.

Gene Expression Analysis in Human Peripheral Blood Cells after 900 MHz RF-EMF Short-Term Exposure

Radiofrequency electromagnetic fields (RF-EMF) are a basic requirement of modern wireless communication technology. Statutory thresholds of RF-EMF are established to limit relevant additional heat supply in human tissue. Nevertheless, to date, questions concerning nonthermal biological effects have yet to be fully addressed. New versions of microarrays (8 × 60K v2) provide a higher resolution of whole genome gene expression to display adaptive processes in cells after irradiation. In this ex vivo/in vitro study, we irradiated peripheral blood cells from five donors with a continuous wave of 900 MHz RF-EMF for 0, 30, 60 and 90 min. Gene expression changes (P ≤ 0.05 and ≥twofold differences above or below the room temperature control exposed samples) were evaluated with microarray analysis. The results were compared with data from room temperature + 2°C samples. Verification of microarray results was performed using bioinformatic analyses and qRT-PCR. We registered a lack of an EMF-specific gene expression response after applying the false discovery rate adjustment (FDR), using a high-stringency approach. Low-stringency analysis revealed 483 statistically significant deregulated transcripts in all RF-EMF groups relative to the room temperature exposed samples without an association with their corresponding room temperature + 2°C controls. Nevertheless, these transcripts must be regarded as statistical artefacts due to the absence of a targeted biological response, including enrichment and network analyses administered to microarray expressed gene subset profiles. Correspondingly, 14 most promising candidate transcripts examined by qRT-PCR displayed an absence of correlation with respect to the microarray results. In conclusion, these findings indicate that 900 MHz EMF exposure establishing an average specific absorption rate of 9.3 W/kg to whole blood cells is insufficient to induce nonthermal effects in gene expression during short-time exposure up to 90 min.