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1.  High-Resolution Mechanical Imaging of Glioblastoma by Multifrequency Magnetic Resonance Elastography 
PLoS ONE  2014;9(10):e110588.
Objective
To generate high-resolution maps of the viscoelastic properties of human brain parenchyma for presurgical quantitative assessment in glioblastoma (GB).
Methods
Twenty-two GB patients underwent routine presurgical work-up supplemented by additional multifrequency magnetic resonance elastography. Two three-dimensional viscoelastic parameter maps, magnitude |G*|, and phase angle φ of the complex shear modulus were reconstructed by inversion of full wave field data in 2-mm isotropic resolution at seven harmonic drive frequencies ranging from 30 to 60 Hz.
Results
Mechanical brain maps confirmed that GB are composed of stiff and soft compartments, resulting in high intratumor heterogeneity. GB could be easily differentiated from healthy reference tissue by their reduced viscous behavior quantified by φ (0.37±0.08 vs. 0.58±0.07). |G*|, which in solids more relates to the material's stiffness, was significantly reduced in GB with a mean value of 1.32±0.26 kPa compared to 1.54±0.27 kPa in healthy tissue (P = 0.001). However, some GB (5 of 22) showed increased stiffness.
Conclusion
GB are generally less viscous and softer than healthy brain parenchyma. Unrelated to the morphology-based contrast of standard magnetic resonance imaging, elastography provides an entirely new neuroradiological marker and contrast related to the biomechanical properties of tumors.
doi:10.1371/journal.pone.0110588
PMCID: PMC4206430  PMID: 25338072
3.  Aberrant ZNF423 impedes B cell differentiation and is linked to adverse outcome of ETV6-RUNX1 negative B precursor acute lymphoblastic leukemia 
The Journal of Experimental Medicine  2013;210(11):2289-2304.
Aberrant ZNF423 inhibits EBF-1 target genes, leads to a B cell maturation arrest in vivo, and is associated with poor outcome of ETV6-RUNX1 negative ALL.
Differentiation arrest is a hallmark of acute leukemia. Genomic alterations in B cell differentiation factors such as PAX5, IKZF1, and EBF-1 have been identified in more than half of all cases of childhood B precursor acute lymphoblastic leukemia (ALL). Here, we describe a perturbed epigenetic and transcriptional regulation of ZNF423 in ALL as a novel mechanism interfering with B cell differentiation. Hypomethylation of ZNF423 regulatory sequences and BMP2 signaling result in transactivation of ZNF423α and a novel ZNF423β-isoform encoding a nucleosome remodeling and histone deacetylase complex–interacting domain. Aberrant ZNF423 inhibits the transactivation of EBF-1 target genes and leads to B cell maturation arrest in vivo. Importantly, ZNF423 expression is associated with poor outcome of ETV6-RUNX1–negative B precursor ALL patients. Our work demonstrates that ALL is more than a genetic disease and that epigenetics may uncover novel mechanisms of disease with prognostic implications.
doi:10.1084/jem.20130497
PMCID: PMC3804944  PMID: 24081948
4.  Are asymmetric metal markings on the cone surface of ceramic femoral heads an indication of entrapped debris? 
Background
The probability of in vivo failure of ceramic hip joint implants is very low (0.004-0.05%). In addition to material flaws and overloading, improper handling during implantation can induce fractures of the ceramic ball head in the long term. Identifying the causes of an in vivo fracture contributes to improved understanding and potentially to further reduction of the fracture probability for patients. Asymmetric metal markings on the cone surface of in vivo ball head fractures have been reported. The question, therefore, is whether asymmetric loading is the sole cause or whether additional factors, specifically contamination entrapped in the taper fit, also contribute or are even the main cause.
Methods
The influence of the asymmetric physiological load configuration on resulting metal markings in the cone surface of an alumina femoral ball head with and without biological contaminants was investigated. Static and cyclic tests on ball heads were carried out in a load configuration of 0° (axisymmetric) and 40° in a physiological environment. The analysis of the metal marking was carried out to gain a better understanding of the processes that contribute to the generation of metal marking. Fractography was carried out to determine the fracture initiation of failed ball heads.
Results
Different types and sizes of residuals entrapped in the conical surface are shown to yield strongly asymmetric metal marking patterns. All heads tested without contaminants exhibited an almost homogenous distribution of residual metal markings around the circumference of the ceramic cone surface at the proximal end of the bore hole. The failure of ball heads that contained entrapped contaminants revealed a common fracture pattern. The site of fracture initiation on two of the failed heads was in the entrance region of the bore hole on the superior half of the head.
Conclusion
Asymmetric metal markings observed on the ball heads tested in this investigation are most probably caused by the presence of contaminants entrapped in the taper fit. Homogenous metal mark distributions around the circumference indicate proper assembly of the ball head without entrapped contaminants. It should, however, be noted that different taper designs may possibly result in different marking patterns.
doi:10.1186/1475-925X-13-38
PMCID: PMC3984399  PMID: 24708695
Total hip replacement; Ceramic femoral ball head; Femoral head fracture; Cone surface; Cleaning procedure; Entrapped debris; Taper fit; Metal marking; Physiological loading; Biological contaminant
5.  Multiscale distribution of oxygen puddles in 1/8 doped YBa2Cu3O6.67 
Scientific Reports  2013;3:2383.
Despite intensive research a physical explanation of high Tc superconductors remains elusive. One reason for this is that these materials have generally a very complex structure making useless theoretical models for a homogeneous system. Little is known on the control of the critical temperature by the space disposition of defects because of lack of suitable experimental probes. X-ray diffraction and neutron scattering experiments used to investigate y oxygen dopants in YBa2Cu3O6+y lack of spatial resolution. Here we report the spatial imaging of dopants distribution inhomogeneity in YBa2Cu3O6.67 using scanning nano X-ray diffraction. By changing the X-ray beam size from 1 micron to 300 nm of diameter, the lattice inhomogeneity increases. The ordered oxygen puddles size distribution vary between 6–8 nm using 1 × 1 μm2 beam, while it is between 5–12 nm with a fat tail using the 300 × 300 nm2 beam. The increased inhomogeneity at the nanoscale points toward a network of superconducting puddles made of ordered oxygen interstitials.
doi:10.1038/srep02383
PMCID: PMC3737503  PMID: 23924946
6.  Identification of an endo-1,4-beta-xylanase of Ustilago maydis 
BMC Biotechnology  2013;13:59.
Background
The utilization of raw biomass components such as cellulose or hemicellulose for the production of valuable chemicals has attracted considerable research interest in recent years. One promising approach is the application of microorganisms that naturally convert biomass constituents into value added chemicals. One of these organisms – Ustilago maydis – can grow on xylan, the second most abundant polysaccharide in nature, while at the same time it produces chemicals of biotechnological interest.
Results
In this study, we present the identification of an endo-1,4-beta xylanase responsible for xylan degradation. Xylanase activity of U. maydis cells was indirectly detected by the quantification of released reducing sugars and could be confirmed by visualizing oligosaccharides as degradation products of xylan by thin layer chromatography. A putative endo-1,4-beta-xylanase, encoded by um06350.1, was identified in the supernatant of xylan-grown cells. To confirm the activity, we displayed the putative xylanase on the surface of the xylanase negative Saccharomyces cerevisiae EBY100. The presented enzyme converted xylan to xylotriose, similar to the source organism U. maydis.
Conclusions
The xylan degradation ability together with its unicellular and yeast-like growth makes U. maydis MB215 a promising candidate for the production of valuable chemicals such as itaconic acid or glycolipids from lignocellulosic biomass. Therefore, the characterization of the endo-1,4-beta-xylanase, encoded by um06350.1, is a further step towards the biotechnological application of U. maydis and its enzymes.
doi:10.1186/1472-6750-13-59
PMCID: PMC3737115  PMID: 23889751
Ustilago maydis; Endo-1,4-beta-xylanase; Xylan; Cell surface display
7.  Site Directed Mutagenesis of Schizosaccharomyces pombe Glutathione Synthetase Produces an Enzyme with Homoglutathione Synthetase Activity 
PLoS ONE  2012;7(10):e46580.
Three different His-tagged, mutant forms of the fission yeast glutathione synthetase (GSH2) were derived by site-directed mutagenesis. The mutant and wild-type enzymes were expressed in E. coli DH5α and affinity purified in a two-step procedure. Analysis of enzyme activity showed that it was possible to shift the substrate specificity of GSH2 from Gly (km 0,19; wild-type) to β-Ala or Ser. One mutation (substitution of Ile471, Cy472 to Met and Val and Ala 485 and Thr486 to Leu and Pro) increased the affinity of GSH2 for β-Ala (km 0,07) and lowered the affinity for Gly (km 0,83), which is a characteristic of the enzyme homoglutathione synthetase found in plants. Substitution of Ala485 and Thr486 to Leu and Pro only, increased instead the affinity of GSH2 for Ser (km 0,23) as a substrate, while affinity to Gly was preserved (km 0,12). This provides a new biosynthetic pathway for hydroxymethyl glutathione, which is known to be synthesized from glutathione and Ser in a reaction catalysed by carboxypeptidase Y. The reported findings provide further insight into how specific amino acids positioned in the GSH2 active site facilitate the recognition of different amino acid substrates, furthermore they support the evolutionary theory that homoglutathione synthetase evolved from glutathione synthetase by a single gene duplication event.
doi:10.1371/journal.pone.0046580
PMCID: PMC3473041  PMID: 23091597
8.  Outcomes after Induction Failure in Childhood Acute Lymphoblastic Leukemia 
The New England Journal of Medicine  2012;366(15):1371-1381.
BACKGROUND
Failure of remission-induction therapy is a rare but highly adverse event in children and adolescents with acute lymphoblastic leukemia (ALL).
METHODS
We identified induction failure, defined by the persistence of leukemic blasts in blood, bone marrow, or any extramedullary site after 4 to 6 weeks of remission-induction therapy, in 1041 of 44,017 patients (2.4%) 0 to 18 years of age with newly diagnosed ALL who were treated by a total of 14 cooperative study groups between 1985 and 2000. We analyzed the relationships among disease characteristics, treatments administered, and outcomes in these patients.
RESULTS
Patients with induction failure frequently presented with high-risk features, including older age, high leukocyte count, leukemia with a T-cell phenotype, the Philadelphia chromosome, and 11q23 rearrangement. With a median follow-up period of 8.3 years (range, 1.5 to 22.1), the 10-year survival rate (±SE) was estimated at only 32±1%. An age of 10 years or older, T-cell leukemia, the presence of an 11q23 rearrangement, and 25% or more blasts in the bone marrow at the end of induction therapy were associated with a particularly poor outcome. High hyperdiploidy (a modal chromosome number >50) and an age of 1 to 5 years were associated with a favorable outcome in patients with precursor B-cell leukemia. Allogeneic stem-cell transplantation from matched, related donors was associated with improved outcomes in T-cell leukemia. Children younger than 6 years of age with precursor B-cell leukemia and no adverse genetic features had a 10-year survival rate of 72±5% when treated with chemotherapy only.
CONCLUSIONS
Pediatric ALL with induction failure is highly heterogeneous. Patients who have T-cell leukemia appear to have a better outcome with allogeneic stem-cell transplantation than with chemotherapy, whereas patients who have precursor B-cell leukemia without other adverse features appear to have a better outcome with chemotherapy. (Funded by Deutsche Krebshilfe and others.)
doi:10.1056/NEJMoa1110169
PMCID: PMC3374496  PMID: 22494120
9.  Clinical Significance of Aberrant DNA Methylation in Childhood Acute Lymphoblastic Leukemia 
Leukemia Research  2011;35(10):1345-1349.
Methylation profile was analyzed in ninety-five patients with childhood acute lymphoblastic leukemia (ALL). Methylation of both MGMT and p16 genes were associated with higher age (p=0.01 and p=0.03, respectively). Methylation of both p15 and SHP1 genes occurred more frequently in T-ALL than in precursor B-ALL (p=0.02 and p=0.01, respectively). In contrast, methylation of the DAPK gene was more frequent in precursor B-ALL (p=0.01). Patients with methylation of multiple genes more likely had T cell phenotype, and are classified as medium/high risk (p=0.004 and p=0.03, respectively). These results suggest that methylation status is associated with clinicopathological features in childhood ALL.
doi:10.1016/j.leukres.2011.04.015
PMCID: PMC3258450  PMID: 21592569
methylation; multiple genes; ALL
10.  Variation in CDKN2A at 9p21.3 influences childhood acute lymphoblastic leukemia risk 
Nature genetics  2010;42(6):492-494.
Using data from a genome-wide association study of 907 individuals with childhood acute lymphoblastic leukemia (cases) and 2,398 controls and with validation in samples totaling 2,386 cases and 2,419 controls, we have shown that common variation at 9p21.3 (rs3731217, intron 1 of CDKN2A) influences acute lymphoblastic leukemia risk (odds ratio = 0.71, P = 3.01 × 10−11), irrespective of cell lineage.
doi:10.1038/ng.585
PMCID: PMC3434228  PMID: 20453839
11.  Isolation of the phe-operon from G. stearothermophilus comprising the phenol degradative meta-pathway genes and a novel transcriptional regulator 
BMC Microbiology  2008;8:197.
Background
Geobacillus stearothermophilus is able to utilize phenol as a sole carbon source. A DNA fragment encoding a phenol hydroxylase catalyzing the first step in the meta-pathway has been isolated previously. Based on these findings a PCR-based DNA walk was performed initially to isolate a catechol 2,3-dioxygenase for biosensoric applications but was continued to elucidate the organisation of the genes encoding the proteins for the metabolization of phenol.
Results
A 20.2 kb DNA fragment was isolated as a result of the DNA walk. Fifteen open reading frames residing on a low-copy megaplasmid were identified. Eleven genes are co-transcribed in one polycistronic mRNA as shown by reverse transcription-PCR. Ten genes encode proteins, that are directly linked with the meta-cleavage pathway. The deduced amino acid sequences display similarities to a two-component phenol hydroxylase, a catechol 2,3-dioxygenase, a 4-oxalocrotonate tautomerase, a 2-oxopent-4-dienoate hydratase, a 4-oxalocrotonate decarboxylase, a 4-hydroxy-2-oxovalerate aldolase, an acetaldehyde dehydrogenase, a plant-type ferredoxin involved in the reactivation of extradiol dioxygenases and a novel regulatory protein. The only enzymes missing for the complete mineralization of phenol are a 2-hydroxymuconic acid-6-semialdehyde hydrolase and/or 2-hydroxymuconic acid-6-semialdehyde dehydrogenase.
Conclusion
Research on the bacterial degradation of aromatic compounds on a sub-cellular level has been more intensively studied in gram-negative organisms than in gram-positive bacteria. Especially regulatory mechanisms in gram-positive (thermophilic) prokaryotes remain mostly unknown. We isolated the first complete sequence of an operon from a thermophilic bacterium encoding the meta-pathway genes and analyzed the genetic organization. Moreover, the first transcriptional regulator of the phenol metabolism in gram-positive bacteria was identified. This is a first step to elucidate regulatory mechanisms that are likely to be distinct from modes described for gram-negative bacteria.
doi:10.1186/1471-2180-8-197
PMCID: PMC2590616  PMID: 19014555

Results 1-11 (11)