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Reclassification of Five BRCA1/2 Variants with Unknown Significance Using Complex Functional Study
Anikó Bozsik,János Papp,Vince Kornél Grolmusz,Attila Patócs,Edit Oláh,Henriett Butz 대한암학회 2022 Cancer Research and Treatment Vol.54 No.4
Purpose While BRCA1/2 genes are commonly investigated, variants of unknown significance (VUS) and variants with potential splice effect are still being detected and they represent a substantial challenge in genetic counseling and therapy. Materials and Methods Out of genetically tested 3,568 hereditary breast and ovarian cancer probands five, functionally not investigated variants with potential splice-modifying effect were subjected to functional characterization. Transcript-level analysis on peripheral blood-derived RNA of the carriers was performed to test aberrant splicing. The completeness of the aberrant splicing event was also studied, existence and extent of nonsense-mediated decay was even addressed. Clinical and phenotype data, pedigree and co-segregation analyses were also done. Locus-specific loss of heterozygosity (LOH) in tumor tissues was additionally tested. Results In case of the BRCA1:c.4484+4dupA and the BRCA1:c.5407-10G>A variants functional results allowed us to reclassify them from VUS into likely pathogenic category. BRCA1:c.4358-31A>C, by producing incomplete aberrant splicing, was highlighted as strong VUS, but in lack of other supporting evidence, re-categorization was not possible. The likely pathogenic assertion of previously not reported BRCA2:c.8487G>T was reinforced based on its spliceogenic property and tumor LOH, while BRCA2:c.793G>A failed to present aberrant splicing in spite of suggestive predictions, which altered its original VUS evaluation into likely benign class. Conclusion We presented molecular and clinical evidence for reclassification of four out of five BRCA1/2 variants. Both up- and down-classification harbour important clinical significance. Patients carrying re-classified pathogenic variants in the future will not be dropped out from medical surveillance, preventive measures, treatment and predictive family screening in relatives at risk.
( George A. Brooks ),( Herve Dubouchaud ),( Marcia Brown ),( James P. Sicurello ),( C. Eric Butz ) 한국스포츠정책과학원(구 한국스포츠개발원) 1999 International Journal of Applied Sports Sciences Vol.11 No.1
To evaluate the potential role of mitochondrial lactate dehydrogenase (LDH) in tissue lactate clearance and oxidation in vivo, isolated rat liver, cardiac, and skeletal muscle mitochondria were incubated with lactate, pyruvate, glutamate, and succinate. As well, a-cyano-4-hydroxycin-namate (CINN), a known monocarboxylate transport inhibitor, and oxamate, a known LDH inhibitor were used. Mitochondria readily oxidized pyruvate and lactate, with similar state 3 and 4 respiratory rates, respiratory control (state 3ystate 4), and ADPyO ratios. With lactate or pyruvate as substrates, a-cyano-4-hydroxycinnamate blocked the respira-tory response to added ADP, but the block was bypassed by addition of glutamate (complex I-linked) and succinate (complex 11 linked) substrates. Oxamate increased pyruvate (`10-40%), but blocked lanctate oxidation. Gel electrophoresis and electron microscopy indicated LDH isoenzyme distribution patterns to display tissue specificity, but the LDH isoenzyme patterns in isolated mitochondria were distinct from those in surrounding cell compartments. In heart, LDH-1 (H4) was concentrated in mitochondria whereas LDH-5 (M4) was present in both mitochondria and surrounding cytosol and organelles. LDH-5 predominated in liver but was more abundant in mitochondria than elsewhere. Because lactate exceeds cytosolic pyruvate concentration by an order of magnitude, we conclude that lactate is the predominant monocarboxylate oxidized by mitochondria in vivo. Mammalian liver and striated muscle mitochondria can oxidize exogenous lactate because of an internal LDH pool that facilitates lactate oxidation.
Aging and Annealing Effects on the Magnetic Ordering Induced by Proton Irradiation in Graphite
K.-H. Han,D. Spemann,H. Schmidt,M. Diaconu,P. Esquinazi,T. Butz 한국물리학회 2006 THE JOURNAL OF THE KOREAN PHYSICAL SOCIETY Vol.48 No.6
Aging and annealing effects on the topography and the magnetic ordering induced by proton irradiation in highly oriented graphite samples have been studied with atomic force and magnetic force (MFM) microscopy. Clear changes in the magnetic and the topographic images after keeping the samples several months at room temperature and annealing at 1000 C in vacuum are observed. These changes appear to be related to the diffusion of hydrogen in graphite. Clear differences are also observed in the magnetic images made with different magnetic probes by using MFM.
Biomechanical and histological behavior of zirconia implants: an experiment in the rat
Kohal, Ralf J.,Wolkewitz, Martin,Hinze, Marc,Han, Jung-Suk,Bä,chle, Maria,Butz, Frank Blackwell Publishing Ltd 2009 Clinical oral implants research Vol.20 No.4
<P>Abstract</P><P>Objective</P><P>This study aimed at evaluating the integration of zirconia implants in a rat femur model.</P><P>Material and methods</P><P>Zirconia implants with two distinct surface topographies were compared with titanium implants with similar topographies. Titanium and zirconia implants were placed into the femurs of 42 male Sprague–Dawley rats. Four groups of implants were utilized: machined zirconia implants, zirconia implants with a rough surface, machined titanium implants, and titanium implants with an electrochemically roughened surface. After a healing period of 28 days, the load-bearing capacity between the bone and the implant surface was evaluated by a push-in test. Additionally, after a healing period of 14 and 28 days, respectively, bone tissue specimens containing the implants were processed and histologically analyzed.</P><P>Results</P><P>The mean mineralized bone-to-implant contact showed the highest values after 14 and 28 days for the rough surfaces (titanium: 36%/45%; zirconia: 45%/59%). Also, the push-in test showed higher values for the textured implant surfaces, with no statistical significance between titanium (34 N) and zirconia (45.8 N).</P><P>Conclusions</P><P>Within the limits of the animal investigation presented, it was concluded that all tested zirconia and titanium implant surfaces were biocompatible and osseoconductive. The presented surface modification of zirconia implants showed no difference regarding the histological and biomechanical results compared with an established electrochemically modified titanium implant surface.</P>