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  • 1
    Online Resource
    Online Resource
    Validation and utilization of NGS-based HEMEaccuTest panel and analysis software for hematological malignancies.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Global Oncology Vol. 5, No. suppl ( 2019-10-07), p. 29-29
    Details
    In: Journal of Global Oncology, American Society of Clinical Oncology (ASCO), Vol. 5, No. suppl ( 2019-10-07), p. 29-29
    Abstract: 29 Background: Hematological malignancies are forms of cancer that originates in blood-forming tissue, such as bone marrow, or in the cells of the immune system. Detection of genetic alteration in hematological malignancies are increasingly important because of diverse variants associated with classification and diagnosis of subtypes, and prognostic and therapeutic-response prediction. Next-generation sequencing (NGS) is a powerful technology to simultaneously analyze multiple genes to identify clinically well-described variants, as well as rare variants related to hematological malignancies for clinical diagnostics. Methods: We developed the targeted NGS panel (HEMEaccuTest) and automatic analysis software (NGeneAnalySys) for estimating pathogenicity of genetic variants related to hematological malignancies. HEMEaccuTest covers entire coding region of 108 genes that have putatively known for associations with the diseases according to the WHO, NCCN and ELN guidelines. The diagnostic utility of HEMEaccuTest and NGeneAnalySys were validated using reference materials and clinical specimens. Results: The results showed that pathogenic variants were effectively detected with an average coverage depth of 600X and a minimum coverage depth of 100X. It demonstrated an excellent limit of detection, with 100% sensitivity for SNVs at 2% VAF and for indel at 4% VAF. In addition, the analytical sensitivity, specificity and precision of the panel were higher compared to conventional methods such as Sanger sequencing, FISH, and real-time PCR. Noticeably, the approximately 300-bp-size insertions of FLT3-ITD was efficiently detected by a simulating algorithm. Conclusions: This analytical validation study demonstrated that HEMEaccuTest and NGeneAnalySys can be an excellent and useful tool for disease definition and therapeutic strategy in hematological malignancies. NGeneAnalySys provides the evidence-based categorization and clinical interpretation supported by Tier classification (Therapeutic, Prognostic, Diagnostic) of professional guidelines (ACMG/AMP, AMP/ASCO/CAP. etc).
    Type of Medium: Online Resource
    ISSN: 2378-9506
    URL: Article
    DOI: 10.1200/JGO.2019.5.suppl.29
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 3018917-2
    detail.hit.zdb_id: 2840981-4
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  • 2
    Online Resource
    Online Resource
    Validation and utilization of NGS based HEMEaccuTest panel and analysis software for hematological malignancies.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. e14606-e14606
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. e14606-e14606
    Abstract: e14606 Background: Hematological malignancies are forms of cancer that originate in blood-forming tissue, such as bone marrow, or in the cells of the immune system. Hematological malignancies can be classified as leukemias, lymphomas, multiple myeloma (MM), myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) based on the cell type where they originate. Detection of genetic alteration in hematological malignancies is increasingly important because of diverse variants associated with classification and diagnosis of subtypes, and prognostic and therapeutic-response prediction. Next-generation sequencing (NGS) is an advanced technology to simultaneously analyze multiple genes to identify clinically well-described variants, as well as rare variants related for clinical diagnostics. Methods: We developed the targeted NGS panel, HEMEaccuTest and automatic analysis software, NGeneAnalySys for estimating the relative pathogenicity of hematological malignancies. HEMEaccuTest covers about the 310 kilobases with exon regions of 108 genes that have putatively known for associations with the diseases according to the WHO, NCCN and ELN guidelines. the diagnostic utility of the panel and software were validated using genotype-known reference materials and clinical specimens. Results: The results showed that pathogenic variants were effectively detected with an average coverage depth of 600x and a minimum coverage depth of 100x. It demonstrated an excellent limit of detection, with 100% sensitivity for SNVs at 2% VAF and for indel at 4% VAF. In addition, the analytical sensitivity and specificity of the panel were high in a comparison to conventional methods such as Sanger sequencing, FISH, and real-time PCR. Noticeably, the approximately 300-bp-size insertions of FLT3-ITD was efficiently detected by an excellent simulating algorithm of NGeneAnalySys. Conclusions: This analytical validation demonstrated that HEMEaccuTest and NGeneAnalySys can be an excellent tool for disease definition and therapeutic strategy in hematological malignancies.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.e14606
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
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  • 3
    Online Resource
    Online Resource
    Evaluation of a Targeted Next-generation Sequencing Assay for BRCA Mutation Screening in Clinical Samples
    Laboratory Medicine Online ; 2021
    In:  Laboratory Medicine Online Vol. 11, No. 4 ( 2021-10-01), p. 283-289
    Details
    In: Laboratory Medicine Online, Laboratory Medicine Online, Vol. 11, No. 4 ( 2021-10-01), p. 283-289
    Type of Medium: Online Resource
    ISSN: 2093-6338
    URL: Article
    DOI: 10.47429/lmo.2021.11.4.283
    Language: English
    Publisher: Laboratory Medicine Online
    Publication Date: 2021
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  • 4
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    Calcium homeostasis is required for contact‐dependent helical and sinusoidal tip growth in Candida albicans hyphae
    Wiley ; 2009
    In:  Molecular Microbiology Vol. 71, No. 5 ( 2009-03), p. 1155-1164
    Details
    In: Molecular Microbiology, Wiley, Vol. 71, No. 5 ( 2009-03), p. 1155-1164
    Abstract: Hyphae of the dimorphic fungus, Candida albicans , exhibit directional tip responses when grown in contact with surfaces. On hard surfaces or in liquid media, the trajectory of hyphal growth is typically linear, with tip re‐orientation events limited to encounters with topographical features (thigmotropism). In contrast, when grown on semisolid surfaces, the tips of C. albicans hyphae grow in an oscillatory manner to form regular two‐dimensional sinusoidal curves and three‐dimensional helices. We show that, like thigmotropism, initiation of directional tip oscillation in C. albicans hyphae is severely attenuated when Ca 2+ homeostasis is perturbed. Chelation of extracellular Ca 2+ or deletion of the Ca 2+ transporters that modulate cytosolic [Ca 2+ ] (Mid1, Cch1 or Pmr1) did not affect hyphal length but curve formation was severely reduced in mid1 Δ and cch1 Δ and abolished in pmr1 Δ. Sinusoidal hypha morphology was altered in the mid1 Δ, chs3 Δ and heterozygous pmr1 Δ/ PMR1 strains. Treatments that affect cell wall integrity, changes in surface mannosylation or the provision of additional carbon sources had significant but less pronounced effects on oscillatory growth. The induction of two‐ and three‐dimensional sinusoidal growth in wild‐type C. albicans hyphae is therefore the consequence of mechanisms that involve Ca 2+ influx and signalling rather than gross changes in the cell wall architecture.
    Type of Medium: Online Resource
    ISSN: 0950-382X , 1365-2958
    URL: Issue
    URL: Article
    DOI: 10.1111/mmi.2009.71.issue-5
    DOI: 10.1111/j.1365-2958.2008.06592.x
    Language: English
    Publisher: Wiley
    Publication Date: 2009
    detail.hit.zdb_id: 1501537-3
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  • 5
    Online Resource
    Online Resource
    Isolation and functional characterization of Sporothrix schenckii ROT2, the encoding gene for the endoplasmic reticulum glucosidase II
    Elsevier BV ; 2012
    In:  Fungal Biology Vol. 116, No. 8 ( 2012-08), p. 910-918
    Details
    In: Fungal Biology, Elsevier BV, Vol. 116, No. 8 ( 2012-08), p. 910-918
    Type of Medium: Online Resource
    ISSN: 1878-6146
    URL: Article
    DOI: 10.1016/j.funbio.2012.06.002
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2012
    detail.hit.zdb_id: 2532164-X
    SSG: 12
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  • 6
    Online Resource
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    Elevated Cell Wall Chitin in Candida albicans Confers Echinocandin Resistance In Vivo
    American Society for Microbiology ; 2012
    In:  Antimicrobial Agents and Chemotherapy Vol. 56, No. 1 ( 2012-01), p. 208-217
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 56, No. 1 ( 2012-01), p. 208-217
    Abstract: Candida albicans cells with increased cell wall chitin have reduced echinocandin susceptibility in vitro . The aim of this study was to investigate whether C. albicans cells with elevated chitin levels have reduced echinocandin susceptibility in vivo . BALB/c mice were infected with C. albicans cells with normal chitin levels and compared to mice infected with high-chitin cells. Caspofungin therapy was initiated at 24 h postinfection. Mice infected with chitin-normal cells were successfully treated with caspofungin, as indicated by reduced kidney fungal burdens, reduced weight loss, and decreased C. albicans density in kidney lesions. In contrast, mice infected with high-chitin C. albicans cells were less susceptible to caspofungin, as they had higher kidney fungal burdens and greater weight loss during early infection. Cells recovered from mouse kidneys at 24 h postinfection with high-chitin cells had 1.6-fold higher chitin levels than cells from mice infected with chitin-normal cells and maintained a significantly reduced susceptibility to caspofungin when tested in vitro . At 48 h postinfection, caspofungin treatment induced a further increase in chitin content of C. albicans cells harvested from kidneys compared to saline treatment. Some of the recovered clones had acquired, at a low frequency, a point mutation in FKS1 resulting in a S645Y amino acid substitution, a mutation known to confer echinocandin resistance. This occurred even in cells that had not been exposed to caspofungin. Our results suggest that the efficacy of caspofungin against C. albicans was reduced in vivo due to either elevation of chitin levels in the cell wall or acquisition of FKS1 point mutations.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.00683-11
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2012
    detail.hit.zdb_id: 1496156-8
    SSG: 12
    SSG: 15,3
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  • 7
    Online Resource
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    Caspofungin Treatment of Aspergillus fumigatus Results in ChsG-Dependent Upregulation of Chitin Synthesis and the Formation of Chitin-Rich Microcolonies
    American Society for Microbiology ; 2015
    In:  Antimicrobial Agents and Chemotherapy Vol. 59, No. 10 ( 2015-10), p. 5932-5941
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 59, No. 10 ( 2015-10), p. 5932-5941
    Abstract: Treatment of Aspergillus fumigatus with echinocandins such as caspofungin inhibits the synthesis of cell wall β-1,3-glucan, which triggers a compensatory stimulation of chitin synthesis. Activation of chitin synthesis can occur in response to sub-MICs of caspofungin and to CaCl 2 and calcofluor white (CFW), agonists of the protein kinase C (PKC), and Ca 2+ -calcineurin signaling pathways. A. fumigatus mutants with the chs gene (encoding chitin synthase) deleted (Δ Afchs ) were tested for their response to these agonists to determine the chitin synthase enzymes that were required for the compensatory upregulation of chitin synthesis. Only the Δ AfchsG mutant was hypersensitive to caspofungin, and all other Δ Afchs mutants tested remained capable of increasing their chitin content in response to treatment with CaCl 2 and CFW and caspofungin. The resulting increase in cell wall chitin content correlated with reduced susceptibility to caspofungin in the wild type and all Δ Afchs mutants tested, with the exception of the Δ AfchsG mutant, which remained sensitive to caspofungin. In vitro exposure to the chitin synthase inhibitor, nikkomycin Z, along with caspofungin demonstrated synergistic efficacy that was again Af ChsG dependent. Dynamic imaging using microfluidic perfusion chambers demonstrated that treatment with sub-MIC caspofungin resulted initially in hyphal tip lysis. However, thickened hyphae emerged that formed aberrant microcolonies in the continued presence of caspofungin. In addition, intrahyphal hyphae were formed in response to echinocandin treatment. These in vitro data demonstrate that A. fumigatus has the potential to survive echinocandin treatment in vivo by Af ChsG-dependent upregulation of chitin synthesis. Chitin-rich cells may, therefore, persist in human tissues and act as the focus for breakthrough infections.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.00862-15
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2015
    detail.hit.zdb_id: 1496156-8
    SSG: 12
    SSG: 15,3
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  • 8
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    Crosstalk between the calcineurin and cell wall integrity pathways prevents chitin overexpression in Candida albicans
    The Company of Biologists ; 2021
    In:  Journal of Cell Science Vol. 134, No. 24 ( 2021-12-15)
    Details
    In: Journal of Cell Science, The Company of Biologists, Vol. 134, No. 24 ( 2021-12-15)
    Abstract: Echinocandins such as caspofungin are frontline antifungal drugs that compromise β-1,3 glucan synthesis in the cell wall. Recent reports have shown that fungal cells can resist killing by caspofungin by upregulation of chitin synthesis, thereby sustaining cell wall integrity (CWI). When echinocandins are removed, the chitin content of cells quickly returns to basal levels, suggesting that there is a fitness cost associated with having elevated levels of chitin in the cell wall. We show here that simultaneous activation of the calcineurin and CWI pathways generates a subpopulation of Candida albicans yeast cells that have supra-normal chitin levels interspersed throughout the inner and outer cell wall, and that these cells are non-viable, perhaps due to loss of wall elasticity required for cell expansion and growth. Mutations in the Ca2+-calcineurin pathway prevented the formation of these non-viable supra-high chitin cells by negatively regulating chitin synthesis driven by the CWI pathway. The Ca2+-calcineurin pathway may therefore act as an attenuator that prevents the overproduction of chitin by coordinating both chitin upregulation and negative regulation of the CWI signaling pathway. This article has an associated First Person interview with the first author of the paper.
    Type of Medium: Online Resource
    ISSN: 0021-9533 , 1477-9137
    URL: Article
    DOI: 10.1242/jcs.258889
    Language: English
    Publisher: The Company of Biologists
    Publication Date: 2021
    detail.hit.zdb_id: 219171-4
    detail.hit.zdb_id: 1483099-1
    SSG: 12
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  • 9
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    Image_2.JPEG
    Frontiers Media SA ; 2019
    In:  Frontiers in Microbiology Vol. 10 ( 2019-8-6)
    Details
    In: Frontiers in Microbiology, Frontiers Media SA, Vol. 10 ( 2019-8-6)
    Type of Medium: Online Resource
    ISSN: 1664-302X
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fmicb.2019.01800
    DOI: 10.3389/fmicb.2019.01800.s001
    DOI: 10.3389/fmicb.2019.01800.s002
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2019
    detail.hit.zdb_id: 2587354-4
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  • 10
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    Cell Wall Remodeling Enzymes Modulate Fungal Cell Wall Elasticity and Osmotic Stress Resistance
    American Society for Microbiology ; 2015
    In:  mBio Vol. 6, No. 4 ( 2015-09)
    Details
    In: mBio, American Society for Microbiology, Vol. 6, No. 4 ( 2015-09)
    Abstract: The C. albicans cell wall is the first line of defense against external insults, the site of immune recognition by the host, and an attractive target for antifungal therapy. Its tensile strength is conferred by a network of cell wall polysaccharides, which are remodeled in response to growth conditions and environmental stress. However, little is known about how cell wall elasticity is regulated and how it affects adaptation to stresses such as sudden changes in osmolarity. We show that elasticity is critical for survival under conditions of osmotic shock, before stress signaling pathways have time to induce gene expression and drive glycerol accumulation. Critical cell wall remodeling enzymes control cell wall flexibility, and its regulation is strongly dependent on host nutritional inputs. We also demonstrate an entirely new level of cell wall dynamism, where significant architectural changes and structural realignment occur within seconds of an osmotic shock.
    Type of Medium: Online Resource
    ISSN: 2161-2129 , 2150-7511
    URL: Article
    DOI: 10.1128/mBio.00986-15
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2015
    detail.hit.zdb_id: 2557172-2
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