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  1. Article ; Online: Simplified Mass Spectrometric Analysis of Ceramides using a Common Collision Energy.

    Picklo, Matthew J / Hanson, Benjamin K / Bukowski, Michael R

    Lipids

    2019  Volume 54, Issue 8, Page(s) 471–477

    Abstract: Ceramides (CER) are biologically active sphingolipid precursors that are mechanistically linked to several pathogenic states including cancer, insulin resistance, and neurodegeneration. CER are commonly quantified through mass spectrometry-based methods ... ...

    Abstract Ceramides (CER) are biologically active sphingolipid precursors that are mechanistically linked to several pathogenic states including cancer, insulin resistance, and neurodegeneration. CER are commonly quantified through mass spectrometry-based methods founded upon a product ion scan (PIS) in positive mode to produce a characteristic m/z 264 ion. The ionization efficiency (IE) of CER species decreases with an increase in CER mass, thus quantitation of CER typically involves application of mass-dependent response factors (RF) for each CER species. In this work, we observed that the RF were systematically dependent on the number of fatty acid acyl carbons and the collision energy (CE) used to generate the m/z 264 ion. Using these complimentary trends, we determined an "isosbestic" CE where the RF for all CER species were equivalent, allowing for CER quantitation without postcollection correction factors. A comparison of this common CE/common RF method to the multiple RF method demonstrated good agreement between the two methods. Use of the common CE/common RF method will reduce data processing and reduce the use of multiple CER species standards.
    MeSH term(s) Animals ; Calibration ; Ceramides/analysis ; Ceramides/blood ; Liver/chemistry ; Male ; Mice ; Mice, Inbred C57BL ; Solvents/chemistry ; Spectrometry, Mass, Electrospray Ionization
    Chemical Substances Ceramides ; Solvents
    Language English
    Publishing date 2019-07-24
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 241539-2
    ISSN 1558-9307 ; 0024-4201
    ISSN (online) 1558-9307
    ISSN 0024-4201
    DOI 10.1002/lipd.12179
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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  2. Article ; Online: R-Loop Accumulation in Spliceosome Mutant Leukemias Confers Sensitivity to PARP1 Inhibition by Triggering Transcription-Replication Conflicts.

    Liu, Zhiyan Silvia / Sinha, Sayantani / Bannister, Maxwell / Song, Axia / Arriaga-Gomez, Erica / McKeeken, Alexander J / Bonner, Elizabeth A / Hanson, Benjamin K / Sarchi, Martina / Takashima, Kouhei / Zong, Dawei / Corral, Victor M / Nguyen, Evan / Yoo, Jennifer / Chiraphapphaiboon, Wannasiri / Leibson, Cassandra / McMahon, Matthew C / Rai, Sumit / Swisher, Elizabeth M /
    Sachs, Zohar / Chatla, Srinivas / Stirewalt, Derek L / Deeg, H Joachim / Skorski, Tomasz / Papapetrou, Eirini P / Walter, Matthew J / Graubert, Timothy A / Doulatov, Sergei / Lee, Stanley C / Nguyen, Hai Dang

    Cancer research

    2023  Volume 84, Issue 4, Page(s) 577–597

    Abstract: RNA splicing factor (SF) gene mutations are commonly observed in patients with myeloid malignancies. Here we showed that SRSF2- and U2AF1-mutant leukemias are preferentially sensitive to PARP inhibitors (PARPi), despite being proficient in homologous ... ...

    Abstract RNA splicing factor (SF) gene mutations are commonly observed in patients with myeloid malignancies. Here we showed that SRSF2- and U2AF1-mutant leukemias are preferentially sensitive to PARP inhibitors (PARPi), despite being proficient in homologous recombination repair. Instead, SF-mutant leukemias exhibited R-loop accumulation that elicited an R-loop-associated PARP1 response, rendering cells dependent on PARP1 activity for survival. Consequently, PARPi induced DNA damage and cell death in SF-mutant leukemias in an R-loop-dependent manner. PARPi further increased aberrant R-loop levels, causing higher transcription-replication collisions and triggering ATR activation in SF-mutant leukemias. Ultimately, PARPi-induced DNA damage and cell death in SF-mutant leukemias could be enhanced by ATR inhibition. Finally, the level of PARP1 activity at R-loops correlated with PARPi sensitivity, suggesting that R-loop-associated PARP1 activity could be predictive of PARPi sensitivity in patients harboring SF gene mutations. This study highlights the potential of targeting different R-loop response pathways caused by spliceosome gene mutations as a therapeutic strategy for treating cancer.
    Significance: Spliceosome-mutant leukemias accumulate R-loops and require PARP1 to resolve transcription-replication conflicts and genomic instability, providing rationale to repurpose FDA-approved PARP inhibitors for patients carrying spliceosome gene mutations.
    MeSH term(s) Humans ; Spliceosomes/genetics ; R-Loop Structures ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; DNA Repair ; Leukemia/drug therapy ; Leukemia/genetics ; RNA Splicing Factors/genetics ; Poly (ADP-Ribose) Polymerase-1/genetics
    Chemical Substances Poly(ADP-ribose) Polymerase Inhibitors ; RNA Splicing Factors ; PARP1 protein, human (EC 2.4.2.30) ; Poly (ADP-Ribose) Polymerase-1 (EC 2.4.2.30)
    Language English
    Publishing date 2023-11-13
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-23-3239
    Database MEDical Literature Analysis and Retrieval System OnLINE

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