Palmlangballe5343

This study aimed to verify whether there is whole-body (WB) count loss due to dead time of gamma camera when high amount of 131I is administered to patients. Planar views of a phantom containing 5751 MBq of 131I were acquired at 24-h intervals for 68 d. Eighty-two patients ≤21 y old were given diagnostic activity (74 MBq) followed by therapeutic activity (1110-5772 MBq). WB scans of patients were acquired at 2 h after diagnostic and therapeutic activity administration. Count loss in patients and phantom were compared. In phantom, there was no count loss up to 139 MBq. At maximum activity of 5751 MBq 131I, the loss was 46%. In patients, the average WB count loss was insignificant after the administration of therapeutic activity. Count loss due to dead time in phantom differed significantly from patient results that can probably be explained by the distribution of activity over a large area in vivo. © The Author(s) 2020. Published by Oxford University Press. BGB-8035 All rights reserved. For Permissions, please email journals.permissions@oup.com.BACKGROUND Glioblastoma is associated with poor prognosis and high mortality. Although the use of first-line temozolomide can reduce tumor growth, therapy-induced stress drives stem cells out of quiescence, leading to chemo-resistance and glioblastoma recurrence. The Sp1 transcription factor is known to protect glioblastoma cells against temozolomide; however, how tumor cells hijack this factor to gain resistance to therapy is not known. METHODS Sp1 acetylation in temozolomide-resistant cells and stem-like tumorspheres was analyzed by immunoprecipitation and immunoblotting experiments. Effects of the HDAC/Sp1 axis on malignant growth were examined using cell proliferation-related assays and in vivo experiments. Furthermore, integrative analysis of gene expression with ChIP-seq and the recurrent glioblastoma omics data were also used to further determine the target genes of the HDAC/Sp1 axis. RESULTS We identified Sp1 as a novel substrate of HDAC6, and observed that the HDAC1/2/6/Sp1 pathway promotes self-renewal of malignancy by upregulating BMI1 and hTERT, as well as by regulating G2/M progression and DNA repair via alteration of the transcription of various genes. Importantly, HDAC1/2/6/Sp1 activation is associated with poor clinical outcome in both glioblastoma and low-grade gliomas. However, treatment with azaindolylsulfonamide, a potent HDAC6 inhibitor with partial efficacy against HDAC1/2, induced G2/M arrest and senescence in both temozolomide-resistant cells and stem-like tumorspheres. CONCLUSIONS Our study uncovers a previously unknown regulatory mechanism in which the HDAC6-Sp1 axis induces cell division and maintains the stem cell population to fuel tumor growth and therapeutic resistance. © The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.Caveolae are an abundant and characteristic surface feature of many vertebrate cells. The uniform shape of caveolae is characterized by a bulb with consistent curvature connected to the plasma membrane (PM) by a neck region with opposing curvature. Caveolae act in mechanoprotection by flattening in response to increased membrane tension, and their disassembly influences the lipid organization of the PM. Here, we review evidence for caveolae as a specialized lipid domain and speculate on mechanisms that link changes in caveolar shape and/or protein composition to alterations in specific lipid species. We propose that high membrane curvature in specific regions of caveolae can enrich specific lipid species, with consequent changes in their localization upon caveolar flattening. In addition, we suggest how changes in the association of lipid-binding caveolar proteins upon flattening of caveolae could allow release of specific lipids into the bulk PM. We speculate that the caveolae-lipid system has evolved to function as a general stress-sensing and stress-protective membrane domain. © 2020 Parton et al.Filopodia are actin-rich protrusions important for sensing and responding to the extracellular environment, but the repertoire of factors required for filopodia formation is only partially understood. Jarsch et al. (2020. J. Cell. Biol. https//doi.org/10.1083/jcb.201909178) combine an in vitro system of filopodia biogenesis with a phage display screen to show that SNX9 drives filopodial assembly. © 2020 Lebek and Campellone.In mitotic cells, DNA damage induces temporary G2 arrest via inhibitory Cdk1 phosphorylation. In contrast, fully grown G2-stage oocytes readily enter M phase immediately following chemical induction of DNA damage in vitro, indicating that the canonical immediate-response G2/M DNA damage response (DDR) may be deficient. Senataxin (Setx) is involved in RNA/DNA processing and maintaining genome integrity. Here we find that mouse oocytes deleted of Setx accumulate DNA damage when exposed to oxidative stress in vitro and during aging in vivo, after which, surprisingly, they undergo G2 arrest. Moreover, fully grown wild-type oocytes undergo G2 arrest after chemotherapy-induced in vitro damage if an overnight delay is imposed following damage induction. Unexpectedly, this slow-evolving DDR is not mediated by inhibitory Cdk1 phosphorylation but by APC-Cdh1-mediated proteolysis of the Cdk1 activator, cyclin B1, secondary to increased Cdc14B-dependent APC-Cdh1 activation and reduced Emi1-dependent inhibition. Thus, oocytes are unable to respond immediately to DNA damage, but instead mount a G2/M DDR that evolves slowly and involves a phosphorylation-independent proteolytic pathway. © 2020 Subramanian et al.The tumor cell-selective killing activity of the adenovirus type 2 early region 4 ORF4 (E4orf4) protein is poorly defined at the molecular level. Here, we show that the tumoricidal effect of E4orf4 is typified by changes in nuclear dynamics that depend on its interaction with the polarity protein Par3 and actomyosin contractility. Mechanistically, E4orf4 induced a high incidence of nuclear bleb formation and repetitive nuclear ruptures, which promoted nuclear efflux of E4orf4 and loss of nuclear integrity. This process was regulated by nucleocytoskeletal connections, Par3 clustering proximal to nuclear lamina folds, and retrograde movement of actin bundles that correlated with nuclear ruptures. Significantly, Par3 also regulated the incidence of spontaneous nuclear ruptures facilitated by the downmodulation of lamins. This work uncovered a novel role for Par3 in controlling the actin-dependent forces acting on the nuclear envelope to remodel nuclear shape, which might be a defining feature of tumor cells that is harnessed by E4orf4.