Control of the eukaryotic G2/M transition by CDC2/CYCLINB is tightly regulated by protein-protein interactions, protein phosphorylations, and nuclear localization of CDC2/CYCLINB. We previously reported a screen, in Aspergillus nidulans, for extragenic suppressors of nimX2 cdc2 that resulted in the identification of the cold-sensitive snxA1 mutation. We demonstrate here that snxA1 suppresses defects in regulators of the CDK1 mitotic induction pathway, including nimX2 cdc2 , nimE6 cyclinB , and nimT23 cdc25 , but does not suppress G2-arresting nimA1/nimA5 mutations, the S-arresting nimE10 cyclinB mutation, or three other G1/S phase mutations. snxA encodes the A. nidulans homolog of Saccharomyces cerevisiae Hrb1/Gbp2; nonessential shuttling messenger RNA (mRNA)-binding proteins belonging to the serine-arginine-rich (SR) and RNA recognition motif (RRM) protein family; and human heterogeneous ribonucleoprotein-M, a spliceosomal component involved in pre-mRNA processing and alternative splicing. snxA Hrb1 is nonessential, its deletion phenocopies the snxA1 mutation, and its overexpression rescues snxA1 and DsnxA mutant phenotypes. snxA1 and a second allele isolated in this study, snxA2, are hypomorphic mutations that result from decreased transcript and protein levels, suggesting that snxA acts normally to restrain cell cycle progression. SNXA HRB1 is predominantly nuclear, but is not retained in the nucleus during the partially closed mitosis of A. nidulans. We show that the snxA1 mutation does not suppress nimX2 by altering NIMX2 CDC2 /NIME CYCLINB kinase activity and that snxA1 or DsnxA alter localization patterns of NIME CYCLINB at the restrictive temperatures for snxA1 and nimX2. Together, these findings suggest a novel and previously unreported role of an SR/RRM family protein in cell cycle regulation, specifically in control of the CDK1 mitotic induction pathway. CONTROL of the eukaryotic G2/M transition by protein kinases has been widely studied and is highly conserved among all eukaryotes from the budding and fission yeasts and filamentous fungi to metazoans (for review, see Ma and Poon 2011). The CDK1/CYCLINB protein kinase complex is a major regulator of this transition in all eukaryotes and is responsible for the phosphorylations of numerous proteins, leading to massive nuclear and cytoplasmic reorganizations that regulate mitosis (for review, see Lindqvist et al. 2009). The complex itself is tightly regulated, both temporally and spatially, to allow mitotic entry.Although CDK1/CYCLINB activity is essential for mitotic entry in all eukaryotes, structural differences in the nucleus in various organisms result in "open" mitosis (more complex eukaryotes) or "closed" mitosis (budding yeasts); these differences likely affect the temporo-spatial functioning of CDK1/ CYCLINB. The partially closed mitosis of the filamentous fungus Aspergillus nidulans is an evolutionary intermediate between open and closed mitoses and provides a system for studying mitotic entry in organisms intermediate between budding ...
Purpose The study aimed to evaluate the adverse event (AE) and hepatotoxicity profile, including radioembolization induced liver disease (REILD), following repeat radioembolization (RE) to the same or overlapping vascular territories in patients with hepatocellular carcinoma (HCC) and limited functional hepatic reserve/cirrhosis. Methods Nine patients (seven male and two female; median age, 66 years) with cirrhosis and HCC who underwent repeat RE (cycle 1 and cycle 2) between January 2012 and August 2019 were included. Patient demographics, clinical and treatment history, and pertinent laboratory values were recorded at baseline and post-treatment time points over a period of four months. Post-RE AE/hepatotoxicity was assessed, organized by type and frequency, and graded by severity according to the National Cancer Institute common terminology criteria for adverse events, version 5.0 (CTCAE v5.0). To assess rudimentary comparisons for post-RE hepatotoxicity vs. factors of interest, Spearman's rank correlation/rho was calculated, and all relevant plots were constructed. Kaplan-Meier analysis was performed along with associated median survival time. All statistical analyses were performed with Stata v16.1. Results Following cycle 1, 22 objective AE were identified according to CTCAE v.5 (17 grade I, four grade II, and one grade III), with grade I, II, and III AE experienced by 78%, 33%, and 11% of patients, respectively. Following cycle 2, 19 objective AE were identified according to CTCAE v.5 (11 grade I, seven grade II, and one grade III), with grade I, II, and III AE experienced by 89%, 56%, and 11% of patients, respectively. A single patient developed REILD after cycle 1, which progressed to fatal REILD following cycle 2. Following cycle 2, an additional patient advanced from less severe hepatotoxicity to REILD. Following cycle 2, positive correlations between the higher model for end-stage liver disease (MELD; rho=0.70) and Child-Pugh (rho=0.74) scores and degree of post-RE hepatotoxicity/REILD appear to emerge. Post-repeat RE median overall survival was 12.5 months. Conclusion Post-RE hepatotoxicity following repeat RE to the same or overlapping vascular territories in patients with limited functional hepatic reserve/cirrhosis is a common occurrence with variable severity ranging from transient laboratory derangement to fatal REILD. Lack of a consensus REILD definition and grading scale results in non-uniform reporting of incidence as well as clinical and laboratory features of the disease process. Strides aimed at improving clinical characterization, forming a more complete diagnostic definition, and establishing a uniform grading system with respect to REILD are of particular importance and would ultimately improve repeat RE patient selection and risk management.
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