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Background: The purpose was to analyse the interrelations between planning and complexity metrics and gamma passing rates (GPRs) obtained from VMAT treatments and build the forecasting models for qualitative prediction (QD) of GPRs results., Materials and Method: 802 treatment arcs from the plans prepared for the head and neck, thorax, abdomen, and pelvic cancers were analysed. The plans were verified by portal dosimetry and analysed twice using the gamma method with 3%|2mm and 2%|2mm acceptance criteria. The tolerance limit of GPR was 95%. Red, yellow, and green QDs were established for GPR examination. The interrelations were examined, as well as the analysis of effective differentiation of QD. Three models for QD forecasting based on discriminant analysis (DA), random decision forest (RDF) methods, and the hybrid model (HM) were built and evaluated., Results: Most of the interrelations were small or moderate. The exception is correlations of the join function with the average number of monitor units per control point (R = 0.893) and the beam aperture with planning target volume (R = 0.897). While many metrics allow for the effective separation of the QDs from each other, the study shows that predicting the values of the QD is possible only through multi-component forecasting models, of which the HM is the most accurate (0.894)., Conclusion: Of the three models explored in this study, the HM, which uses DA methods to predict red QD and RDF methods to predict green and yellow QDs, is the most promising one., Competing Interests: Conflict of interests: Authors declare no conflict of interests, (© 2024 Greater Poland Cancer Centre.)

The complexity of the metazoan proteome is significantly increased by the expression of small proteins (<100 aa) derived from smORFs within lncRNAs, uORFs, 3' UTRs and, reading frames overlapping the CDS. These smORF encoded proteins (SEPs) have diverse roles, ranging from the regulation of cellular physiological to essential developmental functions. We report the characterization of a new member of this protein family, SEP53BP1, derived from a small internal ORF that overlaps the CDS encoding 53BP1. Its expression is coupled to the utilization of an alternative, cell-type specific promoter coupled to translational reinitiation events mediated by a uORF in the alternative 5' TL of the mRNA. This uORF-mediated reinitiation at an internal ORF is also observed in zebrafish. Interactome studies indicate that the human SEP53BP1 associates with components of the protein turnover pathway including the proteasome, and the TRiC/CCT chaperonin complex, suggesting that it may play a role in cellular proteostasis., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Nonreceptor tyrosine kinases such as the newly described 70-kDa (ZAP-70/Syk) and Src-related tyrosine kinases are coupled to a variety of receptors, including the antigen receptors on B- and T-cells and the Fc receptors for IgE (Fc epsilon RI) and IgG (Fc gamma RI, Fc gamma RIII/CD16). Various subunits of these receptors contain homologous activation motifs which appear capable of autonomously triggering cell activation. Two forms of this motif are present in the Fc epsilon RI multimeric complex: one in the beta chain and one in the gamma chain. Here we show that each of the two tyrosine kinases known to be involved in Fc epsilon RI signaling is controlled by a distinct motif-containing chain. Lyn associates with the nonactivated beta chain, whereas gamma promotes the activation of Syk. We also show that neither the beta nor the gamma motif alone can account for the full signaling capacity of the entire receptor. We propose that, upon triggering of the tetrameric receptor, Lyn already bound to beta becomes activated and phosphorylates beta and gamma; the phosphorylation of gamma induces the association of Syk with gamma and also the activation of Syk, resulting in the phosphorylation and activation of phospholipase C gamma 1. Cooperative recruitment of specific kinases by the various signaling chains found in this family of antigen receptors could represent a way to achieve the full signaling capacity of the multimeric complexes.

The high affinity receptor for immunoglobulin (Ig) E on mast cells, along with the antigen receptors on T and B cells and Fc receptors for IgG, belongs to a class of receptors which lack intrinsic kinase activity, but activate non-receptor tyrosine and serine/threonine kinases. Receptor engagement triggers a chain of signaling events leading from protein phosphorylation to activation of phosphatidylinositol-specific phospholipase C, an increase in intracellular calcium levels, and ultimately the activation of more specialized functions. IgE receptor disengagement leads to reversal of phosphorylation by undefined phosphatases and to inhibition of activation pathways. Here we show that phenylarsine oxide, a chemical which reacts with thiol groups and has been reported to inhibit tyrosine phosphatases, uncouples the IgE receptor-mediated phosphorylation signal from activation of phosphatidyl inositol metabolism, the increase in intracellular calcium levels, and serotonin release. Phenylarsine oxide inhibits neither the kinases (tyrosine and serine/threonine) phosphorylating the receptor and various cellular substrates nor, unexpectedly, the phosphatases responsible for the dephosphorylation following receptor disengagement. By contrast, it abolishes the receptor-mediated phosphorylation of phospholipase C-gamma 1, but not phospholipase C activity in vitro. Therefore the phosphorylation and activation of phospholipase C likely requires a phenylarsine oxide-sensitive element. Receptor aggregation thus activates at least two distinct phosphorylation pathways: a phenylarsine oxide-insensitive pathway leading to phosphorylation/dephosphorylation of the receptor and of various substrates and a sensitive pathway leading to phospholipase C-gamma 1 phosphorylation.

In addition to their well characterized high affinity immunoglobulin E (IgE) receptors (Fc epsilon RI) mast cells have long been suspected to express undefined Fc receptors capable of binding IgE with low affinity. In this paper, we show that Fc gamma RII and Fc gamma RIII, but not Mac-2, on mouse mast cells and macrophages bind IgE-immune complexes. This binding is efficiently competed by 2.4G2, a monoclonal antibody against the extracellular homologous region of both Fc gamma RII and Fc gamma RIII. Furthermore, IgE-immune complexes bind specifically to Fc gamma RII or Fc gamma RIII transfected into COS-7 cells. The association constants of IgE binding estimated from competition experiments are about 3.1 x 10(5) M-1 for Fc gamma RII, and 4.8 x 10(5) M-1 for Fc gamma RIII. Engagement of Fc gamma RII and Fc gamma RIII with IgE-immune complexes (after blocking access to Fc epsilon RI) or with IgG-immune complexes triggers C57.1 mouse mast cells to release serotonin. This release is inhibited by 2.4G2, and at maximum, reaches 30-40% of the intracellular content, about half of the maximal release (60-80%) obtained after Fc epsilon RI engagement. These data demonstrate that mouse Fc gamma RII and Fc gamma RIII are not isotype specific, and that the binding of IgE-immune complexes to these receptors induces cell activation.