Production of heavy charged particles in proton-proton ultraperipheral collisions at the Large Hadron Collider: survival factor

Ultraperipheral collisions of high energy protons are a source of approximately real photons colliding with each other. Photon fusion can result in production of yet unknown charged particles in very clean events. The cleanliness of such an event is due to the requirement that the protons survive during the collision. Finite sizes of the protons reduce the probability of such outcome compared to point-like particles. We calculate the survival factors and cross sections for the production of heavy charged particles at the Large Hadron Collider.

Elastic photon-initiated production at the LHC: the role of hadron-hadron interactions

We analyse in detail the role of additional hadron–hadron interactions in elastic photon–initiated (PI) production at the LHC, both in pp and heavy ion collisions. We first demonstrate that the source of difference between our predictions and other results in the literature for PI muon pair production is dominantly due to an unphysical cut that is imposed in these latter results on the dimuon–hadron impact parameter. We in addition show that this is experimentally disfavoured by the shape of the muon kinematic distributions measured by ATLAS in ultraperipheral PbPb collisions. We then consider the theoretical uncertainty due to the survival probability for no additional hadron–hadron interactions, and in particular the role this may play in the tendency for the predicted cross sections to lie somewhat above ATLAS data on PI muon pair production, in both pp and PbPb collisions. This difference is relatively mild, at the \sim 10\%∼10% level, and hence a very good control over the theory is clearly required. We show that this uncertainty is very small, and it is only by taking very extreme and rather unphysical variations in the modelling of the survival factor that this tension can be removed. This underlines the basic, rather model independent, point that a significant fraction of elastic PI scattering occurs for hadron–hadron impact parameters that are simply outside the range of QCD interactions, and hence this sets a lower bound on the survival factor in any physically reasonable approach. Finally, other possible origins for this discrepancy are discussed.

NMNAT1 Is a Survival Factor in Actinomycin D-Induced Osteosarcoma Cell Death

Osteosarcoma is a frequent and extremely aggressive type of pediatric cancer. New therapeutic approaches are needed to improve the overall survival of osteosarcoma patients. Our previous results suggest that NMNAT1, a key enzyme in nuclear NAD+ synthesis, facilitates the survival of cisplatin-treated osteosarcoma cells. A high-throughput cytotoxicity screening was performed to identify novel pathways or compounds linked to the cancer-promoting role of NMNAT1. Nine compounds caused higher toxicity in the NMNAT1 KO U2OS cells compared to their wild type counterparts, and actinomycin D (ActD) was the most potent. ActD-treatment of NMNAT1 KO cells increased caspase activity and secondary necrosis. The reduced NAD+ content in NMNAT1 KO cells was further decreased by ActD, which partially inhibited NAD+-dependent enzymes, including the DNA nick sensor enzyme PARP1 and the NAD+-dependent deacetylase SIRT1. Impaired PARP1 activity increased DNA damage in ActD-treated NMNAT1 knockout cells, while SIRT1 impairment increased acetylation of the p53 protein, causing the upregulation of pro-apoptotic proteins (NOXA, BAX). Proliferation was decreased through both PARP- and SIRT-dependent pathways. On the one hand, PARP inhibitors sensitized wild type but not NMNAT1 KO cells to ActD-induced anti-clonogenic effects; on the other hand, over-acetylated p53 induced the expression of the anti-proliferative p21 protein leading to cell cycle arrest. Based on our results, NMNAT1 acts as a survival factor in ActD-treated osteosarcoma cells. By inhibiting both PARP1- and SIRT1-dependent cellular pathways, NMNAT1 inhibition can be a promising new tool in osteosarcoma chemotherapy.

Small Molecule Cyclotriazadisulfonamide Abrogates the Upregulation of the Human Receptors CD4 and 4-1BB and Suppresses In Vitro Activation and Proliferation of T Lymphocytes

The small molecule cyclotriazadisulfonamide (CADA) down-modulates the human CD4 receptor, an important factor in T cell activation. Here, we addressed the immunosuppressive potential of CADA using different activation models. CADA inhibited lymphocyte proliferation with low cellular toxicity in a mixed lymphocyte reaction, and when human PBMCs were stimulated with CD3/CD28 beads, phytohemagglutinin or anti-CD3 antibodies. The immunosuppressive effect of CADA involved both CD4+ and CD8+ T cells but was, surprisingly, most prominent in the CD8+ T cell subpopulation where it inhibited cell-mediated lympholysis. Immunosuppression by CADA was characterized by suppressed secretion of various cytokines, and reduced CD25, phosphoSTAT5 and CTPS-1 levels. We discovered a direct down-modulatory effect of CADA on 4-1BB (CD137) expression, a survival factor for activated CD8+ T cells. More specifically, CADA blocked 4‑1BB protein biosynthesis by inhibition of its co-translational translocation into the ER in a signal peptide-dependent way. Taken together, this study demonstrates that CADA, as potent down-modulator of human CD4 and 4‑1BB receptor, has promising immunomodulatory characteristics. This would open up new avenues toward chemotherapeutics that act as selective protein down-modulators to treat various human immunological disorders.

BCL2L10 Is Overexpressed in Melanoma Downstream of STAT3 and Promotes Cisplatin and ABT-737 Resistance

The anti-apoptotic proteins from the Bcl-2 family are important therapeutic targets since they convey resistance to anticancer regimens. Despite the suspected functional redundancy among the six proteins of this subfamily, both basic studies and therapeutic approaches have focused mainly on BCL2, Bcl-xL, and MCL1. The role of BCL2L10, another member of this group, has been poorly studied in cancer and never has been in melanoma. We describe here that BCL2L10 is abundantly and frequently expressed both in melanoma cell lines and tumor samples. We established that BCL2L10 expression is driven by STAT3-mediated transcription, and by using reporter assays, site-directed mutagenesis, and ChIP analysis, we identified the functional STAT3 responsive elements in the BCL2L10 promoter. BCL2L10 is a pro-survival factor in melanoma since its expression reduced the cytotoxic effects of cisplatin, dacarbazine, and ABT-737 (a BCL2, Bcl-xL, and Bcl-w inhibitor). Meanwhile, both genetic and pharmacological inhibition of BCL2L10 sensitized melanoma cells to cisplatin and ABT-737. Finally, BCL2L10 inhibited the cell death upon combination treatments of PLX-4032, a BRAF inhibitor, with ABT-737 or cisplatin. In summary, we determined that BCL2L10 is expressed in melanoma and contributes to cell survival. Hence, targeting BCL2L10 may enhance the clinical efficacy of other therapies for malignant melanoma.