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.

A novel combination regimen of BET and FLT3 inhibition for FLT3-ITD acute myeloid leukemia

Acute myeloid leukemia patients with FLT3-ITD mutations have a high risk of relapse and death. FLT3 tyrosine kinase inhibitors improve overall survival, but their efficacy is limited and most patients who relapse will ultimately die of the disease. Even with potent FLT3 inhibition, the disease persists within the bone marrow microenvironment, mainly due to bone marrow stroma activating parallel signaling pathways that maintain pro-survival factors. BET inhibitors suppress pro-survival factors such as MYC and BCL2, but these drugs thus far have shown only limited single-agent clinical potential. We demonstrate here, using pre-clinical and clinical correlative studies, that the novel 4-azaindole derivative, PLX51107, has BET-inhibitory activity in vitro and in vivo. The combination of BET and FLT3 inhibition induces a synergistic antileukemic effect in a murine xenograft model of FLT3-ITD AML, and against primary FLT3-ITD AML cells co-cultured with bone marrow stroma. Using suppression of MYC as a surrogate for BET inhibition, we demonstrate BET inhibition in human patients. The short plasma half-life of PLX51107 results in intermittent target inhibition to enable tolerability while overcoming the protective effect of the microenvironment. Mechanistically, the synergistic cytotoxicity is associated with suppression of key survival genes such as MYC. These data provide the scientific rationale for a clinical trial of a BET plus FLT3 inhibitor for the treatment of relapsed/refractory FLT3-ITD AML. A clinical trial of PLX51107 as monotherapy in patients with different malignancies is underway and will be reported separately.

The chemokine CX3CL1/fractalkine regulates immunopathogenesis during fungal-associated allergic airway inflammation

Individuals that present with difficult-to-control asthma and sensitivity to one or more fungal species are categorized as a subset of severe asthma patients belonging to a group herein referred to as severe asthma with fungal sensitization (SAFS). We have previously reported the identification of numerous cytokines and chemokines that were elevated in human asthmatics that were sensitized to fungi vs. non-fungal sensitized asthmatics. Here, we show that the unique chemokine CX3CL1 (fractalkine) is elevated in both bronchoalveolar lavage fluid and sputum from human asthmatics sensitized to fungi, implicating an association with CX3CL1 in fungal asthma severity. In an experimental model of fungal-associated allergic airway inflammation, we demonstrate that the absence of CX3CR1 signaling unexpectedly resulted in a profound impairment in lung function. Histological assessment of lung tissue revealed an unrestricted inflammatory response that was subsequently characterized by enhanced levels of neutrophils, eosinophils and inflammatory monocytes. Neutrophilic inflammation correlated with elevated IL-17A, proinflammatory cytokines (TNF-α, IL-1α IL-1β), neutrophil survival factors (G-CSF) and neutrophil-targeting chemokines (CCL3, CCL4). Eosinophilia correlated with elevated type 2 responses (IL-5, IL-13) whereas inflammatory monocyte levels correlated with elevated type 1 responses (IFN-γ, CXCL9) and survival factors (M-CSF). Despite enhanced inflammatory responses, the immunoregulatory cytokine IL-10 and the natural inhibitor of IL-1 signaling, IL-1RA, were significantly elevated rather than impaired. Regulatory T cell levels were unchanged, as were levels of the anti-inflammatory cytokines IL-35 and IL-38. Taken together, the CX3CL1/CX3CR1 axis preserves lung function during fungal-associated allergic airway inflammation through a non-classical immunoregulatory mechanism.