We propose a new collider probe for axionlike particles (ALPs), and more generally for pseudo-Goldstone bosons: nonresonant searches that take advantage of the derivative nature of their interactions ...with Standard Model particles. ALPs can participate as off shell mediators in the s channel of 2→2 scattering processes at colliders like the LHC. We exemplify the power of this novel type of search by deriving new limits on ALP couplings to gauge bosons via the processes pp→ZZ, pp→γγ, and pp→jj using run 2 CMS public data, probing previously unexplored areas of the ALP parameter space. In addition, we propose future nonresonant searches involving the ALP coupling to other electroweak bosons and/or the Higgs particle.
A
bstract
We propose a new search for Axion-Like Particles (ALPs), targeting Vector Boson Scattering (VBS) processes at the LHC. We consider nonresonant ALP-mediated VBS, where the ALP participates ...as an off-shell mediator. This process occurs whenever the ALP is too light to be produced resonantly, and it takes advantage of the derivative nature of ALP interactions with the electroweak Standard Model bosons. We study the production of
ZZ
,
Zγ
,
W
±
γ
,
W
±
Z
and
W
±
W
±
pairs with large diboson invariant masses in association with two jets. Working in a gauge-invariant framework, upper limits on ALP couplings to electroweak bosons are obtained from a reinterpretation of Run 2 public CMS VBS analyses. The constraints inferred on ALP couplings to
ZZ
,
Zγ
and
W
±
W
±
pairs are very competitive for ALP masses up to 100 GeV. They have the advantage of being independent of the ALP coupling to gluons and of the ALP decay width. Simple projections for LHC Run 3 and HL-LHC are also calculated, demonstrating the power of future dedicated analyses at ATLAS and CMS.
We aimed to study the impact of size, maturation and cytochrome P450 2D6 (CYP2D6) genotype activity score as predictors of intravenous tramadol disposition.
Tramadol and O-desmethyl tramadol (M1) ...observations in 295 human subjects (postmenstrual age 25 weeks to 84.8 years, weight 0.5-186 kg) were pooled. A population pharmacokinetic analysis was performed using a two-compartment model for tramadol and two additional M1 compartments. Covariate analysis included weight, age, sex, disease characteristics (healthy subject or patient) and CYP2D6 genotype activity. A sigmoid maturation model was used to describe age-related changes in tramadol clearance (CLPO), M1 formation clearance (CLPM) and M1 elimination clearance (CLMO). A phenotype-based mixture model was used to identify CLPM polymorphism.
Differences in clearances were largely accounted for by maturation and size. The time to reach 50 % of adult clearance (TM50) values was used to describe maturation. CLPM (TM50 39.8 weeks) and CLPO (TM50 39.1 weeks) displayed fast maturation, while CLMO matured slower, similar to glomerular filtration rate (TM50 47 weeks). The phenotype-based mixture model identified a slow and a faster metabolizer group. Slow metabolizers comprised 9.8 % of subjects with 19.4 % of faster metabolizer CLPM. Low CYP2D6 genotype activity was associated with lower (25 %) than faster metabolizer CLPM, but only 32 % of those with low genotype activity were in the slow metabolizer group.
Maturation and size are key predictors of variability. A two-group polymorphism was identified based on phenotypic M1 formation clearance. Maturation of tramadol elimination occurs early (50 % of adult value at term gestation).
We propose a new search for Axion-Like Particles (ALPs), targeting Vector Boson Scattering (VBS) processes at the LHC. We consider nonresonant ALP-mediated VBS, where the ALP participates as an ...off-shell mediator. This process occurs whenever the ALP is too light to be produced resonantly, and it takes advantage of the derivative nature of ALP interactions with the electroweak Standard Model bosons. We study the production of \(ZZ\), \(Z\gamma\), \(W^\pm \gamma\), \(W^\pm Z\) and \(W^\pm W^\pm\) pairs with large diboson invariant masses in association with two jets. Working in a gauge-invariant framework, upper limits on ALP couplings to electroweak bosons are obtained from a reinterpretation of Run 2 public CMS VBS analyses. The constraints inferred on ALP couplings to \(ZZ\), \(Z\gamma\) and \(W^\pm W^\pm\) pairs are very competitive for ALP masses up to 100 GeV. They have the advantage of being independent of the ALP coupling to gluons and of the ALP decay width. Simple projections for LHC Run 3 and HL-LHC are also calculated, demonstrating the power of future dedicated analyses at ATLAS and CMS.
Abstract Human xenografts Calu6 (non-small cell lung cancer) and MX1 (breast cancer) were implanted subcutaneously in nude mice and LY2157299, a new type I receptor TGF-β kinase antagonist, was ...administered orally. Plasma levels of LY2157299, percentage of phosphorylated Smad2,3 (pSmad) in tumour, and tumour size were used to establish a semi-mechanistic pharmacokinetic/pharmacodynamic model. An indirect response model was used to relate plasma concentrations with pSmad. The model predicts complete inhibition of pSmad and rapid turnover rates t1/2 (min) = 18.6 (Calu6) and 32.0 (MX1). Tumour growth inhibition was linked to pSmad using two signal transduction compartments characterised by a mean signal propagation time with estimated values of 6.17 and 28.7 days for Calu6 and MX1, respectively. The model provides a tool to generate experimental hypothesis to gain insights into the mechanisms of signal transduction associated to the TGF-β membrane receptor type I.
The Film method provides a simpler methodology to develop PEG-liposomes of oxaliplatin with adequate physico-chemical characteristics to reach a significant efficacy in HT-29 tumor bearing-mice.
In ...this work, the Film Method (FM), Reverse-Phase Evaporation (REV), and the Heating Method (HM) were applied to prepare PEG-coated liposomes of oxaliplatin with natural neutral and cationic lipids, respectively. The formulations developed with the three methods, showed similar physicochemical characteristics, except in the loading of oxaliplatin, which was statistically lower (P<0.05) using the HM.
The incorporation of a semi-synthetic lipid in the formulation developed by FM, provided liposomes with a particle size of 115nm associated with the lowest polydispersity index and the highest drug loading, 35%, compared with the other two lipids, suggesting an increase in the membrane stability. That stability was also evaluated according to the presence of cholesterol, the impact of the temperature, and the application of different cryoprotectants during the lyophilization. The results indicated long-term stability of the developed formulation, because after its intravenous in vivo administration to HT-29 tumor bearing mice was able to induce an inhibition of tumor growth statistically higher (P<0.05) than the inhibition caused by the free drug.
In conclusion, the FM was the simplest method in comparison with REV and HM to develop in vivo stable and efficient PEG-coated liposomes of oxaliplatin with a loading higher than those reported for REV.
Anti-programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) monoclonal antibodies (mAbs) show remarkable clinical anti-tumour efficacy. However, rational combinations are needed to extend ...the clinical benefit to primary resistant tumours. The design of such combinations requires the identification of the kinetics of critical immune cell populations in the tumour microenvironment.
In this study, we compared the kinetics of immune cells in the tumour microenvironment upon treatment with immunotherapy combinations with different anti-tumour efficacies in the non-inflamed tumour model TC-1/A9. Tumour-bearing C57BL/6J mice were treated with all possible combinations of a human papillomavirus (HPV) E7 long peptide, polyinosinic-polycytidylic acid (PIC) and anti-PD-1 mAb. Tumour growth and kinetics of the relevant immune cell populations were assessed over time. The involvement of key immune cells was confirmed by depletion with mAbs and immunophenotyping with multiparametric flow cytometry.
The maximum anti-tumour efficacy was achieved after intratumoural administration of HPV E7 long peptide and PIC combined with the systemic administration of anti-PD-1 mAb. The intratumoural immune cell kinetics of this combination was characterised by a biphasic immune response. An initial upsurge of proinflammatory myeloid cells led to a further rise in effector CD8
T lymphocytes at day 8. Depletion of either myeloid cells or CD8
T lymphocytes diminished the anti-tumour efficacy of the combination.
The anti-tumour efficacy of a successful immunotherapy combination in a non-inflamed tumour model relies on an early inflammatory process that remodels the myeloid cell compartment.
Immune checkpoint inhibitors, administered as single agents, have demonstrated clinical efficacy. However, when treating cold tumors, different combination strategies are needed. This work aims to ...develop a semi-mechanistic model describing the antitumor efficacy of immunotherapy combinations in cold tumors. Tumor size of mice treated with TC-1/A9 non-inflamed tumors and the drug effects of an antigen, a toll-like receptor-3 agonist (PIC), and an immune checkpoint inhibitor (anti-programmed cell death 1 antibody) were modeled using Monolix and following a middle-out strategy. Tumor growth was best characterized by an exponential model with an estimated initial tumor size of 19.5 mm3 and a doubling time of 3.6 days. In the treatment groups, contrary to the lack of response observed in monotherapy, combinations including the antigen were able to induce an antitumor response. The final model successfully captured the 23% increase in the probability of cure from bi-therapy to triple-therapy. Moreover, our work supports that CD8+ T lymphocytes and resistance mechanisms are strongly related to the clinical outcome. The activation of antigen-presenting cells might be needed to achieve an antitumor response in reduced immunogenic tumors when combined with other immunotherapies. These models can be used as a platform to evaluate different immuno-oncology combinations in preclinical and clinical scenarios.
Hadron Outer (HO) scintillators located around the CMS coil are sensitive to muons. They can be used in coincidence with RPC chambers for the Muon Trigger. This paper contains a brief description of ...the two systems and the proposal of how they can be integrated. Backgrounds, efficiencies, and trigger rates have been calculated. The conclusion is that rate reduction factors as high as 100 can be obtained for
∼
90
%
efficiency.
Development of EGF-liposomes (LP-EGF) for selective molecules delivery in tumors expressing EGFR.
In vitro cellular interaction of EGF-LP and nontargeted liposomes (LP-N) was assayed at 37 and 4 °C ...in cells expressing different EGFR levels. Receptor-mediated uptake was investigated by competition with a monoclonal antibody anti-EGFR. Selective intracellular drug delivery and efficacy was tested by oxaliplatin encapsulation. In vivo biodistribution of LP-N and LP-EGF was done in xenograft model.
LP-EGF was internalized by an active and selective mechanism through EGFR without receptor activation. Oxaliplatin LP-EGF decreased IC50 between 48 and 13% in cell EGFR+. LP-EGF was accumulated in tumor over 72 h postdosing, while LP-N in spleen.
LP-EGF represents an attractive nanosystem for cancer therapy or diagnosis.
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