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.
A
bstract
Production of prompt J/
ψ
meson pairs in proton-proton collisions at
s
= 7 TeV is measured with the CMS experiment at the LHC in a data sample corresponding to an integrated luminosity of ...about 4.7 fb
−1
. The two J/
ψ
mesons are fully reconstructed via their decays into
μ
+
μ
−
pairs. This observation provides for the first time access to the high-transverse-momentum region of J/
ψ
pair production where model predictions are not yet established. The total and differential cross sections are measured in a phase space defined by the individual J/
ψ
transverse momentum (
p
T
J/
ψ
) and rapidity (|
y
J/
ψ
|): |
y
J/
ψ
| < 1.2 for
p
T
J/
ψ
> 6.5 GeV/
c
; 1.2 < |
y
J/
ψ
| < 1.43 for a
p
T
threshold that scales linearly with |
y
J/
ψ
| from 6.5 to 4.5 GeV/
c
; and 1.43 < |
y
J/
ψ
| < 2.2 for
p
T
J/
ψ
> 4.5 GeV/
c
. The total cross section, assuming unpolarized prompt J/
ψ
pair production is 1.49 ± 0.07 (stat) ±0.13 (syst) nb. Different assumptions about the J/
ψ
polarization imply modifications to the cross section ranging from −31% to +27%.
V937 is an investigational novel oncolytic non-genetically modified Kuykendall strain of Coxsackievirus A21 which is in clinical development for the treatment of advanced solid tumor malignancies. ...V937 infects and lyses tumor cells expressing the intercellular adhesion molecule I (ICAM-I) receptor. We integrated
in vitro
and
in vivo
data from six different preclinical studies to build a mechanistic model that allowed a quantitative analysis of the biological processes of V937 viral kinetics and dynamics, viral distribution to tumor, and anti-tumor response elicited by V937 in human xenograft models in immunodeficient mice following intratumoral and intravenous administration. Estimates of viral infection and replication which were calculated from
in vitro
experiments were successfully used to describe the tumor response
in vivo
under various experimental conditions. Despite the predicted high clearance rate of V937 in systemic circulation (t
1/2
= 4.3 min), high viral replication was observed in immunodeficient mice which resulted in tumor shrinkage with both intratumoral and intravenous administration. The described framework represents a step towards the quantitative characterization of viral distribution, replication, and oncolytic effect of a novel oncolytic virus following intratumoral and intravenous administrations in the absence of an immune response. This model may further be expanded to integrate the role of the immune system on viral and tumor dynamics to support the clinical development of oncolytic viruses.
Oncolytic viruses (OVs) represent a potential therapeutic strategy in cancer treatment. However, there is currently a lack of comprehensive quantitative models characterizing clinical OV kinetics and ...distribution to the tumor. In this work, we present a mechanistic modeling framework for V937 OV, after intratumoral (i.t.) or intravascular (i.v.) administration in patients with cancer. A minimal physiologically‐based pharmacokinetic model was built to characterize biodistribution of OVs in humans. Viral dynamics was incorporated at the i.t. cellular level and linked to tumor response, enabling the characterization of a direct OV killing triggered by the death of infected tumor cells and an indirect killing induced by the immune response. The model provided an adequate description of changes in V937 mRNA levels and tumor size obtained from phase I/II clinical trials after V937 administration. The model showed prominent role of viral clearance from systemic circulation and infectivity in addition to known tumor aggressiveness on clinical response. After i.v. administration, i.t. exposure of V937 was predicted to be several orders of magnitude lower compared with i.t. administration. These differences could be overcome if there is high virus infectivity and/or replication. Unfortunately, the latter process could not be identified at the current clinical setting. This work provides insights on selecting optimal OV considering replication rate and infectivity.
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).
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.
To sustain and extend its discovery potential, the Large Hadron Collider (LHC) will undergo a major upgrade in the coming years, referred to as High Luminosity LHC (HLLHC), aimed to increase its ...instantaneous luminosity, 5 times larger than the designed limit, and, consequently leading to high levels of radiation, with the goal to collect 10 times larger the original designed integrated luminosity. The drift tube chambers (DT) of CMS muon detector system is built to proficiently measure and trigger on muons in the harsh radiation environment expected during the HL-LHC era. Ageing studies are performed at the CERNs gamma ray irradiation facility (GIF++) by measuring the muon hit efficiency of these detectors at various LHC operation conditions. One such irradiation campaign was started in October 2017, when a spare MB2 chamber moved inside the bunker and irradiated at lower acceleration factors. Two out of twelve layers of the DT chamber were operated while being irradiated with the radioactive source and then their muon hit efficiency was calculated in coincidence with other ten layers which were kept on the standby. The chamber absorbed an integrated dose equivalent to two times the expected integrated luminosity of the HL-LHC. Investigation on the outgassing of cell materials and of the gas components used at the GIF++ are underway and strategies to mitigate the aging effects are also being developed. The effect of radiation on the performance of DT chamber and its impact on the overall muon reconstruction efficiency expected during the HL-LHC are presented.
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.
PDF
