The Compact Muon Solenoid (CMS) experiment prepares its Phase-2 upgrade for the high-luminosity era of the LHC operation (HL-LHC). Due to the increase of occupancy, trigger latency and rates, the ...full electronics of the CMS Drift Tube (DT) chambers will need to be replaced. In the new design, the time bin for the digitization of the chamber signals will be of around 1 ns, and the totality of the signals will be forwarded asynchronously to the service cavern at full resolution. The new backend system will be in charge of building the trigger primitives of each chamber. These trigger primitives contain the information at chamber level about the muon candidates position, direction, and collision time, and are used as input in the L1 CMS trigger. The added functionalities will improve the robustness of the system against ageing. An algorithm based on analytical solutions for reconstructing the DT trigger primitives, called Analytical Method, has been implemented both as a software C++ emulator and in firmware. Its performance has been estimated using the software emulator with simulated and real data samples, and through hardware implementation tests. Measured efficiencies are 96 to 98% for all qualities and time and spatial resolutions are close to the ultimate performance of the DT chambers. A prototype chain of the HL-LHC electronics using the Analytical Method for trigger primitive generation has been installed during Long Shutdown 2 of the LHC and operated in CMS cosmic data taking campaigns in 2020 and 2021. Results from this validation step, the so-called Slice Test, are presented.
Ochratoxin A (OTA) is a mycotoxin that causes renal tumors in rats, particularly in males. In previous kinetic studies performed in fed conditions (
Vettorazzi et al., 2008), mature F344 male rats ...presented a significantly lower OTA bioavailability than females and young animals. The objective of the present study was to evaluate two factors which could explain this different kinetic profile: the presence of food and the male-specific protein alpha-2u-globulin. Therefore, a 24
h kinetic study has been performed in rats under fasting conditions. Food ingestion has been controlled in both sexes during two months. The presence of alpha-2u-globulin in the urine has been analyzed with SDS-gradient mini-gel electrophoresis.
Fasting tends to increase the maximum OTA plasma concentrations and the rate of absorption. The relative bioavailability is significantly increased under fasting conditions only in males. Mature males consumed a higher amount of food but, as the OTA dose administered, it was proportional to body weight. The reason why the OTA bioavailability is more affected in presence of food only in males is unclear. Several possibilities, such as differences in gastric emptying, OTA-food interactions and the involvement of alpha-2u-globulin are discussed.
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.
A biopharmaceutic–pharmacodynamic model is proposed to characterize the antiproliferative effect of controlled release formulations of cisplatin in cancer cell culture. In vitro release profiles from ...PLGA poly(
d,
l-lactide-co-glycolide) systems were described using a model based on the characterization of two drug release processes: diffusion and matrix degradation. Cytotoxicity data available consisting of the number of survival cells after a continuous exposure to free or encapsulated cisplatin were simultaneously modeled under the Gompertz framework incorporating the drug release model.
The release model parameters showed that particle size was inversely related to the diffusion rate. The antiproliferative effect was described as a function of drug concentrations and exposure times. Two mechanisms were included: (i) an inhibition of cell proliferation, where cisplatin released from PLGA systems was mainly involved, followed by (ii) stimulation of cell death due to cisplatin activity and mediated by the activation of a signal transduction process. Cell accumulation in G2/M phase of the cell cycle followed by the activation of caspase-3, supported both mechanisms.
The selected drug-effect model and its model parameters were independent from the formulation, which makes it a suitable tool to explore
in silico, alternative in vitro and in vivo scenarios to optimize these delivery systems.
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.
Purpose To develop a semi-physiological-based model describing simultaneously the time course of immature and mature B-lymphocytes after topotecan (TPT) administration to tumor-bearing rats. Methods ...Twenty-four tumor-bearing BDIX male rats received a single 6 mg/kg intra-peritoneal dose of TPT or saline. Mature and immature B-cell levels were measured every two days during three weeks and showed a very different temporal pattern. Both B-cell populations declined rapidly, reaching the nadir at 3-4 days after TPT administration; however, mature cells returned to baseline at day 8, while immature B-cells stayed at nadir until day 9 instead. Data were modeled using the population approach with NONMEM VI. Results The model developed maintains the proliferation, maturation and degradation elements of previous published models for myelosuppresion. In order to describe the rapid recovery of mature cells, it includes a peripheral compartment providing a constant supply of mature cells to the bloodstream. Conclusions The major contribution of the model is its new structure and the dynamical consequences, demonstrating an independent behavior between mature and immature B-cells during recovery. The final model could represent a good basis for the optimization of cytotoxic drugs oriented to attain a maximum antitumor efficacy while minimizing hematological toxicity.
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