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.
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.
Micro-Abstract We have estimated the pharmacological sensitivity and synergism of 125 individual patient samples for all drugs and combination treatments for acute myeloid leukemia in the context of ...the overall patient population. Each ex vivo pharmacological profile identifies drugs and treatments for which the patient's malignant cells are particularly sensitive or resistant, assisting in the selection of individualized treatments.
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.
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.
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.
B physics at the Tevatron Troconiz, Jorge F. de
AIP conference proceedings,
10/1998, Letnik:
444, Številka:
1
Journal Article
Recenzirano
Precision B-physics results from the CDF and D0 Collaborations based on data collected during the Tevatron 1992-96 run are presented. In particular we discuss the measurement of the B{sub s} meson ...lifetime, B{sub c} meson observation, and B{sup 0}-B-bar{sup 0} mixing results obtained using time-evolution analyses. Prospects for the next Tevatron run, starting in 1999, are also reported.
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.
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