O(N) Quantum fields in curved spacetime

For the O(N) field theory with lambda Phi^4 self-coupling, we construct the two-particle-irreducible (2PI), closed-time-path (CTP) effective action in a general curved spacetime. From this we derive a set of coupled equations for the mean field and the variance. They are useful for studying the nonperturbative, nonequilibrium dynamics of a quantum field when full back reactions of the quantum field on the curved spacetime, as well as the fluctuations on the mean field, are required. Applications to phase transitions in the early Universe such as the Planck scale or in the reheating phase of chaotic inflation are under investigation.Comment: 31 pages, 2 figures, uses RevTeX 3.1, LaTeX 2e, AMSfonts 2.2, graphics 0.6; To appear in Phys. Rev. D (7/15/97

Finite Number and Finite Size Effects in Relativistic Bose-Einstein Condensation

Bose-Einstein condensation of a relativistic ideal Bose gas in a rectangular cavity is studied. Finite size corrections to the critical temperature are obtained by the heat kernel method. Using zeta-function regularization of one-loop effective potential, lower dimensional critical temperatures are calculated. In the presence of strong anisotropy, the condensation is shown to occur in multisteps. The criteria of this behavior is that critical temperatures corresponding to lower dimensional systems are smaller than the three dimensional critical temperature.Comment: 18 pages, 9 figures, Fig.3 replaced, to appear in Physical Review

Layer-by-Layer Nanoparticles for Systemic Codelivery of an Anticancer Drug and siRNA for Potential Triple-Negative Breast Cancer Treatment

A single nanoparticle platform has been developed through the modular and controlled layer-by-layer process to codeliver siRNA that knocks down a drug-resistance pathway in tumor cells and a chemotherapy drug to challenge a highly aggressive form of triple-negative breast cancer. Layer-by-layer films were formed on nanoparticles by alternately depositing siRNA and poly-l-arginine; a single bilayer on the nanoparticle surface could effectively load up to 3500 siRNA molecules, and the resulting LbL nanoparticles exhibit an extended serum half-life of 28 h. In animal models, one dose via intravenous administration significantly reduced the target gene expression in the tumors by almost 80%. By generating the siRNA-loaded film atop a doxorubicin-loaded liposome, we identified an effective combination therapy with siRNA targeting multidrug resistance protein 1, which significantly enhanced doxorubicin efficacy by 4 fold in vitro and led to up to an 8-fold decrease in tumor volume compared to the control treatments with no observed toxicity. The results indicate that the use of layer-by-layer films to modify a simple liposomal doxorubicin delivery construct with a synergistic siRNA can lead to significant tumor reduction in the cancers that are otherwise nonresponsive to treatment with Doxil or other common chemotherapy drugs. This approach provides a potential strategy to treat aggressive and resistant cancers, and a modular platform for a broad range of controlled multidrug therapies customizable to the cancer type in a singular nanoparticle delivery system.Janssen Pharmaceutical Ltd. (TRANSCEND Grant)National Cancer Institute (U.S.) (Koch Institute Support (Core) Grant P30-CA14051)National Health and Medical Research Council (Australia) (CJ Martin Fellowship)National Science Foundation (U.S.). Graduate Research FellowshipNatural Sciences and Engineering Research Council of Canada (Postdoctoral Fellowship

Combining Microenvironment Normalization Strategies to Improve Immunotherapy

Advances in immunotherapy have revolutionized the treatment of multiple cancers. Unfortunately, tumors usually have impaired blood perfusion, which limits the delivery of therapeutics and cytotoxic immune cells to tumors; moreover, it results in hypoxia—a hallmark of the abnormal tumor microenvironment (TME)—that causes immunosuppression. We proposed that normalization of TME using antiangiogenic drugs and/or mechano-therapeutics can overcome these challenges. Recently, immunotherapy with checkpoint blockers was shown to effectively induce vascular normalization in some types of cancer. Although these therapeutic approaches have been used in combination in preclinical and clinical studies, their combined effects on TME are not fully understood. To identify strategies for improved immunotherapy, we developed a mathematical framework that incorporates complex interactions among various types of cancer cells, immune cells, stroma, angiogenic molecules and the vasculature. Model predictions were compared with the data from five previously reported experimental studies. We found that low doses of antiangiogenic treatment improve immunotherapy when the two treatments are administered sequentially, but that high doses are less efficacious because of excessive vessel pruning and hypoxia. Stroma normalization can further increase the efficacy of immunotherapy and the benefit is additive when combined with vascular normalization. We conclude that vessel functionality dictates the efficacy of immunotherapy and thus, increased tumor perfusion should be investigated as a predictive biomarker of response to immunotherapy

Scaling rules for diffusive drug delivery in tumor and normal tissues

Delivery of blood-borne molecules and nanoparticles from the vasculature to cells in the tissue differs dramatically between tumor and normal tissues due to differences in their vascular architectures. Here we show that two simple measures of vascular geometry—δmax and λ—readily obtained from vascular images, capture these differences and link vascular structure to delivery in both tissue types. The longest time needed to bring materials to their destination scales with the square of δmax, the maximum distance in the tissue from the nearest blood vessel, whereas λ, a measure of the shape of the spaces between vessels, determines the rate of delivery for shorter times. Our results are useful for evaluating how new therapeutic agents that inhibit or stimulate vascular growth alter the functional efficiency of the vasculature and more broadly for analysis of diffusion in irregularly shaped domains

Experimental and Computational Analyses Reveal Dynamics of Tumor Vessel Cooption and Optimal Treatment strategies

Cooption of the host vasculature is a strategy that some cancers use to sustain tumor progression without—or before—angiogenesis or in response to antiangiogenic therapy. Facilitated by certain growth factors, cooption can mediate tumor infiltration and confer resistance to antiangiogenic drugs. Unfortunately, this mode of tumor progression is difficult to target because the underlying mechanisms are not fully understood. Here, we analyzed the dynamics of vessel cooption during tumor progression and in response to antiangiogenic treatment in gliomas and brain metastases. We followed tumor evolution during escape from antiangiogenic treatment as cancer cells coopted, and apparently mechanically compressed, host vessels. To gain deeper understanding, we developed a mathematical model, which incorporated compression of coopted vessels, resulting in hypoxia and formation of new vessels by angiogenesis. Even if antiangiogenic therapy can block such secondary angiogenesis, the tumor can sustain itself by coopting existing vessels. Hence, tumor progression can only be stopped by combination therapies that judiciously block both angiogenesis and cooption. Furthermore, the model suggests that sequential blockade is likely to be more beneficial than simultaneous blockade