Search

Industrial production of chemical cement leads to extreme emissions of greenhouse gases. Biological or bio-inspired sustainable materials for soil treatment projects can be employed instead of chemical cement to heal the carbon cycle in the ecosystem. The enzyme-induced calcite precipitation (EICP) method is one of the novel bio-inspired technologies that can be employed in soil treatment projects to increase desired properties of soils. While the monotonic and cyclic behavior of the enzymatically treated sands has been investigated comprehensively, the strain accumulation pattern in these improved soils under cyclic traffic loads has not been evaluated yet. In this paper, confined and unconfined cyclic compression tests are applied to the enzymatically lightly cemented sands, and the effects of the different parameters on their strain accumulation pattern are investigated for the first time in the literature. This study uses two types of specimens with unconfined compression strengths (UCS) equal to 42 ​kPa and 266 ​kPa. It is shown that the treated specimens have a rate-dependent behavior where cyclic loads with low frequencies lead to more resilient and plastic strains in the specimens. The results show that by approaching the maximum applied stresses to the UCS of the specimens (by breaking more calcite bonds between sand particles), the rate dependency behavior of specimens will reduce. Investigation of the effects of the cementation level demonstrated that by increasing the amount of the precipitated calcite from 0.38% to 0.83%, accumulated plastic strains are reduced almost 95% under the same loading condition. Effects of the initial static loads, confining pressures, the number of cycles, and amplitudes of the cyclic loads are also evaluated.

The seismic response of structures can have a significant impact on adjacent structures’ response. Although several numerical studies have been applied in the field of tunnel–soil–pile interaction systems, there is a lack of experimental research specifically focused on the effects of this interaction on tunnel cross-section deformation and the existence of structure on encircling soil response. In this study, shaking table tests were conducted to examine the seismic response of a tunnel and the surrounding soil when an eight-story structure with piles was located in the vicinity of the tunnel. Four series of physical models were analyzed, including free-field soil (S), tunnel–soil (TS), soil-piled structure (SP), and tunnel–soil-piled structure (TSP), under sinusoidal vibration at three frequencies on loose sand. According to the results, the tunnel significantly impacts the surrounding soil response during seismic excitation with reduced acceleration at the tunnel invert and increased acceleration at the tunnel crown. In the TSP model, applied frequency affects the recorded acceleration amplitude at the tunnel invert. Although acceleration amplitude decreases at 3 Hz frequency excitation compared to the free field model, 8 Hz excitation resulted in bigger values in tunnel invert. Displacements are higher at the tunnel crown, indicating tunnel-induced soil deformation and maximum shear strain concentrated near the tunnel crown. The tunnel cross-section exhibited oval shape changes, with higher forces on the tunnel crown in the presence of piles.

Background Adaptive CD19-targeted chimeric antigen receptor (CAR) T-cell transfer has become a promising treatment for leukemia. Although patient responses vary across different clinical trials, reliable methods to dissect and predict patient responses to novel therapies are currently lacking. Recently, the depiction of patient responses has been achieved using in silico computational models, with prediction application being limited.Methods We established a computational model of CAR T-cell therapy to recapitulate key cellular mechanisms and dynamics during treatment with responses of continuous remission (CR), non-response (NR), and CD19-positive (CD19+) and CD19-negative (CD19−) relapse. Real-time CAR T-cell and tumor burden data of 209 patients were collected from clinical studies and standardized with unified units in bone marrow. Parameter estimation was conducted using the stochastic approximation expectation maximization algorithm for nonlinear mixed-effect modeling.Results We revealed critical determinants related to patient responses at remission, resistance, and relapse. For CR, NR, and CD19+ relapse, the overall functionality of CAR T-cell led to various outcomes, whereas loss of the CD19+ antigen and the bystander killing effect of CAR T-cells may partly explain the progression of CD19− relapse. Furthermore, we predicted patient responses by combining the peak and accumulated values of CAR T-cells or by inputting early-stage CAR T-cell dynamics. A clinical trial simulation using virtual patient cohorts generated based on real clinical patient datasets was conducted to further validate the prediction.Conclusions Our model dissected the mechanism behind distinct responses of leukemia to CAR T-cell therapy. This patient-based computational immuno-oncology model can predict late responses and may be informative in clinical treatment and management.

Effective chimeric antigen receptor (CAR)-T cell therapy is dependent on optimal cell culture methods conducive to the activation and expansion of T cells ex vivo, as well as infection with CAR. Media formulations used in CAR-T cell manufacturing have not been optimized for gene delivery, cell expansion, and overall potency. Bioactive components and derivatives that support the generation of functionally-competent T cell progeny with long-lasting persistence are largely undefined. Current media formulations rely on fetal bovine serum (FBS) or human serum (HS), which suffer from a lack of consistency or supply issues. We recognize that components of blood cellular fractions that are absent in serum may have therapeutic value. Here we investigate whether a concentrated growth factor extract, purified from human transfusion grade whole blood fractions, and marketed as PhysiologixTM xeno-free (XF) hGFC (Phx), supports CAR-T cell expansion and function. We show that Phx supports T cell proliferation in clinical and research-grade media. We also show that Phx treatment enhances lentiviral-mediated gene expression across a wide range of multiplicity of infections (MOIs). We compared the ability of anti-GD-2 CAR-T cells expanded ex vivo in medium conditioned with either Phx or HS to clear tumor burden in a human xenograft model of neuroblastoma. We show that T cells expanded in Phx have superior engraftment and potency in vivo, as well as CAR-induced cytolytic activity in vitro. Metabolomic profiling revealed several factors unique to Phx that may have relevance for CAR-T cell preclinical discovery, process development, and manufacturing. In particular, we show that carnosine, a biogenic amine modestly enriched in Phx relative to HS, enhances lentiviral gene delivery in activated T cells. By limiting extracellular acidification, carnosine enhances the metabolic fitness of T cells, shifting their metabolic profile from an acidic, stressed state toward an oxidative, energetic state. These findings are very informative regarding potential derivatives to include in medium customized for gene delivery and overall potency for T cell adoptive immunotherapies.

Chimeric antigen receptor (CAR) T cell therapy has shown unprecedented success in treating advanced hematological malignancies. Its effectiveness in solid tumors has been limited due to heterogeneous antigen expression, a suppressive tumor microenvironment, suboptimal trafficking to the tumor site and poor CAR T cell persistence. Several approaches have been developed to overcome these obstacles through various strategies including the genetic engineering of CAR T cells to blunt the signaling of immune inhibitory receptors as well as to modulate signaling of cytokine/chemokine molecules and their receptors. In this review we offer our perspective on how genetically modifying cytokine/chemokine molecules and their receptors can improve CAR T cell qualities such as functionality, persistence (e.g. resistance to pro-apoptotic signals) and infiltration into tumor sites. Understanding how such modifications can overcome barriers to CAR T cell effectiveness will undoubtedly enhance the potential of CAR T cells against solid tumors.

The metabolic milieu of solid tumors provides a barrier to chimeric antigen receptor (CAR) T-cell therapies. Excessive lactate or hypoxia suppresses T-cell growth, through mechanisms including NADH buildup and the depletion of oxidized metabolites. NADH is converted into NAD+ by the enzyme Lactobacillus brevis NADH Oxidase (LbNOX), which mimics the oxidative function of the electron transport chain without generating ATP. Here we determine if LbNOX promotes human CAR T-cell metabolic activity and antitumor efficacy. CAR T-cells expressing LbNOX have enhanced oxygen as well as lactate consumption and increased pyruvate production. LbNOX renders CAR T-cells resilient to lactate dehydrogenase inhibition. But in vivo in a model of mesothelioma, CAR T-cell’s expressing LbNOX showed no increased antitumor efficacy over control CAR T-cells. We hypothesize that T cells in hostile environments face dual metabolic stressors of excessive NADH and insufficient ATP production. Accordingly, futile T-cell NADH oxidation by LbNOX is insufficient to promote tumor clearance.

Persistent activation of pancreatic stellate cells (PSCs) can perturb the biomechanical homeostasis of the tumour microenvironment. Here the authors show that all-trans retinoic acid reduces retinoic acid receptor beta dependent-actomyosin contractility and restores mechanical quiescence in PSCs.