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"Anderson, Nicholas"
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Human chimeric antigen receptor macrophages for cancer immunotherapy
Chimeric antigen receptor (CAR) T cell therapy has shown promise in hematologic malignancies, but its application to solid tumors has been challenging
1
,
2
,
3
–
4
. Given the unique effector functions of macrophages and their capacity to penetrate tumors
5
, we genetically engineered human macrophages with CARs to direct their phagocytic activity against tumors. We found that a chimeric adenoviral vector overcame the inherent resistance of primary human macrophages to genetic manipulation and imparted a sustained pro-inflammatory (M1) phenotype. CAR macrophages (CAR-Ms) demonstrated antigen-specific phagocytosis and tumor clearance in vitro. In two solid tumor xenograft mouse models, a single infusion of human CAR-Ms decreased tumor burden and prolonged overall survival. Characterization of CAR-M activity showed that CAR-Ms expressed pro-inflammatory cytokines and chemokines, converted bystander M2 macrophages to M1, upregulated antigen presentation machinery, recruited and presented antigen to T cells and resisted the effects of immunosuppressive cytokines. In humanized mouse models, CAR-Ms were further shown to induce a pro-inflammatory tumor microenvironment and boost anti-tumor T cell activity.
Primary macrophages engineered to express chimeric antigen receptors have anti-tumor activity in humanized mice.
Journal Article
Chronic contact with realistic soil concentrations of imidacloprid affects the mass, immature development speed, and adult longevity of solitary bees
The non-target effects of pesticides are an area of growing concern, particularly for ecologically and economically important organisms such as bees. Much of the previous research on the effects of neonicotinoids, a class of insecticide that has gained attention for non-target effects, on bees focused on the consumption of contaminated food resources by a limited number of eusocial species. However, neonicotinoids are known to accumulate and persist in soils at concentrations 2 to 60 times greater than in food resources, and may represent an important route of exposure for diverse and ecologically important ground-nesting bees. This study aimed to assess the effect of chronic contact exposure to realistic soil concentrations of imidacloprid, the most widely used neonicotinoid pesticide, on bee longevity, development speed, and body mass. Cohorts of
Osmia lignaria
and
Megachile rotundata
were used as proxies for ground-nesting species. We observed species- and sex-specific changes to adult longevity, development speed, and mass in response to increasing concentrations of imidacloprid. These results suggest that chronic exposure to nesting substrates contaminated with neonicotinoids may represent an important route of exposure that could have considerable physiological and ecological consequences for bees and plant-pollinator interactions.
Journal Article
A Preface to the First Critique: Reason’s Desire and Kant’s Political History of Metaphysics
Kant begins the 1781 Preface of the Critique of Pure Reason with a history of metaphysics told as a sequence of failed political regimes. This history has been largely passed over both in the literature on Kant’s metaphysics and in that on his political philosophy. This article provides an interpretation of Kant’s history of metaphysical regimes as a way of exploring the political themes and aims of the First Critique. Kant’s opening narrative articulates the role his critique of metaphysics plays in establishing the possibility of a lawful order of reason that defends morality against threats arising from reason’s theoretical dissatisfaction. The political history of metaphysics presented in the A Preface reveals Kant’s understanding of the public role philosophy must undertake in the context of the modern crisis of reason.
Journal Article
Mouse primary follicles experience slow growth rates after activation and progressive increases that influence the duration of the primary follicle phase
There are conflicting estimates of the duration of mouse primary follicle development. An accurate determination is needed for studies examining preantral follicle survival and mathematical modeling of folliculogenesis. Primary follicle granulosa cell proliferation rates are low and variable, which may explain the variation in duration estimates. In the present study, female C57Bl6/J mice were exposed to bromodeoxyuridine for 48 hours, to label the proliferating granulosa cells in a large proportion of primary follicles. The bromodeoxyuridine-containing water was then withdrawn and replaced with drug-free water and the mice were euthanized at 0, 1, 3, 6, 10, or 13 days post-bromodeoxyuridine withdrawal. Granulosa cells were bromodeoxyuridine labeled in 48% of primary follicles at day 0, but this decreased to 5% over the 13-day period, as the labeled primary follicles progressed to the secondary follicle stage. Curve-fitting estimated that the last of the bromodeoxyuridine-labeled primary follicles would progress to the secondary stage by 13.7 days. Mathematical models that assumed constant rates of primary follicle proliferation were fitted to the data, but the observed pattern of bromodeoxyuridine-labeled primary follicle disappearance could not be replicated. The level of immunoreactivity for bromodeoxyuridine and proliferating-cell nuclear antigen in primary follicles revealed follicles with no granulosa cell proliferation during the 48-h bromodeoxyuridine-exposure period had resumed proliferation 1 or 3 days later. Therefore, primary follicle granulosa cells proliferate after follicle activation, but proliferation rates gradually increase as the follicle develops. Prior estimates of primary follicle duration are inaccurate due to the assumption that follicles develop at a constant rate. Summary sentence The length of the primary follicle phase is 14–16 days in mice but follicle development pauses briefly, shortly after primordial follicle activation, and explains why prior mathematical model-based estimates were inaccurate.
Journal Article
A simulation of the random and directed motion of dendritic cells in chemokine fields
Dendritic cells (DCs) are the most effective professional antigen-presenting cell. They ferry antigen from the extremities to T cells and are essential for the initiation of an adaptive immune response. Despite interest in how DCs respond to chemical stimuli, there have been few attempts to model DC migration. In this paper, we simulate the motility of DCs by modeling the generation of forces by filopodia and a force balance on the cell. The direction of fliopodial extension is coupled to differential occupancy of cognate chemokine receptors across the cell. Our model simulates chemokinesis and chemotaxis in a variety of chemical and mechanical environments. Simulated DCs undergoing chemokinesis were measured to have a speed of 5.1 ± 0.07 μm·min-1 and a persistence time of 3.2 ± 0.46 min, consistent with experiment. Cells undergoing chemotaxis exhibited a stronger chemotactic response when exposed to lower average chemokine concentrations, also consistent with experiment. We predicted that when placed in two opposing gradients, cells will cluster in a line, which we call the \"line of equistimulation;\" this clustering has also been observed. We calculated the effect of varying gradient steepness on the line of equistimulation, with steeper gradients resulting in tighter clustering. Moreover, gradients are found to be most potent when cells are in a gradient of chemokine whose mean concentration is close to the binding of the Kd to the receptor, and least potent when the mean concentration is 0.1Kd. Comparing our simulations to experiment, we can give a quantitative measure of the strength of certain chemokines relative to others. Assigning the signal of CCL19 binding CCR7 a baseline strength of 1, we found CCL21 binding CCR7 had a strength of 0.28, and CXCL12 binding CXCR4 had a strength of 0.30. These differences emerge despite both chemokines having virtually the same Kd, suggesting a mechanism of signal amplification in DCs requiring further study.
Journal Article
Microenvironmental CXCL12 deletion enhances Flt3-ITD acute myeloid leukemia stem cell response to therapy by reducing p38 MAPK signaling
Fms-like tyrosine kinase 3 (Flt3) tyrosine kinase inhibitors (Flt3-TKI) have improved outcomes for patients with Flt3-mutated acute myeloid leukemia (AML) but are limited by resistance and relapse, indicating persistence of leukemia stem cells (LSC). Here utilizing a Flt3-internal tandem duplication (Flt3-ITD) and Tet2-deleted AML genetic mouse model we determined that FLT3-ITD AML LSC were enriched within the primitive ST-HSC population. FLT3-ITD LSC showed increased expression of the CXCL12 receptor CXCR4. CXCL12-abundant reticular (CAR) cells were increased in Flt3-ITD AML marrow. CXCL12 deletion from the microenvironment enhanced targeting of AML cells by Flt3-TKI plus chemotherapy treatment, including enhanced LSC targeting. Both treatment and CXCL12 deletion partially reduced p38 mitogen-activated protein kinase (p38) signaling in AML cells and further reduction was seen after treatment in CXCL12 deleted mice. p38 inhibition reduced CXCL12-dependent and -independent maintenance of both murine and human Flt3-ITD AML LSC by MSC and enhanced their sensitivity to treatment. p38 inhibition in combination with chemotherapy plus TKI treatment leads to greater depletion of Flt3-ITD AML LSC compared with CXCL12 deletion. Our studies support roles for CXCL12 and p38 signaling in microenvironmental protection of AML LSC and provide a rationale for inhibiting p38 signaling to enhance Flt3-ITD AML targeting.
Journal Article
In Field Fruit Sizing Using A Smart Phone Application
In field (on tree) fruit sizing has value in assessing crop health and for yield estimation. As the mobile phone is a sensor and communication rich device carried by almost all farm staff, an Android application (“FruitSize”) was developed for measurement of fruit size in field using the phone camera, with a typical assessment rate of 240 fruit per hour achieved. The application was based on imaging of fruit against a backboard with a scale using a mobile phone, with operational limits set on camera to object plane angle and camera to object distance. Image processing and object segmentation techniques available in the OpenCV library were used to segment the fruit from background in images to obtain fruit sizes. Phone camera parameters were accessed to allow calculation of fruit size, with camera to fruit perimeter distance obtained from fruit allometric relationships between fruit thickness and width. Phone geolocation data was also accessed, allowing for mapping fruits of data. Under controlled lighting, RMSEs of 3.4, 3.8, 2.4, and 2.0 mm were achieved in estimation of avocado, mandarin, navel orange, and apple fruit diameter, respectively. For mango fruit, RMSEs of 5.3 and 3.7 mm were achieved on length and width, benchmarked to manual caliper measurements, under controlled lighting, and RMSEs of 5.5 and 4.6 mm were obtained in-field under ambient lighting.
Journal Article
22 Advancing clinical trial reporting and AI integration: Optimizing protocol data extraction using LLMs and regulatory best practices
Objectives/Goals: This study aimed to enhance clinical trial data management through large language model information retrieval and generation techniques within the clinical trial reporting workflow. We focused on improving compliance with reporting, reducing human labor, and promoting standardized reporting structure and data quality oversight. Methods/Study Population: We used approved study protocols from UC Davis IRB-approved investigator-initiated studies compared to the same studies reported to ClinicalTrials.gov. Our baseline data extraction system employs commercial large language models (LLMs) and retrieval augmented generation (RAG) to isolate data sources within the secure extraction environment. We stratified protocol documents into easy, complex, and random categories based on study focus, document complexity, the extent of amendments or modifications, and completion metrics from ClinicalTrials.gov. We developed a pilot web-based architecture to capture variations in categorization, labeling, and reporting style and compared generated extraction data. We primarily focused on qualitative evaluation through a review of expert staff. Results/Anticipated Results: Our results revealed significant variations in reporting quality, with dependencies stemming from multiple authors and stages throughout the clinical trial protocol lifecycle. Based on these variations, we used prompt engineering to improve the pilot application’s output compliance with the protocol registration and results system (PRS) structured data format for various study types. We piloted the assisted workflow with prospective studies by partnering with study investigators and the clinical trial office staff to assist in review and clinical trial reporting creation. Initial studies reported by our system were approved and released to the public by PRS staff. We are refining content generation and workflows to different components of studies and evaluating their use in quality and training areas. Discussion/Significance of Impact: Our system fosters collaboration, efficient review, and compliance with clinical trial reporting standards. It supports the promise of AI-driven assistance in clinical trial management, design, and reporting. We focus on the multiple stakeholders, expertise, and data flows in the organizational management of clinical and translational science.
Journal Article
Technologies for Forecasting Tree Fruit Load and Harvest Timing—From Ground, Sky and Time
The management and marketing of fruit requires data on expected numbers, size, quality and timing. Current practice estimates orchard fruit load based on the qualitative assessment of fruit number per tree and historical orchard yield, or manually counting a subsample of trees. This review considers technological aids assisting these estimates, in terms of: (i) improving sampling strategies by the number of units to be counted and their selection; (ii) machine vision for the direct measurement of fruit number and size on the canopy; (iii) aerial or satellite imagery for the acquisition of information on tree structural parameters and spectral indices, with the indirect assessment of fruit load; (iv) models extrapolating historical yield data with knowledge of tree management and climate parameters, and (v) technologies relevant to the estimation of harvest timing such as heat units and the proximal sensing of fruit maturity attributes. Machine vision is currently dominating research outputs on fruit load estimation, while the improvement of sampling strategies has potential for a widespread impact. Techniques based on tree parameters and modeling offer scalability, but tree crops are complicated (perennialism). The use of machine vision for flowering estimates, fruit sizing, external quality evaluation is also considered. The potential synergies between technologies are highlighted.
Journal Article