UC Davis

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Osteosarcoma is an aggressive primary malignant bone tumor associated with high rates of metastasis and poor 5-year survival rates with limited improvements in approximately 40 years. Standard multimodality treatment includes chemotherapy and surgery, and survival rates have remained stagnant. Overall, response rates to immunotherapy like immune checkpoint inhibitors have been disappointing in osteosarcoma despite exciting results in other epithelial tumor types. The poor response of osteosarcoma to current immunotherapies is multifactorial, but a key observation is that the tumor microenvironment in osteosarcoma is profoundly immunosuppressive, and increasing evidence suggests a significant role of suppressive myeloid cells in tumor progression and immune evasion, particularly by myeloid-derived suppressor cells. Targeting suppressive myeloid cells via novel agents are attractive strategies to develop novel immunotherapies for osteosarcoma, and combination strategies will likely be important for durable responses. In this review, we will examine mechanisms of the immunosuppressive microenvironment, highlight pre-clinical and clinical data of combination strategies including colony-stimulating factor 1 (CSF-1) receptor, phosphoinositide 3-kinase (PI3K), CXCR4, and checkpoint inhibition, as well as the role of canine models in elucidating myeloid cells as targets in osteosarcoma immunotherapy.

A clinical need exists for more effective intravitreal (IVT) drug delivery systems (DDS). This study tested the hypothesis that a novel biodegradable, injectable microsphere-hydrogel drug delivery system loaded with aflibercept (aflibercept-DDS) would exhibit long-term safety and biocompatibility in a non-human primate (NHP) model. We generated aflibercept-loaded poly (lactic-co-glycolic acid) microparticles with a modified double emulsion technique then embedded them into a biodegradable, thermo-responsive poly (ethylene glycol)-co-(L-lactic-acid) diacrylate/N-isopropylacrylamide hydrogel. Aflibercept-DDS (50 µL, 15 µg) was injected into the right eye of 23 healthy rhesus macaques. A complete ophthalmic examination, intraocular pressure (IOP), corneal pachymetry, specular microscopy, A-scan biometry, streak retinoscopy, spectral-domain optical coherence tomography (SD-OCT), fluorescein angiography (FA), and electroretinography (ERG) were performed monthly. Globes from 7 NHPs were histologically examined. Aflibercept-DDS was visualized in the vitreous up to 9 months post-IVT injection, slightly impeding fundoscopy in 4 of 23 eyes; no other consistent abnormalities were appreciated during ophthalmic examination. The IOP and total retinal thickness remained normal in all animals over all timepoints. Central corneal thickness, endothelial cell density, axial globe length, and refractive error did not significantly differ from baseline. Scotopic mixed rod-cone implicit times and amplitudes along with photopic cone response implicit times and amplitudes did not significantly differ from control values. No retinal or choroidal vascular abnormalities were detected with FA and normal retinal architecture was preserved using SD-OCT. Intravitreal injection of a biodegradable aflibercept-DDS was safe and well tolerated in NHPs up to 24 months.

Rational design of multifunctional nanoplatforms capable of combining therapeutic effects with real-time monitoring of drug distribution and tumor status is emerging as a promising approach in cancer nanomedicine. Here, we introduce pyropheophorbide a-bisaminoquinoline conjugate lipid nanoparticles (PPBC LNPs) as a bimodal system for image-guided phototherapy in bladder cancer treatment. PPBC LNPs not only demonstrate both powerful photodynamic and photothermal effects upon light activation, but also exhibit potent autophagy blockage, effectively inducing bladder cancer cell death. Furthermore, PPBC LNPs possess remarkable photoacoustic (PA) and fluorescence (FL) imaging capabilities, enabling imaging with high-resolution, deep tissue penetration and high sensitivity for tracking drug biodistribution and phototherapy efficacy. Specifically, PA imaging confirms the efficient accumulation of PPBC LNPs within tumor and predicts therapeutic outcomes of photodynamic therapy, while FL imaging confirms their prolonged retention at the tumor site for up to 6 days. PPBC LNPs significantly suppress bladder tumor growth, with several tumors completely ablated following just two doses of the nanoparticles and laser treatment. Additionally, PPBC LNPs were formulated with lipid-based excipients and assembled using microfluidic technology to enhance biocompatibility, stability, and scalability, showing potential for clinical translation. This versatile nanoparticle represents a promising candidate for further development in bladder cancer therapy.

The therapeutic benefits of opioids are compromised by the development of analgesic tolerance, which necessitates higher dosing for pain management thereby increasing the liability for drug dependence and addiction. Rodent models indicate opposing roles of the gut microbiota in tolerance: morphine-induced gut dysbiosis exacerbates tolerance, whereas probiotics ameliorate tolerance. Not all individuals develop tolerance, which could be influenced by differences in microbiota, and yet no study design has capitalized upon this natural variation. We leveraged natural behavioral variation in a murine model of voluntary oral morphine self-administration to elucidate the mechanisms by which microbiota influences tolerance. Although all mice shared similar morphine-driven microbiota changes that largely masked informative associations with variability in tolerance, our high-resolution temporal analyses revealed a divergence in the progression of dysbiosis that best explained sustained antinociception. Mice that did not develop tolerance maintained a higher capacity for production of the short-chain fatty acid (SCFA) butyrate known to bolster intestinal barriers and promote neuronal homeostasis. Both fecal microbial transplantation (FMT) from donor mice that did not develop tolerance and dietary butyrate supplementation significantly reduced the development of tolerance independently of suppression of systemic inflammation. These findings could inform immediate therapies to extend the analgesic efficacy of opioids.

Contact detection and contact geometry are among the most important steps in Discrete Element Method (DEM) simulations. Accurately representing the contact between two particles is crucial, and when modeling fractured rock using polyhedral particles, the accuracy of the contact point calculation is essential for obtaining realistic and reliable simulation results. The point of contact is where contact forces are applied to particles in a DEM simulation and, thus, an inaccurate representation of that point leads to artificial torque acting on particles, resulting in non-physical rotation and particle interactions. Herein we present a new algorithm for accurately calculating the contact point between two colliding polyhedral particles. The algorithm uses the topology of the particles to assert their interaction with the plane of contact and not directly with each other. The new algorithm provides improved performance in terms of global stability of DEM models by mitigating numerically induced instability associated with errors and sporadic movement in the contact point calculation. The performance of the new algorithm is showcased in several examples that illustrate how accurately representing the contact point is a requirement for generating reliable numerical simulations.

Multimodal analgesic administration is a promising strategy for mitigating side effects typically associated with analgesia; nevertheless, variation in analgesic effectiveness still poses a considerable safety concern for both horses and veterinarians. Pharmacogenomic studies have started delving into genetic influences on varying drug effectiveness and related side effects. However, current findings have narrow implications and are limited in their ability to individualize analgesic dosages in horses. Hydromorphone and detomidine were administered to a cohort of 48 horses at standardized time intervals, with dosage rates recorded. Analgesic effectiveness was scored (1-3) based on pain response to dura penetration during cerebrospinal fluid centesis. Genome-wide association (GWA) analyses identified two SNVs passing the nominal significance threshold (P < 1 ×10^-5) in association with analgesic effectiveness. One SNV identified on chromosome 27 (rs1142378599) is contained within the LOC100630731 disintegrin and metalloproteinase domain-containing protein 5 gene. The second identified SNV is an intergenic variant located on chromosome 29 (rs3430772468) These SNVs accounted for 26.11 % and 31.72 % of explained variation in analgesic effectiveness respectively, with all eight of the horses with the lowest analgesic effectiveness expressing the A/C genotype at rs3430772468, with six of which also expressing the C/T genotype at rs1142872965. Whilst highlighting the multifactorial nature of analgesic efficacy, this study serves as an important step in the application of genome-wide approaches to better understand genetic factors underpinning commonly observed variation in analgesic effectiveness in horses, with the goal of tailoring analgesic dosage to minimize commonly observed side effects and improve the outcomes of equine pain management.

We present a system for dynamic triangle mesh processing entirely on the GPU. Our system features an efficient data structure that enables rapid updates to mesh connectivity and attributes. By partitioning the mesh into small patches, we process all dynamic updates for each patch within the GPU’s fast shared memory. This approach leverages speculative processing for conflict handling, minimizing rollback costs, maximizing parallelism, and reducing locking overhead. Additionally, we introduce a new programming model for dynamic mesh processing. This model provides concise semantics for dynamic updates, abstracting away concerns about conflicting updates during parallel execution. At the core of our model is the cavity operator, a general mesh update operator that facilitates any dynamic operation by removing a set of mesh elements and inserting new ones into the resulting void. We applied our system to various GPU applications, including isotropic remeshing, surface tracking, mesh decimation, and Delaunay edge flips. On large inputs, our system achieves an order-of-magnitude speedup compared to multi-threaded CPU solutions and is more than two orders of magnitude faster than state-of-the-art single-threaded CPU solutions. Furthermore, our data structure outperforms state-of-the-art GPU static data structures in terms of both speed and memory efficiency.

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