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Conventional dendritic cells subtype 1 (cDC1) play a vital role in the priming and expansion of tumor‐specific CD8+ T cells and their recruitment to tumor microenvironment. However, cDC1s are often underrepresented in the microenvironment. Systemic administration of Fms‐like tyrosine kinase 3 ligand, a hematopoietic growth factor that binds to FLT3 on myeloid and lymphoid progenitor cells, leads to cDC1 expansion in the periphery and recruitment into the microenvironment. FLT3 pathway stimulation using GS‐3583, a novel FLT3 agonistic Fc fusion protein, has the potential to promote T‐cell mediated antitumor activity. This was a first‐in‐human, placebo‐controlled study of GS‐3583 in healthy participants to evaluate the safety, pharmacokinetics (PK), and pharmacodynamic (PD) of escalating single doses (75–2000 μg) of GS‐3583. Each dose cohort enrolled 8–12 healthy participants who received GS‐3583 or placebo as single IV infusion at 3:1 ratio. As part of the PD evaluation, the changes in the number of cDC1 cells were investigated. GS‐3583 was well‐tolerated in healthy participants up to the highest evaluated dose (2000 μg). There have been no serious or grade III or higher adverse events. PK analysis suggested a dose‐dependent increase in GS‐3583 exposure with target‐mediated disposition characteristics at low doses. PD analysis shows that administration of GS‐3583 resulted in transient, dose‐dependent increases in cDC1 cells that returned to baseline within 3 weeks of drug administration. The pharmacokinetics and pharmacodynamics of GS‐3583 following single dosing were characterized in this study which enabled subsequent phase Ib assessments in patients with advanced solid tumors.

Hypertensive retinopathy (HR) can potentially lead to vision loss if left untreated. Early screening and treatment are critical in reducing the risk of vision loss. The computer-aided diagnostic system presents an opportunity to improve the efficiency and reliability of HR screening and diagnosis, particularly given the shortage of specialized medical professionals and the challenges faced by primary care physicians in making precise diagnoses. A notable barrier to the development of such diagnostic algorithms is the lack of publicly available benchmarks and datasets. To address these issues, we organized a challenge named “HRDC—Hypertensive Retinopathy Diagnosis Challenge” in conjunction with the Computer Graphics International (CGI) 2023 conference. The challenge provided a fundus image dataset for two clinical tasks: hypertension classification and HR classification, with each task containing 1000 images. This paper presents a concise summary and analysis of the submitted methods and results for the two challenge tasks. For hypertension classification, the best performing algorithm achieved a Kappa score of 0.3819, an F1 score of 0.6337, and a specificity of 0.8472. For HR classification, the best performing algorithm achieved a Kappa score of 0.4154, an F1 score of 0.6122, and a specificity of 0.8444. We also explored an ensemble approach to the top-ranking methods, which further improved performance beyond the individual best performing algorithm for each task. The challenge results show that there is room for further optimization of these methods, but the insights and methodologies derived from this challenge provide valuable directions for developing more precise and reliable classification models for hypertension and HR.

Hypertensive retinopathy (HR) can potentially lead to vision loss if left untreated. Early screening and treatment are critical in reducing the risk of vision loss. The computer-aided diagnostic system presents an opportunity to improve the efficiency and reliability of HR screening and diagnosis, particularly given the shortage of specialized medical professionals and the challenges faced by primary care physicians in making precise diagnoses. A notable barrier to the development of such diagnostic algorithms is the lack of publicly available benchmarks and datasets. To address these issues, we organized a challenge named “HRDC—Hypertensive Retinopathy Diagnosis Challenge” in conjunction with the Computer Graphics International (CGI) 2023 conference. The challenge provided a fundus image dataset for two clinical tasks: hypertension classification and HR classification, with each task containing 1000 images. This paper presents a concise summary and analysis of the submitted methods and results for the two challenge tasks. For hypertension classification, the best performing algorithm achieved a Kappa score of 0.3819, an F1 score of 0.6337, and a specificity of 0.8472. For HR classification, the best performing algorithm achieved a Kappa score of 0.4154, an F1 score of 0.6122, and a specificity of 0.8444. We also explored an ensemble approach to the top-ranking methods, which further improved performance beyond the individual best performing algorithm for each task. The challenge results show that there is room for further optimization of these methods, but the insights and methodologies derived from this challenge provide valuable directions for developing more precise and reliable classification models for hypertension and HR.

Paclitaxel is a common chemotherapeutic agent that is effective against various cancers. The poor aqueous solubility of paclitaxel necessitates a large percentage of Cremophor EL:ethanol (USP) in its commercial formulation which leads to hypersensitivity reactions in patients. We evaluate the use of a crystalline nanosuspension versus the USP formulation to deliver paclitaxel to tumor-bearing xenograft mice. Anti-tumor efficacy was assessed following intravenous administration of three 20 mg/kg doses of paclitaxel. Paclitaxel pharmacokinetics and tissue distribution were evaluated, and differences were observed between the two formulations. Plasma clearance and tissue to plasma ratio of mice that were dosed with the nanosuspension are approximately 33- and 11-fold higher compared to those of mice that were given the USP formulation. Despite a higher tumor to plasma ratio for the nanosuspension treatment group, absolute paclitaxel tumor exposure was higher for the USP group. Accordingly, a higher anti-tumor effect was observed in the xenograft mice that were dosed with the USP formulation (90% versus 42% tumor growth inhibition). This reduction in activity of nanoparticle formulation appeared to result from a slower than anticipated dissolution in vivo. This study illustrates a need for careful consideration of both dose and systemic solubility prior utilizing nanosuspension as a mode of intravenous delivery.

Drug polymer-based amorphous solid dispersions (ASD) are widely used in the pharmaceutical industry to improve bioavailability for poorly water-soluble compounds. Spray-drying is the most common process involved in the manufacturing of ASD material. However, spray-drying involves a high investment of material quantity and time. Lower investment manufacturing processes such as fast evaporation and freeze-drying (lyophilization) have been developed to manufacture ASD at the bench level. The general belief is that the overall performance of ASD material is thermodynamically driven and should be independent of the manufacturing process. However, no formal comparison has been made to assess the in vivo performance of material generated by different processes. This study compares the in vitro and in vivo properties of ASD material generated by fast evaporation, lyophilization, and spray-drying methods using griseofulvin as a model compound and hydroxypropyl methylcellulose acetate succinate as the polymer matrix. Our data suggest that despite minor differences in the formulation release properties and stability of the ASD materials, the overall exposure is comparable between the three manufacturing processes under the conditions examined. These results suggest that fast evaporation and lyophilization may be suitable to generate ASD material for oral evaluation. However, caution should be exercised since the general applicability of the present findings will need to be further evaluated.