What role does GPR65 play in the progression of osteosarcoma? Its mechanism and clinical significance.

BACKGROUND: GPR65 is a pH-sensing G-protein-coupled receptor that acts as a key innate immune checkpoint in the human tumor microenvironment, inhibiting the release of inflammatory factors and inducing significant upregulation of tissue repair genes. However, the expression pattern and function of GPR65 in osteosarcoma (OS) remain unclear. The purpose of this study was to investigate and elucidate the role of GPR65 in the microenvironment, proliferation and migration of OS. METHODS: Retrospective RNA-seq data analysis was conducted in a cohort of 97 patients with OS data in the TAEGET database. In addition, single-cell sequencing data from six surgical specimens of human OS patients was used to analyze the molecular evolution process during OS genesis. Tissues chips and bioinformatics results were used to verify GPR65 expression level in OS. MTT, colony formation, EdU assay, wound healing, transwell assay and F-actin assay were utilized to analyze cell proliferation and invasion of OS cancer cells. RNA-seq was used to explore the potential mechanism of GPR65's role in OS. RESULTS: GPR65 expression was significantly low in OS, and subgroup analysis found that younger OS patients, OS patients in metastatic status, and overall survival and progression free survival OS patients had lower GPR65 expression. From ScRNA-seq data of GSE162454, we found the expression of GPR65 is significantly positively correlated with CD4 + T cells CD8 + T cells and OS related macrophage infiltration. Verification experiment found that silencing the expression of GPR65 in osteosarcoma cells U2OS and HOS could promote the proliferation and invasion process, RNA-seq results showed that the role of GPR65 in OS cells was related to immune system, metabolism and signal transduction. CONCLUSION: The low expression of GPR65 in OS leads to high metastasis rate and poor prognosis in OS patients. The suppression of immune escape and inhibition of proliferation may be a key pathway for GPR65 to participate in the progression of OS. The current study strengthens the role of GPR65 in OS development and provides a potential biomarker for the prognosis of OS patients.

Pediatric model-based dose optimization using a pooled exposure-response safety analysis for nivolumab and nivolumab plus ipilimumab combination in melanoma.

An exposure-response (E-R) safety analysis was conducted across adult and pediatric (<18 years) studies to evaluate the potential impact of higher nivolumab and/or ipilimumab exposures in adolescents (≥12 to <18 years) versus adults with melanoma using the approved adult dosing regimens for nivolumab alone or in combination with ipilimumab. Data from 3507 patients across 15 studies were used to examine the relationship between nivolumab-ipilimumab daily average exposure and time to grade 2+ immune-mediated adverse events (gr2+ IMAEs). Results from the E-R safety model showed ipilimumab, but not nivolumab, exposure to be a statistically significant predictor of gr2+ IMAEs. Significant covariates included sex (41% higher risk for women than men), line of therapy (19% higher for first-line than later-line), and treatment setting (26% lower for adjuvant than advanced melanoma). Younger age and lower body weight (BW) were each associated with a lower risk of gr2+ IMAEs (hazard ratio [HR]: 0.830 for 15-year-olds versus 60-year-olds and 0.84 for BW 52 kg versus 75 kg). For adolescents with melanoma treated with nivolumab in the advanced or adjuvant settings, these results are supportive of nivolumab flat dosing regimens for adolescents greater than or equal to 40 kg and BW-based dosing for adolescents less than 40 kg. These results also support adult weight-based dosing regimens for nivolumab plus ipilimumab in adolescents with advanced melanoma. This analysis suggests that although higher exposures are predicted in adolescents with lower weight compared with adults, there is no predicted immune-mediated safety risk when treated with the approved adult dosing of nivolumab with/without ipilimumab.

Nivolumab and ipilimumab population pharmacokinetics in support of pediatric dose recommendations-Going beyond the body-size effect.

Body size has historically been considered the primary source of difference in the pharmacokinetics (PKs) of monoclonal antibodies (mAbs) between children aged greater than or equal to 2 years and adults. The contribution of age-associated differences (e.g., ontogeny) beyond body-size differences in the pediatric PKs of mAbs has not been comprehensively evaluated. In this study, the population PK of two mAbs (nivolumab and ipilimumab) in pediatric oncology patients were characterized. The effects of age-related covariates on nivolumab or ipilimumab PKs were assessed using data from 13 and 10 clinical studies, respectively, across multiple tumor types, including melanoma, lymphoma, central nervous system tumors (CNSTs), and other solid tumors. Clearance was lower in pediatric patients (aged 1-17 years) with solid tumors or CNST than in adults after adjusting for other covariates, including the effect of body size. In contrast, clearance was similar in pediatric patients with lymphoma to that in adults with lymphoma. The pediatric effects characterized have increased the accuracy of the predictions of the model, facilitating its use in subsequent exposure comparisons between pediatric and adult patients, as well as for exposure-response analyses to inform pediatric dosing. This study approach may be applicable to the optimization of pediatric dosing of other mAbs and possibly other biologics.

Platinum nanoflowers stabilized with aloe polysaccharides for detection of organophosphorus pesticides in food.

Organophosphorus pesticides can inhibit the activity of acetylcholinesterase and cause neurological diseases. Therefore, it is crucial to establish an efficient and sensitive platform for organophosphorus pesticide detection. In this work, we extracted aloe polysaccharide (AP) from aloe vera with the number average molecular weight of 27760 Da and investigated its reducing property. We prepared aloe polysaccharide stabilized platinum nanoflowers (AP-Ptn NFs), their particle size ranges were 29.4-67.3 nm. Furthermore, AP-Ptn NFs exhibited excellent oxidase-like activity and the catalytic kinetics followed the typical Michaelis-Menten equation. They showed strong affinity for 3,3',5,5'-tetramethylbenzidine substrates. More importantly, we developed a simple and effective strategy for the sensitive colorimetric detection of organophosphorus pesticides in food using biocompatible AP-Ptn NFs. The detection range was 0.5 µg/L - 140 mg/L, which was wider than many previously reported nanozyme detection systems. This colorimetric biosensor had good selectivity and good promise for bioassay analysis.

Polymers in Engineering Extracellular Vesicle Mimetics: Current Status and Prospective.

The maintenance of a high delivery efficiency by traditional nanomedicines during cancer treatment is a challenging task. As a natural mediator for short-distance intercellular communication, extracellular vesicles (EVs) have garnered significant attention owing to their low immunogenicity and high targeting ability. They can load a variety of major drugs, thus offering immense potential. In order to overcome the limitations of EVs and establish them as an ideal drug delivery system, polymer-engineered extracellular vesicle mimics (EVMs) have been developed and applied in cancer therapy. In this review, we discuss the current status of polymer-based extracellular vesicle mimics in drug delivery, and analyze their structural and functional properties based on the design of an ideal drug carrier. We anticipate that this review will facilitate a deeper understanding of the extracellular vesicular mimetic drug delivery system, and stimulate the progress and advancement of this field.

Pharmacokinetics and pharmacodynamics of ropinirole in patients with prolactinomas.

AIMS: Treatment of prolactinomas with ergoline dopamine agonists can be complicated by intolerance and resistance. This study investigated the pharmacokinetics and pharmacodynamics of the nonergot dopamine agonist ropinirole, to assess its therapeutic potential as a novel therapy for prolactinomas. METHODS: Five female subjects with prolactinomas participated in this dose-response study. Subjects received up to three doses of ropinirole (0.5, 1.0 and 2.0 mg), each on separate occasions. Frequent blood samples for prolactin and ropinirole were collected for 24 h following drug administration. Data were analysed using noncompartmental and compartmental pharmacokinetic-pharmacodynamic (PKPD) techniques. RESULTS: Seven 24-h curves revealed increased systemic drug exposure with increasing ropinirole doses. Ropinirole concentrations peaked at 4.4 ± 2.7 h and exhibited a half-life of 5.8 ± 1.7 h. A dose-dependent prolactin nadir occurred 4.4 ± 1.2 h after drug intake and prolactin concentrations transiently normalized in two of five subjects. PKPD modelling revealed that single-dose PK of ropinirole is dose-independent and can be described with a one-compartment model with linear absorption and elimination. An indirect response model successfully captures the inhibitory effect of ropinirole on prolactin secretion and incorporates time-dependent receptor desensitization for three of five subjects whose prolactin concentrations nadired before ropinirole reached Cmax . CONCLUSIONS: This data-rich study has informed our understanding of the clinical pharmacokinetics and pharmacodynamics of ropinirole, which are successfully captured by the proposed semi-mechanistic PKPD model. This model can be used to further investigate the PKPD of ropinirole and may facilitate the identification of optimal dose regimens for the treatment of prolactinomas and the establishment of a new therapeutic option for patients impacted by this rare disease.

Methylphenidate exerts dose-dependent effects on glutamate receptors and behaviors.

BACKGROUND: Methylphenidate (MPH), a psychostimulant drug used to treat attention-deficit/hyperactivity disorder, produces the effects of increasing alertness and improving attention. However, misuse of MPH has been associated with an increased risk of aggression and psychosis. We sought to determine the molecular mechanism underlying the complex actions of MPH. METHODS: Adolescent (4-week-old) rats were given one injection of MPH at different doses. The impact of MPH on glutamatergic signaling in pyramidal neurons of prefrontal cortex was measured. Behavioral changes induced by MPH were also examined in parallel. RESULTS: Administration of low-dose (.5 mg/kg) MPH selectively potentiated N-methyl-D-aspartate receptor (NMDAR)-mediated excitatory postsynaptic currents (EPSCs) via adrenergic receptor activation, whereas high-dose (10 mg/kg) MPH suppressed both NMDAR-mediated and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor-mediated EPSCs. The dual effects of MPH on EPSCs were associated with bidirectional changes in the surface level of glutamate receptor subunits. Behavioral tests also indicated that low-dose MPH facilitated prefrontal cortex-mediated temporal order recognition memory and attention. Animals injected with high-dose MPH exhibited significantly elevated locomotive activity. Inhibiting the function of synaptosomal-associated protein 25, a key SNARE protein involved in NMDAR exocytosis, blocked the increase of NMDAR-mediated EPSCs by low-dose MPH. In animals exposed to repeated stress, administration of low-dose MPH effectively restored NMDAR function and temporal order recognition memory via a mechanism dependent on synaptosomal-associated protein 25. CONCLUSIONS: These results provide a potential mechanism underlying the cognitive-enhancing effects of low-dose MPH as well as the psychosis-inducing effects of high-dose MPH.