High Clearance Research Articles

Impact of relative cisplatin dose to skeletal muscle mass on adverse events in patients with head and neck cancer undergoing chemoradiotherapy.

Chemoradiotherapy (CRT) with high-dose cisplatin (CDDP) is the standard treatment for locally advanced head and neck squamous cell carcinoma (HNSCC). Although dosing is based on body surface area (BSA), some patients experience CDDP-related adverse events (AEs). We aimed to evaluate the impact of relative CDDP dose to skeletal muscle mass (SMM) on chemotherapy-associated AEs in patients with HNSCC undergoing CRT with high-dose CDDP. We retrospectively analyzed data of patients who underwent CRT with high-dose CDDP (80-100 mg/m2, triweekly) between 2010 and 2023. SMM was measured as the cross-sectional muscle area at the third cervical vertebra (C3-SMM) using computed tomography; the skeletal muscle index (SMI) was defined as SMM normalized by squared height. The CDDP index was defined as the prescribed CDDP dose divided by SMI. CDDP-related AEs were assessed during the first cycle using Common Terminology Criteria for Adverse Events v5.0. Overall, 306 patients were identified. The CDDP index cutoff value best associated with grade ≥ 3 AEs was 10.312. Grade ≥ 3 hematological toxicities exhibited stronger association with high CDDP index value than with low CDDP index value (26.9% vs 16.3%, P = .033). Multivariate analysis revealed that high CDDP index value and creatinine clearance < 70 mL/minute were predictive factors for grade ≥ 3 AEs (odds ratio [OR] 2.55, P = .008; OR 3.68, P = .002, respectively). The CDDP index based on C3-SMM was an independent predictive factor for grade ≥ 3 CDDP-related AEs. C3-SMM is potentially more useful than BSA for determining the optimal CDDP dose in patients with HNSCC.

Efficacy and safety of chloroquine plus primaquine for the treatment of Plasmodium vivax malaria in Hamusit site, Northwestern Ethiopia

BackgroundPlasmodium vivax malaria is still an important public health problem in Ethiopia. Unlike Plasmodium falciparum, P. vivax has a dormant liver stage (hypnozoite) that can be a risk of recurrent vivax malaria unless treated by radical cure with primaquine. Drug resistance to chloroquine is threatening malaria control and elimination efforts. This study assessed the therapeutic efficacy and safety of chloroquine plus 14 days of primaquine on P. vivax infection based on parasitological, clinical, and haematological parameters.MethodsA single-arm in vivo prospective therapeutic efficacy study was conducted to assess the clinical and parasitological response to the first-line treatment of P. vivax in Ethiopia, chloroquine plus 14 days low dose of (0.25 mg/kg/day) primaquine between December 2022 and March 2023 at Hamusit Health Centre using the standard World Health Organization (WHO) protocol. A total of 100 study participants with P. vivax mono-infection who were over 6 months old were enrolled and monitored for adequate clinical and parasitological responses for 42 days. The WHO double-entry Excel sheet and SPSS v.25 software were used for Kaplan–Meier survival analysis, and a paired t-test was used for analysis of haemoglobin improvements between follow up days.ResultsA total of 100 patients were enrolled among those, 96% cases were rural residents, 93% had previous malaria exposure, and predominant age group was 5–15 years (61%). 92.6% (95% CI 85.1–96.4%) of enrolled patients were adequate clinical and parasitological response, and 7.4% (95% CI 3.6–14.9%) recurrences were observed among treated patients. The fever and parasite clearance rate on day 3 were 98% and 94%, respectively. The baseline haemoglobin levels improved significantly compared to those days 14 and 42 (p < 0.001). No serious adverse event was observed during the study period.ConclusionsIn this study, co-administration of chloroquine with primaquine was efficacious and well-tolerated with fast resolution of fever and high parasites clearance rate. However, the 7.4% failure is reported is alarming that warrant further monitoring of the therapeutic efficacy study of P. vivax.

Discovery of N′-benzyl-3-chloro-N-((1S,3R,4R)-3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)cyclohexyl)benzenesulfonamide as a novel selective KOR ligand

The effective management of moderate to severe pain often relies on the use of analgesic agents. However, the widespread utility of these medications is hindered by the occurrence of several undesirable side effects. In light of this challenge, there is growing interest in the development of κ opioid receptor (KOR) agonists, which have shown promise in mitigating these adverse effects. In this study, leveraging the structural scaffold of compound D (our previous study), we embarked on the design, synthesis, and evaluation of a series of N′-benzyl-3-chloro-N- ((1S,3R,4R)-3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)cyclohexyl)benzenesulfonamide derivatives. These compounds were subjected to comprehensive in vitro and in vivo test. Through systematic structure-activity relationship (SAR) exploration, we successfully identified compound 23p (Ki(KOR):1.9 nM) as a highly selective KOR ligand of new chemotype. 23p showed high clearance in vitro PK test, and abdominal contraction test showed potent antinociceptive effect. 23p and its O-demethyl metabolite 25 were both found in the plasma of mouse, 25 also showed potent affinity toward KOR (Ki(KOR): 3.1 nM), both they contribute to the analgesic effect. Moreover, 23p exhibited potent antinociceptive activity in abdominal constriction test, which was effectively abolished by pre-treatment of nor-BNI, a selective KOR antagonist.

Comparison of the efficacy and safety of ciprofol and propofol in sedating patients in the operating room and outside the operating room: a meta-analysis and systematic review

BackgroundAs a new type of intravenous anesthetic, ciprofol has the advantages of fast onset of action, fast recovery and high clearance rate. This study aimed to investigate the effectiveness and safety of ciprofol versus traditional propofol for anesthesia and sedation in and out of the operating room.MethodsWe searched the literature in PubMed, Web of Science, Cochrane Library, and Embase databases from January 2021 to December 2023. All clinical studies comparing the sedative effects of propofol and ciprofol, both inside and outside the operating room, were included in our trial. The main outcome measures were induction time and incidence of injection-site pain. Data are merged using risk ratio and standardized mean difference with 95% confidence interval. Subgroup analysis, meta-regression, sensitivity analysis, and publication bias were performed. The study protocol was prospectively registered with PROSPERO (CRD42023447747).ResultsA total of 15 randomized, controlled trials involving 2002 patients were included in this study. Compared with propofol, ciprofol has a longer induction time in the operating room but a shorter induction time in non-operating room settings. Ciprofol can effectively reduce the risk of injection-site pain and respiratory depression both inside and outside the operating room. In addition, the risk of drug-related hypotension induced with ciprofol in the operating room is lower, but the awakening time is also longer. Meta-regression analysis showed that neither age nor BMI were potential sources of heterogeneity. Funnel plot, egger and begg tests showed no significant publication bias. Sensitivity analyzes indicate that our results are robust and reliable.ConclusionCiprofol has absolute advantages in reducing the risk of injection-site pain and respiratory depression, both in and outside operating room. Intraoperative use of ciprofol reduces the risk of drug-related hypotension and may also reduce the risk of intraoperative physical movements. However, ciprofol may have longer induction and awakening time than propofol.

Design and synthesis of novel and potent allosteric HIV-1 integrase inhibitors with a spirocyclic moiety

We report herein the design and discovery of novel allosteric HIV-1 integrase inhibitors. Our design concept utilized the spirocyclic moiety to restrain the flexibility of the conformation of the lipophilic part of the inhibitor. Compound 5 showed antiviral activity by binding to the nuclear lens epithelium-derived growth factor (LEDGF/p75) binding site of HIV-1 integrase (IN). The introduction of a lipophilic amide substituent into the central benzene ring resulted in a significant increase in antiviral activity against HIV-1 WT X-ray crystallography of compound 15 in complex with the integrase revealed the presence of a hydrogen bond between the oxygen atom of the amide of compound 15 and the hydroxyl group of the T125 side chain. Chiral compound 17 showed high antiviral activity, good bioavailability, and low clearance in rats.

B2R-Targeting Radiotracer for PET/MR Imaging of Hepatocellular Carcinoma and Guiding Anti-B2R Therapy.

The bradykinin B2 receptor (B2R) is overexpressed in a wide variety of tumors and is a well-defined target for tumor imaging and therapy. The hybrid positron emission tomography/magnetic resonance imaging (PET/MRI) scanner is considered a noninvasive and advanced instrument for precise tumor imaging. In this work, we developed a novel B2R-targeting radiotracer, 68Ga-DOTA-icatibant, for quantifying B2R expression. 68Ga-DOTA-icatibant showed high stability, fast clearance and specific binding to B2R. PET/MR imaging revealed excellent tumor accumulation, and the uptake in tumors could be blocked by DOTA-icatibant. Icatibant-mediated anti-B2R therapy downregulated B2R expression in tumor cells and inhibited the growth of HepG2 tumors, and the decrease in tumor uptake was monitored by timely PET/MR imaging. Hematoxylin and eosin (H&E) and immunohistochemical staining results further demonstrated that the efficacy of anti-B2R could be accurately monitored with the developed PET/MR imaging radiotracer. 68Ga-DOTA-icatibant can be utilized to noninvasively determine B2R expression and dynamically and sensitively monitor the efficacy of anti-B2R therapy.

Cysteinylprolyl ester-mediated drug release from a lipid–drug conjugate

For small-molecule drugs, lipidation via a cleavable linkage can extend half-life in circulation through interaction with albumin. Here we modified the cysteinylprolyl ester (CPE) system used in peptide thioester synthesis, which normally requires basic conditions, for use as an self-immolative linker and release device for a lipid-gemcitabine conjugate. To improve release under physiological conditions for medical application, a methyl group at the α-position of cysteine on the CPE unit was incorporated in anticipation of the Thorpe-Ingold effect. As a result, Ac-Gly-(α-Me)Cys(SH)-Pro-gemcitabine 11 drastically promoted the release of gemcitabine in comparison with Ac-Gly-Cys(SH)-Pro-gemcitabine 10. Furthermore, in the presence of bovine serum albumin and/or 2-mercaptoethanesulfonic acid, the gentle and continuous release of gemcitabine from the lipid–gemcitabine conjugate 16 was achieved. In addition to gemcitabine, this method could allow high clearance drugs, including nucleic acid and prostacyclin derivatives, to maintain their biological activity long enough to become effective.

Discovery, Multiparametric Optimization, and Solid-State Driven Identification of CHF-6550, a Novel Soft Dual Pharmacology Muscarinic Antagonist and β2 Agonist (MABA) for the Inhaled Treatment of Respiratory Diseases.

Clinical guidelines for COPD and asthma recommend inhaled β-adrenergic agonists, muscarinic antagonists, and, for frequent exacerbators, inhaled corticosteroids, with the challenge of combining them into a single device. The MABA (muscarinic antagonist and β2 agonist) concept has the potential to simplify this complexity while increasing the efficacy of both pharmacologies. In this article, we report the outcome of our solid-state driven back-up program that led to the discovery of the MABA compound CHF-6550. A soft drug approach was applied, aiming at high plasma protein binding and high hepatic clearance, concurrently with an early stage assessment of crystallinity through a dedicated experimental workflow. A new chemotype was identified, the diphenyl hydroxyacetic esters, able to generate crystalline material. Among this class, CHF-6550 demonstrated in vivo efficacy, suitability for dry powder inhaler development, favorable pharmacokinetics, and safety in preclinical settings and was selected as a back-up candidate, fulfilling the desired pharmacological and solid-state profile.

Research and Experiment on Cruise Control of a Self-Propelled Electric Sprayer Chassis

In order to address the issues of poor stability in vehicle speed and deteriorated spraying quality caused by changes in road slope and the decrease in overall mass due to liquid spraying, this study focuses on analyzing the structure and longitudinal dynamic characteristics of a 4WID high ground clearance self-propelled electric sprayer. By utilizing MATLAB/Simulink software, three subsystems, namely, the inverse longitudinal dynamics model, torque distribution model, and motor model, are established. The model takes into account the effects of longitudinal driving resistance, slope, and vehicle roll angle on the distribution of loads among the four wheels during slope driving. A seven-degrees-of-freedom dynamic model is developed. A hierarchical control structure is designed, incorporating an upper-level PID controller and a lower-level fuzzy PID controller, to control the overall system. The control algorithms are tailored to the specific characteristics of the sprayer’s operation, and simulation experiments are conducted under the corresponding operating conditions. Building upon this, a sensor-equipped experimental platform is set up in the self-propelled sprayer manufactured by the team in the preliminary stage. Real vehicle tests are conducted in two scenarios: transition transportation and field operations, with the evaluation of the overall vehicle speed serving as the performance metric to validate the correctness of the model and the control theory.

The use of a surgical logbook to improve training and patient safety: A retrospective analysis of 6years' experience in Bristol, UK.

Logbooks can be a useful educational tool. Although their use in medical training has been greatly explored, there is limited research into their application throughout a clinician's career. We created a surgical logbook to allow clinicians to record their skin surgery procedures and reflect on the histological diagnosis and clearance margins achieved. We provide a retrospective analysis to evaluate the usefulness of the logbook as an analytical and educational tool in a dermatology department, particularly for maintaining exemplary complete excision rates. Data was collected from clinicians who conducted skin surgery in Bristol, UK. Cases were entered at the time of surgery, collecting data on body site, clinical margin, suspected diagnosis, type of procedure and closure. Following receipt of histological results, data on histological excision margins and tumour type was entered. Each clinician submitted data for a minimum of 3months each year, and data collection ran from April 2012 until March 2018. Data from 5161 excision surgeries was collected over the 6-year period. On histological diagnosis, excisions constituted 50% Basal Cell Carcinoma (BCC), 12% Squamous Cell Carcinoma (SCC), 9% Malignant Melanoma (MM) and 1% Lentigo Maligna (LM), and 28% 'Other' (rarer malignancies, melanoma wide local excision scars and pre-cancerous/benign lesions). The department was found to have good diagnostic concordance: BCC 92%, SCC 87%, MM 80% and LM 53%. Overall complete excision rate was high at 97.07%. The most successfully excised cancer was BCC (97.50%), then SCC (97.14%) MM (96.48%) and LM (95.23%). The department provided many complex surgeries including 8.3% flaps and 8.5% grafts. Average lesion diameter was 11mm (range 2-90mm). There was a significant improvement in excision rates seen over the years for BCC, MM and LM. Although there was no significant difference found for SCC, this group began the study with already high clearance rates. This surgical logbook supports improved training and continues professional development. We encourage more departments to use this logbook and share the data that they produce. This could improve their excision rates, patient experience, and save them up to £28000 per year.

Preclinical pharmacokinetic studies of villocarine A, an active Uncaria alkaloid.

Villocarine A is a bioactive indole alkaloid isolated from the Uncaria genus. It has demonstrated vasorelaxation activity and potential to protect the central nervous system. To identify the pharmacokinetic properties of villocarine A, a series of in vitro and in vivo studies have been performed. Villocarine A was found to be highly permeable (15.6 ± 1.6*10-6cm/s) across human colorectal adenocarcinoma cell monolayer with high protein binding (>91%) in both rat and human plasma. Hepatic extraction ratio of villocarine A was 0.1 in pooled rat liver and 0.2 in human liver microsomes and was found stable in rat plasma at 37°C. Due to the high permeability and low rate of metabolism properties, villocarine A was initially considered suitable for preclinical development and an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for quantification (linearity: 1-150 ng/ml) in rat plasma was developed and validated for in vivo studies. Essential pharmacokinetic parameters included the volume of distribution and clearance of villocarine A, which were found to be 100.3 ± 15.6L/kg and 8.2 ± 1.1L/h/kg, respectively, after intravenous administration in rats. Following oral dosing, villocarine A exhibited rapid absorption as the maximum plasma concentration (53.2 ± 10.4ng/ml) occurred at 0.3 ± 0.1h, post-dose. The absolute oral bioavailability of villocarine A was 16.8 ± 0.1%. To our knowledge, this was the first pharmacokinetic study of villocarine A, which demonstrated the essential pharmacokinetic properties of villocarine A: large volume distribution, high clearance, and low oral bioavailability in rats.

Evaluating the biomolecular interaction between delamanid/formulations and human serum albumin by fluorescence, CD spectroscopy and SPR: Effects on protein conformation, kinetic and thermodynamic parameters

Delamanid is an anti-tuberculosis drug used for the treatment of drug-resistant tuberculosis. Since delamanid has a high protein bound potential, even patients with low albumin levels should experience high and rapid delamanid clearance. However, the interaction between delamanid and albumin should be better controlled to optimize drug efficacy. This study was designed to evaluate the binding characteristics of delamanid to human serum albumin (HSA) using various methods: fluorescence spectroscopy, circular dichroism (CD), surface plasmon resonance (SPR), and molecular docking simulation. The fluorescence emission band without any shift indicated the interaction was not affected by the polarity of the fluorophore microenvironment. The reduction of fluorescence intensity at 344 nm was proportional to the increment of delamanid concentration as a fluorescence quencher. UV-absorbance measurement at the maximum wavelength (λmax, 280 nm) was evaluated using inner filter effect correction. The HSA conformation change was explained by the intermolecular energy transfer between delamanid and HSA during complex formation. The study, which was conducted at temperatures of 298 K, 303 K, and 310 K, revealed a static quenching mechanism that correlated with a decreased of bimolecular quenching rate constant (kq) and binding constant (Ka) at increased temperatures. The Ka was 1.75–3.16 × 104 M−1 with a specific binding site with stoichiometry 1:1. The negative enthalpy change, negative entropy change, and negative Gibbs free energy change demonstrated an exothermic-spontaneous reaction while van der Waals forces and hydrogen bonds played a vital role in the binding. The molecular displacement approach and molecular docking confirmed that the binding occurred mainly in subdomain IIA, which is a hydrophobic pocket of HSA, with a theoretical binding free energy of −9.33 kcal/mol. SPR exhibited a real time negative sensorgram that resulted from deviation of the reflex angle due to ligand delamanid-HSA complex forming. The binding occurred spontaneously after delamanid was presented to the HSA surface. The SPR mathematical fitting model revealed that the association rate constant (kon) was 2.62 × 108 s−1M−1 and the dissociation rate constant (koff) was 5.65 × 10−3 s−1. The complexes were performed with an association constant (KA) of 4.64 × 1010 M−1 and the dissociation constant (KD) of 2.15 × 10−11 M. The binding constant indicated high binding affinity and high stability of the complex in an equilibrium. Modified CD spectra revealed that conformation of the HSA structure was altered by the presence of delamanid during preparation of the proliposomes that led to the reduction of secondary structure stabilization. This was indicated by the percentage decrease of α-helix. These findings are beneficial to understanding delamanid-HSA binding characteristics as well as the drug administration regimen.

Plane and vertical design research on end-around taxiways at high plateau airports

The end-around taxiways have been proven to effectively reduce the risk of runway incursions caused by frequent aircraft crossings on closely spaced parallel runways, thus enhancing airport capacity. This practice has gained popularity in recent years, especially in large airports. However, there is currently limited experience in designing and operating end-around taxiways, particularly in high plateau airports facing challenging conditions such as a high water table and low obstacle clearance gradient. In this paper, we present a case study of the second runway project at a specific airport and propose various operational schemes for end-around taxiway construction, including straight, oblique, and controlled designs. We calculate aircraft payload under different obstacle clearance gradients using flight performance analysis. Taking into account both operational and groundwater levels, we determine the appropriate plane and vertical design of end-around taxiways. The findings of this research provide valuable references for the design of end-around taxiways.

Charge-Switchable nanoparticles to enhance tumor penetration and accumulation

Nanoparticle-based drug delivery systems hold potential in chemotherapy, but their limited accumulation in tumor tissues hinders effective drug concentration for combating tumor growth. Hence, altering the physicochemical properties of nanoparticles, particularly their surface charge, can enhance their performance. This study utilized a computational model to explore a nanoparticle drug delivery system capable of dynamically adjusting its surface charge. In the model, nanoparticles in the bloodstream were assigned a neutral or positive charge, which, upon reaching the tumor microenvironment, switched to a neutral or negative charge, and releasing chemotherapy drugs into the extracellular space. Results revealed that circulating nanoparticles with a positive surface charge, despite having a shorter circulation and high clearance rate compared to their neutral counterparts, could accumulate significantly in the tissue due to their high transvascular rate. After extravasation, neutralized surface-charged nanoparticles tended to accumulate only near blood microvessels due to their low diffusion rate, resulting in substantial released drug drainage back into the bloodstream. On the other hand, nanoparticles with a negative surface charge in the tumor’s extracellular space, due to the reduction of nano-bio interactions, were able to penetrate deeper into the tumor, and increasing drug bioavailability by reducing the volume of drained drugs. Furthermore, the analysis suggested that burst drug release yields a higher drug concentration than sustained drug release, however their creation of bioavailability dependent on nanoparticle accumulation in the tissue. The study’s findings demonstrate the potential of this delivery system and offer valuable insights for future research in this area.

Percutaneous nephrolithotomy or flexible ureteral lithotripsy, which one is better for patients with upper ureteral calculi of 1.5–2.0 cm in diameter

PurposeFirst research to evaluate the clinical efficacy and safety of flexible ureteral lithotripsy (FURSL) and percutaneous nephrolithotomy (PCNL) in the treatment of the upper ureteral stone is between 1.5 cm and 2.0 cm in diameter since there is no consensus with such ureteral stone yet.MethodsFrom December 2018 to October 2022, 104 patients with calculi in the upper ureter received percutaneous nephrolithotomy (PCNL)or flexible ureteroscopic lithotripsy (FURSL) in our institution. The clinical data of the patients in the two groups were retrospectively searched. Stone removal rate, operation time, blood loss, postoperative pain score, postoperative inflammatory factor, postoperative complication rates and ureteral obstruction three months after the operation were compared between the two groups.ResultsA total of 104 patients were included in the study. The stone clearance rate and the secondary surgery rate were 88.89% and 7.41% in the FURSL group, the figures were 97.96% and 2.0% in the PCNL group (p = 0.067, 0.497). Regarding ureteral obstruction three months after the operation, there were 2 patients in FURSL group and 0 patients in PCNL group(p = 0.497).Compared to patients in FURSL group, patients in the PCNL group had shorter operation time(PCNL 71.81 ± 18.94 min vs. FURSL 86.80 ± 22.49 min, p = 0.0004), fewer complications(PCNL 20.37% vs. FURSL 6.12%), and lower postoperative inflammatory factor(p = 0.0004), yet they got more hemoglobin drop (PCNL 13.14 ± 9.81 g/L vs. FURSL 4.77 ± 3.55 g/L, p < 0.0001), higher postoperative pain scores(p = 0.0017) in the first three postoperative days and longer hospital stay (PCNL 4.96 ± 1.21 days vs. FURSL 3.60 ± 0.83 days).ConclusionBoth FURSL and PCNL were effective methods for treating upper ureteral stones of 1.5–2.0 cm in diameter given the extremely high stone clearance rate and a very low secondary surgery rate, as long as rare ureteral obstruction in medium-long term observation. Additionally, FURSL can effectively reduce surgical bleeding, postoperative pain, and hospital stay, while PCNL can decrease operation time, the risk of infection, and complications. Therefore, doctors could select suitable surgical treatment for those patients depending on their different clinical situations based on these findings.

Continuous-variable quantum key distribution over 28.6 km fiber with an integrated silicon photonic receiver chip

Quantum key distribution, which ensures information-theoretically secret key generation, is currently advancing through photonic integration to achieve high performance, cost reduction, and compact size, thereby facilitating the large-scale deployment. Continuous-variable quantum key distribution is an attractive approach for photonic integrations due to its compatibility with off-the-shelf optical communication devices. However, its chip-based systems have encountered significant limitations primarily related to the shot-noise-limited receiver design, which demands low noise, wide bandwidth, high clearance, and well stability. Here, we report the implementation of a real local oscillator continuous-variable quantum key distribution system with an integrated silicon photonic receiver chip. Thanks to the well-designed chip-based homodyne detectors with a bandwidth up to 1.5 GHz and a clearance up to 7.42 dB, the transmission distance of the system has been extended to 28.6 km, achieving a secret key generation rate of Mbps level. This technological advancement enables the quantum key distribution systems with photonic integrated receivers to achieve the coverage in both access network scenarios and short-distance metropolitan interconnections, paving the way for the development of the next-generation quantum key distribution networks on a large scale.

Fabrication and characterization of TiO2‐hydroxyapatite composite‐loaded Polysulfone membranes with integrated biocompatibility for dialysis application

AbstractBackgroundThe use of Polysulfone (PSf) as membrane material for dialysis therapy is becoming more common. However, the PSf membrane can cause the adsorption of blood proteins followed by the adhesion of platelets, destruction of red blood cells, and thrombus formation. One of the biggest challenges in creating membranes for hemodialysis (HD) applications is ensuring biocompatibility. Therefore, to maintain the biocompatibility of PSf membranes, further modifications are necessary.MethodsIn this study, the performance and biocompatibility of PSf membranes were improved by the impregnation of TiO2‐hydroxyapatite composite as an additive. The TiO2‐hydroxyapatite composite was first synthesized via sintering at 1200°C, and then a dope solution composed of pristine PSf polymer solution in N‐Methyl‐2‐pyrrolidone solvent (NMP) and different wt% ratios of the synthesized composite were prepared, and resultant membranes were fabricated using a film applicator via a phase inversion scheme using water as a non‐solvent exchange medium. The synthesized composite was characterized using SEM, EDX, and XRD techniques.ResultsThe FTIR analysis confirmed the weak interaction of PSf polymer with the hydroxyapatite moiety of the composite. The interaction of the synthesized composite within the membrane matrix was evaluated via leaching ratio results. The hydrophilicity, pore profile, and pure water permeation flux rates were also determined. The results of the biocompatibility study showed that membranes based on TiO2‐hydroxyapatite composite had reduced adsorption of BSA protein by 34.41% as well as less than 5% hemolysis ratio. Additionally, the study displayed thrombus formation ranging from 2.08% to 8.69%, respectively. The dialysis results indicated that compared with the original PSf membrane, the TiO2‐hydroxyapatite composite showed high clearance rates for urea (73.81%) and creatinine (72.13%) solutes, respectively.ConclusionTherefore, blending TiO2‐hydroxyapatite composite in the PSf membrane significantly improved the biocompatibility and removal ability of uremic solutes.

A Low Transition Temperature Mixture-based viscosupplementation complemented with celecoxib for osteoarthritis treatment

Viscosupplementation consists of hyaluronic acid (HA) intra-articular injections, commonly applied for osteoarthritis treatment while non-steroidal anti-inflammatory drugs (NSAIDs) are widely administered for pain relief. Here, HA and a NSAID (celecoxib) were combined in a formulation based on a low transition temperature mixture (LTTM) of glycerol:sorbitol, reported to increase celecoxib’s solubility, thus rendering a potential alternative viscosupplement envisioning enhanced therapeutic efficiency. The inclusion of glucosamine, a cartilage precursor, was also studied. The developed formulations were assessed in terms of rheological properties, crucial for viscosupplementation: the parameters of crossover frequency, storage (G’) and loss (G’’) moduli, zero-shear-rate viscosity, stable viscosity across temperatures, and shear thinning behaviour, support viscoelastic properties suitable for viscosupplementation. Additionally, the gels biocompatibility was confirmed in chondrogenic cells (ATDC5). Regarding drug release studies, high and low clearance scenarios demonstrated an increased celecoxib (CEX) release from the gel (6 to 73-fold), compared to dissolution in PBS. The low clearance setup presented the highest and most sustained CEX release, highlighting the importance of the gel structure in CEX delivery. NMR stability studies over time demonstrated the LTTM+HA+CEX (GHA+CEX) gel as viable candidate for further in vivo evaluation. In sum, the features of GHA+CEX support its potential use as alternative viscosupplement.

Research on Path Tracking of Unmanned Spray Based on Dual Control Strategy

The high clearance spray is a type of large and efficient agricultural machinery used for plant protection, and path tracking control is the key to ensure the efficient and safe operation of spray. Sliding mode control and other methods are commonly used abroad to track vehicles, while fuzzy control, neural networks and other methods are commonly used at home. However, domestic and foreign research on autonomous agricultural machinery is mainly focused on tractors and other machinery, while research on self-propelled spray in high clearance is less abundant. This paper takes the path tracking algorithm in the integrated navigation system of spray as the main research goal, studies the path tracking control algorithm for straight lines and turning curves that can realize the automatic driving of spray by establishing the path tracking algorithm for unmanned spray based on dual control strategies, designs the path tracking controller, including the preview model theoretical path tracking controller and variable domain fuzzy controller, and determines the preview model through the design of the preview model theoretical path tracking controller. The lateral and longitudinal errors of the model algorithm are analyzed, and the driving characteristics under the complex spray road surface are analyzed. The design of the variable domain fuzzy predictor theory path tracking controller is proposed, and the design of the road model selection controller is calculated and analyzed in detail, including the determination of the road roughness coefficient and the selection of the range of the difference between the average value of the excitation before and after sampling, which improves the performance of the spray path tracking algorithm. The experiment shows that the proposed path tracking control algorithm can meet the path tracking requirements of unmanned spray in the current road environment, and provide a reliable solution for the automatic control of high clearance spray.

Abstract 4070: CIS-demasking cytokine linker technology allows a selective cytokine delivery to activated immune cells while sparing others and peripheral toxicity

Abstract Immunocytokines are promising new therapeutic approaches to enhance T-cell response by delivering interleukins into the tumoral site. Fusion of wild-type or attenuated interleukins to anti-PD-1 antibody has shown some efficacy to preferentially cis-activate PD1-expressing T-cells but on-target/off-tumor activity on PD-1-negative cells is still observed due to the high affinity of the cytokine to its receptor leading a broad systemic effect, toxicity, high clearance and low tumor biodistribution limiting the potential of some immunocytokines (e.g. anti-PD-1/IL-2/IL-15/IL-21). Various strategies have emerged to achieve localized cytokine activation using conditional strategies (e.g. allosteric modulators, MMP-cleavable linkers or pH-dependent binding) that remain challenging due to high dependency to specific TME composition (MMP, acidosis...). We developed the OSE-Cytomask® Platform, a universal and innovative linker technology allowing exclusive cytokine CIS-demasking upon binding of the fused antibody to its target without TRANS-activation associated with undesired effects (e.g. Toxicity). A series of different linkers were screened for optimal cis-activation of cytokine on PD1-expressing vs PD1-negative T-cells using different cytokines fused to a high-affinity anti-PD1. OSE-Cytomask® linker technology decreases IL-2 or IL-15 cytokine activity (pSTAT5 signaling) on PD1-negative cells while maintaining high activation of PD1-transduced T-cells even in co-culture. We confirmed activity of OSE-Cytomask® Immunocytokine on (PD1+) human T-cells while very low activation has been observed in naïve T-cells. Importantly, Cytomask® linker technology does not induce TRANS-activation on PD1-negative T-cells illustrating an innovative and strict CIS-demasking mechanism of action. In vivo, Anti-PD-1/IL-15 and/or anti-PD1/IL-2 OSE-Cytomask® molecules illustrated reduced toxicity after single or multiple injections (2mg/kg). High T-cell proliferation has been observed in tumor-micro-environment where PD1-expressing T cells are located. Low T-cell proliferation in periphery was seen, illustrating the potential of CIS-demasking technology to target the right T-cells at the right place. Altogether, OSE-Cytomask® linker technology illustrates specific intrinsic property to mask cytokine on naïve peripheral immune cells not expressing the target of the antibody while allowing selective CIS-demasking of the cytokine and CIS-activation of activated immune cells expressing (e.g. PD-1). This linker technology could be used with a broad range of cytokine to abrogate OFF-tumor cytokine activity associated with toxicity while selectively CIS-activating activated immune cells in the TME. Citation Format: Aurore Morello, Caroline Mary, Virginie Thepenier, Margaux Seité, Justine Durand, Cécile Batty, Kévin Biteau, Julien Taurelle, Géraldine Teppaz, Amandine Georges, Nicolas Poirier. CIS-demasking cytokine linker technology allows a selective cytokine delivery to activated immune cells while sparing others and peripheral toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4070.