A Phase I Clinical Study Comparing the Pharmacokinetics, Safety, and Immunogenicity of GB221 Injection and Trastuzumab (Herceptin®) in Healthy Chinese Adults.

BACKGROUND AND OBJECTIVE: GB221 is a recombinant humanized anti-HER2 monoclonal antibody. The purpose of this study was to evaluate the pharmacokinetic, safety, and immunogenicity of GB221 in healthy Chinese adults in comparison to trastuzumab (Herceptin®). METHODS: In this randomized, double-blind, parallel-group phase I clinical trial, 88 subjects were randomized 1:1 to receive a single intravenous infusion (90-100 min) of GB221 or trastuzumab (6 mg/kg). The primary pharmacokinetic parameters-maximum observed serum concentration (Cmax), area under the serum concentration-time curve from zero to the last quantifiable concentration at time t (AUC0-t), and area under the serum concentration-time curve from time zero to infinity (AUC0-∞)-of GB221 and trastuzumab were compared to establish whether the 90% confidence interval (CI) attained the 80-125% bioequivalence standard. Safety and immunogenicity were also evaluated. RESULTS: The GB221 group (n = 43) and the trastuzumab group (n = 44) showed similar pharmacokinetic characteristics. The geometric mean ratios (90% CI) of Cmax, AUC0-t, and AUC0-∞ between the two groups were 107.53% (102.25-113.07%), 108.31% (103.57-113.26%), and 108.34% (103.57-113.33%), respectively. The incidence of treatment-emergent adverse events (TEAEs) was 83.7% (36/43) of the subjects in the GB221 group and 95.5% (42/44) of the subjects in the trastuzumab group. No subjects withdrew from the trial due to TEAEs, and there were no occurrences of serious adverse events. All subjects tested negative for antidrug antibodies (ADA). CONCLUSION: GB221 demonstrated similar pharmacokinetics to trastuzumab and comparable safety and immunogenicity in healthy Chinese adults.

Deep Reinforcement Learning for Integration of Train Trajectory Optimization and Timetable Rescheduling Under Disturbances.

High-speed trains are susceptible to unexpected events such as strong winds and equipment failures, which can result in deviations from the scheduled timetable. As the density of traffic increases, these delays can quickly spread to other trains, eventually leading to conflicts in the timetable. To ensure the efficiency of high-speed railways, quickly resolving potential conflicts and generating appropriate rescheduling schemes are essential. The existing hierarchical structure of train control and online rescheduling tends to be inefficient in terms of information communication and can even lead to unfeasible rescheduled timetables and trajectories. To address these issues, an integrated structure of timetable rescheduling and train trajectory optimization is proposed by introducing the train minimum running time into the process of timetable rescheduling and using the adjusted running time as the objective of trajectory optimization. The integration model is formulated by considering the constraints of timetable rescheduling such as the maximum number of trains overtaking trains, platforms at stations, and the priority of the train, as well as the constraints of trajectory optimization. A deep reinforcement learning (DRL)-based approach is proposed to solve the problem. Numerical experiments are conducted on a segment of the Beijing-Shanghai high-speed railway line, using adapted data to demonstrate the effectiveness of the proposed method in rescheduling timetables and optimizing train trajectories. The results show that the integrated rescheduled timetable and the optimized train trajectory can be generated simultaneously and the computation time exhibits a linear increase with respect to the size of the problem.

Efficacy, Safety, and Population Pharmacokinetics of MW032 Compared With Denosumab for Solid Tumor-Related Bone Metastases: A Randomized, Double-Blind, Phase 3 Equivalence Trial.

Importance: The bioequivalence of denosumab biosimilar has yet to be studied in a 53-week, multicenter, large-scale, and head-to-head trial. A clinically effective biosimilar may help increase access to denosumab in patients with solid tumor-related bone metastases. Objectives: To establish the biosimilarity of MW032 to denosumab in patients with solid tumor-related bone metastases based on a large-scale head-to-head study. Design, Setting, and Participants: In this 53-week, randomized, double-blind, phase 3 equivalence trial, patients with solid tumors with bone metastasis were recruited from 46 clinical sites in China. Overall, 856 patients were screened and 708 eligible patients were randomly allocated to receive either MW032 or denosumab. Interventions: Patients were randomly assigned (1:1) to receive MW032 or reference denosumab subcutaneously every 4 weeks until week 49. Main Outcomes and Measures: The primary end point was percentage change from baseline to week 13 of natural logarithmic transformed urinary N-telopeptide/creatinine ratio (uNTx/uCr). Results: Among the 701 evaluable patients (350 in the MW032 group and 351 in the denosumab group), the mean (range) age was 56.1 (22.0-86.0) years and 460 patients were women (65.6%). The mean change of uNTx/uCr from baseline to week 13 was -72.0% (95% CI, -73.5% to -70.4%) in the MW032 group and -72.7% (95% CI, -74.2% to -71.2%) in the denosumab group. These percent changes corresponded to mean logarithmic ratios of -1.27 and -1.30, or a difference of 0.02. The 90% CI for the difference (-0.04 to 0.09) was within the equivalence margin (-0.13 to 0.13); the mean changes of uNTx/uCr and bone-specific alkaline phosphatase (s-BALP) at each time point were also similar during 53 weeks. The differences of uNTx/uCr change were 0.015 (95% CI, -0.06 to 0.09), -0.02 (95% CI, -0.09 to 0.06), -0.05 (95% CI, -0.13 to 0.03) and 0.001 (95% CI, -0.10 to 0.10) at weeks 5, 25, 37, and 53, respectively. The differences of s-BALP change were -0.006 (95% CI, 0.06 to 0.05), 0.00 (95% CI, -0.07 to 0.07), -0.085 (95% CI, -0.18 to 0.01), -0.09 (95% CI, -0.20 to 0.02), and -0.13 (95% CI, -0.27 to 0.004) at weeks 5, 13, 25, 37 and 53, respectively. No significant differences were observed in the incidence of skeletal-related events (-1.4%; 95% CI, -5.8% to 3.0%) or time to first on-study skeletal-related events (unadjusted HR, 0.86; P = .53; multiplicity adjusted HR, 0.87; P = .55) in the 2 groups. Conclusions and Relevance: MW032 and denosumab were biosimilar in efficacy, population pharmacokinetics, and safety profile. Availability of denosumab biosimilars may broaden the access to denosumab and reduce the drug burden for patients with advanced tumors. Trial Registration: ClinicalTrials.gov Identifier: NCT04812509.

Research on the sustainable development of tourism coupled with economic and environment data--a case study of Hangzhou.

The scale of tourism has continued to expand in recent years, and many associated activities cause damage to the natural environment. The tourism, economy and natural environment constitute a system: destruction of the natural environment reduces the value of tourism and a lack of tourism affects the development of the economy. To explore the relationship between the tourism, economy and natural environment, and to explore possibilities for sustainable development, this paper takes Hangzhou, a tourist city in China, as a research object. An analysis of time series data is carried out. First, the tourism, economy and natural environment subsystems are constructed by extracting time series data acquired between 2010 and 2020. Second, a tourism evaluation model with coupled economic and natural environment data is constructed and the coupling degree and coupling coordination level in Hangzhou are evaluated. Third, the time series of each subsystem and the coupling coordination level of the whole system are analyzed. Finally, an optimization strategy is proposed for the coupled coordinated development of the tourism, economy and natural environment in Hangzhou. A key result is that the tertiary industry represented by tourism has become the main source of local income. Hangzhou's tourism coupling coordination level has changed from slight disorder in 2010 to good in 2020. It is also found that the COVID-19 pandemic has become a major factor restricting the development of tourism. Before the outbreak of COVID-19, Hangzhou's tourism industry and economy were synchronized. After the outbreak of COVID-19, both the number of tourists and tourism revenue in Hangzhou fell by nearly 15%.

Evaluating the Performance of Different Large Language Models on Health Consultation and Patient Education in Urolithiasis.

OBJECTIVES: To evaluate the effectiveness of four large language models (LLMs) (Claude, Bard, ChatGPT4, and New Bing) that have large user bases and significant social attention, in the context of medical consultation and patient education in urolithiasis. MATERIALS AND METHODS: In this study, we developed a questionnaire consisting of 21 questions and 2 clinical scenarios related to urolithiasis. Subsequently, clinical consultations were simulated for each of the four models to assess their responses to the questions. Urolithiasis experts then evaluated the model responses in terms of accuracy, comprehensiveness, ease of understanding, human care, and clinical case analysis ability based on a predesigned 5-point Likert scale. Visualization and statistical analyses were then employed to compare the four models and evaluate their performance. RESULTS: All models yielded satisfying performance, except for Bard, who failed to provide a valid response to Question 13. Claude consistently scored the highest in all dimensions compared with the other three models. ChatGPT4 ranked second in accuracy, with a relatively stable output across multiple tests, but shortcomings were observed in empathy and human caring. Bard exhibited the lowest accuracy and overall performance. Claude and ChatGPT4 both had a high capacity to analyze clinical cases of urolithiasis. Overall, Claude emerged as the best performer in urolithiasis consultations and education. CONCLUSION: Claude demonstrated superior performance compared with the other three in urolithiasis consultation and education. This study highlights the remarkable potential of LLMs in medical health consultations and patient education, although professional review, further evaluation, and modifications are still required.

Doubly Screened Coulomb Correction Approach for Strongly Correlated Systems.

Strongly correlated systems containing d/f electrons present a challenge to conventional density functional theory such as the local density approximation or generalized gradient approximation. We developed a doubly screened Coulomb correction (DSCC) approach to perform on-site Coulomb interaction correction for strongly correlated materials. The on-site Coulomb interaction between localized d/f electrons is self-consistently determined from a model dielectric function that includes both the static dielectric and Thomas-Fermi screening. We applied DSCC to simulate the electronic and magnetic properties of typical 3d, 4f, and 5f strongly correlated systems. The accuracy of DSCC is comparable to that of hybrid functionals but an order of magnitude faster. In addition, DSCC can reflect the difference in the Coulomb interaction between metallic and insulating situations, similar to the popular but computationally expensive constrained random phase approximation approach. This feature suggests that DSCC is also a promising method for simulating Coulomb interaction parameters.

Jackstone in the renal calyx: A rare case report.

BACKGROUND: Jackstone is a rare entity of calculi in urinary tracts and has the characteristic appearance resembling toy jacks. They are nearly always reported to occur in the urinary bladder, we first report a rare case of jackstone located in the obstructed renal calyx. CASE SUMMARY: We report a 46-year-old man presenting with intermittent, painless gross hematuria and left flank pain. Urinary computed tomography revealed staghorn stones and secondary hydronephrosis. A jackstone with radiating branches was found in one of the dilated renal calyx. Percutaneous nephrolithotomy was performed and endoscopic images were recorded during the operation. Postoperative stone composition analysis revealed it as calcium oxalate monohydrate stones. CONCLUSION: Jackstones can occur in the renal collecting system besides the bladder. The unique appearance and imaging manifestations are the most important factors in the diagnosis of jackstones, and further exploration of the formation mechanism is required.

Phase I, Randomized, Placebo-Controlled, Dose-Escalation Study of GB223, a Fully-Humanized Monoclonal Antibody to RANKL, in Healthy Chinese Adults.

BACKGROUND: GB223 is a novel, fully-humanized monoclonal antibody against the receptor activator of nuclear factor-kappa B ligand (RANKL). In this phase I study, the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of GB223 were investigated. PATIENTS AND METHODS: This was a randomized, double-blinded, placebo-controlled, single-dose escalation study conducted in 44 healthy Chinese adults. Participants were randomly assigned to receive a single subcutaneous injection dose of 7, 21, 63, 119, or 140 mg of GB223 (n = 34) or placebo (n = 10) and were followed up for 140-252 days. RESULTS: The results of noncompartmental analysis showed that GB223 was slowly absorbed after dosing, with a time to reach maximum concentration (Tmax) ranging from 5 to 11 days. Serum GB223 concentrations decreased slowly, with a long half-life ranging from 7.91 to 19.60 days. A two-compartment Michaelis-Menten model was found to best describe the pharmacokinetics of GB223, and the absorption rate of GB223 differed between males (0.0146 h-1) and females (0.0081 h-1). Serum C-terminal telopeptide of type I collagen decreased significantly postdose, and the inhibition lasted 42-168 days. No deaths or drug-related serious adverse events occurred. The most frequent adverse events were blood parathyroid hormone increased (94.1%), blood phosphorus decreased (67.6%) and blood calcium decreased (58.8%). In the GB223 group, 44.1% (15/34) of subjects were antidrug antibody positive after dosing. CONCLUSION: In this study, we demonstrated for the first time that a single subcutaneous injection of GB223, from 7 to 140 mg, is safe and well tolerated in healthy Chinese subjects. GB223 has a nonlinear pharmacokinetic profile, and sex was a potential covariate that may affect the absorption rate of GB223. CLINICAL TRIAL REGISTRATION: NCT04178044 and ChiCTR1800020338.

Construction and immunogenicity of an mRNA vaccine against chikungunya virus.

Chikungunya fever (CHIKF) has spread to more than 100 countries worldwide, with frequent outbreaks in Europe and the Americas in recent years. Despite the relatively low lethality of infection, patients can suffer from long-term sequelae. Until now, no available vaccines have been approved for use; however, increasing attention is being paid to the development of vaccines against chikungunya virus (CHIKV), and the World Health Organization has included vaccine development in the initial blueprint deliverables. Here, we developed an mRNA vaccine using the nucleotide sequence encoding structural proteins of CHIKV. And immunogenicity was evaluated by neutralization assay, Enzyme-linked immunospot assay and Intracellular cytokine staining. The results showed that the encoded proteins elicited high levels of neutralizing antibody titers and T cell-mediated cellular immune responses in mice. Moreover, compared with the wild-type vaccine, the codon-optimized vaccine elicited robust CD8+ T-cell responses and mild neutralizing antibody titers. In addition, higher levels of neutralizing antibody titers and T-cell immune responses were obtained using a homologous booster mRNA vaccine regimen of three different homologous or heterologous booster immunization strategies. Thus, this study provides assessment data to develop vaccine candidates and explore the effectiveness of the prime-boost approach.

Initial decomposition mechanisms and the inverse effects of temperature and PH2 on the thermodynamic stability of UH3.

The thermodynamic stability of uranium hydrides is of broad interest and fundamental importance for understanding the hydriding corrosion of uranium, and the storage and isotope separation of hydrogen. Based on the first-principles calculations, we reveal the initial decomposition mechanism, interpret the experimental pyrolysis results, and discuss the inverse effects of temperature and hydrogen pressure (PH2) on the thermodynamic stability of ß-UH3. The decomposition mechanism of ß-UH3 is found to be closely related to the changes of U-H bonding properties in UH12 cages. Specifically, at the beginning it is difficult to break the first U-H covalent bond in each UH12 cage, which brings in the existence of a concave region in the experimental PH2-C-T curve; however, it boosts the itinerant character of U-5f electrons. Thereafter, the formation energy of H-vacancies in the degraded UH11 cages is almost changeless when the H/U atom ratio decreases, resulting in the van't Hoff plateau of the PH2-C-T curve. Based on the above mechanisms, we propose a theoretical method to evaluate the thermodynamic stability of ß-UH3. The calculated PH2-C-T curve is consistent with experiment, showing that temperature promotes ß-UH3 decomposition and PH2 plays an opposite role. Moreover, this method is independent of experimental calibration and is applied to discuss the isotope effect of hydrogen in ß-UH3. This work provides new insight and a practical method for the scientific studies of uranium hydride, which is also essential to industrial applications in hydrogen isotope separation.

The responses of poplars to fungal pathogens: A review of the defensive pathway.

Long-lived tree species need to cope with changing environments and pathogens during their lifetime. Fungal diseases cause damage to trees growth and forest nurseries. As model system for woody plants, poplars are also hosts of a large variety of fungus. The defense strategies to fungus are generally associated with the type of fungus, therefore, the defense strategies of poplar against necrotrophic and biotrophic fungus are different. Poplars initiate constitutive defenses and induced defenses based on recognition of the fungus, hormone signaling network cascades, activation of defense-related genes and transcription factors and production of phytochemicals. The means of sensing fungus invasion in poplars are similar with herbs, both of which are mediated by receptor proteins and resistance (R) proteins, leading to pattern-triggered immunity (PTI) and effector-triggered immunity (ETI), but poplars have evolved some unique defense mechanisms compared with Arabidopsis due to their longevity. In this paper, current researches on poplar defensive responses to necrotrophic and biotrophic fungus, which mainly include the physiological and genetic aspects, and the role of noncoding RNA (ncRNA) in fungal resistance are reviewed. This review also provides strategies to enhance poplar disease resistance and some new insights into future research directions.

Comparative study of first-principles approaches for effective Coulomb interaction strength Ueff between localized f-electrons: Lanthanide metals as an example.

As correlation strength has a key influence on the simulation of strongly correlated materials, many approaches have been proposed to obtain the parameter using first-principles calculations. However, a comparison of the different Coulomb strengths obtained using these approaches and an investigation of the mechanisms behind them are still needed. Taking lanthanide metals as an example, we research the factors that affect the effective Coulomb interaction strength, Ueff, by local screened Coulomb correction (LSCC), linear response (LR), and constrained random-phase approximation (cRPA) in the Vienna Ab initio Simulation Package. The Ueff LSCC value increases from 4.75 to 7.78 eV, Ueff LR is almost stable at about 6.0 eV (except for Eu, Er, and Yb), and Ueff cRPA shows a two-stage decreasing trend in both light and heavy lanthanides. To investigate these differences, we establish a scheme to analyze the coexistence and competition between the orbital localization and the screening effect. We find that LSCC and cRPA are dominated by the orbital localization and the screening effect, respectively, whereas LR shows the balance of the competition between the two factors. Additionally, the performance of these approaches is influenced by different starting points from the Perdew-Burke-Ernzerhof (PBE) and PBE + U, especially for cRPA. Our results provide useful knowledge for understanding the Ueff of lanthanide materials, and similar analyses can also be used in the research of other correlation strength simulation approaches.

Multi-modal brain MRI images enhancement based on framelet and local weights super-resolution.

Magnetic resonance (MR) image enhancement technology can reconstruct high-resolution image from a low-resolution image, which is of great significance for clinical application and scientific research. T1 weighting and T2 weighting are the two common magnetic resonance imaging modes, each of which has its own advantages, but the imaging time of T2 is much longer than that of T1. Related studies have shown that they have very similar anatomical structures in brain images, which can be utilized to enhance the resolution of low-resolution T2 images by using the edge information of high-resolution T1 images that can be rapidly imaged, so as to shorten the imaging time needed for T2 images. In order to overcome the inflexibility of traditional methods using fixed weights for interpolation and the inaccuracy of using gradient threshold to determine edge regions, we propose a new model based on previous studies on multi-contrast MR image enhancement. Our model uses framelet decomposition to finely separate the edge structure of the T2 brain image, and uses the local regression weights calculated from T1 image to construct a global interpolation matrix, so that our model can not only guide the edge reconstruction more accurately where the weights are shared, but also carry out collaborative global optimization for the remaining pixels and their interpolated weights. Experimental results on a set of simulated MR data and two sets of real MR images show that the enhanced images obtained by the proposed method are superior to the compared methods in terms of visual sharpness or qualitative indicators.

An effective pre-treatment method for eliminating interference by serum albumin for analysis of anti-rHSA antibodies.

Analysis of anti-drug antibodies (ADAs) is important for risk assessment in clinical trials. ADA detection can be very difficult in the presence of high circulating levels of drugs or target proteins. We present an effective pretreatment method for eliminating interference by endogenous albumin for analyses of recombinant human serum albumin (rHSA) ADAs. Polyethylene glycol (PEG) precipitation was used to extract albumin-ADA immune complexes from serum samples. Following acid dissociation, albumin-reactive antibodies could be detected through an electrochemiluminescence (ECL) method. Normal human serum was used to establish detectable cut points. Goat anti-human albumin was used as the positive control to evaluate the assay performance. With regard to detection of anti-HSA antibodies, pretreatment with PEG could reduce the interference from albumin in serum. We discovered that the optimized PEG precipitation and acid dissociation (PandA) method had good performance in terms of sensitivity, drug tolerance, and selectivity.

Differences in phytohormone and flavonoid metabolism explain the sex differences in responses of Salix rehderiana to drought and nitrogen deposition.

Due to global warming and the increase in nitrogen oxide emissions, plants experience drought and nitrogen (N) deposition. However, little is known about the acclimation to drought and N deposition of Salix species, which are dioecious woody plants. Here, an investigation into foliar N deposition combined with drought was conducted by assessing integrated phenotypes, phytohormones, transcriptomics, and metabolomics of male and female Salix rehderiana. The results indicated that there was greater transcriptional regulation in males than in females. Foliar N deposition induced an increase in foliar abscisic acid (ABA) levels in males, resulting in the inhibition of stomatal conductance, photosynthesis, carbon (C) and N accumulation, and growth, whereas more N was assimilated in females. Growth as well as C and N accumulation in drought-stressed S. rehderiana females increased after N deposition. Interestingly, drought decreased flavonoid biosynthesis whereas N deposition increased it in females. Both drought and N deposition increased flavonoid methylation in males and glycosylation in females. However, in drought-exposed S. rehderiana, N deposition increased the biosynthesis and glycosylation of flavonoids in females but decreased glycosylation in males. Therefore, foliar N deposition affects the growth and drought tolerance of S. rehderiana by altering the foliar ABA levels and the biosynthesis and modification of flavonoids. This work provides a basis for understanding how S. rehderiana may acclimate to N deposition and drought in the future.

Pharmacokinetics, pharmacodynamics, safety, and immunogenicity of Gerilimzumab (GB224), a recombinant humanized interleukin-6 monoclonal antibody, in healthy Chinese adults: A randomized controlled dose-escalation study.

OBJECTIVES: This study aimed to investigate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of Gerilimzumab (GB224), a recombinant humanized IgG1λ monoclonal antibody against interleukin-6, in healthy Chinese adults. METHODS: Fifty-eight subjects were randomly assigned to receive a single subcutaneous dose of 2, 5, 10, 15, 20, 30 mg GB224 or placebo. Safety assessments were performed, and blood samples were collected for PK, PD, and immunogenicity analyses during a follow-up of 112 days. RESULTS: The most frequent adverse event was decreased fibrinogen (43.1%). GB224 was absorbed relatively fast with a median Tmax of 48 h (24-168 h) but eliminated slowly with a long mean half-life (839.38-981.63 h). Dose proportionality was shown to be in the dose range of 10-30 mg. A dose-dependent increase in serum interleukin-6 concentration from baseline was observed in the subjects receiving GB224. Only two subjects tested positive for antidrug antibodies after administration of GB224. CONCLUSION: GB224 had a well-tolerated safety profile, desirable PK, and a low immunogenicity following a single-dose subcutaneous administration in healthy Chinese subjects. These findings warrant further investigation.

Surface Engineering of HEK293 Cell-Derived Extracellular Vesicles for Improved Pharmacokinetic Profile and Targeted Delivery of IL-12 for the Treatment of Hepatocellular Carcinoma.

Background: Extracellular vesicles (EVs) are considered a promising drug delivery platform. Naïve EVs face numerous issues that limit their applications, such as fast clearance, hepatic accumulations, and a lack of target-specific tropism. We aimed to explore a series of surface engineering approaches to: 1) reduce the non-specific adhesion of EVs, and 2) improve their enrichment in the target tissue. As a proof-of-concept, we investigated the therapeutic potentials of a multi-modal EVs system carrying a tumor-specific nanobody and the immuno-stimulant interleukin-12 (IL12) using in vivo models of hepatocellular carcinoma. Methods: The major cell adhesion molecule on the HEK293-derived EVs, integrin ß1 (ITGB1), was knocked out (KO) by CRISPR/Cas9-mediated gene editing, followed by deglycosylation to generate ITGB1-Deg EVs for the subsequent pharmacokinetic and biodistribution analyses. ITGB1-Deg EVs were further loaded with glypican-3 (GPC3)-specific nanobody (HN3) and mouse single-chain IL12 (mscIL12) to generate ITGB1-mscIL12+HN3+Deg EVs, for evaluation of tumor tropism and therapeutic potential in a mice model of hepatocellular carcinoma. Results: Removal of ITGB1 led to the broad suppression of integrins on the EVs surface, resulting in a decrease in cellular uptake. Deglycosylation of ITGB1- EVs gave rise to inhibition of the EVs uptake by activated RAW264.7 cells. ITGB1 removal did not significantly alter the pharmacokinetic behaviors of HEK293-EVs, whereas the ITGB1-Deg EVs exhibited enhanced systemic exposure with reduced hepatic accumulation. Loading of HN3 conferred the ITGB1-Deg EVs with tumor-specific tropism for both subcutaneous and metastasized tumors in mice. The ITGB1-mscIL12+HN3+Deg EVs activated mouse splenocytes with high potency. Systemic administration of the EVs with the equivalent dose of 1.5µg/kg of exosomal IL12 achieved satisfactory tumor growth inhibition and good tolerability. Conclusion: The combinatorial approach of EVs surface engineering conferred HEK293-EVs with reduced non-specific clearance and enhanced tumor targeting efficacy, which constituted an efficient delivery platform for critical cancer therapeutics like IL12.

Mirabegron for medical expulsive therapy of ureteral stones: a systematic review and meta-analysis.

Objective: To systematically review and quantitively evaluate the efficacy and safety of mirabegron as a medical expulsive therapy for ureteral stones. Methods: We performed an extensive search of the EMBASE and PubMed databases for studies examining the use of mirabegron as a medical expulsive therapy for ureteral stones. The primary outcome measure assessed was the stone expulsion rate (SER), while the secondary outcomes evaluated were the stone expulsion interval (SEI) and the occurrence of pain episodes during follow-up. Risk ratios (RRs) and mean differences (MDs) with their respective 95% CIs were calculated. Results: We included a total of seven studies involving 728 participants. Our analysis revealed a significant increase in the stone expulsion rate (SER) with mirabegron (RR = 1.40; 95% CI = 1.17-1.67; p < 0.001) and a reduction in the frequency of pain episodes (MD = -0.80; 95% CI = -0.39 to -0.21; p = 0.008) compared to the control group. No significant difference was found in SEI between the two groups (MD = -3.04; 95% CI = -6.33 to 0.25; p = 0.07). Subgroup analysis revealed that the increased SER was significant for distal ureteral stones, but not for proximal and middle ureter stones. Compared to tamsulosin or silodosin, mirabegron showed no significant difference in SER, SEI, or pain episode frequency. The adverse effects of mirabegron were relatively rare and mild. Conclusion: Mirabegron appears to be a promising candidate for the MET of distal ureteral stones rather than proximal and middle ureteral stones, as it significantly increases SER and reduces pain episode frequency. Further well-designed randomised controlled trials are needed to validate and affirm these findings. Systematic Review Registration: PROSPERO (CRD42022341603).

Anti-c-MET Fab-Grb2-Gab1 Fusion Protein-Mediated Interference of c-MET Signaling Pathway Induces Methuosis in Tumor Cells.

Bio-macromolecules have potential applications in cancer treatment due to their high selectivity and efficiency in hitting therapeutic targets. However, poor cell membrane permeability has limited their broad-spectrum application in cancer treatment. The current study developed highly internalizable anti-c-MET antibody Fab fusion proteins with intracellular epitope peptide chimera to achieve the dual intervention from the extracellular to intracellular targets in tumor therapy. In vitro experiments demonstrated that the fusion proteins could interfere with the disease-associated intracellular signaling pathways and inhibit the uncontrolled proliferation of tumor cells. Importantly, investigation of the underlying mechanism revealed that these protein chimeras could induce vacuolation in treated cells, thus interfering with the normal extension and arrangement of microtubules as well as the mitosis, leading to the induction of methuosis-mediated cell death. Furthermore, in vivo tumor models indicated that certain doses of fusion proteins could inhibit the A549 xenograft tumors in NOD SCID mice. This study thus provides new ideas for the intracellular delivery of bio-macromolecules and the dual intervention against tumor cell signaling pathways.

ChAd155-RSV vaccine is immunogenic and efficacious against bovine RSV infection-induced disease in young calves.

Respiratory syncytial virus (RSV) infection causes a substantial lower-respiratory-tract disease burden in infants, constituting a global priority for vaccine development. We evaluated immunogenicity, safety and efficacy of a chimpanzee adenovirus (ChAd)-based vaccine candidate, ChAd155-RSV, in a bovine RSV (bRSV) challenge model. This model closely reproduces the pathogenesis/clinical manifestations of severe pediatric RSV disease. In seronegative calves, ChAd155-RSV elicits robust neutralizing antibody responses against human RSV. Two doses protect calves from clinical symptoms/lung pathological changes, and reduce nasal/lung virus loads after both a short (4-week) and a long (16-week) interval between last immunization and subsequent bRSV challenge. The one-dose regimen confers near-complete or significant protection after short-term or long-term intervals before challenge, respectively. The presence of pre-existing bRSV-antibodies does not affect short-term efficacy of the two-dose regimen. Immunized calves present no clinical signs of enhanced respiratory disease. Collectively, this supports the development of ChAd155-RSV as an RSV vaccine candidate for infants.