Structural Modulation of Covalent Organic Frameworks for Efficient Hydrogen Peroxide Electrocatalysis.

The electrochemical production of hydrogen peroxide (H2O2) using metal-free catalysts has emerged as a viable and sustainable alternative to the conventional anthraquinone process. However, the precise architectural design of these electrocatalysts poses a significant challenge, requiring intricate structural engineering to optimize electron transfer during the oxygen reduction reaction (ORR). Herein, we introduce a novel design of covalent organic frameworks (COFs) that effectively shift the ORR from a four-electron to a more advantageous two-electron pathway. Notably, the JUC-660 COF, with strategically charge-modified benzyl moieties, achieved a continuous high H2O2 yield of over 1200 mmol g-1 h-1 for an impressive duration of over 85 hours in a flow cell setting, marking it as one of the most efficient metal-free and non-pyrolyzed H2O2 electrocatalysts reported to date. Theoretical computations alongside in-situ infrared spectroscopy indicate that JUC-660 markedly diminishes the adsorption of the OOH* intermediate, thereby steering the ORR towards the desired pathway. Furthermore, the versatility of JUC-660 was demonstrated through its application in the electro-Fenton reaction, where it efficiently and rapidly removed aqueous contaminants. This work delineates a pioneering approach to altering the ORR pathway, ultimately paving the way for the development of highly effective metal-free H2O2 electrocatalysts.

MOF-Enhanced Aluminosilicate Ceramic Membranes Using Non-Firing Processes for Pesticide Filtration and Phytochrome Removal.

Aluminosilicates, abundant and crucial in both natural environments and industry, often involve uncontrollable chemical components when derived from minerals, making further chemical purification and reaction more complicated. This study utilizes pure alumina and fumed silica powders as more controllable sources, enhancing aluminosilicate reactivity through room temperature (non-firing) processing and providing a robust framework that resists mechanical stress and high temperature. By embedding iron-based metal-organic frameworks (Fe-MOF/non-firing aluminosilicate membranes) within the above matrix, these ceramic membranes not only preserve their mechanical robustness but also gain significant chemical functionality, enhancing their capacity to removing phytochromes from the vegetables. Sodium hydroxide and sodium silicate were selected as activators to successfully prepare high-strength, non-firing aluminosilicate membranes. These membranes demonstrated a flexural strength of 8.7 MPa under wet-culture conditions with a molar ratio of Al2O3:SiO2:NaOH:Na2SiO3 at 1:1:0.49:0.16. The chlorophyll adsorption of spinach conducted on these membranes showed a removal rate exceeding 90% at room temperature and pH = 9, highlighting its potential for the selective adsorption of chlorophyll. This study underscores the potential of MOF-enhanced aluminosilicate ceramic membranes in environmental applications, particularly for agricultural pollution control.

Do Health and Housing Attributes Motivate Residential Moves Among Older Chinese Adults? Evidence From an 8­Year Follow­up Study.

Background and Objectives: Despite the widespread belief in aging-in-place as the preferred housing arrangement for older adults, they are increasingly embracing moving. The person-environment fit theory explains that environmental changes due to residential moves can pose health risks, discouraging older people from moving. However, it also suggests that moves may be suitable when living conditions no longer meet their physical needs. The correlation between older people's health, housing, and their subsequent moving or staying actions in China remains underexplored. Research Design and Methods: Using alternative operating variables of key concepts and the China Family Panel Studies 2012-2018 data sets, this study examines the effects of health and housing status on older people's residential moves in China. The study outlines changes in health indicators and housing characteristics during multiple moves, as well as examines the relationship between the health and housing status of older adults and moving over a relatively long period of time using both regression models with lagged explanatory variables and fixed effects binary choice models. Results: The results reveal that: (1) higher rates of subsequent moves were observed among older adults with better self-rated health, positive self-rated health changes, and no ADL impairment, but no significant associations were found between most health variables and moving; and (2) the correlation between older persons' house ownership/type and their residential moves was significant and consistent over time, steady and lasting. Discussion and Implications: Potential mechanisms explaining the association between specific housing types and ownership statuses on moving are discussed. The findings encourage a focus on the positive benefits of moving in later life and how to provide additional housing options for older individuals.

Generating Synthetic Electronic Health Record Data Using Generative Adversarial Networks: Tutorial.

Synthetic electronic health record (EHR) data generation has been increasingly recognized as an important solution to expand the accessibility and maximize the value of private health data on a large scale. Recent advances in machine learning have facilitated more accurate modeling for complex and high-dimensional data, thereby greatly enhancing the data quality of synthetic EHR data. Among various approaches, generative adversarial networks (GANs) have become the main technical path in the literature due to their ability to capture the statistical characteristics of real data. However, there is a scarcity of detailed guidance within the domain regarding the development procedures of synthetic EHR data. The objective of this tutorial is to present a transparent and reproducible process for generating structured synthetic EHR data using a publicly accessible EHR data set as an example. We cover the topics of GAN architecture, EHR data types and representation, data preprocessing, GAN training, synthetic data generation and postprocessing, and data quality evaluation. We conclude this tutorial by discussing multiple important issues and future opportunities in this domain. The source code of the entire process has been made publicly available.

[64Cu]Cu-FAP-NOX, a N-oxalyl modified cyclic peptide for FAP PET imaging with a flexible imaging time window.

BACKGROUND: The aim of the present study was to develop a novel 64Cu-labeled cyclic peptide ([64Cu]Cu-FAP-NOX) that targets fibroblast activation protein (FAP) and may offer advantages in terms of image contrast, imaging time window, and low uptake in normal tissues. METHODS: The novel cyclic peptide featuring with a N-oxalyl modified tail was constructed and conjugated to NOTA for 64Cu labeling. Biochemical and cellular assays were performed with A549.hFAP cells. The performance of [64Cu]Cu-FAP-NOX was compared to that of two established tracers ([64Cu]Cu-FAPI-04 and [68Ga]Ga-FAP-2286) and three different NOTA-conjugates in HEK-293T.hFAP xenograft mice using micro-PET imaging. Ex vivo biodistribution studies were performed to confirm the FAP specificity and to validate the PET data. Furthermore, a first-in-human study of this novel tracer was conducted on one patient with lung cancer. RESULTS: Compared to [64Cu]Cu-FAPI-04, [64Cu]Cu-FAP-NOX demonstrated faster and higher rates of cellular uptake and internalization in A549.hFAP cells, but lower rates of cellular efflux. All six radiotracers were rapidly taken up by the tumor within the first 4 h post-injection. However, [64Cu]Cu-FAP-NOX had more intense tumor accumulation and slower washout from the target. The ratios of the tumor to normal tissue (including kidneys and muscles) increased significantly over time, with [64Cu]Cu-FAP-NOX reaching the highest ratio among all tracers. In the patient, [64Cu]Cu-FAP-NOX PET showed a comparable result to FDG PET in the primary malignant lesion while exhibiting higher uptake in pleural metastases, consistent with elevated FAP expression as confirmed by immunohistochemistry. CONCLUSION: [64Cu]Cu-FAP-NOX is a promising FAP-targeted tracer with a highly flexible imaging time window, as evidenced by preclinical evaluation encompassing biodistribution and micro-PET studies, along with a successful patient application. Furthermore, [64Cu]Cu-FAP-NOX showed enhanced image contrast and favorable pharmacokinetic properties for FAP PET imaging, warranting translation into large cohort studies.

Strategically constructed AlGaN doping barriers for efficient deep ultraviolet light-emitting diodes: erratum.

We present an erratum to our Letter [Opt. Lett.49, 2049 (2024)10.1364/OL.522212]. There is a careless omission of some references because our Letter is longer than the maximum allowed four pages. The missing references and their specific quote location are listed in the following. These corrections do not affect the data plotted in figures, discussion, or conclusion of the original Letter.

Comprehensive understanding of glioblastoma molecular phenotypes: classification, characteristics, and transition.

Among central nervous system-associated malignancies, glioblastoma (GBM) is the most common and has the highest mortality rate. The high heterogeneity of GBM cell types and the complex tumor microenvironment frequently lead to tumor recurrence and sudden relapse in patients treated with temozolomide. In precision medicine, research on GBM treatment is increasingly focusing on molecular subtyping to precisely characterize the cellular and molecular heterogeneity, as well as the refractory nature of GBM toward therapy. Deep understanding of the different molecular expression patterns of GBM subtypes is critical. Researchers have recently proposed tetra fractional or tripartite methods for detecting GBM molecular subtypes. The various molecular subtypes of GBM show significant differences in gene expression patterns and biological behaviors. These subtypes also exhibit high plasticity in their regulatory pathways, oncogene expression, tumor microenvironment alterations, and differential responses to standard therapy. Herein, we summarize the current molecular typing scheme of GBM and the major molecular/genetic characteristics of each subtype. Furthermore, we review the mesenchymal transition mechanisms of GBM under various regulators.

Selective ion migration in a polyelectrolyte driving a high-performance flexible moisture-electric generator.

We propose a novel moisture-electric generator that utilizes the unique properties of a blended poly(4-styrene sulfonic acid) and poly(vinyl alcohol) with phytic acid by screen printing and scrape coating, achieving an impressive open-circuit voltage of 0.88 V from ambient humidity. This innovative design significantly enhances ion transport, moisture adsorption, and flexibility, making a marked improvement in converting environmental humidity to electrical energy.

Design and Synthesis of Electrocatalysts Base on Catalysis-Unit Engineering.

It is a pressing need to develop new energy materials to address the existing energy crisis. However, screening optimal targets out of thousands of material candidates remains a great challenge. Herein, an alternative concept for highly effective materials screening based on dual-atom salphen catalysis units, is proposed and validated. Such an approach simplifies the design of catalytic materials and reforms the trial-and-error experimental model into a building-blocks-assembly like process. First, density functional theory (DFT) calculations are performed on a series of potential catalysis units that are possible to synthesize. Then, machine learning (ML) is employed to define the structure-performance relationship and acquire chemical insights. Afterward, the projected catalysis units are integrated into covalent organic frameworks (COFs) to validate the concept Electrochemical tests confirming that Ni-SalphenCOF and Co-SalphenCOF are promising conductive agent-free oxygen evolution reaction (OER) catalysts. This work provides a fast-tracked strategy for the design and development of functional materials, which serves as a potentially workable framework for seamlessly integrating DFT calculations, ML, and experimental approaches.

Co-utilization of wastewater sludge and heavy metals for single-atom electrocatalytic reduction of gaseous CO2.

Synergetic management of waste activated sludge, heavy metals (HMs) and CO2 for their valorization and cyclic utilization is rarely reported. Herein, we employed sludge-derived extracellular polymeric substances (EPS) and HMs in wastewater to fabricate a gas diffusion electrode (GDE) for electrochemical CO2 reduction. This approach atomically dispersed Ni at each nanofiber of the GDE. Abundant N element in the EPS proved to play a key role in the formation of Nx-Ni (mixture of N3-Ni and N4-Ni) sites for highly efficient CO2 to CO conversion. The atomical Ni3+ shows high catalytic activity. Direct gaseous CO2 reduction in a membrane electrode assembly generated a current density up to 50 mA·cm-2 with CO:H2 ratio of ∼100 and ∼75% FECO under 2.69 cell voltage. This strategy takes advantage of all waste streams generated on site and consolidates traditionally separated treatment processes to save costs, produces value-added products and generates carbon benefits during wastewater treatment.

Activation of ASIC3/ERK pathway by paeoniflorin improves intestinal fluid metabolism and visceral sensitivity in slow transit constipated rats.

Slow transit constipation (STC) is one of the most common gastrointestinal disorders in children and adults worldwide. Paeoniflorin (PF), a monoterpene glycoside compound extracted from the dried root of Paeonia lactiflora, has been found to alleviate STC, but the mechanisms of its effect remain unclear. The present study aimed to investigate the effects and mechanisms of PF on intestinal fluid metabolism and visceral sensitization in rats with compound diphenoxylate-induced STC. Based on the evaluation of the laxative effect, the abdominal withdrawal reflex test, enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, western blot, and immunohistochemistry were used to detect the visceral sensitivity, fluid metabolism-related proteins, and acid-sensitive ion channel 3/extracellular signal-regulated kinase (ASIC3/ERK) pathway-related molecules. PF treatment not only attenuated compound diphenoxylate-induced constipation symptoms and colonic pathological damage in rats but also ameliorated colonic fluid metabolic disorders and visceral sensitization abnormalities, as manifested by increased colonic goblet cell counts and mucin2 protein expression, decreased aquaporin3 protein expression, improved abdominal withdrawal reflex scores, reduced visceral pain threshold, upregulated serum 5-hydroxytryptamine, and downregulated vasoactive intestinal peptide levels. Furthermore, PF activated the colonic ASIC3/ERK pathway in STC rats, and ASIC3 inhibition partially counteracted PF's modulatory effects on intestinal fluid and visceral sensation. In conclusion, PF alleviated impaired intestinal fluid metabolism and abnormal visceral sensitization in STC rats and thus relieved their symptoms through activation of the ASIC3/ERK pathway.

The fate and transport of neonicotinoid insecticides and their metabolites through municipal wastewater treatment plants in South China.

Neonicotinoid insecticides (NEOs) have gained widespread usage as the most prevalent class of insecticides globally and are frequently detected in the environment, posing potential risks to biodiversity and human health. Wastewater discharged from wastewater treatment plants (WWTPs) is a substantial source of environmental NEOs. However, research tracking NEO variations in different treatment units at the WWTPs after being treated by the treatment processes remains limited. Therefore, this study aimed to comprehensively investigate the fate of nine parent NEOs (p-NEOs) and five metabolites in two municipal WWTPs using distinct treatment processes. The mean concentrations of ∑NEOs in influent (effluent) for the UNITANK, anaerobic-anoxic-oxic (A2/O), and cyclic activated sludge system (CASS) processes were 189 ng/L (195 ng/L), 173 ng/L (177 ng/L), and 123 ng/L (138 ng/L), respectively. Dinotefuran, imidacloprid, thiamethoxam, acetamiprid, and clothianidin were the most abundant p-NEOs in the WWTPs. Conventional wastewater treatment processes were ineffective in removing NEOs from wastewater (-4.91% to -12.1%), particularly major p-NEOs. Moreover, the behavior of the NEOs in various treatment units was investigated. The results showed that biodegradation and sludge adsorption were the primary mechanisms responsible for eliminating NEO. An anoxic or anaerobic treatment unit can improve the removal efficiency of NEOs during biological treatment. However, the terminal treatment unit (chlorination disinfection tank) did not facilitate the removal of most of the NEOs. The estimated total amount of NEOs released from WWTPs to receiving waters in the Pearl River of South China totaled approximately 6.90-42.6 g/d. These findings provide new insights into the efficiency of different treatment processes for removing NEOs in current wastewater treatment systems.

Dynamics of evolutionary succession and coordination between opposite adaptations in cuckoo hosts under antagonistic coevolution.

Adaptations are driven by specific natural selection pressures throughout biological evolution. However, these cannot inherently align with future shifts in selection dynamics, thus manifesting in opposing directions. We performed field experiments on cuckoo hosts to investigate the coexistence and conflict between two evolutionarily successive but opposing behavioral adaptations-egg retrieval and rejection. Our findings provide key insights. (1) Egg rejection against brood parasites in hosts reshapes egg retrieval to flexible reactions-retrieval, ignoring, or outright rejection of foreign eggs outside the nest cup, departing from instinctual retrieval. (2) Parasitism pressure and egg mimicry by parasites remarkably alter the proportions of the three host reactions. Host species with higher parasitism pressure exhibit frequent and rapid rejection of non-mimetic foreign eggs and reduced ignoring or retrieval responses. Conversely, heightened egg mimicry enhances retrieval behaviors while diminishing ignoring responses. (3) Cuckoos employ consistent mechanisms for rejecting foreign eggs inside or outside the nest cup. Direct rejection of eggs outside the nest cup shows that rejection precedes retrieval, indicating prioritization of specific adaptation over instinct. (4) Cuckoo hosts navigate the conflict between the intentions and motivations associated with egg rejection and retrieval by ignoring foreign eggs, a specific outcome of the rejection-retrieval tradeoff.

Strategically constructed AlGaN doping barriers for efficient deep ultraviolet light-emitting diodes.

Here, we propose a sandwich-like Si-doping scheme (undoped/Si-doped/undoped) in Al0.6Ga0.4N quantum barriers (QBs) to simultaneously promote the optoelectronic performances and reliability of deep ultraviolet light-emitting diodes (DUV-LEDs). Through experimental and numerical analyses, in the case of DUV-LEDs with conventional uniform Si-doping QB structure, severe operation-induced reliability degradation, including the increase of reverse leakage current (IR) and reduction of light output power (LOP), will offset the enhancement of optoelectronic performances as the Si-doping levels increase to an extent, which hinders further development of DUV-LEDs. According to a transmission electron microscope characterization and a numerical simulation, an improved interfacial quality in multiple quantum wells (MQWs) and more uniform carrier distribution within MQWs are demonstrated for our proposed Si-doping structure in comparison to the uniform Si-doping structure. Consequently, the proposed DUV-LED shows superior wall-plug efficiency (4%), IR at -6 V reduced by almost one order of magnitude, and slower LOP degradation after 168-h 100 mA-current-stress operation. This feasible doping scheme provides a promising strategy for the high-efficiency and cost-competitive DUV-LEDs.

Siglec9 + tumor-associated macrophages predict prognosis and therapeutic vulnerability in patients with colon cancer.

BACKGROUND: Siglec9 has been identified as an immune checkpoint molecule on tumor-associated macrophages (TAMs). Nevertheless, the expression profile and clinical significance of Siglec9 + TAMs in colon cancer (CC) are still not fully understood. METHODS: Two clinical cohorts from distinct medical centers were retrospectively enrolled. Immunohistochemistry and immunofluorescence were conducted to evaluate the infiltration of immune cells. Single-cell RNA sequencing and flow cytometry were utilized to identify the impact of Siglec9 + TAMs on the tumor immune environment, which was subsequently validated through bioinformatics analysis of the TCGA database. Prognosis and the benefit of adjuvant chemotherapy (ACT) were also evaluated using Cox regression analysis and the Kaplan-Meier method. RESULTS: High infiltration of Siglec9 + TAMs was associated with worse prognosis and better benefit from 6-month ACT. Siglec9 + TAMs contributed to immunoevasion by promoting the infiltration of immunosuppressive cells and the dysfunction process of CD8 + T cells. Additionally, high infiltration of Siglec9 + TAMs was associated with the mesenchymal-featured subtype and overexpression of the VEGF signaling pathway, which was validated by the strongest communication between Siglec9 + TAMs and vascular endothelial cells. CONCLUSIONS: Siglec9 + TAMs may serve as a biomarker for prognosis and response to ACT in CC. Furthermore, the immunoevasive contexture and angiogenesis stimulated by Siglec9 + TAMs suggest potential treatment combinations for CC patients.

MoMkk1 and MoAtg1 dichotomously regulating autophagy and pathogenicity through MoAtg9 phosphorylation in Magnaporthe oryzae.

Autophagy is a central biodegradation pathway critical in eliminating intracellular cargo to maintain cellular homeostasis and improve stress resistance. At the same time, the key component of the mitogen-activated protein kinase cascade regulating cell wall integrity signaling MoMkk1 has an essential role in the autophagy of the rice blast fungus Magnaporthe oryzae. Still, the mechanism of how MoMkk1 regulates autophagy is unclear. Interestingly, we found that MoMkk1 regulates the autophagy protein MoAtg9 through phosphorylation. MoAtg9 is a transmembrane protein subjected to phosphorylation by autophagy-related protein kinase MoAtg1. Here, we provide evidence demonstrating that MoMkk1-dependent MoAtg9 phosphorylation is required for phospholipid translocation during isolation membrane stages of autophagosome formation, an autophagic process essential for the development and pathogenicity of the fungus. In contrast, MoAtg1-dependent phosphorylation of MoAtg9 negatively regulates this process, also impacting growth and pathogenicity. Our studies are the first to demonstrate that MoAtg9 is subject to MoMkk1 regulation through protein phosphorylation and that MoMkk1 and MoAtg1 dichotomously regulate autophagy to underlie the growth and pathogenicity of M. oryzae.IMPORTANCEMagnaporthe oryzae utilizes multiple signaling pathways to promote colonization of host plants. MoMkk1, a cell wall integrity signaling kinase, plays an essential role in autophagy governed by a highly conserved autophagy kinase MoAtg1-mediated pathway. How MoMkk1 regulates autophagy in coordination with MoAtg1 remains elusive. Here, we provide evidence that MoMkk1 phosphorylates MoAtg9 to positively regulate phospholipid translocation during the isolation membrane or smaller membrane structures stage of autophagosome formation. This is in contrast to the negative regulation of MoAtg9 by MoAtg1 for the same process. Intriguingly, MoMkk1-mediated MoAtg9 phosphorylation enhances the fungal infection of rice, whereas MoAtg1-dependant MoAtg9 phosphorylation significantly attenuates it. Taken together, we revealed a novel mechanism of autophagy and virulence regulation by demonstrating the dichotomous functions of MoMkk1 and MoAtg1 in the regulation of fungal autophagy and pathogenicity.

Single-atom platinum with asymmetric coordination environment on fully conjugated covalent organic framework for efficient electrocatalysis.

Two-dimensional (2D) covalent organic frameworks (COFs) and their derivatives have been widely applied as electrocatalysts owing to their unique nanoscale pore configurations, stable periodic structures, abundant coordination sites and high surface area. This work aims to construct a non-thermodynamically stable Pt-N2 coordination active site by electrochemically modifying platinum (Pt) single atoms into a fully conjugated 2D COF as conductive agent-free and pyrolysis-free electrocatalyst for the hydrogen evolution reaction (HER). In addition to maximizing atomic utilization, single-atom catalysts with definite structures can be used to investigate catalytic mechanisms and structure-activity relationships. In this work, in-situ characterizations and theoretical calculations reveal that a nitrogen-rich graphene analogue COF not only exhibits a favorable metal-support effect for Pt, adjusting the binding energy between Pt sites to H* intermediates by forming unique Pt-N2 instead of the typical Pt-N4 coordination environment, but also enhances electron transport ability and structural stability, showing both conductivity and stability in acidic environments.

Influence of nano-BN inclusion and mechanism involved on aluminium-copper alloy.

Taking advantage of the high specific surface area of the nanoparticles, boron nitride (BN) nanoparticles were incorporated into the semi-solidified aluminium-copper alloy Al-5Cu-Mn (ZL201) system during the casting process, and its properties and enhancement mechanism were studied. The results shown that the BN in the new composite material is more uniformly distributed in the second phase (Al2Cu), which can promote grain refinement and enhance the bonding with the aluminium-based interface, and the formation of stable phases such as AlB2, AlN, CuN, etc. makes the tensile strength and hardness of the material to be significantly improved (8.5%, 10.2%, respectively). The mechanism of the action of BN in Al2Cu was analyzed by establishing an atomic model and after calculation: BN can undergo strong adsorption on the surface of Al2Cu (0 0 1), and the adsorption energy is lower at the bridge sites on the two cut-off surfaces, which makes the binding of BN to the aluminum base more stable. The charge transfer between B, N and each atom of the matrix can promote the formation of strong covalent bonds Al-N, Cu-N and Al-B bonds, which can increase the dislocation density and hinder the grain boundary slip within the alloy.

A noncanonical splicing variant c.875-5 T > G in von Willebrand factor causes in-frame exon skipping and type 2A von Willebrand disease.

INTRODUCTION: A novel variant involving noncanonical splicing acceptor site (c.875-5 T > G) in propeptide coding region of von Willebrand factor (VWF) was identified in a patient with type 2A von Willebrand disease (VWD), who co-inherited with a null variant (p.Tyr271*) and presented characteristic discrepancy of plasma level of VWF antigen and activity, and a selective reduction of both intermediate-molecular-weight (IMWMs) and high-molecular-weight VWF multimers (HMWMs). MATERIALS AND METHODS: VWF mRNA transcripts obtained from peripheral leukocytes and platelets of the patients were investigated to analyze the consequence of c.875-5 T > G on splicing. The impact of the variant on expression and multimer assembly was further analyzed by in vitro expression studies in AtT-20 cells. The intracellular processing of VWF mutant and the Weibel-Palade bodies (WPBs) formation was evaluated by immunofluorescence staining and electron microscopy. RESULTS: The mRNA transcript analysis revealed that c.875-5 T > G variant led to exon 8 skipping and an in-frame deletion of 41 amino acids in the D1 domain of VWF (p.Ser292_Glu333delinsLys), yielding a truncated propeptide. Consistent with the patient's laboratory manifestations, the AtT-20 cells transfected with mutant secreted less VWF, with the VWF antigen level in conditioned medium 47 % of wild-type. A slight retention in the endoplasmic reticulum was observed for the mutant. Almost complete loss of IMWMs and HMWMs in the medium and impaired WPBs formation in the cell, indicating truncated VWF propeptide lost its chaperon-like function for VWF multimerization and tubular storage. CONCLUSIONS: The VWF splicing site variant (c.875-5 T > G) causes propeptide truncation, severely compromising VWF multimer assembly and tubular storage.

Preclinical study and first-in-human imaging of [18F]FAP-2286, and comparison with 2-[18F]FDG PET/CT in various cancer patients.

PURPOSE: Fibroblast-activated protein (FAP) is highly expressed in cancer-associated fibroblasts (CAFs) of many solid cancers, but low or absent in normal tissues. Our study aimed to develop a novel FAP-specific tracer, namely [18F]FAP-2286, and evaluated its performance in comparison with well-established agents such as [18F]FAPI-42 and [68Ga]Ga-FAP-2286 in preclinical research, as well as 2-[18F]FDG in pilot clinical study. METHODS: [18F]FAP-2286 was manually synthesized in accordance with Good Manufacturing Practice (GMP). Subsequent investigations encompassed cell uptake, competitive binding affinity, internalization and efflux assays using HT-1080hFAP cell lines. PET imaging and biodistribution studies were conducted in HEK-293ThFAP, A549hFAP, HT-1080hFAP tumor-bearing mice as well as HEK-293T, A549 and HT-1080 control groups. Furthermore, clinical evaluation of [18F]FAP-2286 was performed in fifteen patients with various cancers compared to 2-[18F]FDG PET. RESULTS: The radiolabeling yield of [18F]FAP-2286 was 30.53 ± 5.20%, with a radiochemical purity exceeding 97%. In cell assays, [18F]FAP-2286 showed specific uptake, high internalization fraction and low cellular efflux. Rapid tumor uptake and satisfactory tumor retention was observed on micro-PET imaging and cancer patients. Meanwhile, the clinical research demonstrated that [18F]FAP-2286 may represent an alternative for low glucose-metabolism malignant tumors PET imaging such as gastric cancers. CONCLUSION: [18F]FAP-2286 showed superior imaging quality including rapid and high target uptake and satisfactory retention in both tumor-bearing mice and cancer patients. It may emerge as a promising candidate for early or delayed phase imaging and 2-[18F]FDG non-avid cancers PET scan.