A lava-inspired proteolytic enzyme therapy on cancer with a PEG-based hydrogel enhances tumor distribution and penetration of liposomes.

The enhanced permeability and retention (EPR) effect has become the guiding principle for nanomedicine against cancer for a long time. However, several biological barriers severely resist therapeutic agents' penetration and retention into the deep tumor tissues, resulting in poor EPR effect and high tumor mortality. Inspired by lava, we proposed a proteolytic enzyme therapy to improve the tumor distribution and penetration of nanomedicine. A trypsin-crosslinked hydrogel (Trypsin@PSA Gel) was developed to maintain trypsin's activity. The hydrogel postponed trypsin's self-degradation and sustained the release. Trypsin promoted the cellular uptake of nanoformulations in breast cancer cells, enhanced the penetration through endothelial cells, and degraded total and membrane proteins. Proteomic analysis reveals that trypsin affected ECM components and down-regulated multiple pathways associated with cancer progression. Intratumoral injection of Trypsin@PSA Gel significantly increased the distribution of liposomes in tumors and reduced tumor vasculature. Combination treatment with intravenous injection of gambogic acid-loaded liposomes and intratumoral injection of Trypsin@PSA Gel inhibited tumor growth. The current study provides one of the first investigations into the enhanced tumor distribution of liposomes induced by a novel proteolytic enzyme therapy.

Region-Specific CD16+ Neutrophils Promote Colorectal Cancer Progression by Inhibiting Natural Killer Cells.

The colon is the largest compartment of the immune system, with innate immune cells exposed to antigens in the environment. However, the mechanisms by which the innate immune system is instigated are poorly defined in colorectal cancer (CRC). Here, a population of CD16+ neutrophils that specifically accumulate in CRC tumor tissues by imaging mass cytometry (IMC), immune fluorescence, and flow cytometry, which demonstrated pro-tumor activity by disturbing natural killer (NK) cells are identified. It is found that these CD16+ neutrophils possess abnormal cholesterol accumulation due to activation of the CD16/TAK1/NF-κB axis, which upregulates scavenger receptors for cholesterol intake including CD36 and LRP1. Consequently, these region-specific CD16+ neutrophils not only competitively inhibit cholesterol intake of NK cells, which interrupts NK lipid raft formation and blocks their antitumor signaling but also release neutrophil extracellular traps (NETs) to induce the death of NK cells. Furthermore, CD16-knockout reverses the pro-tumor activity of neutrophils and restored NK cell cytotoxicity. Collectively, the findings suggest that CRC region-specific CD16+ neutrophils can be a diagnostic marker and potential therapeutic target for CRC.

A Simple and Low-Cost CRISPR/Cas9 Knockout System Widely Applicable to Insects.

The CRISPR/Cas9 gene-editing system is a standard technique in functional genomics, with widespread applications. However, the establishment of a CRISPR/Cas9 system is challenging. Previous studies have presented numerous methodologies for establishing a CRISPR/Cas9 system, yet detailed descriptions are limited. Additionally, the difficulties in obtaining the necessary plasmids have hindered the replication of CRISPR/Cas9 techniques in other laboratories. In this study, we share a detailed and simple CRISPR/Cas9 knockout system with optimized steps. The results of gene knockout experiments in vitro and in vivo show that this system successfully knocked out the target gene. By sharing detailed information on plasmid sequences, reagent codes, and methods, this study can assist researchers in establishing gene knockout systems.

Predictive models for delay in medical decision-making among older patients with acute ischemic stroke: a comparative study using logistic regression analysis and lightGBM algorithm.

OBJECTIVE: To explore the factors affecting delayed medical decision-making in older patients with acute ischemic stroke (AIS) using logistic regression analysis and the Light Gradient Boosting Machine (LightGBM) algorithm, and compare the two predictive models. METHODS: A cross-sectional study was conducted among 309 older patients aged ≥ 60 who underwent AIS. Demographic characteristics, stroke onset characteristics, previous stroke knowledge level, health literacy, and social network were recorded. These data were separately inputted into logistic regression analysis and the LightGBM algorithm to build the predictive models for delay in medical decision-making among older patients with AIS. Five parameters of Accuracy, Recall, F1 Score, AUC and Precision were compared between the two models. RESULTS: The medical decision-making delay rate in older patients with AIS was 74.76%. The factors affecting medical decision-making delay, identified through logistic regression and LightGBM algorithm, were as follows: stroke severity, stroke recognition, previous stroke knowledge, health literacy, social network (common factors), mode of onset (logistic regression model only), and reaction from others (LightGBM algorithm only). The LightGBM model demonstrated the more superior performance, achieving the higher AUC of 0.909. CONCLUSIONS: This study used advanced LightGBM algorithm to enable early identification of delay in medical decision-making groups in the older patients with AIS. The identified influencing factors can provide critical insights for the development of early prevention and intervention strategies to reduce delay in medical decisions-making among older patients with AIS and promote patients' health. The LightGBM algorithm is the optimal model for predicting the delay in medical decision-making among older patients with AIS.

A new therapeutic perspective: Erastin inhibits tumor progression by driving ferroptosis in myelodysplastic syndromes.

Ferroptosis is a recently identified and evolutionarily conserved form of programmed cell death. This process is initiated by an imbalance in iron metabolism, leading to an overload of ferrous ions. These ions promote lipid peroxidation in the cell membrane through the Fenton reaction. As the cell's antioxidant defenses become overwhelmed, a fatal buildup of reactive oxygen species (ROS) occurs, resulting in the rupture of the plasma membrane. Ferroptosis is implicated in conditions such as ischemia-reperfusion injuries and a range of cancers. In our research, we explored ferroptosis in myelodysplastic syndromes (MDS) by measuring iron levels, transferrin receptor expression, and glutathione peroxidase 4 (GPX4) mRNA. Our findings revealed that MDS patients had significantly higher Fe2+ levels in CD33+ cells and increased transferrin receptor mRNA compared to healthy individuals. GPX4 expression was also higher in MDS but not statistically significant. To investigate potential treatments for myeloid hematological diseases through ferroptosis induction, we treated the myelodysplastic syndrome cell line (SKM-1) and two myeloid leukemia cell lines (KG-1 and K562) with erastin, an iron transfer inducer. We observed that erastin treatment led to glutathione depletion, reduced GPX4 activity, and increased ROS, culminating in cell death by ferroptosis. Furthermore, combining erastin with azacitidine demonstrated a synergistic effect on MDS and leukemia cell lines, suggesting a promising approach for treating these hematological conditions with this drug combination. Our experiments confirm erastin's ability to induce ferroptosis in MDS and highlight its potential synergistic use with azacitidine for treatment.

The coordination of bimaxillary alveolar arch widths in subjects with normal occlusion or posterior crossbite: A CBCT retrospective study.

OBJECTIVES: To propose a method for evaluating the coordination of maxillomandibular alveolar arch in transverse dimension with cone-beam computed tomography (CBCT) and to apply this method to subjects with normal occlusion at different dentition stages or transverse discrepancy. MATERIALS AND METHODS: Digital data of 130 patients with normal occlusion at different dentition stages or transverse discrepancy were collected for three-dimensional reconstruction. The patients with normal occlusion were divided into Group 1 (>16 years) and Group 2 (≤16 years) based on their age. Adult patients with posterior crossbite were divided into the Group 3. According to the proposed method, the average alveolar arch coordination angle (AACA) and other parameters were analysed in each group. Group 1 was considered as the control group and compared with Group 2 and Group 3. RESULTS: Significant differences were observed in the maxillary posterior segment width among patients with normal occlusion. Group 3 demonstrated increased AACA and mandibular alveolar arch width compared with the normal occlusion group. Pearson correlation analysis indicated a positive relationship between maxillomandibular alveolar arch widths in the normal occlusion groups, with a strong correlation between AACA and the disparity in maxillomandibular widths. CONCLUSION: Adults with normal occlusion exhibit significantly wider maxillary posterior alveolar arches than adolescents, with no marked difference in mandibular widths. The posterior crossbite group showed broader mandibular alveolar arches. There was a strong correlation between AACA and the difference in maxillomandibular widths. This study's method shows potential value for orthodontic transverse diagnosis.

Quantifying the Impact of Environment Loads on Displacements in a Suspension Bridge with a Data-Driven Approach.

Long-span bridges are susceptible to damage, aging, and deformation in harsh environments for a long time. Therefore, structural health monitoring (SHM) systems need to be used for reasonable monitoring and maintenance. Among various indicators, bridge displacement is a crucial parameter reflecting the bridge's health condition. Due to the simultaneous bearing of multiple environmental loads on suspension bridges, determining the impact of different loads on displacement is beneficial for the better understanding of the health conditions of the bridges. Considering the fact that extreme gradient boosting (XGBoost) has higher prediction performance and robustness, the authors of this paper have developed a data-driven approach based on the XGBoost model to quantify the impact between different environmental loads and the displacement of a suspension bridge. Simultaneously, this study combined wavelet threshold (WT) denoising and the variational mode decomposition (VMD) method to conduct a modal decomposition of three-dimensional (3D) displacement, further investigating the interrelationships between different loads and bridge displacements. This model links wind speed, temperature, air pressure, and humidity with the 3D displacement response of the span using the bridge monitoring data provided by the GNSS and Earth Observation for Structural Health Monitoring (GeoSHM) system of the Forth Road Bridge (FRB) in the United Kingdom (UK), thus eliminating the temperature time-lag effect on displacement data. The effects of the different loads on the displacement are quantified individually with partial dependence plots (PDPs). Employing testing, it was found that the XGBoost model has a high predictive effect on the target variable of displacement. The analysis of quantification and correlation reveals that lateral displacement is primarily affected by same-direction wind, showing a clear positive correlation, and vertical displacement is mainly influenced by temperature and exhibits a negative correlation. Longitudinal displacement is jointly influenced by various environmental loads, showing a positive correlation with atmospheric pressure, temperature, and vertical wind and a negative correlation with longitudinal wind, lateral wind, and humidity. The results can guide bridge structural health monitoring in extreme weather to avoid accidents.

Comparison of the osteogenic potential of fibroblasts from different sources.

OBJECTIVE: With the growing interest in the role of fibroblasts in osteogenesis, this study presents a comparative evaluation of the osteogenic potential of fibroblasts derived from three distinct sources: human gingival fibroblasts (HGFs), mouse embryonic fibroblasts (NIH3T3 cells), and mouse subcutaneous fibroblasts (L929 cells). MC3T3-E1 pre-osteoblast cells were employed as a positive control for osteogenic behavior. DESIGN: Our assessment involved multiple approaches, including vimentin staining for cell origin verification, as well as ALP and ARS staining in conjunction with RT-PCR for osteogenic characterization. RESULTS: Our findings revealed the superior osteogenic differentiation capacity of HGFs compared to MC3T3-E1 and NIH3T3 cells. Analysis of ALP staining confirmed that early osteogenic differentiation was most prominent in MC3T3-E1 cells at 7 days, followed by NIH3T3 and HGFs. However, ARS staining at 21 days demonstrated that HGFs produced the highest number of calcified nodules, indicating their robust potential for late-stage mineralization. This late-stage osteogenic potential of HGFs was further validated through RT-PCR analysis. In contrast, L929 cells displayed no significant osteogenic differentiation potential. CONCLUSIONS: In light of these findings, HGFs emerge as the preferred choice for seed cells in bone tissue engineering applications. This study provides valuable insights into the potential utility of HGFs in the fields of bone tissue engineering and regenerative medicine.

Gut microbial co-metabolite 2-methylbutyrylcarnitine exacerbates thrombosis via binding to and activating integrin α2ß1.

Thrombosis represents the leading cause of death and disability upon major adverse cardiovascular events (MACEs). Numerous pathological conditions such as COVID-19 and metabolic disorders can lead to a heightened thrombotic risk; however, the underlying mechanisms remain poorly understood. Our study illustrates that 2-methylbutyrylcarnitine (2MBC), a branched-chain acylcarnitine, is accumulated in patients with COVID-19 and in patients with MACEs. 2MBC enhances platelet hyperreactivity and thrombus formation in mice. Mechanistically, 2MBC binds to integrin α2ß1 in platelets, potentiating cytosolic phospholipase A2 (cPLA2) activation and platelet hyperresponsiveness. Genetic depletion or pharmacological inhibition of integrin α2ß1 largely reverses the pro-thrombotic effects of 2MBC. Notably, 2MBC can be generated in a gut-microbiota-dependent manner, whereas the accumulation of plasma 2MBC and its thrombosis-aggravating effect are largely ameliorated following antibiotic-induced microbial depletion. Our study implicates 2MBC as a metabolite that links gut microbiota dysbiosis to elevated thrombotic risk, providing mechanistic insight and a potential therapeutic strategy for thrombosis.

Janus silk fibroin/polycaprolactone-based scaffold with directionally aligned fibers and porous structure for bone regeneration.

To promote bone repair, it is desirable to develop three-dimensional multifunctional fiber scaffolds. The densely stacked and tightly arranged conventional two-dimensional electrospun fibers hinder cell penetration into the scaffold. Most of the existing three-dimensional structural materials are isotropic and monofunctional. In this research, a Janus nanofibrous scaffold based on silk fibroin/polycaprolactone (SF/PCL) was fabricated. SF-encapsulated SeNPs demonstrated stability and resistance to aggregation. The outside layer (SF/PCL/Se) of the Janus nanofiber scaffold displayed a structured arrangement of fibers, facilitating cell growth guidance and impeding cell invasion. The inside layer (SF/PCL/HA) featured a porous structure fostering cell adhesion. The Janus fiber scaffold containing SeNPs notably suppressed S. aureus and E. coli activities, correlating with SeNPs concentration. In vitro, findings indicated considerable enhancement in alkaline phosphatase (ALP) activity of MC3T3-E1 osteoblasts and upregulation of genes linked to osteogenic differentiation with exposure to the SF/PCL/HA/Se Janus nanofibrous scaffold. Moreover, in vivo, experiments demonstrated successful critical bone defect repair in mouse skulls using the SF/PCL/HA/Se Janus nanofiber scaffold. These findings highlight the potential of the SF/PCL-based Janus nanofibrous scaffold, integrating SeNPs and nHA, as a promising biomaterial in bone tissue engineering.

Ordered sulfonated polystyrene particle chains organized through AC electroosmosis as reinforcing phases in Polyacrylamide hydrogels.

Polyacrylamide (PAM) hydrogels have garnered significant attention due to their unique swelling properties, biocompatibility, and stability, resulting in them being promising candidates for various applications, ranging from drug delivery to tissue engineering. However, traditional PAM hydrogels suffer from low strength and poor toughness, which limits their widespread use. In this study, based on the theory of filler-reinforced composites, we introduced ordered sulfonated polystyrene (SPS) particles into PAM hydrogels using electric field-assisted techniques. The effects of the geometric dimensions and filling concentration of SPS particles on thermal stability, swelling/deswelling behavior, and mechanical properties of composite hydrogels were investigated. When filled with ordered 100 nm SPS particles at a concentration of 2.0 g·L-1, the resulting SPS/PAM composite exhibited improved water retention capacity, as well as a fracture elongation of 316 % and a tensile strength of 23 kPa. These findings in the paper provide valuable insights into the understanding of PAM hydrogels and open up new avenues for the development of advanced hydrogel-based systems with enhanced performance and functionality.

Root-specific photoreception directs early root development by HY5-regulated ROS balance.

Root development is tightly controlled by light, and the response is thought to depend on signal transmission from the shoot. Here, we show that the root apical meristem perceives light independently from aboveground organs to activate the light-regulated transcription factor ELONGATED HYPOCOTYL5 (HY5). The ROS balance between H2O2 and superoxide anion in the root is disturbed under darkness with increased H2O2. We demonstrate that root-derived HY5 directly activates PER6 expression to eliminate H2O2. Moreover, HY5 directly represses UPBEAT1, a known inhibitor of peroxidases, to release the expression of PERs, partially contributing to the light control of ROS balance in the root. Our results reveal an unexpected ability in roots with specific photoreception and provide a mechanistic framework for the HY5-mediated interaction between light and ROS signaling in early root development.

Review on Abrasive Machining Technology of SiC Ceramic Composites.

Ceramic matrix composites have the advantages of low density, high specific strength, high specific die, high-temperature resistance, wear resistance, chemical corrosion resistance, etc., which are widely used in aerospace, energy, transportation, and other fields. CMCs have become an important choice for engine components and other high-temperature component manufacturing. However, ceramic matrix composite is a kind of multi-phase structure, anisotropy, high hardness material, due to the brittleness of the ceramic matrix, the weak bonding force between fiber and matrix, and the anisotropy of composite material. Burr, delamination, tearing, chips, and other surface damage tend to generate in the machining, resulting in surface quality and strength decline. This paper reviewed the latest abrasive machining technology for SiC ceramic composites. The characteristics and research directions of the main abrasive machining technology, including grinding, laser-assisted grinding, ultrasonic-assisted grinding, and abrasive waterjet machining, are introduced first. Then, the commonly used numerical simulation research for modeling and simulating the machining of ceramic matrix composites is briefly summarized. Finally, the processing difficulties and research hotspots of ceramic matrix composites are summarized.

SCFormer: Spectral Coordinate Transformer for Cross-Domain Few-Shot Hyperspectral Image Classification.

Cross-domain (CD) hyperspectral image classification (HSIC) has been significantly boosted by methods employing Few-Shot Learning (FSL) based on CNNs or GCNs. Nevertheless, the majority of current approaches disregard the prior information of spectral coordinates with limited interpretability, leading to inadequate robustness and knowledge transfer. In this paper, we propose an asymmetric encoder-decoder architecture, Spectral Coordinate Transformer (SCFormer), for the CDFSL HSIC task. Several dense Spectral Coordinate blocks (SC blocks) are embedded in the backbone of the encoder to establish feature representation with better generalization, which integrates spectral coordinates via Rotary Position Embedding (RoPE) to minimize spectral position disturbance caused by the convolution operation. Due to a large amount of hyperspectral image data and the high demand for model generalization ability in cross-domain scenarios, we design two mask patterns (Random Mask and Sequential Mask) built on unexploited spectral coordinates within the SC blocks, which are unified with the asymmetric structure to learn high-capacity models efficiently and effectively with satisfactory generalization. Besides, from the perspective of the loss function, we devise an intra-domain loss function founded on the Orthogonal Complement Space Projection (OCSP) theory to facilitate the aggregation of samples in the metric space, which promotes intra-domain consistency and increases interpretability. Finally, the strengthened class expression capacity of the intra-domain loss function contributes to the inter-domain loss function constructed by Wasserstein Distance (WD) for realizing domain alignment. Experimental results on four benchmark data sets demonstrate the superiority of the SCFormer.

Clinical applications of stem cell-derived exosomes.

Although stem cell-based therapy has demonstrated considerable potential to manage certain diseases more successfully than conventional surgery, it nevertheless comes with inescapable drawbacks that might limit its clinical translation. Compared to stem cells, stem cell-derived exosomes possess numerous advantages, such as non-immunogenicity, non-infusion toxicity, easy access, effortless preservation, and freedom from tumorigenic potential and ethical issues. Exosomes can inherit similar therapeutic effects from their parental cells such as embryonic stem cells and adult stem cells through vertical delivery of their pluripotency or multipotency. After a thorough search and meticulous dissection of relevant literature from the last five years, we present this comprehensive, up-to-date, specialty-specific and disease-oriented review to highlight the surgical application and potential of stem cell-derived exosomes. Exosomes derived from stem cells (e.g., embryonic, induced pluripotent, hematopoietic, mesenchymal, neural, and endothelial stem cells) are capable of treating numerous diseases encountered in orthopedic surgery, neurosurgery, plastic surgery, general surgery, cardiothoracic surgery, urology, head and neck surgery, ophthalmology, and obstetrics and gynecology. The diverse therapeutic effects of stem cells-derived exosomes are a hierarchical translation through tissue-specific responses, and cell-specific molecular signaling pathways. In this review, we highlight stem cell-derived exosomes as a viable and potent alternative to stem cell-based therapy in managing various surgical conditions. We recommend that future research combines wisdoms from surgeons, nanomedicine practitioners, and stem cell researchers in this relevant and intriguing research area.

Biphasic calcium phosphate recruits Tregs to promote bone regeneration.

The use of bone substitute materials is crucial for the healing of large bone defects. Immune response induced by bone substitute materials is essential in bone regeneration. Prior research has mainly concentrated on innate immune cells, such as macrophages. Existing research suggests that T lymphocytes, as adaptive immune cells, play an indispensable role in bone regeneration. However, the mechanisms governing T cell recruitment and specific subsets that are essential for bone regeneration remain unclear. This study demonstrates that CD4+ T cells are indispensable for ectopic osteogenesis by biphasic calcium phosphate (BCP). Subsequently, the recruitment of CD4+ T cells is closely associated with the activation of calcium channels in macrophages by BCP to release chemokines Ccl3 and Ccl17. Finally, these recruited CD4+ T cells are predominantly Tregs, which play a significant role in ectopic osteogenesis by BCP. These findings not only shed light on the immune-regenerative process after bone substitute material implantation but also establish a theoretical basis for developing bone substitute materials for promoting bone tissue regeneration. STATEMENT OF SIGNIFICANCE: Bone substitute material implantation is essential in the healing of large bone defects. Existing research suggests that T lymphocytes are instrumental in bone regeneration. However, the specific mechanisms governing T cell recruitment and specific subsets that are essential for bone regeneration remain unclear. In this study, we demonstrate that activation of calcium channels in macrophages by biphasic calcium phosphate (BCP) causes them to release the chemokines Ccl3 and Ccl17 to recruit CD4+ T cells, predominantly Tregs, which play a crucial role in ectopic osteogenesis by BCP. Our findings provide a theoretical foundation for developing bone substitute material for bone tissue regeneration.

Identification and function of the Pax gene Bmgsb in the silk gland of Bombyx mori.

Paired box (Pax) genes are highly conserved throughout evolution, and the Pax protein is an important transcription factor of embryonic development. The Pax gene Bmgsb is expressed in the silk glands of silkworm, but its biological functions remain unclear. This study aimed to investigate the expression pattern of Bmgsb in the silk gland and explore its functions using RNA interference (RNAi). Here, we identified eight Pax genes in Bombyx mori. Phylogenetic analysis showed that the B. mori Pax genes were highly homologous to the Pax genes in other insects and highly evolutionarily conserved. The tissue expression profile showed that Bmgsb was expressed in the anterior silk gland and anterior part of the middle silk gland (AMSG). RNAi of Bmgsb resulted in defective development of the AMSG, and the larvae were mostly unable to cocoon in the wandering stage. RNA-seq analysis showed that the fibroin genes fib-l, fib-h and p25, cellular heat shock response-related genes and phenol oxidase genes were considerably upregulated upon Bmgsb knockdown. Furthermore, quantitative reverse transcription-PCR results showed that the fibroin genes and ubiquitin proteolytic enzyme-related genes were significantly upregulated in the AMSG after Bmgsb knockdown. This study provides a foundation for future research on the biological functions of B. mori Pax genes. In addition, it demonstrates the important roles of Bmgsb in the transcriptional regulation of fibroin genes and silk gland development.

CT-Based Radiomics for the Preoperative Prediction of Occult Peritoneal Metastasis in Epithelial Ovarian Cancers.

RATIONALE AND OBJECTIVES: The objective of this study was to develop a comprehensive combined model for predicting occult peritoneal metastasis (OPM) in epithelial ovarian cancers (EOCs) using radiomics features derived from computed tomography (CT) and clinical-radiological predictors. MATERIALS AND METHODS: A total of 224 patients with EOCs were randomly divided into training dataset (N = 156) and test dataset (N = 86). Five clinical factors and seven radiological features were collected. The radiomics features were extracted from CT images of each patient. Multivariate logistic regression was employed to construct clinical and radiological models. The correlation analysis and least absolute shrinkage and selection operator algorithm were used to select radiomics features and build radiomics model. The important clinical, radiological factors, and radiomics features were integrated into a combined model by multivariate logistic regression. Receiver operating characteristics curve with area under the curve (AUC) were used to evaluate and compare predictive performance. RESULTS: Carbohydrate antigen 125 (CA-125) and human epididymal protein 4 (HE-4) were independent clinical predictors. Laterality, thickened septa and margin were independent radiological predictors. In the training dataset, the AUCs for the clinical, radiological and radiomics models in evaluating OPM were 0.759, 0.819, and 0.830, respectively. In the test dataset, the AUCs for these models were 0.846, 0.835, and 0.779, respectively. The combined model outperformed other models in both the training and the test datasets with AUCs of 0.901 and 0.912, respectively. Decision curve analysis indicated that the combined model yielded a higher net benefit compared to the other models. CONCLUSION: The combined model, integrating radiomics features with clinical and radiological predictors exhibited improved accuracy in predicting OPM in EOCs.

Validation and Comparison of Four Mortality Prediction Models in a Geriatric Ward in China.

Purpose: The efficacy of mortality risk prediction models among older patients in China remains uncertain. We aimed to validate and compare the performances of the Walter Index, Geriatric Prognostic Index (GPI), Charlson Comorbidity Index (CCI), and FRAIL Scale in predicting 1-year all-cause mortality post-discharge in geriatric inpatients in China. Patients and Methods: This study was conducted at a geriatric ward of a tertiary Hospital in Beijing, including patients aged 70 years or older with a documented comprehensive geriatric assessment, discharged between January 1, 2016, and December 31, 2021. Patients with a hospital stay ≤24 h or >60 days were excluded. All-cause mortality data within one year of discharge were collected from medical files and telephone interviews between August 2022 and February 2023. Multiple imputation, Logistic regression analysis, Brier scores, C-statistics, Hosmer-Lemeshow goodness-of-fit-test, and calibration plots were employed for statistical analysis. Results: We included 832 patients with a median (interquartile range) age of 77 (74-82) years. One-hundred patients (12.0%) died within one year. After adjusting for covariates-marital status, social support, cigarette use, length of stay, number of medications, hemoglobin levels, handgrip strength, and Short Physical Performance Battery-CCI scores of 3-4 and >4, and increased Walter Index, GPI, and FRAIL Scale scores were significantly associated with 1-year mortality risk. The Brier scores varied from 0.07 (Walter Index) to 0.10 (FRAIL Scale). The C-statistic ranged from 0.74 (95% confidence interval, 0.69-0.78) for FRAIL Scale to 0.88 (95% confidence interval, 0.84-0.91) for the Walter Index. Calibration curves showed that the Walter Index, GPI, and FRAIL Scale were well calibrated, while the CCI was poor. Conclusion: Combining the Brier score, discrimination and calibration, the Walter Index was confirmed for the first time to be the best model to predict the 1-year mortality risk of geriatric inpatients in China among the four models.

Development of a fibroblast activation protein-targeted PET/NIR dual-modality probe and its application in head and neck cancer.

Purpose: The combination of near-infrared (NIR) and positron emission tomography (PET) imaging presents an opportunity to utilize the benefits of dual-modality imaging for tumor visualization. Based on the observation that fibroblast activation protein (FAP) is upregulated in cancer-associated fibroblasts (CAFs) infiltrating all solid tumors, including head and neck squamous cell carcinoma (HNSCC), we developed the novel PET/NIR probe [68Ga]Ga-FAP-2286-ICG. Preclinically, the specificity, biodistribution and diagnostic properties were evaluated. Methods: Cell uptake assays were completed with the U87MG cell to evaluate the specificity of the [68Ga]Ga-FAP-2286-ICG. The tumor-targeting efficiency, biodistribution and optimal imaging time window of the [68Ga]Ga-FAP-2286-ICG were studied in mice bearing U87MG xenografts. HNSCC tumor-bearing mice were used to evaluate the feasibility of [68Ga]Ga-FAP-2286-ICG for tumor localization and guided surgical resection of HNSCC tumors. Results: The in vitro experiments confirmed that [68Ga]Ga-FAP-2286-ICG showed good stability, specific targeting of the probe to FAP, and the durable retention effect in high-expressing FAP tumors U87MG cell. Good imaging properties such as good tumor uptake, high tumor-to-background ratios (5.44 ± 0.74) and specificity, and tumor contouring were confirmed in studies with mice bearing the U87MG xenograft. PET/CT imaging of the probe in head and neck cancer-bearing mice demonstrated specific uptake of the probe in the tumor with a clear background. Fluorescence imaging further validated the value of the probe in guiding surgical resection and achieving precise removal of the tumor and residual lesions. Conclusion: In a preclinical model, these attractive [68Ga]Ga-FAP-2286-ICG PET/NIR imaging acquired in head and neck cancer make it a promising FAP-targeted multimodal probe for clinical translation.