Identification of Comprehensive Biomarkers in Patients With Mismatch Repair-Deficient Colon Adenocarcinoma Based on Parallel Multiomics.

Immunocheckpoint inhibitors have shown impressive efficacy in patients with colon cancer and other types of solid tumor that are mismatch repair-deficient (dMMR). Currently, PCR-capillary electrophoresis is one of the mainstream detection methods for dMMR, but its accuracy is still limited by germline mismatch repair (MMR) mutations, the functional redundancy of the MMR system, and abnormal methylation of MutL Homolog 1 promoter. Therefore, this study aimed to develop new biomarkers for dMMR based on artificial intelligence (AI) and pathologic images, which may help to improve the detection accuracy. To screen for the differential expression genes (DEGs) in dMMR patients and validate their diagnostic and prognostic efficiency, we used the expression profile data from the Cancer Genome Atlas (TCGA). The results showed that the expression of Immunoglobulin Lambda Joining 3 in dMMR patients was significantly downregulated and negatively correlated with the prognosis. Meanwhile, our diagnostic models based on pathologic image features showed good performance with area under the curves (AUCs) of 0.73, 0.86, and 0.81 in the training, test, and external validation sets (Jiangsu Traditional Chinese Medicine Hospital cohort). Based on gene expression and pathologic characteristics, we developed an effective prognosis model for dMMR patients through multiple Cox regression analysis (with AUC values of 0.88, 0.89, and 0.88 at 1-, 3-, and 5-year intervals, respectively). In conclusion, our results showed that Immunoglobulin Lambda Joining 3 and nucleus shape-related parameters (such as nuclear texture, nuclear eccentricity, nuclear size, and nuclear pixel intensity) were independent diagnostic and prognostic factors, suggesting that they could be used as new biomarkers for dMMR patients.

Broadband mid-infrared non-reciprocal absorption using magnetized gradient epsilon-near-zero thin films.

The study of magneto-optical absorption has stimulated diverse energy-technology-related explorations, showing potential in breaking the current theoretical efficiency limits of energy devices compared with reciprocal counterparts. However, experimentally realizing strong infrared non-reciprocal absorption remains an open challenge, and existing proposals of non-reciprocal absorbers are restricted to a narrow working waveband. Here we observe highly asymmetric absorption spectra over a broad mid-infrared band (nearly 10 µm) using doped InAs multilayers with gradient epsilon-near-zero frequencies. We reveal that the magnetized epsilon-near-zero behaviours and material loss play important roles in achieving strongly non-reciprocal absorption under a moderate external magnetic field using a thin epsilon-near-zero film (<λ/40, λ is the wavelength). Our approach enables flexible control over the working frequencies and non-reciprocal bandwidths by designing magnetized InAs films with different doping concentrations. The proposed principles can also be generalized to other III-V semiconductors, magnetized metals, topological Weyl semimetals, magnetized zero-index metamaterials and metasurfaces.

The impact of SOX4-activated CTHRC1 transcriptional activity regulating DNA damage repair on cisplatin resistance in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the predominant subtype within the spectrum of lung malignancies. CTHRC1 has a pro-oncogenic role in various cancers. Here, we observed the upregulation of CTHRC1 in LUAD, but its role in cisplatin resistance in LUAD remains unclear. Bioinformatics analysis was employed to detect CTHRC1 and SRY-related HMG-box 4 (SOX4) expression in LUAD. Gene Set Enrichment Analysis predicted the enriched pathways related to CTHRC1. JASPAR and MotifMap databases predicted upstream transcription factors of CTHRC1. Pearson analysis was conducted to analyze the correlation between genes of interest. The interaction and binding relationship between CTHRC1 and SOX4 were validated through dual-luciferase and chromatin immunoprecipitation assays. Quantitative real-time polymerase chain reaction determined the expression of CTHRC1 and SOX4 genes. CCK-8 was performed to assess cell viability and calculate IC50 value. Flow cytometry examined the cell cycle. Comet assay and western blot assessed DNA damage. CTHRC1 and SOX4 were upregulated in LUAD. CTHRC1 exhibited higher expression in cisplatin-resistant A549 cells compared to cisplatin-sensitive A549 cells. Knockdown of CTHRC1 enhanced DNA damage during cisplatin treatment and increased the sensitivity of LUAD cells to cisplatin. Additionally, SOX4 modulated DNA damage repair (DDR) by activating CTHRC1 transcriptional activity, promoting cisplatin resistance in LUAD cells. SOX4 regulated DDR by activating CTHRC1, thereby enhancing cisplatin resistance in LUAD cells. The finding provides a novel approach to address clinical cisplatin resistance in LUAD, with CTHRC1 possibly serving as a candidate for targeted therapies in addressing cisplatin resistance within LUAD.

STING-targeted PET tracer for early assessment of tumor immunogenicity in colorectal cancer after chemotherapy.

PURPOSE: To optimize chemotherapy regimens and improve the effectiveness of chemotherapy combined with immunotherapy, a PET tracer specifically targeting the stimulator of interferon genes (STING), denoted as [18F]FBTA was used to monitor the early changes in tumor immunogenicity after chemotherapy in colorectal cancer (CRC) mice. METHODS: The toluene sulfonate precursor was labeled with 18F to produce the STING targeted probe-[18F]FBTA. [18F]FBTA-PET imaging and biodistribution were performed using CRC mice treated with oxaliplatin (OXA) or cisplatin (CDDP). CRC mice were also treated with low (CDDP-LD: 1 mg/kg) or medium (CDDP-MD: 2.5 mg/kg) doses of CDDP, and subjected to PET imaging and biodistribution. The effects of different chemotherapeutic agents and different doses of CDDP on tumor innate immunity were verified by flow cytometry and immunohistochemistry. RESULTS: PET imaging of CRC mice exhibited notably enhanced tumor uptake in the early phase of chemotherapy with treatment with OXA (3.09 ± 0.25%ID/g) and CDDP (4.01 ± 0.18%ID/g), especially in the CDDP group. The PET-derived tumor uptake values have strong correlations with STING immunohistochemical score. Flow cytometry showed both agents led to DCs and macrophages infiltration in tumors. Compared with OXA, CDDP treatment recruits more DCs and macrophages in CRC tumors. Both CDDP-LD and CDDP-MD treatment elevated uptake in CRC tumors, especially in CDDP-MD group. Immunohistochemistry and flow cytometry confirmed CDDP-MD treatment recruits more DCs and macrophages than CDDP-LD treatment. CONCLUSION: Overall, the STING-targeted tracer-[18F]FBTA was demonstrated to monitor early changes in tumor immunogenicity in CRC mice after chemotherapy. Besides, the STING-targeted strategy may help to select the appropriate chemotherapy regimen, including chemotherapeutic agents and doses, which further improve clinical decision making for combination immunotherapy after chemotherapy for CRC.

STING-Targeted PET Imaging for Specific Detection and Therapeutic Monitoring of Myocarditis.

Imaging strategies for the specific detection and therapeutic monitoring of myocarditis are still lacking. Stimulator of interferon genes (STING) is a signal transduction molecule involved in an innate immune response. Here, we evaluated the feasibility of the recently developed STING-targeted radiotracer [18F]FBTA for positron emission tomography (PET) imaging to detect myocardial inflammation and monitor treatment in myocarditis mice. [18F]FBTA-PET imaging was performed in myocarditis mice and normal mice to verify the specificity of [18F]FBTA for the diagnosis of myocarditis. We also performed PET imaging in mice with myocarditis treated to verify the ability of [18F]FBTA in therapeutic monitoring. The expression of STING and inflammatory cell types was confirmed by flow cytometry and immunohistochemistry. [18F]FDG-PET imaging of myocarditis was used as a contrast. [18F]FBTA-PET imaging showed that the average radioactive uptake was significantly higher in the hearts of the myocarditis group than in the control group. STING was highly overexpressed in cardiac inflammatory cells, including macrophages, dendritic cells (DCs), and T cells. However, there was no significant difference in cardiac radiotracer uptake of [18F]FDG between the myocarditis group and the control group. Moreover, cardiac uptake of [18F]FBTA was significantly reduced in cyclosporin A-treated myocarditis mice and myocardial STING expression was also significantly reduced after the treatment. Overall, we showed that a STING-targeted PET tracer [18F]FBTA can be used to monitor changes in the inflammatory microenvironment in myocarditis. Besides, [18F]FBTA-PET is also suitable for real-time monitoring of myocarditis treatment, representing a promising diagnostic and therapeutic monitoring approach for myocarditis.

Associations of Bisphenols Exposure and Hyperuricemia Based on Human Investigation and Animal Experiments.

Hyperuricemia is characterized by elevated blood uric acid (UA) levels, which can lead to certain diseases. Epidemiological studies have explored the association between environmental contaminant exposure and hyperuricemia. However, few studies have investigated the role of chemical exposure in the development of hyperuricemia. Here, we sought to investigate the effects of bisphenol exposure on the occurrence of hyperuricemia. Fifteen bisphenol chemicals (BPs) were detected in human serum and urine samples collected from an area with a high incidence of hyperuricemia in China. Serum UA levels positively correlated with urinary bisphenol S (BPS), urinary bisphenol P (BPP), and serum bisphenol F (BPF). The effects of these three chemicals on UA levels in mice were explored at various exposure concentrations. An increase in serum UA levels was observed in BPS- and BPP-exposed mice. The results showed that BPS exposure increased serum UA levels by damaging the structure of the kidneys, whereas BPP exposure increased serum UA levels by disturbing purine metabolism in the liver. Moreover, BPF did not induce an increase in serum UA levels owing to the inhibition of guanine conversion to UA. In summary, we provide evidence of the mechanisms whereby exposure to three BPs disturbs UA homeostasis. These findings provide new insights into the risks of exposure to bisphenol chemicals.

MiR-27a-3p exacerbates cell migration and invasion in right-sided/left-sided colorectal cancer by targeting TGFBR2/TCF7L2.

Left-sided colorectal cancer (LSCC) and right-sided colorectal cancer (RSCC) belong to colorectal cancer happening at different positions, which exhibit different pathogenesis. MicroRNA (miRNA)s are widely known regulators in diverse carcinomas. This research aims to identify a differentially expressed miRNA that simultaneously regulates genes associated with LSCC and RSCC and reveal their regulatory relation in cell migration and invasion. Bioinformatics analyses were conducted to uncover the dysregulated functional genes in LSCC/RSCC and obtain their common targeted miRNAs. The expression pattern of miR-27a-3p, TCF7L2, and TGFBR2 in cancerous and adjacent tissues from LSCC/RSCC patients was assessed through qRT-PCR, followed by Pearson's correlation coefficients analysis. The interaction of miR-27a-3p with TCF7L2 or TGFBR2 was thereafter confirmed through luciferase reporter assay. TCF7L2 and TGFBR2 protein levels were assessed by western blotting after overexpressing level of miR-27a-3p. Cell migration and invasion were routinely examined by wound healing and transwell experiments, respectively. TCF7L2 and TGFBR2 were respectively identified and verified to be lowly expressed in LSCC and RSCC, both of them were predicted and confirmed as targets of miR-27a-3p. MiR-27a-3p elevation exacerbated migration and invasion of both LSCC and RSCC cells. The impacts of miR-27a-3p on migration and invasion could be blocked by overexpressing TCF7L2 in LSCC cells and also reversed by up-regulating TGFBR2 in RSCC cells. In general, miR-27a-3p accelerated the migration and invasion capabilities of LSCC and RSCC cells through negatively regulating TCF7L2 and TGFBR2, respectively, which might be an effective molecular target for the treatment of LSCC/RSCC.

An updated meta-analysis of optimal medical therapy with or without invasive therapy in patients with stable coronary artery disease.

BACKGROUND: The efficacy of optimal medical therapy (OMT) with or without revascularization therapy in patients with stable coronary artery disease (SCAD) remains controversial. We performed a meta-analysis of randomized controlled trials (RCTs) that compared OMT with or without revascularization therapy for SCAD patients. METHODS: Studies were searched in PubMed, EMBASE, and the Cochrane Central Register of Clinical Trials from January 1, 2005, to December 30, 2023. The main efficacy outcome was a composite of all-cause death, myocadiac infarction, revascularization, and cerebrovascular accident. Results were pooled using random effects model and fixed effects model and are presented as odd ratios (ORs) with 95% confidence intervals (CI). RESULTS: Ten studies involving 12,790 participants were included. The arm of OMT with revascularization compared with OMT alone was associated with decreased risks for MACCE (OR 0.55 [95% CI 0.38-0.80], I²=93%, P = 0.002), CV death (OR 0.84 [95% CI 0.73-0.97], I²=36%, P = 0.02), revascularization (OR 0.32 [95% CI 0.20-0.50], I²=92%, P < 0.001), and MI (OR 0.85 [95% CI 0.76-0.96], I²=45%, P = 0.007). While there was no significant difference between OMT with revascularization and OMT alone in the odds of all-cause death (OR 0.94 [95% CI 0.84-1.05], I²=0%, P = 0.30). CONCLUSIONS: The current updated meta-analysis of 10 RCTs shows that in patients with SCAD, OMT with revascularization would reduce the risk for MACCE, cardiovascular death, and MI. However, the invasive strategy does not decrease the risks for all-cause mortality when comparing with OMT alone.

Associations of five blood heavy metals with hepatitis B virus infection and immunity in adults: a cross-sectional study.

BACKGROUND: Heavy metal pollution has emerged as a significant concern for human health, prompting increased awareness of its potential adverse effects. While previous research has established a connection between heavy metals and liver function biomarkers, the specific relationship between heavy metals and HBV infection remains unexplored. This cross-sectional study aims to investigate the potential correlations between five blood heavy metals - lead, cadmium, mercury, manganese, and selenium - and the presence of HBsAg, HBsAb, and HBcAb in adults. METHODS: The study utilized data from NHANES 2007-2018. Participants were classified into four groups based on their infectious status, and the association between heavy metals and HBV infection was analyzed using multiple logistic regression and stratification analysis. RESULTS: A total of 8431 participants were included, with 5 436 classified as Susceptible, 1 765 as Vaccinated, 865 as Natural Infection, and 103 as Acute/Chronic HBV Infection. The Vaccinated group exhibited a lower mean age (34.52 ± 14.16 years) compared to the other groups. Statistically significant differences in heavy metal concentrations (except selenium) were observed among the groups (P < 0.001). After adjusting for covariates, lead was significantly associated with HBV infection (Q2: OR 2.37, 95%CI 1.04-5.39; Q3: OR 2.34, 95%CI 1.01-5.40), and positive trends were observed for high blood concentrations of mercury (Q4: OR 3.03, 95%CI 1.31-7.04) and manganese (Q4: OR 2.52, 95%CI 1.20-5.28). Furtherly, the presence of lead reduced the protection of HBsAb (Q2: OR 0.84, 95%CI 0.73-0.97; Q3: OR 0.77, 95%CI 0.66-0.90; Q4: OR 0.83, 95%CI 0.70-0.98). Subgroup analysis indicated that cadmium was associated with an increased risk of HBV infection in Asians (OR 1.36, 95%CI 1.03-1.78) and individuals with a BMI range of 25 to 30 (OR 1.60, 95%CI 1.17-2.18). CONCLUSIONS: The study's findings suggest a correlation between elevated blood Pb concentrations and reduced immunization rates against hepatitis B. Individuals with a positive HBsAg exhibit lower blood Se concentrations and higher blood Hg and Mn concentrations.

Ganshuang granule plays a pharmacological role in anti-alcoholic and anti-hangover via regulating alcohol metabolism and affecting neurotransmitters.

BACKGROUND: To explore the effect of Ganshuang granule on anti-alcoholic and anti-hangover and its potential mechanism. METHODS: SPF SD rats' drunken model and SPF Kunming mice's hangover model were used as models. RESULTS: Ganshuang granule could significantly reduce sleep time, the time to climb in mice, and significantly prolong the tolerance time and shorten sleep time in rats (p < 0.05). The blood ethanol concentration of rats in each administration group was lower than that in the model group at each time point (p < 0.05). Compared with the control group, the activities of ADH and ALDH in the liver of the model group were significantly decreased (p < 0.05); the content of DA and 5-HT in the striatum of the model group was significantly increased (p < 0.05); and the activity of AchE in the hippocampus was significantly decreased (p < 0.05). The above processes could be improved and regulated in the drug administration group. Compared with the control group, there was no significant difference between ADH and ALDH in the serum of the model group (p > 0.05). However, the activities of ADH and ALDH in the liver of drunk rats could be upregulated by Ganshuang granule (p < 0.05). CONCLUSION: Ganshuang granule has the pharmacological effects of anti-alcoholic and anti-hangover, which is related to regulating the activities of ADH and ALDH in the liver, the contents of DA and 5-HT in striatum, and the activity of AchE in the hippocampus.

Improvements to a GLCM-based machine-learning approach for quantifying posterior capsule opacification.

BACKGROUND: Posterior capsular opacification (PCO) is a common complication following cataract surgery that leads to visual disturbances and decreased quality of vision. The aim of our study was to employ a machine-learning methodology to characterize and validate enhancements applied to the grey-level co-occurrence matrix (GLCM) while assessing its validity in comparison to clinical evaluations for evaluating PCO. METHODS: One hundred patients diagnosed with age-related cataracts who were scheduled for phacoemulsification surgery were included in the study. Following mydriasis, anterior segment photographs were captured using a high-resolution photographic system. The GLCM was utilized as the feature extractor, and a supported vector machine as the regressor. Three variations, namely, GLCM, GLCM+C (+axial information), and GLCM+V (+regional voting), were analyzed. The reference value for regression was determined by averaging clinical scores obtained through subjective analysis. The relationships between the predicted PCO outcome scores and the ground truth were assessed using Pearson correlation analysis and a Bland-Altman plot, while agreement between them was assessed through the Bland-Altman plot. RESULTS: Relative to the ground truth, the GLCM, GLCM+C, and GLCM+V methods exhibited correlation coefficients of 0.706, 0.768, and 0.829, respectively. The relationship between the PCO score predicted by the GLCM+V method and the ground truth was statistically significant (p < 0.001). Furthermore, the GLCM+V method demonstrated competitive performance comparable to that of two experienced clinicians (r = 0.825, 0.843) and superior to that of two junior clinicians (r = 0.786, 0.756). Notably, a high level of agreement was observed between predictions and the ground truth, without significant evidence of proportional bias (p > 0.05). CONCLUSIONS: Overall, our findings suggest that a machine-learning approach incorporating the GLCM, specifically the GLCM+V method, holds promise as an objective and reliable tool for assessing PCO progression. Further studies in larger patient cohorts are warranted to validate these findings and explore their potential clinical applications.

Quantifying the coherent backscatter enhancement of non-spherical particles with discrete dipole approximation.

The prevailing backscattering peak associated with the scattering phase function of large non-absorptive particles can be interpreted with the coherent backscatter enhancement (CBE) theory, but has not been explicitly quantified with numerical simulations based on solving Maxwell's equations. In this paper, representative numerical simulations performed with the discrete-dipole-approximation (DDA) model are used to quantify the effect of CBE on the single-scattering phase function. For each scattering case, the particle volume was divided into multiple thin slices parallel to the incident beam. The dipole polarizations in the j'th slice in response to the incident field of the i'th slice were computed, and then the corresponding contribution to the scattering phase function was calculated. Interference between conjugate terms representing reversible wave paths is constructive at the backscattering direction, which corresponds to the CBE. Subsequently, the contribution of CBE to the scattering phase function was quantified by comparing the electric fields calculated with and without the interference between conjugate terms. Results from these numerical simulations are consistent with conclusions obtained from the CBE theory. The simulations also quantitatively explain why it is difficult to identify a CBE-induced backscattering peak for the phase function of small particles and strong-absorptive particles.

Flexible implementation of the particle shape and internal inhomogeneity in the invariant imbedding T-matrix method.

We report a new implementation of the invariant imbedding T-matrix (IITM) method based on a discrete spherical grid approach for representing the particle shape and internal inhomogeneity. The new version of the IITM (referred to as the IITM-discrete) improves the flexibility of the IITM-especially for inhomogeneous particles. It is much more convenient for specifying the particle morphology in the electromagnetic wave scattering simulations. Particle shape is represented by a series of discrete spherical layers ranging from the inscribed sphere to the circumscribed sphere. Spherical layers are discretized by the centroidal Voronoi tessellation (CVT) approach. The procedure of computing the U-matrix (the only shape-dependent module in the T-matrix program) is simplified upon using the gridded particle shape and refractive index information saved in an external file. The grid resolution is a key factor that determines the numerical accuracy and computational cost. Numerical tests of IITM-discrete show its compatibility with other light scattering methods. Using IITM-discrete, we found that the internal inhomogeneity could have large impact on dust optical properties.

Distinct linear polarization of core-shell particles at near-backscattering directions.

The degree of linear polarization (-P12/P11) of scattered light by particles with a core-shell structure may display a distinct negative minimum at near-backscattering directions. However, the specific range of microphysical parameters within which this phenomenon occurs and the underlying physical mechanism are still unclear. Therefore, this study systematically investigated the impacts of particle size, shell-core ratio and refractive index on the negative minimum of -P12/P11 at near-backscattering angles for both coated spheres and coated super-spheroids. The findings reveal that the pronounced negative minimum at near-backscattering angles mostly appeared when the size parameter defined in terms of the mean radius was smaller than approximately 14.5 (e.g., the mean radius is smaller than approximately 2 µm at 0.865 µm wavelength) and the shell-core ratio was in a range of 1.4-1.9. The presence of weakly- and moderately-absorptive shells would lead to pronounced negative polarization at near backscattering directions. However, as the core absorption increased, the amplitude of negative minimum decreased and then stabilized. As for coated super-spheroids, the non-sphericity of the shell tended to suppress the negative polarization at near-backscattering directions. As a result, the pronounced negative minimum (<-0.4) mostly appeared when the aspect ratio and roundness of the shell were close to unity (the overall shape of the particle was nearly-spherical). However, the negative minimum of -P12/P11 showed little dependence on the shape of the core. Furthermore, the Debye series approach was employed to investigate the underlying mechanism of the negative minimum of -P12/P11 for coated spheres. The results demonstrated that the interference among the partial waves underwent one internal reflection on the shell-medium interface and, without internal reflection on the core-shell interface, led to the pronounced negative polarization at near-backscattering angles. When the core absorption was significant, the interference became negligible and the amplitude of the negative minimum was suppressed. This study enhances our understanding the scattering characteristic of coated particles and has implications in aerosol classification and polarized remote sensing.

Polarization-dependent reconfigurable light field manipulation by liquid-immersion metasurface.

Traditional grating lenses can accumulate phase for adjusting wavefronts, and plasmonic resonances can be excited in metasurfaces with discrete structures for optical field modulation. Diffractive and plasma optics have been developing in parallel, with easy processing, small size, and dynamic control advantages. Due to theoretical hybridization, structural design can combine advantages and show great potential value. Changing the shape and size of the flat metasurface can easily produce light field reflections, but changes in height are rarely cross-explored. We propose a graded metasurface with a single-structure periodic arrangement, which can mix the effects of plasmonic resonance and grating diffraction. As for solvents of different polarities, strong polarization-dependent beam reflections are produced, enabling versatile beam convergence and deflection. Dielectric/metal nanostructures with selective hydrophobic/hydrophilic properties can be arranged by the structural material specification to selectively settle the location of the solution in a liquid environment. Furthermore, the wetted metasurface is actively triggered to achieve spectral control and initiate polarization-dependent beam steering in the broadband visible light region. Actively reconfigurable polarization-dependent beam steering has potential applications in tunable optical displays, directional emission, beam manipulation and processing, and sensing technologies.

Multi-task deep learning-based radiomic nomogram for prognostic prediction in locoregionally advanced nasopharyngeal carcinoma.

PURPOSE: Prognostic prediction is crucial to guide individual treatment for locoregionally advanced nasopharyngeal carcinoma (LA-NPC) patients. Recently, multi-task deep learning was explored for joint prognostic prediction and tumor segmentation in various cancers, resulting in promising performance. This study aims to evaluate the clinical value of multi-task deep learning for prognostic prediction in LA-NPC patients. METHODS: A total of 886 LA-NPC patients acquired from two medical centers were enrolled including clinical data, [18F]FDG PET/CT images, and follow-up of progression-free survival (PFS). We adopted a deep multi-task survival model (DeepMTS) to jointly perform prognostic prediction (DeepMTS-Score) and tumor segmentation from FDG-PET/CT images. The DeepMTS-derived segmentation masks were leveraged to extract handcrafted radiomics features, which were also used for prognostic prediction (AutoRadio-Score). Finally, we developed a multi-task deep learning-based radiomic (MTDLR) nomogram by integrating DeepMTS-Score, AutoRadio-Score, and clinical data. Harrell's concordance indices (C-index) and time-independent receiver operating characteristic (ROC) analysis were used to evaluate the discriminative ability of the proposed MTDLR nomogram. For patient stratification, the PFS rates of high- and low-risk patients were calculated using Kaplan-Meier method and compared with the observed PFS probability. RESULTS: Our MTDLR nomogram achieved C-index of 0.818 (95% confidence interval (CI): 0.785-0.851), 0.752 (95% CI: 0.638-0.865), and 0.717 (95% CI: 0.641-0.793) and area under curve (AUC) of 0.859 (95% CI: 0.822-0.895), 0.769 (95% CI: 0.642-0.896), and 0.730 (95% CI: 0.634-0.826) in the training, internal validation, and external validation cohorts, which showed a statistically significant improvement over conventional radiomic nomograms. Our nomogram also divided patients into significantly different high- and low-risk groups. CONCLUSION: Our study demonstrated that MTDLR nomogram can perform reliable and accurate prognostic prediction in LA-NPC patients, and also enabled better patient stratification, which could facilitate personalized treatment planning.

Ankylosing spondylitis PET imaging and quantifications via P2X7 receptor-targeting radioligand [18F]GSK1482160.

PURPOSE: Ankylosing spondylitis (AS) is a chronic inflammatory disease of the axial spine; however, the quantitative detection of inflammation in AS remains a challenge in clinical settings. We aimed to investigate the feasibility of using a specific P2X7R-targeting 18F-labeled tracer [18F]GSK1482160 for positron emission tomography (PET) imaging and the quantification of AS. METHODS: The radioligand [18F]GSK1482160 was obtained based on nucleophilic aliphatic substitution. Dynamic [18F]GSK1482160 and [18F]FDG micro-PET/CT imaging were performed on AS mice (n = 8) and age-matched controls (n = 8). Tracer kinetics modeling was performed using Logan's graphical arterial input function analysis to quantify the in vivo expression of P2X7R. The post-PET tissues were collected for hematoxylin-eosin (H&E), immunohistochemical (IHC), and immunofluorescence (IF) staining. RESULTS: [18F]GSK1482160 PET/CT imaging revealed that the specific binding in the ankle joint and sacroiliac joint (SIJ) of the AS at 8 weeks group (BPNDankle-AS-8W (non-displaceable binding potential of the ankle) 3.931 ± 0.74; BPND SIJ-AS-8W (BPBD of the SIJ) 4.225 ± 0.84) were significantly higher than the controls at 8 weeks group (BPNDankle-Ctr-8W 0.325 ± 0.15, BPNDSJJ-Ctr-8W 0.319 ± 0.17) respectively, and the AS at 14 weeks group (BPNDankle-AS-14W 12.212 ± 2.25; BPNDSJJ-AS-14W 13.389 ± 3.60) were significantly higher than the controls at 14 weeks group (BPNDankle-Ctr-14W 0.204 ± 0.16, BPNDSJJ-Ctr-14W 0.655 ± 0.35) respectively. The four groups had no significant difference in the [18F]FDG uptake of ankle and SIJ. IHC and IF staining revealed that the overexpression of P2X7R was colocalized with activated macrophages from the ankle synovium and spinal endplate in mice with AS, indicating that quantification of P2X7R may contribute to the understanding of the pathogenesis of inflammation in human AS. CONCLUSION: This study developed a novel P2X7R-targeting PET tracer [18F]GSK1482160 to detect the expression of P2X7R in AS mouse models and provided powerful non-invasive PET imaging and quantification for AS.

Identification of a CEACAM5 targeted nanobody for positron emission tomography imaging and near-infrared fluorescence imaging of colorectal cancer.

PURPOSE: Here, we aim to identify a CEACAM5-targeted nanobody and demonstrate its application in positron emission tomography (PET) imaging and near-infrared (NIR) fluorescence imaging in colorectal cancer (CRC). METHODS: Immunohistochemistry was applied to verify CEACAM5 expression in CRC and metastatic lymph nodes (mLNs). CEACAM5-targeted nanobodies were obtained by immunization of human CEACAM5 protein in a dromedary, followed by several rounds of phage screenings. Immunofluorescence staining and flow cytometry was carried out to determine the binding affinity of the nanobodies. The nanobodies were radiolabeled by coupling 18F-SFB for PET imaging of CRC subcutaneous xenografts and lymph node metastasis (LNM). IRDye800CW (IR800) were conjugated to form NIR probes for NIR imaging in CRC subcutaneous models. RESULTS: CEACAM5 was overexpressed in either human CRC tissues or mLNs. A CEACAM5 targeted nanobody, Nb41 was successfully generated, with excellent in vitro binding properties. Incorporation of albumin binding domain (ABD) did not affect the affinity of Nb41. In vivo imaging showed that both 18F-FB-Nb41 and 18F-FB-Nb41-ABD showed obvious accumulation in the tumor. Due to the longer retention in the blood, 18F-FB-Nb41-ABD enrichment in tumors was significantly delayed but higher compared to 18F-FB-Nb41. Both 18F-FB-Nb41 and 18F-FB-Nb41-ABD showed prominent LNM enrichment. Similarly, the IR800-conjugated nanobodies Nb41-IR800 and Nb41-ABD-IR800 exhibited superior imaging effects in subcutaneous models, while Nb41-ABD-IR800 exhibited higher fluorescence intensity in the tumor accompanied with a remarkedly delay compared to Nb41-IR800. CONCLUSION: Collectively, we presented the identification and in vivo validation of a CEACAM5-targeted nanobody and a fused nanobody with an ABD, which enabled to the non-invasive visualization of malignancy of CRC using PET imaging and NIR imaging in subcutaneous models as well as LNM models.

Integrated Transcriptomic and Metabolomics Analysis of the Root Responses of Orchardgrass to Submergence Stress.

Submergence stress can severely affect plant growth. Orchardgrass (Dactylis glomerata L.) is an important forage grass, and the molecular mechanisms of orchardgrass to submergence stress are not well understood. The roots of the flood-tolerant cultivar "Dian Bei" were harvested at 0 h, 8 h and 24 h of submergence stress. The combined transcriptomic and metabolomic analyses showed that ß-alanine metabolism, flavonoid biosynthesis, and biosynthesis of amino acid pathways were significantly enriched at 8 h and 24 h of submergence stress and were more pronounced at 24 h. Most of the flavonoid biosynthesis-related genes were down-regulated for the synthesis of metabolites such as naringenin, apigenin, naringin, neohesperidin, naringenin chalcone, and liquiritigenin in response to submergence stress. Metabolites such as phenylalanine, tyrosine, and tryptophan were up-regulated under stress. The predominant response of flavonoid and amino acids biosynthesis to submergence stress suggests an important role of these pathways in the submergence tolerance of orchardgrass.

A sustained-release microcarrier effectively prolongs and enhances the antibacterial activity of lysozyme.

Bacterial infections have become a great threat to public health in recent years. A primary lysozyme is a natural antimicrobial protein; however, its widespread application is limited by its instability. Here, we present a poly (N-isopropylacrylamide) hydrogel inverse opal particle (PHIOP) as a microcarrier of lysozyme to prolong and enhance the efficiency against bacteria. This PHIOP-based lysozyme (PHIOP-Lys) formulation is temperature-responsive and exhibits long-term sustained release of lysozyme for up to 16 days. It shows a potent antibacterial effect toward both Escherichia coli and Staphylococcus aureus, which is even higher than that of free lysozyme in solution at the same concentration. PHIOPs-Lys were demonstrated to effectively inhibit bacterial infections and enhance wound healing in a full-thickness skin wound rat model. This study provides a novel pathway for prolonging the enzymatic activity and antibacterial effects of lysozyme.