Imaging and Downstaging Bladder Cancer with the 177Lu-Labeled Bioorthogonal Nanoprobe.

Efforts on bladder cancer treatment have been shifting from extensive surgery to organ preservation in the past decade. To this end, we herein develop a multifunctional nanoagent for bladder cancer downstaging and bladder-preserving therapy by integrating mucosa penetration, reduced off-target effects, and internal irradiation therapy into a nanodrug. Specifically, an iron oxide nanoparticle was used as a carrier that was coated with hyaluronic acid (HA) for facilitating mucosa penetration. Dibenzocyclooctyne (DBCO) was introduced into the HA coating layer to react through bioorthogonal reaction with azide as an artificial receptor of bladder cancer cells, to improve the cellular internalization of the nanoprobe labeled with 177Lu. Through magnetic resonance imaging, the targeted imaging of both nonmuscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) was realized after intravesical instillation of the multifunctional probe, both NMIBC and MIBC were found downstaged, and the metastasis was inhibited, which demonstrates the potential of the multifunctional nanoprobe for bladder preservation in bladder cancer treatment.

Surface ligand-regulated renal clearance of MRI/SPECT dual-modality nanoprobes for tumor imaging.

BACKGROUND: The general sluggish clearance kinetics of functional inorganic nanoparticles tend to raise potential biosafety concerns for in vivo applications. Renal clearance is a possible elimination pathway for functional inorganic nanoparticles delivered through intravenous injection, but largely depending on the surface physical chemical properties of a given particle apart from its size and shape. RESULTS: In this study, three small-molecule ligands that bear a diphosphonate (DP) group, but different terminal groups on the other side, i.e., anionic, cationic, and zwitterionic groups, were synthesized and used to modify ultrasmall Fe3O4 nanoparticles for evaluating the surface structure-dependent renal clearance behaviors. Systematic studies suggested that the variation of the surface ligands did not significantly increase the hydrodynamic diameter of ultrasmall Fe3O4 nanoparticles, nor influence their magnetic resonance imaging (MRI) contrast enhancement effects. Among the three particle samples, Fe3O4 nanoparticle coated with zwitterionic ligands, i.e., Fe3O4@DMSA, exhibited optimal renal clearance efficiency and reduced reticuloendothelial uptake. Therefore, this sample was further labeled with 99mTc through the DP moieties to achieve a renal-clearable MRI/single-photon emission computed tomography (SPECT) dual-modality imaging nanoprobe. The resulting nanoprobe showed satisfactory imaging capacities in a 4T1 xenograft tumor mouse model. Furthermore, the biocompatibility of Fe3O4@DMSA was evaluated both in vitro and in vivo through safety assessment experiments. CONCLUSIONS: We believe that the current investigations offer a simple and effective strategy for constructing renal-clearable nanoparticles for precise disease diagnosis.

Synthesis and characterization of polyaniline-based composites using cellulose nanocrystals as biological templates.

Polyaniline (PANI) is considered as an ideal electrode material due to its remarkable Faradaic activity, exceptional conductivity, and ease of processing. However, the agglomeration and poor cycling stability of PANI largely limit its practical utilization in energy storage devices. To address these challenges, PANI was synthesized via a facile one-pot, two-step process using cellulose nanocrystals (CNCs) as bio-templates in this work. Zeta potential and particle size measurements revealed that the CNC template could impart improved dispersion stability to the synthesized PANI, which exhibited a decrease in average particle size from 1100 nm to 300 nm as a function of 10 % CNCs. Furthermore, the effect of CNC loadings on the performance of PANI was systematically investigated. The results showed that the specific capacitance of PANI/CNC increased from 102.52 F·g-1 to 138.12 F·g-1 with the CNC loading increase from 0 to 10 wt%. Particularly, the PANI/CNC composite film with a 1:9 ratio (C-P-10 %) demonstrated a capacity retention of 84.45 % after 6000 cycles and an outstanding conductivity of 526 S·m-1. This work generally offers an effective solution for the preparation of high-performance PANI-based composites, which might hold great promise in energy storage device applications.

Exploring the oxidative rancidity mechanism and changes in volatile flavors of watermelon seed kernels based on lipidomics.

Watermelon seed kernels (WSK) are prone to oxidative rancidity, while their evaluation biomarkers and changes in volatile flavor are still unknown. The research tracked the changes in volatile compounds and lipid components before and after rancidity using HS-SPME-GC-O-MS and lipidomic techniques. The results showed the flavor of watermelon seed kernels changed significantly before and after rancidity, from mild aroma to rancidity. A total of 42 volatile compounds were detected via GC-O-MS, and a total of 220 lipid molecules were detected via lipidomic technology. 55 lipids with significant differences were screened via multivariate statistical analysis. Combining the above analysis, it found that glycerol phospholipid and glyceride pathways were the most important metabolic pathways and 1-Pentanol and styrene could be used as potential biomarkers to judge the rancidity process of watermelon seed kernels. The research could provide powerful technical support for the storage, transportation and freshness preservation of watermelon seed kernels.

Exploring atherosclerosis imaging with contrast-enhanced MRI using PEGylated ultrasmall iron oxide nanoparticles.

Plaque rupture is a critical concern due to its potential for severe outcomes such as cerebral infarction and myocardial infarction, underscoring the urgency of noninvasive early diagnosis. Magnetic resonance imaging (MRI) has gained prominence in plaque imaging, leveraging its noninvasiveness, high spatial resolution, and lack of ionizing radiation. Ultrasmall iron oxides, when modified with polyethylene glycol, exhibit prolonged blood circulation and passive targeting toward plaque sites, rendering them conducive for MRI. In this study, we synthesized ultrasmall iron oxide nanoparticles of approximately 3 nm via high-temperature thermal decomposition. Subsequent surface modification facilitated the creation of a dual-modality magnetic resonance/fluorescence probe. Upon intravenous administration of the probes, MRI assessment of atherosclerotic plaques and diagnostic evaluation were conducted. The application of Flash-3D sequence imaging revealed vascular constriction at lesion sites, accompanied by a gradual signal amplification postprobe injection. T1-weighted imaging of the carotid artery unveiled a progressive signal ratio increase between plaques and controls within 72 h post-administration. Fluorescence imaging of isolated carotid arteries exhibited incremental lesion-to-control signal ratios. Additionally, T1 imaging of the aorta demonstrated an evolving signal enhancement over 48 h. Therefore, the ultrasmall iron oxide nanoparticles hold immense promise for early and noninvasive diagnosis of plaques, providing an avenue for dynamic evaluation over an extended time frame.

Biomimetic Upconversion Nanoplatform Synergizes Photodynamic Therapy and Enhanced Radiotherapy against Tumor Metastasis.

The easy recurrence and high metastasis of fatal tumors require the development of a combination therapy, which is able to overcome the drawbacks of monomodal strategies such as surgery, photodynamic therapy (PDT), and radiotherapy (RT). Taking the complementary advantages of PDT and RT, we present herein the integration of lanthanide-doped upconversion nanoparticles (UCNPs) with chlorin e6 (Ce6)-imbedded RBC membrane vesicles as a near-infrared-induced PDT agent for achieving synchronous depth PDT and RT with reduced radiation exposure. In such a nanoagent, gadolinium-doped UCNPs with strong X-ray attenuation ability act not only as a light transductor to activate the loaded photosensitizer Ce6 to allow PDT but also as a radiosensitizer to enhance RT. PDT with enhanced low-dose RT can achieve synergistic inhibition of tumor growth by producing reactive oxygen species to destroy local tumor cells and inducing strong T-cell-dependent immunogenic cell death to arrest systemic cancer metastasis. This combination of PDT and RT might be a potential appealing strategy for tumor eradication.

Reversing Acute Kidney Injury through Coordinated Interplay of Anti-Inflammation and Iron Supplementation.

Acute kidney injury (AKI) induced by ischemia reperfusion is closely related to mitochondrial dysfunction. Nicotinamide adenine dinucleotide (NAD+ ) can enhance the mitochondrial function and restrain the following inflammation, but it is hardly delivered and lacks renal targeting ability. To address these problems, herein, an ultrasmall Fe3 O4 nanoparticle is used as a carrier to deliver nicotinamide mononucleotide (NMN), a precursor of NAD+ . An outstanding sophistication of the current design is that once NMN is attached on the surface of Fe3 O4 nanoparticles through its phosphate group, the remaining part is structurally highly similar to nicotinamide riboside, which provides an opportunity to deliver the NAD+ precursor into renal cells through nicotinamide riboside kinase 1 on the cell membrane. It is demonstrated that NMN-loaded Fe3 O4 nanoparticles can effectively reverse AKI induced by ischemia reperfusion. In-depth studies indicate that a well-timed iron replenishment following anti-inflammation treatment plays a determined role in recovering AKI, which distinguishes the current study from previous strategies centering on anti-ROS (reactive oxygen species), anti-inflammation, or even iron elimination.

A Tumor-Microenvironment-Activatable Molecular Pro-Theranostic Agent for Photodynamic and Immunotherapy of Cancer.

Cancer-associated fibroblasts (CAFs) are the major components of the tumor-associated matrix and play an important role in tumor progression and immunosuppression. Therefore, precise theranostics of CAFs are beneficial for CAFs-targeted therapies. However, imaging agents enabling precise theranostics of CAFs have been rarely exploited. To tackle this issue, a molecular pro-theranostic probe (FMP) with activatable fluorescence, photoacoustic (PA) imaging, and photodynamic therapy (PDT) is developed in response to fibroblast activation protein α (FAPα) overexpressed in >90% types of CAFs and some tumor cells. Attributed to efficient activatable phototoxicity toward CAFs and tumor cells, together with activated immunogenic cell death (ICD), complete tumor regression of primary tumors and abscopal effect of distant tumors are observed in a 4T1-tumor-bearing mice model. By integration with PD-L1 checkpoint blockade immunotherapy, enhanced systemic immune responses are evoked to obtain long-lasting tumor suppression of both primary and distant tumors as well as arrest systemic cancer metastasis in living mice.

Intranasal Pathway for Nanoparticles to Enter the Central Nervous System.

Intranasal administration was previously proposed for delivering drugs for central nervous system (CNS) diseases. However, the delivery and elimination pathways, which are very imperative to know for exploring the therapeutic applications of any given CNS drugs, remain far from clear. Because lipophilicity has a high priority in the design of CNS drugs, the as-prepared CNS drugs tend to form aggregates. Therefore, a PEGylated Fe3O4 nanoparticle labeled with a fluorescent dye was prepared as a model drug and studied to elucidate the delivery pathways of intranasally administered nanodrugs. Through magnetic resonance imaging, the distribution of the nanoparticles was investigated in vivo. Through ex vivo fluorescence imaging and microscopy studies, more precise distribution of the nanoparticles across the entire brain was disclosed. Moreover, the elimination of the nanoparticles from cerebrospinal fluid was carefully studied. The temporal dose levels of intranasally delivered nanodrugs in different parts of the brain were also investigated.

The profile and prognostic value of circulating lymphocyte subsets in metastatic colon cancer.

OBJECTIVE: Colon cancer (CC) are the most common malignant cancer in human digestive system, however, the profile and prognostic value of circulating lymphocyte subsets in CC patients has not been systemically clarified. METHODS: In this study, 158 patients with metastatic CC were enrolled. Chi-square test was used to analyze the relationship between baseline peripheral blood lymphocyte subsets and clinicopathological parameters. Kaplan-Meier and Log-rank tests were used to analyze the relationship between clinicopathological parameters and baseline peripheral lymphocyte subsets and overall survival (OS) of patients with metastatic CC. Univariate/multivariate COX regression analysis was used to identify the independent factors in metastatic CC. RESULTS: The baseline peripheral blood CD3+T cells, CD4+T cells, NK cells and B cells of BRAF mutant patients were significantly lower than those in BRAF wild-type patients; The baseline CD8+T cells of KRAS mutation group was lower than that in KRAS wild type group. Peripheral blood CA19-9 > 27, left-sided colon cancer (LCC), KRAS and BRAF mutation were poor prognostic factors, and ALB > 40, NK cells were protective prognostic factors for metastatic CC. In patients with liver metastases subgroup, higher NK cells also indicated a longer OS. Finally, LCC (HR = 0.56), CA19-9 (HR = 2.13), ALB (HR = 0.46) and circulating NK cells (HR = 0.55) were independent prognostic factors for metastatic CC. CONCLUSION: LCC, higher level of ALB and NK cells at baseline are protective factors, and higher CA19-9, KRAS/BRAF gene mutation are adverse prognostic factors. Sufficient circulating NK cells are independent prognostic factor for metastatic CC patients.

KFWC: A Knowledge-Driven Deep Learning Model for Fine-grained Classification of Wet-AMD.

BACKGROUND AND OBJECTIVES: Automated diagnosis using deep neural networks can help ophthalmologists detect the blinding eye disease wet Age-related Macular Degeneration (AMD). Wet-AMD has two similar subtypes, Neovascular AMD and Polypoidal Choroidal Vasculopathy (PCV). However, due to the difficulty in data collection and the similarity between images, most studies have only achieved the coarse-grained classification of wet-AMD rather than a fine-grained one of wet-AMD subtypes. Therefore, designing and building a deep learning model to diagnose neovascular AMD and PCV is a great challenge. METHODS: To solve this issue, in this paper, we propose a Knowledge-driven Fine-grained Wet-AMD Classification Model (KFWC) to enhance the model's accuracy in the fine-grained disease classification with insufficient data. We innovatively introduced a two-stage method. In the first stage, we present prior knowledge of 10 lesion signs through pre-training; in the second stage, the model implements the classification task with the help of human knowledge. With the pre-training of priori knowledge of 10 lesion signs from input images, KFWC locates the powerful image features in the fine-grained disease classification task and therefore achieves better classification. RESULTS: To demonstrate the effectiveness of KFWC, we conduct a series of experiments on a clinical dataset collected in cooperation with a Grade III Level A ophthalmology hospital in China. The AUC score of KFWC reaches 99.71%, with 6.69% over the best baseline and 4.14% over ophthalmologists. KFWC can also provide good interpretability and effectively alleviate the pressure of data collection and annotation in the field of fine-grained disease classification for wet-AMD. CONCLUSIONS: The model proposed in this paper effectively solves the difficulties of small data volume and high image similarity in the wet-AMD fine-grained classification task through a knowledge-driven approach. Besides, this method effectively relieves the pressure of data collection and annotation in the field of fine-grained classification. In the diagnosis of wet-AMD, KFWC is superior to previous work and human ophthalmologists.

Effects of PEG Chain Length on Relaxometric Properties of Iron Oxide Nanoparticles-Based MRI Contrast Agent.

Iron oxide nanoparticles (IONPs) as magnetic resonance imaging (MRI) contrast agents have received considerable interest due to their superior magnetic properties. To increase the biocompatibility and blood circulation time, polyethylene glycol (PEG) is usually chosen to decorate IONPs. Although the surface effect induced by the PEGylation has an impact on the relaxometric properties of IONPs and can subsequently affect the imaging results, the occurrence of particle aggregation has troubled researchers to deeply explore this correlation. To shed light on this relationship, three diphosphonate PEGs with molecular weights of 1000, 2000, and 5000 Da were used to replace the hydrophobic oleate ligands of 3.6 nm and 10.9 nm IONPs. Then, the contrast enhancement properties of the resultant "aggregation-free" nanoparticles were carefully evaluated. Moreover, related theories were adopted to predict certain properties of IONPs and to compare with the experimental data, as well as obtain profound knowledge about the impacts of the PEG chain length on transverse relaxivity (r2) and longitudinal relaxivity (r1). It was found that r2 and the saturated magnetization of the IONPs, independent of particle size, was closely related to the chain length of PEG. The results unveiled the correlation between the chain length of the coated PEG and the relaxometric properties of IONPs, providing valuable information which might hold great promise in designing optimized, high-performance IONPs for MRI-related applications.

Corporate governance, environmental sustainability performance, and normative isomorphic force of national culture.

With the increasing concern regarding climate change, academics and practitioners are devoting attention to corporate environmental sustainability development. However, corporate environmental responsibility as an outcome of corporate governance (CG) practice is also constrained by national culture as an institutional factor, and research on the relationship between CG and environmental sustainability performance (ESP) with consideration for national culture remains scarce. Therefore, this study investigates the ESP data of Forbes' listed multinational corporations (MNCs) through content analysis and applies STATA software with stepwise regression models to empirically test the relationship between CG and MNCs' ESP and the moderating effects of national culture on this relationship. The results show that board independence and board size positively affect MNCs' ESP, and the relationship between board independence and MNCs' ESP is negatively moderated by masculinity and uncertainty avoidance. Our results emphasize the importance of CG in environmental decision-making by board management supervision enhancement and explain how national culture affects ESP because of its influence on CG. Our study explains the agency effect of board composition on MNCs' environmental sustainability development and the influence of national culture, which establishes a link between CG, ESP, and national culture. Moreover, policymakers and MNCs' suggestions for enhancing ESP through CG measures, while considering national culture, are also provided.

A questionnaire-based validation of metacognitive strategies in writing and their predictive effects on the writing performance of English as foreign language student writers.

Introduction: This study-drawing upon data from a questionnaire-examined 503 Chinese university students' metacognitive strategies in writing (MSW). The focus was on Chinese student writers who are learning English as a foreign language (EFL). Methods: The examination was conducted through a survey on MSW and a writing test administered at the end of the semester. We employed exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) for data analysis. Multiple regression analysis was also adopted for understanding the predictive effects of strategies on writing performance. Results: The findings provided validity to MSW, including person, task, strategies, planning, monitoring, and evaluating. The different components of MSW were reported to significantly affect the participants' writing performance. The findings highlight that EFL student writers were aware of metacognitive writing strategies. The MSW survey could be used to assess EFL students' metacognitive writing strategies and develop curricula in writing strategy training. Conclusion: Writing instruction can direct learners' ability to acquire metacognitive writing strategies, particularly those of planning, monitoring, and evaluating, to build their awareness as agents in EFL writing. Relevant pedagogical implications are discussed.

MBNM: Multi-branch network based on memory features for long-tailed medical image recognition.

BACKGROUND AND OBJECTIVES: Deep learning algorithms show revolutionary potential in computer-aided diagnosis. These computer-aided diagnosis techniques often rely on large-scale, balanced standard datasets. However, there are many rare diseases in real clinical scenarios, which makes the medical datasets present a highly imbalanced long-tailed distribution, leading to the poor generalization ability of deep learning models. Currently, most algorithms to solve this problem involve more complex modules and loss functions. But for complicated tasks in the medical domain, usually suffer from issues such as increased inference time and unstable performance. Therefore, it is a great challenge to develop a computer-aided diagnosis algorithm for long-tailed medical data. METHODS: We proposed the Multi-Branch Network based on Memory Features (MBNM) for Long-Tailed Medical Image Recognition. MBNM includes three branches, where each branch focuses on a different learning task: 1) the regular learning branch learns the generalizable feature representations; 2) the tail learning branch gains extra intra-class diversity for the tail classes through the feature memory module and the improved reverse sampler to improve the classification performance of the tail classes; 3) the fusion balance branch integrates various decision-making advantages and introduces an adaptive loss function to re-balance the classification performance of easy and difficult samples. RESULTS: We conducted experiments on the multi-disease Ophthalmic OCT datasets with imbalance factors of 98.48 and skin image datasets Skin-7 with imbalance factors of 58.3. The Accuracy, MCR, F1-Score, Precision, and AUC of our model were significantly improved over the strong baselines in the auxiliary diagnosis scenario where the clinical medical data is extremely imbalanced. Furthermore, we demonstrated that MBNM outperforms the state-of-the-art models on the publicly available natural image datasets (CIFAR-10 and CIFAR-100). CONCLUSIONS: The proposed algorithm can solve the problem of imbalanced data distribution with little added cost. In addition, the memory module does not act in the inference phase, thereby saving inference time. And it shows outstanding performance on medical images and natural images with a variety of imbalance factors.

The 2-(2-benzofuranyl)-2-imidazoline provides neuroprotection against focal cerebral ischemia-reperfusion injury in diabetic rats: Influence of microglia and possible mechanisms of action.

Increased microglial NADPH oxidase (NOX2) production may make an important contribution to the increased incidence and severity of ischemic stroke associated with diabetes. Imidazoline receptors are closely associated with neuroprotection, but the neuroprotective effects of the selective I2-imidazoline receptor ligand 2-(2-benzofuranyl)-2-imidazoline (2BFI) in diabetes has not been established. The effect of 2BFI on microglial NOX2 production was investigated using a co-culture of neurons and microglia, and the effect on cerebral ischemia-reperfusion (IR) injury was determined in diabetic rats. Garcia neurological scores, brain infarct volumes, brain water content, TUNEL staining, blood-brain barrier, and immunofluorescent labeling for microglia were evaluated. Western blots were used to determine gp91phox and Tyr1472 expression. Anti-inflammatory cytokine (IL-10) and inflammatory cytokine secretion was determined using ELISA kits. The brain infarct volumes, TUNEL-positive neurons, expression of microglia, brain water content, blood-brain barrier structure damage, and gp91phox and Tyr1472 expression were increased, the Garcia neurological scores were significantly decreased in the IR group, and 2BFI relieved these alterations. The IL-10 concentration was increased in the IR group; 2BFI significantly improved this increase. The neuron apoptosis and necrosis rates, and production of reactive oxygen species (ROS) and inflammatory cytokines, including IL-6, IL-8, TNF-α, and 8-iso-PGF2α, were significantly increased by high glucose stimulation combined with oxygen-glucose deprivation treatment, which were inhibited by 2BFI. The 2BFI ameliorated cerebral ischemia-reperfusion injury in diabetes and decreased neuron death in an in vitro model. The mechanism underlying these findings may be related to the decreased production of inflammatory factors and reactive oxygen species from microglia.

Gp91phox (NOX2) in Activated Microglia Exacerbates Neuronal Damage Induced by Oxygen Glucose Deprivation and Hyperglycemia in an in Vitro Model.

BACKGROUND/AIMS: Peri-operative cerebral ischemia reperfusion injury is one of the most serious peri-operative complications that can be aggravated in patients with diabetes. A previous study showed that microglia NOX2 (a NADPH oxidase enzyme) may play an important role in this process. Here, we investigated whether increased microglial derived gp91phox, also known as NOX2, reduced oxygen glucose deprivation (OGD) after induction of hyperglycemia (HG). METHODS: A rat neuronal-microglial in vitro co-culture model was used to determine the effects of gp91phox knockdown on OGD after HG using six treatment groups: A rat microglia and neuron co-culture model was established and divided into the following six groups: high glucose + scrambled siRNA transfection (HG, n = 5); HG + gp91phoxsiRNA transfection (HG-gp91siRNA, n = 5); oxygen glucose deprivation + scrambled siRNA transfection (OGD, n = 5); OGD + gp91phoxsiRNA transfection (OGD-gp91siRNA, n = 5); HG + OGD + scrambled siRNA transfection (HG-OGD, n = 5); and HG + OGD + gp91phoxsiRNA transfection (HG-OGD-gp91siRNA, n = 5). The neuronal survival rate was measured by the MTT assay, while western blotting was used to determine gp91phox expression. Microglial derived ROS and neuronal apoptosis rates were analyzed by flow cytometry. Finally, the secretion of cytokines, including IL-6, IL-8, TNF-α, and 8-iso-PGF2α was determined using an ELISA kit. RESULTS: Neuronal survival rates were significantly decreased by HG and OGD, while knockdown of gp91phox reversed these rates. ROS production and cytokine secretion were also significantly increased by HG and OGD but were significantly inhibited by knockdown of gp91phoxsiRNA. CONCLUSION: Knockdown of gp91phoxsiRNA significantly reduced oxidative stress and the inflammatory response, and alleviated neuronal damage after HG and OGD treatment in a rat neuronal-microglial co-culture model.