A Network Meta-Analysis of the Systemic Therapies in Unresectable Head and Neck Squamous Cell Carcinoma.

The current standard treatment for locally advanced squamous cell carcinoma of the head and neck (LASCCHN) comprises concurrent radiotherapy (CRT) alongside platinum-based chemotherapy. However, innovative therapeutic alternatives are being evaluated in phase II/III randomized trials. This study employed a Bayesian network meta-analysis (NMA) using fixed effects to provide both direct and indirect comparisons of all existing treatment modalities for unresectable LASCCHN. METHODS: We referenced randomized controlled trials (RCTs) from January 2000 to July 2023 by extensively reviewing PubMed, EMBASE, and Web of Science databases, adhering to the Cochrane methodology. Relevant data, including summary estimates of overall survival (OS) and progression-free survival (PFS), were extracted from these selected studies and recorded in a predefined database sheet. Subsequently, we conducted a random effects network meta-analysis using a Bayesian framework. RESULTS: Based on the Surface Under the Cumulative Ranking (SUCRA) values, the league table organizes the various treatments for OS in the following order: IC + RT&MTT, MTT-CRT, IC + CRT&MTT, CRT, IC + CRT, MTT-RT, IC + MTT-RT, and RT. In a similar order, the treatments rank as follows according to the league table: IC + CRT&MTT, MTT-CRT, IC + CRT, IC + RT&MTT, CRT, IC + MTT-RT, MTT-RT, and RT. Notably, none of these treatments showed significant advantages over concurrent chemoradiotherapy. CONCLUSION: Despite concurrent chemoradiotherapy being the prevailing treatment for LASCCHN, our findings suggest the potential for improved outcomes when concurrent chemoradiotherapy is combined with targeted therapy or induction chemotherapy.

The current standard treatment for advanced head and neck cancer involves combining radiation therapy with chemotherapy. However, there are ongoing trials exploring alternative therapies. In this study, we conducted a comprehensive analysis of existing treatments using a statistical method called network meta-analysis. Our analysis included data from randomized controlled trials published between January 2000 and July 2023. We focused on overall survival and progression-free survival as key outcome measures. The results of our analysis showed that none of the alternative treatments demonstrated significant advantages over the standard concurrent chemoradiotherapy. Nevertheless, there is potential for improved outcomes when targeted therapy or induction chemotherapy is combined with concurrent chemoradiotherapy.

Zinc Finger-Homeodomain Transcriptional Factors (ZHDs) in Cucumber (Cucumis sativus L.): Identification, Evolution, Expression Profiles, and Function under Abiotic Stresses.

Cucumber (Cucumis sativus L.) is a globally prevalent and extensively cultivated vegetable whose yield is significantly influenced by various abiotic stresses, including drought, heat, and salinity. Transcription factors, such as zinc finger-homeodomain proteins (ZHDs), a plant-specific subgroup of Homeobox, play a crucial regulatory role in stress resistance. In this study, we identified 13 CsZHDs distributed across all six cucumber chromosomes except chromosome 7. Phylogenetic analysis classified these genes into five clades (ZHDI-IV and MIF) with different gene structures but similar conserved motifs. Collinearity analysis revealed that members of clades ZHD III, IV, and MIF experienced amplification through segmental duplication events. Additionally, a closer evolutionary relationship was observed between the ZHDs in Cucumis sativus (C. sativus) and Arabidopsis thaliana (A. thaliana) compared to Oryza sativa (O. sativa). Quantitative real-time PCR (qRT-PCR) analysis demonstrated the general expression of CsZHD genes across all tissues, with notable expression in leaf and flower buds. Moreover, most of the CsZHDs, particularly CsZHD9-11, exhibited varying responses to drought, heat, and salt stresses. Virus-induced gene silencing (VIGS) experiments highlighted the potential functions of CsZHD9 and CsZHD10, suggesting their positive regulation of stomatal movement and responsiveness to drought stress. In summary, these findings provide a valuable resource for future analysis of potential mechanisms underlying CsZHD genes in response to stresses.

PractiCPP: a deep learning approach tailored for extremely imbalanced datasets in cell-penetrating peptide prediction.

MOTIVATION: Effective drug delivery systems are paramount in enhancing pharmaceutical outcomes, particularly through the use of cell-penetrating peptides (CPPs). These peptides are gaining prominence due to their ability to penetrate eukaryotic cells efficiently without inflicting significant damage to the cellular membrane, thereby ensuring optimal drug delivery. However, the identification and characterization of CPPs remain a challenge due to the laborious and time-consuming nature of conventional methods, despite advances in proteomics. Current computational models, however, are predominantly tailored for balanced datasets, an approach that falls short in real-world applications characterized by a scarcity of known positive CPP instances. RESULTS: To navigate this shortfall, we introduce PractiCPP, a novel deep-learning framework tailored for CPP prediction in highly imbalanced data scenarios. Uniquely designed with the integration of hard negative sampling and a sophisticated feature extraction and prediction module, PractiCPP facilitates an intricate understanding and learning from imbalanced data. Our extensive computational validations highlight PractiCPP's exceptional ability to outperform existing state-of-the-art methods, demonstrating remarkable accuracy, even in datasets with an extreme positive-to-negative ratio of 1:1000. Furthermore, through methodical embedding visualizations, we have established that models trained on balanced datasets are not conducive to practical, large-scale CPP identification, as they do not accurately reflect real-world complexities. In summary, PractiCPP potentially offers new perspectives in CPP prediction methodologies. Its design and validation, informed by real-world dataset constraints, suggest its utility as a valuable tool in supporting the acceleration of drug delivery advancements. AVAILABILITY AND IMPLEMENTATION: The source code of PractiCPP is available on Figshare at https://doi.org/10.6084/m9.figshare.25053878.v1.

Self-Disassembling and Oxygen-Generating Porphyrin-Lipoprotein Nanoparticle for Targeted Glioblastoma Resection and Enhanced Photodynamic Therapy.

The dismal prognosis for glioblastoma multiform (GBM) patients is primarily attributed to the highly invasive tumor residual that remained after surgical intervention. The development of precise intraoperative imaging and postoperative residual removal techniques will facilitate the gross total elimination of GBM. Here, a self-disassembling porphyrin lipoprotein-coated calcium peroxide nanoparticles (PLCNP) is developed to target GBM via macropinocytosis, allowing for fluorescence-guided surgery of GBM and improving photodynamic treatment (PDT) of GBM residual by alleviating hypoxia. By reducing self-quenching and enhancing lysosome escape efficiency, the incorporation of calcium peroxide (CaO2) cores in PLCNP amplifies the fluorescence intensity of porphyrin-lipid. Furthermore, the CaO2 core has diminished tumor hypoxia and improves the PDT efficacy of PLCNP, enabling low-dose PDT and reversing tumor progression induced by hypoxia aggravation following PDT. Taken together, this self-disassembling and oxygen-generating porphyrin-lipoprotein nanoparticle may serve as a promising all-in-one nanotheranostic platform for guiding precise GBM excision and empowering post-operative PDT, providing a clinically applicable strategy to combat GBM in a safe and effective manner.

A fault diagnosis method for wireless sensor network nodes based on a belief rule base with adaptive attribute weights.

Due to the harsh operating environment and ultralong operating hours of wireless sensor networks (WSNs), node failures are inevitable. Ensuring the reliability of the data collected by the WSN necessitates the utmost importance of diagnosing faults in nodes within the WSN. Typically, the initial step in the fault diagnosis of WSN nodes involves extracting numerical features from neighboring nodes. A solitary data feature is often assigned a high weight, resulting in the failure to effectively distinguish between all types of faults. Therefore, this study introduces an enhanced variant of the traditional belief rule base (BRB), called the belief rule base with adaptive attribute weights (BRB-AAW). First, the data features are extracted as input attributes for the model. Second, a fault diagnosis model for WSN nodes, incorporating BRB-AAW, is established by integrating parameters initialized by expert knowledge with the extracted data features. Third, to optimize the model's initial parameters, the projection covariance matrix adaptive evolution strategy (P-CMA-ES) algorithm is employed. Finally, a comprehensive case study is designed to verify the accuracy and effectiveness of the proposed method. The results of the case study indicate that compared with the traditional BRB method, the accuracy of the proposed model in WSN node fault diagnosis is significantly improved.

Targeted dexamethasone nano-prodrug for corneal neovascularization management.

BACKGROUND: To overcome the drawbacks of traditional therapy for corneal neovascularization (CNV), we evaluated the efficacy of polyethylene glycol (PEG)-conjugated Ala-Pro-Arg-Pro-Gly (APRPG) peptide modified dexamethasone (Dex), a novel nano-prodrug (Dex-PEG-APRPG, DPA). METHODS: Characterization of DPA nano-prodrug were measured with transmission electron microscopy (TEM) and dynamic light scattering (DLS) analyses. Cytotoxicity and effects on cell migration and tube formation of DPA were evaluated in vitro. A murine CNV model was established by cornea alkali burn. The injured corneas were given eye drops of DPA (0.2 mM), Dex solution (0.2 mM), Dexp (2 mM), or normal saline three times a day. After two weeks, eyes were obtained for the analysis of histopathology, immunostaining, and mRNA expression. RESULTS: DPA with an average diameter of 30 nm, presented little cytotoxicity and had good ocular biocompatibility. More importantly, DPA showed specific targeting to vascular endothelial cells with efficient inhibition on cell migration and tube formation. In a mouse CNV model, clinical, histological, and immunohistochemical examination results revealed DPA had a much stronger angiogenesis suppression than Dex, resembling a clinical drug with an order of magnitude higher concentration. This was ascribed to the significant downregulations in the expression of pro-angiogenic and pro-inflammatory factors in the corneas. In vivo imaging results also demonstrated that APRPG could prolong ocular retention time. CONCLUSIONS: This study suggests that DPA nano-prodrug occupies advantages of specific targeting ability and improved bioavailability over conventional therapy, and holds great potential for safe and efficient CNV therapy.

Comprehensive Insights into the Health Effects of Selenium Exposure and Supplementation Among the Chinese Community Middle-Aged and Elderly: a Combined Retrospective Cohort Study and Intervention Study.

Selenium (Se) is an essential trace element for maintaining human health, for example, plays a crucial role in preventing aging-related diseases. However, most studies on the health effects of Se among the community middle-aged and elderly have been observational or the health indices were single, and the related study among the Chinese population is limited. Additionally, China is recognized as among the countries facing a significant deficiency in Se, and Se contents in the human body may decrease with age. Therefore, a two-step study was conducted to explore the health effects of Se exposure and supplementation among such populations in China. Firstly, a retrospective cohort study was conducted to compare the health outcomes between such populations residing in Se-rich regions and non-Se-rich regions, involving a total of 102 subjects, with 51 residing in Se-rich regions and 51 in non-Se-rich regions. The hair-Se (H-Se) contents, serum-Se (S-Se) contents, and total cholesterol of subjects from Se-rich regions were significantly higher than their counterparts. Notably, significant positive associations were observed between S-Se and lipids. Secondly, a before-after self-control Se supplementation study among subjects residing in non-Se-rich regions was conducted. A total of 40 subjects administered Se tablets orally for 30 days, with Se of 120 µg/day. The results showed significant increases in H-Se and S-Se. Se supplementation also exhibited positive effects on alanine aminotransferase, homocysteine, and fasting glucose; however, high-density lipoprotein cholesterol significantly decreased. Overall, the community middle-aged and elderly residing in Se-rich regions or receiving quantitative Se supplementation could effectively improve Se contents in bodies and certain health indices, excluding lipids. These improvements encompass liver function, cardiovascular health, and glucose metabolism. These findings enhance our understanding of how Se impacts the health of the middle-aged and elderly, emphasizing the significance of targeted interventions for such populations in non-Se-rich regions. Trial registration: ChiCTR2000040987 ( https://www.chictr.org.cn ).

Treatment for T1 colorectal cancers substratified by site and size: "horses for courses".

Background: Owing to advances in diagnostic technology, the diagnosis of T1 colorectal cancers (CRCs) continues to increase. However, the optimal management of T1 CRCs in the Western Hemisphere remains unclear due to limited population-based data directly comparing the efficacy of endoscopic therapy (ET) and surgical resection (SR). The purpose of this study was to report outcome data from a large Western cohort of patients who underwent ET or SR for early CRCs. Methods: The SEER-18 database was used to identify patients with T1 CRCs diagnosed from 2004 to 2018 treated with ET or SR. Multivariable logistic regression models were employed to identify variables related to lymph node metastasis (LNM). Rates of ET and 1-year relative survival were calculated for each year. Effect of ET or SR on overall survival and cancer-specific survival was compared using Kaplan-Meier method stratified by tumor size and site. Results: A total of 28,430 T1 CRCs patients were identified from 2004 to 2018 in US, with 22.7% undergoing ET and 77.3% undergoing SR. The incidence of T1 CRCs was 6.15 per 100,000 person-years, with male patients having a higher incidence. Left-sided colon was the most frequent location of tumors. The utilization of ET increased significantly from 2004 to 2018, with no significant change in 1-year relative survival rate. Predictors of LNM were age at diagnosis, sex, race, tumor size, histology, grade, and location. The 5-year relative survival rates were 91.4 and 95.4% for ET and SR, respectively. Subgroup analysis showed that OS and CSS were similar between ET and SR in T1N0M0 left-sided colon cancers with tumors 2 cm or less and in rectal cancers with tumors 1 cm or less. Conclusion: Our study showed that ET was feasible and safe for patients with left-sided T1N0M0 colon cancers and tumors of 2 cm or less, as well as T1N0M0 rectal cancers and tumors of 1 cm or less. Therefore, the over- and under-use of ET should be avoided by carefully selecting patients based on tumor size and site.

The role of ZBP1 in eccentric exercise-induced skeletal muscle necroptosis.

This study aimed to explore the occurrence of necroptosis in skeletal muscle after eccentric exercise and investigate the role and possible mechanisms of ZBP1 and its related pathway proteins in the process, providing a theoretical basis for the study of exercise-induced skeletal muscle injury and recovery. Forty-eight male adult Sprague-Dawley rats were randomly divided into a control group (C, n = 8) and an exercise group (E, n = 40). The exercise group was further divided into 0 h (E0), 12 h (E12), 24 h (E24), 48 h (E48), and 72 h (E72) after exercise, with 8 rats in each subgroup. At each time point, gastrocnemius muscle was collected under general anesthesia. The expression levels of ZBP1 and its related pathway proteins were assessed using Western blot analysis. The colocalization of pathway proteins was examined using immunofluorescence staining. After 48 h of eccentric exercise, the expression of necroptosis marker protein MLKL reached its peak (P < 0.01), and the protein levels of ZBP1, RIPK3, and HMGB1 also peaked (P < 0.01). At 48 h post high-load eccentric exercise, there was a significant increase in colocalization of ZBP1/RIPK3 pathway proteins, reaching a peak (P < 0.01). (1) Eccentric exercise induced necroptosis in skeletal muscle, with MLKL, p-MLKLS358, and HMGB1 significantly elevated, especially at 48 h after exercise. (2) After eccentric exercise, the ZBP1/RIPK3-related pathway proteins ZBP1, RIPK3, and p-RIPK3S232 were significantly elevated, particularly at 48 h after exercise. (3) Following high-load eccentric exercise, there was a significant increase in the colocalization of ZBP1/RIPK3 pathway proteins, with a particularly pronounced elevation observed at 48 h post-exercise.

Rapidly separating dissolving microneedles with sustained-release colchicine and stabilized uricase for simplified long-term gout management.

Despite growing prevalence and incidence, the management of gout remains suboptimal. The intermittent nature of the gout makes the long-term urate-lowering therapy (ULT) particularly important for gout management. However, patients are reluctant to take medication day after day to manage incurable occasional gout flares, and suffer from possible long-term toxicity. Therefore, a safe and easy-to-operate drug delivery system with simple preparation for the long-term management of gout is very necessary. Here, a chitosan-containing sustained-release microneedle system co-loaded with colchicine and uricase liposomes were fabricated to achieve this goal. This microneedle system was confirmed to successfully deliver the drug to the skin and maintain a one-week drug retention. Furthermore, its powerful therapeutic potency to manage gout was investigated in both acute gouty and chronic gouty models. Besides, the drug co-delivery system could help avoid long-term daily oral colchicine, a drug with a narrow therapeutic index. This system also avoids mass injection of uricase by improving its stability, enhancing the clinical application value of uricase. In general, this two-drug system reduces the dosage of uricase and colchicine and improves the patient's compliance, which has a strong clinical translation.

A biologically inspired auto-associative network with sparse temporal population coding.

Associative system has attracted increasing attention for it can store basic information and then infer details to match perception with an efficient self-organization algorithm. However, the implementation of the associative system with the application of real-world data is relatively difficult. To address this issue, we propose a novel biologically inspired auto-associative (BIAA) network to explore the structure, encoding and formation of associative memory as well as to extend the ability to real-world application. Our network is constructed by imitating the organization of the cortical minicolumns where each minicolumn contains plenty of parallel biological spiking neurons. To allow the network to learn and predict one symbol per theta cycle, we incorporate synaptic delay and theta oscillation into the neuron dynamic process. Subsequently, we design a sparse temporal population (STP) coding scheme that allows each input symbol to be represented as stable, unique, and easily recallable sparsely distributed representations. By combining associative learning dynamics with the STP coding, our network realizes efficient storage and inference in an ordered manner. Experimental results indicate that the proposed network successfully performs sequence retrieval from partial text and sequence recovery from distorted information. BIAA network provides new insight into introducing biologically inspired mechanisms into associative system and has enormous potential for hardware and software applications.

Survival prediction of hepatocellular carcinoma by measuring the extracellular volume fraction with single-phase contrast-enhanced dual-energy CT imaging.

Purpose: This study aimed to investigate the value of quantified extracellular volume fraction (fECV) derived from dual-energy CT (DECT) for predicting the survival outcomes of patients with hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE). Materials and methods: A total of 63 patients with HCC who underwent DECT before treatment were retrospectively included. Virtual monochromatic images (VMI) (70 keV) and iodine density images (IDI) during the equilibrium phase (EP) were generated. The tumor VMI-fECV and IDI-fECV were measured and calculated on the whole tumor (Whole) and maximum enhancement of the tumor (Maximum), respectively. Univariate and multivariate Cox models were used to evaluate the effects of clinical and imaging predictors on overall survival (OS) and progression-free survival (PFS). Results: The correlation between tumor VMI-fECV and IDI-fECV was strong (both p< 0.001). The Bland-Altman plot between VMI-fECV and IDI-fECV showed a bias of 5.16% for the Whole and 6.89% for the Maximum modalities, respectively. Increasing tumor VMI-fECV and IDI-fECV were positively related to the effects on OS and PFS (both p< 0.05). The tumor IDI-fECV-Maximum was the only congruent independent predictor in patients with HCC after TACE in the multivariate analysis on OS (p = 0.000) and PFS (p = 0.028). Patients with higher IDI-fECV-Maximum values had better survival rates above the optimal cutoff values, which were 35.42% for OS and 29.37% for PFS. Conclusion: The quantified fECV determined by the equilibrium-phase contrast-enhanced DECT can potentially predict the survival outcomes of patients with HCC following TACE treatment.

Mussel-inspired "plug-and-play" hydrogel glue for postoperative tumor recurrence and wound infection inhibition.

Currently, clinical tumor resection is faced with two options: open and minimally invasive surgery. Open surgery is easy to completely remove the lesion but is prone to infection, while minimally invasive surgery recovers faster but may cause tumor recurrence. To fill the shortcomings of the two surgical modes and make the choice for tumor resection more effortlessly, we developed a postoperative black phosphorus-Ag nanocomposites-loaded dopamine-modified hyaluronic acid-Pluronic® F127 (BP-Ag@HA-DA-Plu) hydrogel implantation system that can prevent tumor recurrence and wound infection simultaneously. Experiments have shown that the hydrogel system combined with 808 nm near-infrared (NIR) irradiation has excellent anti-tumor, antibacterial, and wound healing abilities. Additionally, unlike existing surgical hydrogel products that require inconvenient in-situ cross-linking, the BP-Ag@HA-DA-Plu hydrogel system offers "plug-and-play" functionality during surgery due to its thermo-responsiveness, injectability, and adhesion, thereby greatly improving the efficiency of surgery.

Spiking neural network with working memory can integrate and rectify spatiotemporal features.

In the real world, information is often correlated with each other in the time domain. Whether it can effectively make a decision according to the global information is the key indicator of information processing ability. Due to the discrete characteristics of spike trains and unique temporal dynamics, spiking neural networks (SNNs) show great potential in applications in ultra-low-power platforms and various temporal-related real-life tasks. However, the current SNNs can only focus on the information a short time before the current moment, its sensitivity in the time domain is limited. This problem affects the processing ability of SNN in different kinds of data, including static data and time-variant data, and reduces the application scenarios and scalability of SNN. In this work, we analyze the impact of such information loss and then integrate SNN with working memory inspired by recent neuroscience research. Specifically, we propose Spiking Neural Networks with Working Memory (SNNWM) to handle input spike trains segment by segment. On the one hand, this model can effectively increase SNN's ability to obtain global information. On the other hand, it can effectively reduce the information redundancy between adjacent time steps. Then, we provide simple methods to implement the proposed network architecture from the perspectives of biological plausibility and neuromorphic hardware friendly. Finally, we test the proposed method on static and sequential data sets, and the experimental results show that the proposed model can better process the whole spike train, and achieve state-of-the-art results in short time steps. This work investigates the contribution of introducing biologically inspired mechanisms, e.g., working memory, and multiple delayed synapses to SNNs, and provides a new perspective to design future SNNs.

Novel players in organogenesis and flavonoid biosynthesis in cucumber glandular trichomes.

Glandular trichomes (GTs) are outgrowths of plant epidermal cells that secrete and store specialized secondary metabolites that protect plants against biotic and abiotic stresses and have economic importance for human use. While extensive work has been done to understand the molecular mechanisms of trichome organogenesis in Arabidopsis (Arabidopsis thaliana), which forms unicellular, nonglandular trichomes (NGTs), little is known about the mechanisms of GT development or regulation of secondary metabolites in plants with multicellular GTs. Here, we identified and functionally characterized genes associated with GT organogenesis and secondary metabolism in GTs of cucumber (Cucumis sativus). We developed a method for effective separation and isolation of cucumber GTs and NGTs. Transcriptomic and metabolomic analyses showed that flavonoid accumulation in cucumber GTs is positively associated with increased expression of related biosynthesis genes. We identified 67 GT development-related genes, the functions of 7 of which were validated by virus-induced gene silencing. We further validated the role of cucumber ECERIFERUM1 (CsCER1) in GT organogenesis by overexpression and RNA interference transgenic approaches. We further show that the transcription factor TINY BRANCHED HAIR (CsTBH) serves as a central regulator of flavonoid biosynthesis in cucumber GTs. Work from this study provides insight into the development of secondary metabolite biosynthesis in multicellular GTs.

Identification and Functional Characterization of CsMYCs in Cucumber Glandular Trichome Development.

Glandular trichomes (GTs), specialized structures formed by the differentiation of plant epidermal cells, are known to play important roles in the resistance of plants to external biotic and abiotic stresses. These structures are capable of storing and secreting secondary metabolites, which often have important agricultural and medicinal values. In order to better understand the molecular developmental mechanisms of GTs, studies have been conducted in a variety of crops, including tomato (Solanum lycopersicum), sweetworm (Artemisia annua), and cotton (Gossypium hirsutum). The MYC transcription factor of the basic helix-loop-helix (bHLH) transcription factor family has been found to play an important role in GT development. In this study, a total of 13 cucumber MYC transcription factors were identified in the cucumber (Cucumis sativus L.) genome. After performing phylogenetic analyses and conserved motifs on the 13 CsMYCs in comparison to previously reported MYC transcription factors that regulate trichome development, seven candidate MYC transcription factors were selected. Through virus-induced gene silencing (VIGS), CsMYC2 is found to negatively regulate GT formation while CsMYC4, CsMYC5, CsMYC6, CsMYC7, and CsMYC8 are found to positively regulate GT formation. Furthermore, the two master effector genes, CsMYC2 and CsMYC7, are observed to have similar expression patterns indicating that they co-regulate the balance of GT development in an antagonistic way.

Polydopamine-Coated Radiolabeled Microspheres for Combinatorial Radioembolization and Photothermal Cancer Therapy.

Transarterial radioembolization (TARE) is a local radionuclide therapy and is successfully used in hepatocellular carcinoma (HCC) treatment. Radioactive microspheres have been widely studied for TARE. Preparation of ideal radioactive microspheres is significant for clinical research and patient treatment. In this study, we have designed a novel multifunctional microsphere, i.e., polydopamine (PDA)-coated 177Lu-radiolabeled silica microspheres (MS) denoted as 177Lu-MS@PDA, which can be used for TARE and photothermal therapy (PTT). The radiostability of 177Lu-MS@PDA was significantly improved by coating 177Lu-MS with PDA. In addition, the coating of PDA makes microspheres have excellent photothermal performance. MicroSPECT/CT images showed that 177Lu-MS@PDA was accurately embolized and remained in the tumor during the observation time. At the time, it also showed that 177Lu-MS@PDA was very stable in vivo. Furthermore, the anti-tumor results demonstrated that TARE combined with PTT of 177Lu-MS@PDA can significantly inhibit tumor growth without obvious side effects. 177Lu-MS@PDA holds great potential as a promising radioactive microsphere for HCC.

Nuclear receptor modulators inhibit osteosarcoma cell proliferation and tumour growth by regulating the mTOR signaling pathway.

Osteosarcoma is the most common primary malignant bone tumour in children and adolescents. Chemoresistance leads to poor responses to conventional therapy in patients with osteosarcoma. The discovery of novel effective therapeutic targets and drugs is still the main focus of osteosarcoma research. Nuclear receptors (NRs) have shown substantial promise as novel therapeutic targets for various cancers. In the present study, we performed a drug screen using 29 chemicals that specifically target 17 NRs in several different human osteosarcoma and osteoblast cell lines. The retinoic acid receptor beta (RARb) antagonist LE135, peroxisome proliferator activated receptor gamma (PPARg) antagonist T0070907, liver X receptor (LXR) agonist T0901317 and Rev-Erba agonist SR9011 significantly inhibited the proliferation of malignant osteosarcoma cells (U2OS, HOS-MNNG and Saos-2 cells) but did not inhibit the growth of normal osteoblasts. The effects of these NR modulators on osteosarcoma cells occurred in a dose-dependent manner and were not observed in NR-knockout osteosarcoma cells. These NR modulators also significantly inhibited osteosarcoma growth in vivo and enhanced the antitumour effect of doxorubicin (DOX). Transcriptomic and immunoblotting results showed that these NR modulators may inhibit the growth of osteosarcoma cells by regulating the PI3K/AKT/mTOR and ERK/mTOR pathways. DDIT4, which blocks mTOR activation, was identified as one of the common downstream target genes of these NRs. DDIT4 knockout significantly attenuated the inhibitory effects of these NR modulators on osteosarcoma cell growth. Together, our results revealed that modulators of RARb, PPARg, LXRs and Rev-Erba inhibit osteosarcoma growth both in vitro and in vivo through the mTOR signaling pathway, suggesting that treatment with these NR modulators is a novel potential therapeutic strategy.

Downhill running induced DNA damage enhances mitochondrial membrane permeability by facilitating ER-mitochondria signaling.

To observe whether downhill running can lead to DNA damage in skeletal muscle cells and changes in mitochondrial membrane permeability and to explore whether the DNA damage caused by downhill running can lead to changes in mitochondrial membrane permeability by regulating the components of the endoplasmic reticulum mitochondrial coupling structure (MAM). A total of 48 male adult Sprague-Dawley rats were randomly divided into a control group (C, n = 8) and a motor group (E, n = 40). Rats in Group E were further divided into 0 h (E0), 12 h (E12), 24 h (E24), 48 h (E48) and 72 h (E72) after prescribed exercise, with 8 rats in each group. At each time point, flounder muscle was collected under general anaesthesia. The DNA oxidative damage marker 8-hydroxydeoxyguanosine (8-OHdG) was detected by immunofluorescence. The expression levels of the DNA damage-related protein p53 in the nucleus and the EI24 protein and reep1 protein in whole cells were detected by Western blot. The colocalization coefficients of the endoplasmic reticulum protein EI24 and the mitochondrial protein Vdac2 were determined by immunofluorescence double staining, and the concentration of Ca2+ in skeletal muscle mitochondria was detected by a fluorescent probe. Finally, the opening of the mitochondrial membrane permeability transition pore (mPTP) was detected by immunofluorescence. Twelve hours after downhill running, the mitochondrial membrane permeability of the mPTP opened the most (P < 0.05), the content of 8-OHdG in skeletal muscle peaked (P < 0.05), and the levels of the regulatory protein p53, mitochondrial Ca2+, and the EI24 and reep1 proteins peaked (P < 0.01). Moreover, the colocalization coefficients of EI24 and Vdac2 and the Mandes coefficients of the two proteins increased first and then recovered 72 h after exercise (P < 0.05). (1) Downhill running can lead to DNA damage in skeletal muscle cells, overload of mitochondrial Ca2+ and large opening of membrane permeability transformation pores. (2) The DNA damage caused by downhill running may result in p53 promoting the transcriptional activation of reep1 and EI24, enhancing the interaction between EI24 and Vdac2, and then leading to an increase in Ca2+ in skeletal muscle mitochondria and the opening of membrane permeability transition pores.