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Abstract Aims This study aimed to explore the causal relationships between cathepsins and cardiovascular diseases (CVDs) by Mendelian randomization (MR) analysis. Methods and results Single nucleotide polymorphisms (SNPs) associated with nine cathepsin types (cathepsins B, E, F, G, H, O, S, L2, and Z) were obtained from the INTERVAL study (3301 individuals). CVDs data were acquired from the UK Biobank (coronary atherosclerosis: 14 334 cases, 346 860 controls) and a genome‐wide association study (GWAS) (myocardial infarction: 20 917 cases, 440 906 controls; myocarditis: 633 cases, 427 278 controls; chronic heart failure: 14 262 cases, 471 898 controls; angina pectoris: 30 025 cases, 440 906 controls; stable angina pectoris: 17 894 cases, 325 132 controls; unstable angina pectoris: 9481 cases, 446 987 controls; pericarditis: 1795 cases, 453 370 controls). Inverse variance weighted (IVW), MR‐Egger, weighted median methods were adopted to conduct univariable MR (UVMR), reverse MR, multivariable MR (MVMR) analyses to estimate causality. The UVMR analyses demonstrated significant causal relationships between higher cathepsin E levels and increased risk of coronary atherosclerosis [IVW: P = 0.0051, odds ratio (OR) = 1.0033, 95% confidence interval (CI) = 1.0010–1.0056] and myocardial infarction (IVW: P = 0.0097, OR = 1.0553, 95% CI = 1.0131–1.0993), while elevated cathepsin L2 levels were causally related to reduced risk of myocarditis (IVW: P = 0.0120, OR = 0.6895, 95% CI = 0.5158–0.9216) and chronic heart failure (IVW: P = 0.0134, OR = 0.9316, 95% CI = 0.8807–0.9854). Reverse MR analyses revealed that myocardial infarction increased cathepsin O levels (IVW: P = 0.0400, OR = 1.0708, 95% CI = 1.0031–1.1431). MVMR analyses treating nine cathepsins together revealed that the positive causality between cathepsin E levels and coronary atherosclerosis risk (IVW: P = 0.0390, OR = 1.0030, 95% CI = 1.0000–1.0060), and the protective effect of cathepsin L2 levels on myocarditis (IVW: P = 0.0030, OR = 0.6610, 95% CI = 0.5031–0.8676) and chronic heart failure (IVW: P = 0.0090, OR = 0.9259, 95% CI = 0.8737–0.9812) remained, as higher cathepsin O levels were found to be causally related to increased risks of myocarditis (IVW: P = 0.0030, OR = 1.6145, 95% CI = 1.1829–2.2034) and chronic heart failure (IVW: P = 0.0300, OR = 1.0779, 95% CI = 1.0070–1.1537). Conclusions The study highlights the causalities of cathepsin E, L2, and O on CVDs, offering insights into their roles in cardiovascular biomarkers and therapeutic targets development. Further research is required to apply these genetic findings clinically.

This study aimed to optimize the formula of plant-based almond yogurt to improve its quality and storage stability. Using sweet almonds as the main ingredient and adding conventional yogurt stabilizers such as emulsifiers and thickeners, plant-based almond yogurt was produced through lactic acid fermentation. The optimal stabilizer formula for yogurt was determined using principal component synthesis evaluation analysis and response surface optimization methodology, and the physical properties were characterized. The results showed that the optimal formula for plant-based almond yogurt was 0.4% tartaric acid mono-diglyceride, 2.0% hydroxypropyl distarch phosphate, and 0.1% glutamine transaminase, with a comprehensive score of 0.990. The predicted and verified comprehensive scores of plant-based yogurt were close. The quality and acceptability of the plant-based yogurt significantly improved after adjustment, and the micro-particles of the mixed plant-based almond yogurt (MPBAY) were fuller, the distribution of milk fat was more uniform, and the texture was richer. This study provides a certain research idea and scientific theoretical value reference for the development of plant-based yogurt and the study of plant protein gel aggregation systems.

To explore the preparation, enrichment, and structural analysis of bitter almond antimicrobial peptides, in this experiment, the protein was extracted from the defatted bitter almonds, and the protein was hydrolyzed by enzymes to prepare bitter almond protein antibacterial peptides. The preparation process was optimized, and the resulting peptides' antibacterial activity was detected. The peptides were further purified and enriched. The components with the strongest antibacterial activity were isolated, and their structure was analyzed. The results showed that the papain hydrolysate had the strongest bacteriostatic effect on Gram-positive bacteria, especially Staphylococcus aureus. The optimal conditions for the preparation of bitter almond antibacterial peptides were as follows: The enzymatic hydrolysis temperature was 74℃, the enzyme-to-substrate ratio was 2.5%, and the pH was 7. The protein concentration of the antibacterial peptides was 19.21%, and the minimum inhibitory concentration was 3.13 mg/mL. The antibacterial peptides were isolated and purified by ultrafiltration and gel filtration chromatography (Sephadex G-25). Peptide component A-II-b was screened out to have the strongest inhibitory activity against Staphylococcus aureus. The gel filtration conditions were optimized with a sample concentration of 9.38 mg/mL, an elution rate of 0.68 mL/min, and pure water as the eluent. Under these conditions, the peak area ratio of peptide component A-II-b was 13.15%. The structure of peptide component A-II-b was analyzed by liquid chromatography-mass spectrometry, and the results were imported into the UniProt database and the APD3 database for matching. Seven kinds of bitter almond peptides with potential antibacterial activity with molecular weights of 1500~2500 Da were screened out, including ALPDEVLQNAFRIS, ESWNPRDPQFQWAGVA, VAYWSYNNGEQPLVA, FLDLSNDQNQLDQVPR, GENDNRNQIIRVR, RNLQGENDNRNQIIRVR, and RALPDEVLQNAFRIS. This study promoted the in-depth development and resource reuse of almond active peptides and also provided a theoretical basis for their research and further development and utilization as an antibacterial peptide.

Abstract The blockade of cytoprotective autophagy has been demonstrated to effectively enhance the efficacy of sonodynamic therapy (SDT). However, the limited recognition of antiautophagy agents for autophagosomes impedes the clinical application of autophagy inhibition. To efficiently deliver hydroxychloroquine (HCQ), an autophagy inhibitor, to autophagosomes, we utilized a strategy based on in situ click chemistry between sulfhydryl (‐SH) and maleimide (Mal) groups to trigger autophagosomes tracking and suppress tumor growth synergistically. A cascade nanoreactor was synthesized by encapsulating Mal‐modified HCQ (MHCQ) into a manganese porphyrin‐based metal‐organic framework with sonosensitizer properties, followed by poly(ethylene glycol)ylated liposomal membrane coating. After ultrasound irradiation, SDT‐induced apoptotic cells released damaged proteins with free ‐SH groups, which MHCQ rapidly captured in situ via a Mal‐thiol click reaction. When autophagosomes actively wrapped damaged proteins for detoxification, they simultaneously internalized HCQ anchored on proteins. In this scenario, antiautophagy drugs could actively track intracellular autophagosomes instead of undergoing passive diffusion in the cytosol. The interaction between HCQ and autophagic vesicles was greatly enhanced, which strengthened the blocking efficiency of autophagy and resulted in complete cell death. Overall, this study with smart design provides a promising strategy for improving intracellular targeted delivery to autophagosomes, thereby enhancing antitumor therapy.

BackgroundDermatitis is one of the most common skin disorders across the world. Atopic dermatitis (AD) and contact dermatitis (CD) are its two primary types. Few studies have focused on the causal relationship between fluid intake and dermatitis. With an Mendelian Randomization (MR), this study investigated the potential causal effects of alcohol, coffee, tea, and water intake on the risk of AD and CD.MethodsUtilizing genetic variants as instrumental variables (IVs), a two-sample MR analysis was implemented based on data from the UK Biobank and FinnGen r9 consortium. Fluid intake was categorized into alcohol, coffee, tea, and water intake. Causal estimates were analyzed through Inverse Variance Weighted (IVW), MR-Egger, and weighted median methods. Cochran’s Q, MR-Egger intercept, and MR-PRESSO tests were conducted to assess potential heterogeneity and pleiotropy.ResultsWater intake exhibited a significant causal effect on raised CD risk (IVW OR = 2.92, 95% CI: 1.58–5.41, p =

BackgroundAlzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder that has become one of the major health concerns for the elderly. Computer-aided AD diagnosis can assist doctors in quickly and accurately determining patients' severity and affected regions.MethodsIn this paper, we propose a method called MADNet for computer-aided AD diagnosis using multimodal datasets. The method selects ResNet-10 as the backbone network, with dual-branch parallel extraction of discriminative features for AD classification. It incorporates long-range dependencies modeling using attention scores in the decision-making layer and fuses the features based on their importance across modalities. To validate the effectiveness of our proposed multimodal classification method, we construct a multimodal dataset based on the publicly available ADNI dataset and a collected XWNI dataset, which includes examples of AD, Mild Cognitive Impairment (MCI), and Cognitively Normal (CN).ResultsOn this dataset, we conduct binary classification experiments of AD vs. CN and MCI vs. CN, and demonstrate that our proposed method outperforms other traditional single-modal deep learning models. Furthermore, this conclusion also confirms the necessity of using multimodal sMRI and DTI data for computer-aided AD diagnosis, as these two modalities complement and convey information to each other. We visualize the feature maps extracted by MADNet using Grad-CAM, generating heatmaps that guide doctors' attention to important regions in patients' sMRI, which play a crucial role in the development of AD, establishing trust between human experts and machine learning models.ConclusionWe propose a simple yet effective multimodal deep convolutional neural network model MADNet that outperforms traditional deep learning methods that use a single-modality dataset for AD diagnosis.

BackgroundAberrant lipid metabolism is intricately linked to the development of endometrial cancer, and statin lipid-lowering medications are regarded as promising adjunctive therapies for future management of this malignancy. This study employed Mendelian randomization (MR) to explore the causal association between lipid traits and endometrial cancer while assessing the potential impact of drug targets on lower lipids on endometrial cancer.MethodTwo-sample Mendelian randomization was employed to probe the causal association between lipid traits and endometrial carcinoma. Drug-target Mendelian randomization was also utilized to identify potential drug-target genes for managing endometrial carcinoma. In instances where lipid-mediated effects through particular drug targets were notable, the impacts of these drug targets on endometrial carcinoma risk factors were investigated to bolster the findings.ResultNo causal association between genetically predicted lipid traits (LDL-C, TG, TC, and HDL-C) and EC was found in two-sample Mendelian randomization. In drug target Mendelian randomization, genetic modeling of apolipoprotein B (APOB) (OR [95%CI]=0.31, [0.16-0.60]; p=4.73e-04) and cholesteryl ester transfer protein (CETP) (OR [95%CI]=1.83, [1.38-2.43]; p=2.91e-05) genetic mimicry was associated with non-endometrioid carcinoma.ConclusionThe results of our MR study revealed no causal association between genetically predicted lipid traits (LDL-C, TG, TC, and HDL-C) and EC. Among the six lipid-lowering drug targets, we observed a significant association between lower predicted APOB levels and higher CETP levels with an increased risk of endometrioid carcinoma. These findings provide novel insights into the importance of lipid regulation in individuals with endometrial carcinoma, warranting further clinical validation and mechanistic investigations.

Wind power, as a pivotal technology in the fight against climate change and the advancement of sustainable energy, occupies an essential role in the global shift towards a new energy paradigm. However, the inherent fluctuation and episodic nature of wind power output pose formidable challenges to achieving precise forecasts, thereby impeding the accuracy of traditional forecasting methodologies. To address this, the paper introduces a novel forecasting approach, the VMD-IMPA-BiLSTM method. This method begins by applying the VMD technique to decompose wind power output into several sub-sequences, significantly reducing data non-stationarity and thus mitigating the negative impact of data volatility on forecasting accuracy. The IMPA method, an improvement over the traditional MPA, incorporates a Tent chaotic mapping for population initialization and a priority selection strategy based on average fitness, enhancing the model’s ability to perform global searches and local optimizations. Moreover, the IMPA is leveraged to optimize critical parameters of the BiLSTM, such as maximum training iterations, hidden layer units, and learning rate, thereby curtailing the subjectivity inherent in manual tuning and bolstering the model’s forecasting robustness. A thorough comparative analysis with other models has been conducted to evaluate the performance of the developed VMD-IMPA-BiLSTM forecasting model comprehensively. Simulation results indicate that the proposed method significantly outperforms the benchmark models in terms of prediction accuracy across various application scenarios, showcasing not only exceptional stability in forecasts but also a robust generalization capability across diverse contexts.

Summary: Mounting evidence supports the role of neuroinflammation in radiation-induced brain injury (RIBI), a chronic disease characterized by delayed and progressive neurological impairment. Asparagine endopeptidase (AEP), also known as legumain (LGMN), participates in multiple malignancies and neurodegenerative diseases and may potentially be involved in RIBI. Here, we found AEP expression was substantially elevated in the cortex and hippocampus of wild-type (Lgmn+/+) mice following whole-brain irradiation. Lgmn knockout (Lgmn−/−) alleviated neurological impairment caused by whole-brain irradiation by suppressing neuronal senescence. Bulk RNA and metabolomic sequencing revealed AEP’s involvement in the antigen processing and presentation pathway and neuroinflammation. This was further confirmed by co-culturing Lgmn+/+ primary neurons with the conditioned media derived from irradiated Lgmn+/+ or Lgmn−/− primary microglia. Furthermore, esomeprazole inhibited the enzymatic activity of AEP and RIBI. These findings identified AEP as a critical factor of neuroinflammation in RIBI, highlighting the prospect of targeting AEP as a therapeutic approach.

Abstract Overproduction of reactive oxygen species (ROS), metal ion accumulation, and tricarboxylic acid cycle collapse are crucial factors in mitochondria‐mediated cell death. However, the highly adaptive nature and damage‐repair capabilities of malignant tumors strongly limit the efficacy of treatments based on a single treatment mode. To address this challenge, a self‐reinforced bimetallic Mito‐Jammer is developed by incorporating doxorubicin (DOX) and calcium peroxide (CaO2) into hyaluronic acid (HA) ‐modified metal‐organic frameworks (MOF). After cellular, Mito‐Jammer dissociates into CaO2 and Cu2+ in the tumor microenvironment. The exposed CaO2 further yields hydrogen peroxide (H2O2) and Ca2+ in a weakly acidic environment to strengthen the Cu2+‐based Fenton‐like reaction. Furthermore, the combination of chemodynamic therapy and Ca2+ overload exacerbates ROS storms and mitochondrial damage, resulting in the downregulation of intracellular adenosine triphosphate (ATP) levels and blocking of Cu‐ATPase to sensitize cuproptosis. This multilevel interaction strategy also activates robust immunogenic cell death and suppresses tumor metastasis simultaneously. This study presents a multivariate model for revolutionizing mitochondria damage, relying on the continuous retention of bimetallic ions to boost cuproptosis/immunotherapy in cancer.

Energy conservation and carbon reduction in buildings have become important concerns and, at the same time, the value of low-tech approaches employed in indigenous architecture is increasingly acknowledged as a pertinent reference for contemporary design practices. The research on vernacular dwellings in Jiangxi has many perspectives and fruitful results, but not enough attention has been paid to the research on climate adaptation. This article verifies the vernacular dwellings’ climate adaptation and summarizes the low-tech methods embedded in vernacular dwellings, aiming to provide guidelines for future exploration of energy-saving and carbon-reducing practices in architecture. By selecting different types of vernacular dwellings in Nanfeng County, this article verifies three aspects of the ecological characteristics of vernacular dwellings: the light environment, wind environment, and energy consumption, by comparing them with those of local modern residential buildings. It is concluded that the average daylight factor of the hall area of vernacular dwellings is better than that of the modern residential buildings in rural areas, and the vernacular dwellings regulate the indoor wind environment and maintain indoor comfort through natural ventilation in winter and summer seasons. Also, the annual energy consumption of the vernacular dwellings per unit area per year can be reduced by up to about 32% in comparison with modern residential buildings. Subsequently, the article concludes that patio space has a positive impact on the indoor physical environment through comparative experiments. Vernacular dwellings are well adapted to the local climate in terms of form, structure, and materials, and these low-tech methods should be applied to the design of rural dwellings in the future.

Cordierite is a violet-blue gem mineral primarily composed of magnesium aluminum silicate. This study employed three samples of Mg-cordierite and conducted tests on their gemological characteristics, spectroscopic features, and chemical composition using Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy, ultraviolet spectrophotometry, X-ray photoelectron spectroscopy (XPS), and electron microprobe. The study also explored and analyzed the polychroism and coloration mechanisms of the samples. The results indicate that the lattice vibrations of the Mg-cordierite samples differ along the directions parallel to the a, b, and c crystallographic axes, leading to certain variations in spectral characteristics among these directions. The article provides experimental evidence for the reasons for the polychroism of cordierite in different crystal axes, which is of great significance in the quality evaluation of cordierite.

Abstract Fluoropyridine-based chemotherapy remains the most widely used treatment for colorectal cancer (CRC). In this study, we investigated the mechanism by which the natural product Scutellaria baicalensis (Huang Qin; HQ) and one of its main components baicalin enhanced 5-fluorouracil (5-FU) antitumor activity against CRC. Cell proliferation assays, cell cycle analysis, reverse-phase protein array (RPPA) analysis, immunoblot analysis, and qRT-PCR were performed to investigate the mechanism(s) of action of HQ and its active components on growth of CRC cells. HQ exhibited in vitro antiproliferative activity against drug resistant human CRC cells, against human and mouse CRC cells with different genetic backgrounds and normal human colon epithelial cells. In vivo animal models were used to document the antitumor activity of HQ and baicalin. The mechanism of growth inhibitory activity of HQ is due to inhibition of proliferative signaling pathways including the CDK-RB pathway. In addition, HQ enhanced the antitumor effects of 5-FU and capecitabine in vivo. Furthermore, we identified baicalin as an active component of HQ. The combination of baicalin and 5-FU demonstrated synergistic activity against 5-FU-resistant RKO-R10 cells. The combination significantly inhibited in vivo tumor growth greater than each treatment alone. RPPA results showed that the signaling pathway alterations in CRC cells were similar following HQ and baicalin treatment. Together, these results indicate that HQ and its component baicalin enhance the effect of 5-fluorouracil-based chemotherapy via inhibition of CDK-RB pathway. These findings may provide the rational basis for developing agents that can overcome the development of cellular drug resistance. Video Abstract

Insufficient infiltration of T cells severely compromises the antitumor efficacy of adoptive cell therapy (ACT) against solid tumors. Here, we present a facile immune cell surface engineering strategy aiming to substantially enhance the anti-tumor efficacy of Th9-mediated ACT by rapidly identifying tumor-specific binding ligands and improving the infiltration of infused cells into solid tumors. Non-genetic decoration of Th9 cells with tumor-targeting peptide screened from phage display not only allowed precise targeted ACT against highly heterogeneous solid tumors but also substantially enhanced infiltration of CD8+ T cells, which led to improved antitumor outcomes. Mechanistically, infusion of Th9 cells modified with tumor-specific binding ligands facilitated the enhanced distribution of tumor-killing cells and remodeled the immunosuppressive microenvironment of solid tumors via IL-9 mediated immunomodulation. Overall, we presented a simple, cost-effective, and cell-friendly strategy to enhance the efficacy of ACT against solid tumors with the potential to complement the current ACT.

Abstract Background Combined therapy based on the effects of cascade reactions of nanoplatforms to combat specific solid tumor microenvironments is considered a cancer treatment strategy with transformative clinical value. Unfortunately, an insufficient O2 supply and the lack of a visual indication hinder further applications of most nanoplatforms for solid tumor therapy. Results A visualizable nanoplatform of liposome nanoparticles loaded with GOD, H(Gd), and PFP and grafted with the peptide tLyP-1, named tLyP-1H(Gd)-GOD@PFP, was constructed. The double-domain peptide tLyP-1 was used to specifically target and penetrate the tumor cells; then, US imaging, starvation therapy and sonodynamic therapy (SDT) were then achieved by the ultrasound (US)-activated cavitation effect under the guidance of MR/PA imaging. GOD not only deprived the glucose for starvation therapy but also produced H2O2, which in coordination with 1O2 produced by H(Gd), enable the effects of SDT to achieve a synergistic therapeutic effect. Moreover, the synergistic therapy was enhanced by O2 from PFP and low-intensity focused ultrasound (LIFU)-accelerated redox effects of the GOD. The present study demonstrated that the nanoplatform could generate a 3.3-fold increase in ROS, produce a 1.5-fold increase in the maximum rate of redox reactions and a 2.3-fold increase in the O2 supply in vitro, and achieve significant tumor inhibition in vivo. Conclusion We present a visualizable nanoplatform with tumor-penetrating ability that can be unlocked by US to overcome the current treatment problems by improving the controllability of the O2 supply, which ultimately synergistically enhanced cascade therapy.

The design of street canyons has become a focus of attention under the requirements of high-quality urban modernization, while existing research has gradually broken through the basic norms of aesthetic design to include ecological considerations. However, it is only in recent decades that relevant research has been carried out in super and super-large cities in China. In this article, we take Nanchang, one of the largest cities in China, as an example, and use ENVI-met software (v5.5.1.) to simulate and analyze the street canyon of the city. Certain measurements were made and verified to compare the microclimatic conditions of street canyons at different scales. The relationship between street canyon morphology and outdoor thermal comfort was explored in terms of near-surface air temperature, wind speed, and thermal comfort indicators. The results show that there is a high correlation between the morphology of street canyons, such as orientation, aspect ratio interface continuity, and outdoor thermal comfort. Therefore, starting from adjusting the morphological characteristics of street canyons, practical suggestions can be provided for urban planners to guide the sustainable development of contemporary cities and improve the comfort of urban street spaces.

Abstract The emergence of aggregation‐induced emission luminogens (AIEgens) has attracted substantial scientific attention. However, their antitumor efficacy in photodynamic therapy (PDT) is significantly restricted by the poor water solubility and limited treatment depth. Therefore, a novel AIEgens‐involved therapeutic platform with good permeability and bioavailability is urgently required. Herein, supramolecular chemistry is combined with the AIEgen bis‐pyrene (BP) to construct a peptide–AIEgen hybrid nanosystem (PAHN). After intravenous injection, the versatile nanoplatform not only improved the hydrophilicity of BP but also achieved stratified targeting from tumor to mitochondrial and induced mitochondrial dysfunction, thus activating caspase‐3 upregulation. Then, sonodynamic therapy (SDT), an alternative modality with high tissue penetrability, is performed to evoke reactive oxygen species (ROS) generation for BP. More importantly, since the hydrophilic shell is separated from the nanosystem by the specific cleavage of caspase‐3, the resulting decrease in hydrophilicity induced tight self‐aggregation of PAHN residues in situ, further allowing more absorbed energy to be used for ROS generation under ultrasound irradiation and enhancing SDT efficacy. Moreover, severe oxidative stress resulting from ROS imbalance in the mitochondria initiates the immunogenic cell death process, thus evoking antitumor immunogenicity. This PAHN provides prospective ideas into AIE‐involved antitumor therapy and design of peptide‐AIEgens hybrids.

The incidence of hepatocellular carcinoma (HCC) associated with extrahepatic primary malignancy (EHPM) is extremely rare, especially for those that involve primary renal cell carcinoma (PRC). Here we present a case of a 66-year-old male who was diagnosed with HCC complicated with lymph node metastasis at posterior pancreas head and PRC. Biopsy results of the liver and the lymph node confirmed the diagnosis of HCC. The disease progressions of both HCC and PRC are controlled effectively following the initiation of comprehensive therapy including pembrolizumab, lenvatinib, radiotherapy, and transcatheter arterial chemo-embolization (TACE). Ultimately, the patient had successfully access to surgery and complete response (CR) of all the tumors were achieved after surgery.

Abstract Background Recent studies have demonstrated that multidrug resistance (MDR) is a critical factor in the low efficacy of cancer chemotherapy. The main mechanism of MDR arises from the overexpression of P-glycoprotein (P-gp), which actively enhances drug efflux and limits the effectiveness of chemotherapeutic agents. Results In this study, we fabricated a “combo” nanoagent equipping with triple synergistic strategies for enhancing antitumor efficacy against MDR cells. Tumor homing-penetrating peptide endows the nanosystem with targeting and penetrating capabilities in the first stage of tumor internalization. The abundant amine groups of polyethylenimine (PEI)-modified nanoparticles then trigger a proton sponge effect to promote endo/lysosomal escape, which enhances the intracellular accumulation and retention of anticancer drugs. Furthermore, copper tetrakis(4-carboxyphenyl)porphyrin (CuTCPP) encapsulated in the nanosystem, effectively scavenges endogenous glutathione (GSH) to reduce the detoxification mediated by GSH and sensitize the cancer cells to drugs, while simultaneously serving as a photoacoustic imaging (PAI) contrast agent for image visualization. Moreover, we also verify that these versatile nanoparticles in combination with PD-1/PD-L1 blockade therapy can not only activate immunological responses but also inhibit P-gp expression to obliterate primary and metastatic tumors. Conclusion This work shows a significant enhancement in therapeutic efficacy against MDR cells and syngeneic tumors by using multiple MDR reversing strategies compared to an equivalent dose of free paclitaxel. Graphic Abstract

Background: PBRM1 gene abnormalities were recently found to play a role in tumor development and tumor immune activity. This article will explore the clinicopathological and molecular changes and tumor immune activity of the abnormal SWI/SNF complex subunit PBRM1 in gastric adenocarcinoma (GAC) and its significance.Methods: The cBioPortal, LinkedOmics and TISIDB datasets were used to analyze the abnormality of the PBRM1 gene in GAC and its relationship with prognosis, related molecular changes and tumor-infiltrating lymphocytes (TILs). In addition, 198 GAC cases were collected to further study the relationship between the loss/attenuation of PBRM1 expression and clinicopathology, prognosis, microsatellite stability, PD-L1 expression and TIL in GAC. DNA whole-exome sequencing was performed on 7 cases of gastric cancer with loss of PBRM1 expression.Results: The cBioPortal data showed that PBRM1 deletion/mutation accounted for 7.32% of GAC and was significantly associated with several molecular changes, such as molecular subtypes of GAC. The LinkedOmics dataset showed that PBRM1 mutation and its promoter DNA methylation showed lower PBRM1 mRNA expression, and PBRM1 mutation cases showed significantly higher mRNA expression of PD-L1 (CD274). TISIDB data showed that PBRM1 abnormalities were significantly positively associated with multiple TILs. In our group of 198 cases, the loss/attenuation of PBRM1 expression was significantly positively correlated with intra-tumoral tumor infiltrating lymphocytes (iTILs) and deficient MMR and PD-L1 expression. Kaplan–Meier survival analysis showed that the overall survival of GAC patients with loss/attenuation of PBRM1 expression was significantly better (p = 0.023). iTIL was an independent prognostic factor of GAC. Loss of PBRM1 expression often co-occurs with mutations in other SWI/SNF complex subunit genes, and there are some repetitive KEGG signaling changes.Conclusion: Abnormality of the PBRM1 gene may be related to the occurrence of some GACs and can affect tumor immune activity, thereby affecting clinicopathology and prognosis. It may be a potentially effective predictive marker for immunotherapy and a novel therapeutic approach associated with synthetic lethality.

Deep learning models have shown excellent performance in the hyperspectral remote sensing image (HSI) classification. In particular, convolutional neural networks (CNNs) have received widespread attention because of their powerful feature-extraction ability. Recently, a capsule network (CapsNet) was introduced to boost the performance of CNNs, marking a remarkable progress in the field of HSI classification. In this article, we propose a novel deep convolutional capsule neural network (DC-CapsNet) based on spectral–spatial features to improve the performance of CapsNet in the HSI classification while significantly reducing the computation cost of the model. Specifically, a convolutional capsule layer based on the extension of dynamic routing using 3-D convolution is used to reduce the number of parameters and enhance the robustness of the learned spectral–spatial features. Furthermore, a lighter and stronger decoder network composed of deconvolutional layers as a better regularization term and capable of acquiring more spatial relationships is used to further improve the HSI classification accuracy with low computation cost. In this study, we tested the performance of the proposed model on four widely used HSI datasets: the Kennedy Space Center, Indian Pines, Pavia University, and Salinas datasets. We found that the DC-CapsNet achieved high classification accuracy with limited training samples and effectively reduced the computation cost.

ObjectiveThe aim of this study was to establish a nomogram model for predicting the risk of short-term recurrence in glioma patients.MethodsThe clinical data of recurrent glioma patients were summarized and analyzed in this study. Univariate and multivariate logistic regression analyses were performed to analyze the correlation between clinical data and the risk of short-term recurrence after operation. A nomogram was established based on the multivariate logistic regression model results.ResultsA total of 175 patients with recurrent glioma were enrolled, with 53 patients in the short-term recurrence (STR) group (recurrent time ≤6 months) and 122 patients in the long-term recurrence (LTR) group (recurrent time ≥36 months). Univariate analysis revealed that age at diagnosis, Karnofsky performance scores (KPSs), tumor location, glioma grade, glioma type, extent of resection (EOR), adjuvant chemotherapy (ad-CT), concurrent chemotherapy (co-CT), and isocitrate dehydrogenase (IDH) status were significantly associated with the short-term glioma recurrence. Multivariate analyses revealed that age at diagnosis, KPS, glioma grade, EOR, and IDH were independent risk factors for short-term glioma recurrence. A risk nomogram for the short-term recurrence of glioma was established, with the concordance index (C-index) of 0.971. The findings of calibration and receiver operating characteristic (ROC) curves showed that our nomogram model had good performance and discrimination to estimate short-term recurrence probability.ConclusionThis nomogram model provides reliable information about the risk of short-term glioma recurrence for oncologists and neurosurgeons. This model can predict the short-term recurrence probability and give assistance to decide the interval of follow-up or formulate individualized treatment strategies based on the predicted results. A free online prediction risk tool for this nomogram is provided: https://rj2021.shinyapps.io/Nomogram_ recurrence-risk/.

The diagnosis of precancerous lesions or early gastric cancer (EGC) is very important for patient survival. Molecular imaging is a visualized method that can easily and precisely diagnose tumors. However, there are currently few studies about molecular imaging diagnosis of EGC. Here, we studied the expression of carcinoembryonic antigen related cell adhesion molecule 6 (CEACAM6) in the progression of GC. Then, the regulatory roles of CEACAM6 in GC cells were investigated. Furthermore, both the fluorescent-labeled and near infrared molecular-labeled probes were synthesized, and the diagnostic value of anti-CEACAM6 probes in GC was evaluated in vivo using a GC mice model as well as in vitro using fresh dysplastic gastric mucosa obtained from endoscopic submucosal dissection (ESD) operations. Our study showed that CEACAM6 was over expressed in GC tissues compared to adjacent tissues, and the patients with higher CEACAM6 expression had lower survival time. Moreover, the CEACAM6 expression was higher in the dysplastic gastric mucosa than in the adjacent normal mucosa. CEACAM6 accelerated the growth, proliferation, and invasion of GC cells in the in vitro and in vivo studies. Moreover, up regulated CEACAM6 can induce the expression of proteins related to GC progression. Furthermore, the anti-CEACAM6 probes exhibited good affinity with GC cell lines. The probes can track tumors as well as metastases in the mice model in vivo, and can precisely identify the area of dysplastic gastric mucosa using specimens obtained from ESD operations by wide field fluorescent endoscopy. The surface micro features of the mucosa can also be observed using fluorescent micro endoscopy, and the degree of atypia can be distinguished by both the signal intensity and surface micro morphology. CEACAM6 is a key molecular marker in GC progression, and the anti-CEACAM6 probe-assisted fluorescent endoscopy may be a potential option for the diagnosis of precancerous lesions.

Abstract Background Malignant glioma is one of the essentially incurable tumors with chemoresistance and tumor recurrence. As a histone methyltransferase, SUV39H2 can trimethylate H3K9. SUV39H2 is highly expressed in many types of human tumors, while the function of SUV39H2 in the development and progression of glioma has never been elucidated. Methods RT-qPCR and IHC were used to test SUV39H2 levels in glioma tissues and paired normal tissues. The clinical relevance of SUV39H2 in glioma was analyzed in a public database. Colony formation assays, CCK-8 assays, and flow cytometry were conducted to explore the role of SUV39H2 in the growth of glioma cells in vitro. A cell line-derived xenograft model was applied to explore SUV39H2’s role in U251 cell proliferation in vivo. Sphere formation assays, RT-qPCR, flow cytometry, and IF were conducted to illustrate the role of SUV39H2 in the stemness and chemosensitivity of glioma. Luciferase reporter assays and WB were applied to determine the function of SUV39H2 in Hh signaling. Results SUV39H2 was highly expressed in glioma tissues relative to normal tissues. SUV39H2 knockdown inhibited cell proliferation and stemness and promoted the chemosensitivity of glioma cells in vitro. In addition, SUV39H2 knockdown also significantly inhibited glioma cell growth in vivo. Moreover, we further uncovered that SUV39H2 regulated hedgehog signaling by repressing HHIP expression. Conclusions Our findings delineate the role of SUV39H2 in glioma cell growth and chemosensitivity as a pivotal regulator of the hedgehog signaling pathway and may support SUV39H2 as a potential target for diagnosis and therapy in glioma management.

Abstract Background Metastasis is the main cause of lung cancer death. As a seed of metastasis, circulating tumor cells are an important target for metastasis intervention. The traditional Chinese medicine, Jinfukang, has been clinically available for the treatment of non-small cell lung cancer (NSCLC). In this study, we investigated the action and underlying mechanisms of Jinfukang against circulating lung tumor cells. Methods The cell counting kit-8 (CCK-8), colony formation and cell cycle assays were used to study the cell proliferation ability. Flow cytometry was used to detect the apoptosis and the expression level of ROS and Caspase-3. Comet and TUNEL assays were used to detect DNA damage. DNA damage related pathway protein was detected by western blot. Results Jinfukang significantly inhibits the proliferation of CTC-TJH-01 cells by inducing G1 phase arrest and inhibits their colony formation in a dose-dependent manner. Moreover, Jinfukang induces apoptosis in CTC-TJH-01 cells through the ROS-mediated ATM/ATR-p53 pathway and DNA damage. Conclusions Our findings suggest that Jinfukang may be a potential drug for lung cancer metastasis.

Abstract Background Circulating tumor cells (CTCs) have been described as a population of cells that may seed metastasis, which is a reliable target for the prevention of metastases in lung cancer patients at the early stage. The culturing of CTCs in vitro can be used to study the mechanism of lung cancer metastasis and to screen antimetastasis drugs. This study aims to establish CTC cell line in vitro and explore the potential mechanism of its metastasis. Methods A mixture of EpCAM- and EGFR-coated immunomagnetic microbeads in microfluidic Herringbone-Chip was used to capture CTCs. The CTCs, 95-D and A549 cells was evaluated by cell proliferation assays, clonal formation assays, migration assays and drug resistance. Flow cytometry and cytokine protein chip were used to detect the difference in phenotype and cytokine secretion between CTCs, 95-D and A549 cells. The NOD/SCID mice were used to study tumorigenicity, lung organ colonization and metastasis of CTCs. The H&E staining, immunohistochemistry and immunofluorescence assay were used to detect the pathological status of CTCs. Results The number of EpCAM(+)/EGFR(+)/CK(+)/CD45(−) lung CTCs showed a weak negative correlation with clinical stages in patients with non-small cell lung cancer (NSCLC). In a phase IIa lung cancer patient, we successfully establish a permanent CTC cell line, named CTC-TJH-01. In vitro studies showed the CTC-TJH-01 cells were in the intermediate stage of epithelial to mesenchymal transition (EMT), had stem cell characteristics and were drug resistant. In vivo studies showed that CTC-TJH-01 cells can induce tumorigenesis, lung organ colonization and metastasis after xenografting in immunodeficient mice. In addition, the low expression level of CX3CL1 and high expression level of CXCL5 in the CTC-TJH-01 cells may be an important mechanism for their metastasis. Conclusions We successfully established a permanent CTC cell line with metastatic ability, which can be used to screen antimetastatic drugs and study the mechanism of lung cancer metastasis.

Background and objectiveWe aimed to predict the targets and signal pathways of Xiao-Chai-Hu-Tang (XCHT) in the treatment of colorectal cancer (CRC) based on network pharmacology, just as well as to further analyze its anti-CRC material basis and mechanism of action.MethodsWe adopted Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) and Traditional Chinese Medicine Integrated Database (TCMID) databases to screen the active ingredients and potential targets of XCHT. CRC-related targets were retrieved by analyzing published microarray data (accession number GSE110224) from the Gene Expression Omnibus (GEO) database. The common targets were used to construct the "herb-active ingredient-target" network using the Cytoscape 3.8.0 software. Next, we constructed and analyzed protein-to-protein interaction (PPI) using BisoGenet and CytoNCA plug-in in Cytoscape. We then performed Gene Ontology (GO) functional and the Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analyses of target genes using the R package of clusterProfiler. Furthermore, we used the AutoDock Tools software to conduct molecular docking studies on the active ingredients and key targets to verify the network pharmacological analysis results.ResultsWe identified a total of 71 active XCHT ingredients and 20 potential anti-CRC targets. The network analysis revealed quercetin, stigmasterol, kaempferol, baicalein, and acacetin as potential key compounds, and PTGS2, NR3C2, CA2, and MMP1 as potential key targets. The active ingredients of XCHT interacted with most CRC disease targets. We showed that XCHT's therapeutic effect was attributed to its synergistic action (multi-compound, multi-target, and multi-pathway). Our GO enrichment analysis showed 46 GO entries, including 20 biological processes, 6 cellular components, and 20 molecular functions. We identified 11 KEGG signaling pathways, including the IL-17, TNF, Toll-like receptor, and NF-kappa B signaling pathways. Our results showed that XCHT could play a role in CRC treatment by regulating different signaling pathways. The molecular docking experiment confirmed the correlation between five core compounds (quercetin, stigmasterol, kaempferol, baicalein, and acacetin) just as well as PTGS2, NR3C2, CA2, and MMP1.ConclusionIn this study, we described the potential active ingredients, possible targets, and key biological pathways responsible for the efficacy of XCHT in CRC treatment, providing a theoretical basis for further research.

Arctigenin (ATG), a major bioactive substance of Fructus Arctii, counters renal fibrosis; however, whether it protects against paraquat (PQ)-induced lung fibrosis remains unknown. The present study was to determine the effect of ATG on PQ-induced lung fibrosis in a mouse model and the underlying mechanism. Firstly, we found that ATG suppressed PQ-induced pulmonary fibrosis by blocking the epithelial-mesenchymal transition (EMT). ATG reduced the expressions of Vimentin and α-SMA (lung fibrosis markers) induced by PQ and restored the expressions of E-cadherin and Occludin (two epithelial markers) in vivo and in vitro. Besides, the Wnt3a/β-catenin signaling pathway was significantly activated in PQ induced pulmonary fibrosis. Further analysis showed that pretreatment of ATG profoundly abrogated PQ-induced EMT-like phenotypes and behaviors in A549 cells. The Wnt3a/β-catenin signaling pathway was repressed by ATG treatment. The overexpression of Wnt3a could weaken the therapeutic effect of ATG in A549 cells. These findings suggested that ATG could serve as a new therapeutic candidate to inhibit or even reverse EMT-like changes in alveolar type II cells during PQ-induced lung fibrosis, and unraveled that the Wnt3a/β-catenin pathway might be a mechanistic tool for ATG to control pulmonary fibrosis.

Abstract Background 5-Fluorouracil (5-FU) remains the most widely used agent to treat colorectal cancer (CRC). However, its clinical efficacy is currently limited by the development of drug resistance. Traditional Chinese Herbal Medicine (TCM) has been shown to enhance the efficacy of standard anticancer agents. However, there are only a limited number of well-controlled preclinical and clinical studies documenting the potential benefit of TCM. Herein, we screened a series of TCM formulas in in vitro and in vivo animal models to identify biologically active formulas that were effective against CRC. Methods Cell proliferation and clonogenic assays, cell cycle analysis, immunoblot analysis and qRT-PCR were performed to investigate the mechanism(s) of action of the most active formula Huang-Qin-Ge-Gen-Tang (HQGGT) on growth of human CRC cells. In vivo animal models were used to document the antitumor activity of HQGGT alone and HQGGT in combination with 5-FU. Results We identified HQGGT, which suppressed the in vivo growth of human colon cancer HT-29 xenografts without associated toxicities. HQGGT displayed anti-proliferative activity against a wide range of CRC cell lines. This growth suppression correlated with induction of apoptosis. HQGGT enhanced the cytotoxicity of 5-FU against human 5-FU-resistant cells (H630R1) and mouse colon cancer cells (MC38). Our studies showed that the mechanism of action of this synergism was the result of suppression of thymidylate synthase (TS) expression by HQGGT. We analyzed different batches of HQGGT and observed consistent chemical fingerprints and biological activity. Finally, we show that orally administered HQGGT significantly enhanced the antitumor effect of 5-FU in mice bearing MC38 xenografts. Conclusions These findings provide support for the potential role of HQGGT as a novel modulator of fluoropyrimidine chemotherapy in the treatment of CRC.

Abstract Background Many of the deaths that occur shortly after injury or in hospitals are caused by mild trauma. Slight morphological changes are often found in the brain stems of these patients during autopsy. The purpose of this study is to investigate the histopathological changes involved in primary brain stem injuries (PBSI) and their diagnostic significance. Methods A total of 65 patients who had died of PBSI and other conditions were randomly selected. They were divided into 2 groups, an injury group (25 cases) and a control group (20 cases). Slides of each patient’s midbrain, pons, and medulla oblongata were prepared and stained with HE, argentaffin, and immunohistochemical agents (GFAP, NF, amyloid-ß, MBP). Under low power (×100) and NF staining, the diameter of the thickest longitudinal axon was measured at its widest point. Ten such diameters were collected for each part of the brain (midbrain, pons, and medulla oblongata). Data were recorded and analyzed statistically. Results Brain stem contusions, astrocyte activity, edema, and pathological changes in the neurons were visibly different in the injury and control groups (P P Conclusions These histopathological changes may prove beneficial to the pathological diagnosis of PBSI during autopsy. The measurement of axon diameters provides a referent quantitative index for the diagnosis of the specific causes of death involved in PBSI. Virtual Slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1345298818712204

Background: Surgical treatment of complex giant pituitary adenomas (GPAs) presents significant challenges. The efficacy and safety of combining transsphenoidal and transcranial approaches for these tumors remain controversial. In this largest cohort of patients with complex GPAs, we compared the surgical outcomes between those undergoing a combined regimen and a noncombined regimen. We also examined the differences in risks of complications, costs, and logistics between the two groups, which might offer valuable information for the appropriate management of these patients. Patients and Methods: This was a multicenter retrospective cohort study conducted at 13 neurosurgical centers. Consecutive patients who received a combined or non-combined regimen for complex GPAs were enrolled. The primary outcome was gross total resection, while secondary outcomes included complications, surgical duration, and relapse. A propensity score-based weighting method was used to account for differences between the groups. Results: Out of 647 patients [298 (46.1%) women, mean age: 48.5 ± 14.0 years] with complex GPAs, 91 were in the combined group and 556 were in the noncombined group. Compared with the noncombined regimen, the combined regimen was associated with a higher probability of gross total resection [50.5% vs. 40.6%, odds ratio (OR): 2.18, 95% confidence interval (CI): 1.30-3.63, P = 0.003]. The proportion of patients with life-threatening complications was lower in the combined group than in the non-combined group (4.4% vs. 11.2%, OR: 0.25, 95% CI: 0.08-0.78, P = 0.017). No marked differences were found between the groups in terms of other surgical or endocrine-related complications. However, the combined regimen exhibited a longer average surgery duration of 1.3 h (P < 0.001) and higher surgical costs of 22,000 CNY (~ 3,000 USD, P = 0.022) compared with the noncombined approach. Conclusions: The combined regimen offered increased rates of total resection and decreased incidence of life-threatening complications, which might be recommended as the first-line choice for these patients. [ABSTRACT FROM AUTHOR]