Prognostic significance of refractory thrombus in STEMI patients and the role of red cell distribution width: A case-control study.

The high thrombus burden of the infarct-related artery (IRA) is associated with the adverse prognosis in ST-segment elevation myocardial infarction (STEMI) patients. Our objectives were to investigate the predictors and evaluate the prognosis of refractory thrombus in STEMI patients. A total of 1305 consecutive patients with STEMI who underwent primary percutaneous coronary intervention (pPCI) were screened. The refractory thrombus group (n = 15) was defined as IRA thrombolysis in myocardial infarction flow < grade 2 after multiple thrombus aspiration (TA). The control group (n = 45) was age- and sex-matched and was selected from the same batch of patients. Baseline hematologic indices were measured before the pPCI. The major adverse cardiovascular events (MACE) were recorded during follow-up. The refractory thrombus group had significantly higher red cell distribution width (RDW) at baseline compared with the control group (13.1 [12.4-13.7] vs 12.6 [12.3-12.8], P = .008). In multivariate logistic regression analysis, RDW was an independent predictor of refractory thrombus (odds ratio: 8.799, 95% CI: 1.240-62.454, P = .030). The area under the receiver-operating characteristic curve of the RDW was 0.730 (95%CI: 0.548-0.912, P = .008). During a mean period of 26 months follow-up, patients in the refractory thrombus group tended to have higher percent MACEs compared with patients in the control group (53.3% vs 6.7%, P < .001). In the present study, we found that the refractory thrombus in STEMI patients was associated with the worse prognosis and the increased RDW might be a potential independent predictor.

Properties, extraction and purification technologies of Stevia rebaudiana steviol glycosides: A review.

For health and safety reasons, the search for green, healthy, and low-calorie sweeteners with good taste has become the demand of many consumers. Furthermore, the need for sugar substitutes of natural origin has increased dramatically. In this review, we briefly discussed the safety and health benefits of stevia sweeteners and enumerated some examples of physiological functions of steviol glycosides (SGs), such as anti-inflammatory, anti-obesity, antihypertensive, anti-diabetes, and anticaries, citing various evidence related to their application in the food industry. The latest advances in emerging technologies for extracting and purifying SGs and the process variables and operational strategies were discussed. The impact of the extraction methods and their comparison against the conventional techniques have also been demonstrated. These technologies use minimal energy solvents and simplify subsequent purification stages, making viable alternatives suitable for a possible industrial application. Furthermore, we also elucidated the potential for advancing and applying the natural sweeteners SGs.

[Mechanisms of NLRP3 inflammasome-mediated pyroptosis in chronic heart failure and research progress in traditional Chinese medicine].

Chronic heart failure(CHF) is a severe cardiovascular disease characterized by a complex pathogenesis involving myocardial structural and functional abnormalities and the activation of inflammatory responses. The NOD-like receptor thermal protein domain-associated protein 3(NLRP3) inflammasome, acting as a sensor for inflammatory cells, plays a pivotal role in the development of CHF. Research indicates that the activation of the NLRP3 inflammasome can induce inflammatory responses, leading to cardiac inflammation and impairing myocardial function, and it is correlated with the severity of CHF. Traditional Chinese medicine(TCM) has garnered increasing attention as a traditional therapeutic approach in recent years. Various TCM drugs and treatment methods have exhibited potential efficacy in suppressing inflammatory responses, alleviating myocardial cell pyroptosis, improving myocardial structure and function, and inhibiting myocardial fibrosis. Several TCM drugs and their extracts have been utilized in CHF treatment, with mechanisms potentially involving the inhibition of NLRP3 inflammasomes and the mitigation of inflammatory responses. The article provided an overview of the composition, structural characteristics, initiation, and activation modes of the NLRP3 inflammasome, its mechanisms in CHF, and the research progress of TCM in CHF treatment. It aims to offer references and foundations for a deeper understanding of CHF pathogenesis and subsequent development of new therapeutic strategies.

Effects of combined drying techniques and cellulase hydrolysis on the nutritional value and sensory properties of shiitake mushrooms (Lentinus edodes).

Dried shiitake mushrooms offer rich nutritional value and unique sensory properties, prompting further investigation. The effects of different drying techniques (hot air drying (HAD), infrared hot air drying (IRHAD), pulsed vacuum drying (PVD), vacuum freeze drying (VFD), and natural drying (ND)) combined with enzymatic hydrolysis on the release of flavor compounds and nutrients from shiitake mushrooms were explored. The combination of HAD with cellulase hydrolysis yielded notably high levels of umami amino acids (5.4723 ± 0.1501 mg/g) and 5'-nucleotides (4.0536 ± 0.0062 mg/g), and superior volatile flavors. Combined with cellulase hydrolysis, IRHAD achieved the highest level of total sugars (6.57 ± 0.34 mg/mL), VFD resulted in the greatest soluble protein content (153.21 ± 0.23 µg/mL), PVD yielded the highest total phenolics content (93.20 ± 0.41 µg GAE/mL), and ND produced the maximum reducing sugar content (5.79 ± 0.13 mg/mL). This study addresses crucial gap in the post-drying processing of shiitake mushrooms, offering valuable insights for further product development of shiitake mushrooms.

[Protective effect of Shenfu Injection on regulation of autophagy in rats with chronic heart failure based on PI3K/Akt/mTOR pathway].

This study aimed to investigate the mechanism and target sites of Shenfu Injection in the intervention of chronic heart fai-lure based on the PI3K/Akt/mTOR autophagy signaling pathway. The chronic heart failure model was induced in rats by subcutaneous injection of isoproterenol. The model rats were randomly divided into model group, Shenfu Injection group, and 3-methyladenine autophagy inhibitor(3-MA) group. A normal group was also set up. After 15 days of administration, cardiac function indexes of the rats were detected by echocardiography. The serum N-terminal pro-B-type natriuretic peptide(NT-proBNP) levels were measured using the ELISA. HE and Masson staining was performed to observe the morphological changes in myocardial tissues, and electron microscopy was used to observe the autophagosomes in myocardial tissues. Western blot was conducted to measure the changes in autophagy-related proteins(LC3 Ⅱ/Ⅰ and p62), PI3K, Akt, mTOR, and phosphorylation levels. The results showed that compared with normal group, model group in rats led to reduced cardiac function, significant activation of cardiac autophagy, increased fibrotic lesions in myocardial tissues, structural disorder of the myocardium, increased autophagosomes, and cytoplasmic vacuolization. Compared with model group, Shenfu Injection group in rats led to cardiac function significantly improved, myocardial fibrosis decreased, and the number of autophagosomes and cytoplasmic vacuolization decreased. The phosphorylation levels of PI3K, Akt, and mTOR were significantly increased(P<0.01). In the 3-MA group, autophagy was inhibited through the activation of the PI3K/Akt/mTOR signaling pathway, resulting in improved cardiac function, reduced myocardial fibrosis, and no significant cytoplasmic vacuolization. The findings suggest that Shenfu Injection can activate the PI3K/Akt/mTOR signaling pathway and inhibit autophagy, thereby improving cardiac function.

The occurrence and development of vertebral osteoporosis regulated by IL-8.

Vertebral osteoporotic fracture is a common type of fracture, and the incidence is higher in the elderly. However, the relationship between vertebral osteoporotic fractures and interleukin-8 (IL-8) remains unclear. A total of 163 patients with osteoporotic vertebral fractures were recruited. Clinical and follow-up data were recorded, and the expression levels of IL1, MMP9, IL-8, and C-reactive protein in blood were measured. Pearson Chi-square test and Spearman correlation coefficient were used to analyze the relationship between vertebral osteoporotic fractures and related parameters. Univariate and multivariate logistic regression and univariate and multivariate Cox proportional hazards regression were used for further analysis. Pearson chi-square test, Spearman correlation coefficient and Logistic regression analysis showed that IL1 and IL-8 were significantly associated with vertebral osteoporotic fractures. Univariate Cox regression analysis showed that age and IL-8 expression level were significantly associated with maintenance time from recovery to recurrence of vertebral osteoporotic fractures. Multivariate Cox regression analysis showed that IL-8 expression level was significantly associated with maintenance time from recovery to recurrence of vertebral osteoporotic fractures. The higher the expression level of IL-8, the more likely it is to develop vertebral osteoporotic fracture, and the more likely it is to relapse in a short time.

The formation mechanism of the precursor film in high temperature molten metal systems: insight into structural disjoining pressure.

A precursor film is a unique microfluidic entity that arises at the liquid/solid interface. The formation mechanism of this entity in high-temperature systems is yet to be explained, mainly due to the limitations posed by the increased reaction at the solid/liquid interface. In this study, we investigate the formation process of the precursor film in high-temperature molten metal systems (Ag/Ni, Au/Ni, and Cu/Ni) using molecular dynamics simulations. The alloying energies for different alloying pairs were determined to extract the excess energy, which was found to be distributed from the interface to the upper liquid. The pattern of this energy distribution determines the shape of the near-surface liquid, including the precursor film. This relationship is further reflected by the structural disjoining pressure, which is the excess pressure exerted by the ordered microstructures within the wedge-shaped area of the droplet. Strong nonlinearity has been found in the structural disjoining pressure of Ag/Ni and Au/Ni systems, which is considered to be the main reason for the formation of the precursor film. The fluctuation of the dissolution rate is also reflected in the disjoining pressure, and the inhibition of dissolution on the precursor film formation is phenomenally clarified.

Dulaglutide Protects Mice against Diabetic Sarcopenia-Mediated Muscle Injury by Inhibiting Inflammation and Regulating the Differentiation of Myoblasts.

Background: Type 2 diabetes mellitus increases the risk of sarcopenia, which is characterized by decreased muscle mass, strength, and function. However, there are no effective drugs to treat diabetic sarcopenia, and its underlying mechanism remains unknown. Here, we aimed to determine whether the GLP-1 receptor agonist (GLP-1RA) dulaglutide (Dul) affects the progression of diabetic sarcopenia. Methods: db/db mice were injected intraperitoneally with 0.6 mg/kg dulaglutide for 10 weeks. Mouse muscle tissues were then pathologically evaluated and stained with F4/80 or MPO to detect macrophages and neutrophils, respectively. In addition, inflammatory factors and FNDC5 in the muscle tissues were detected using qRT-PCR. Moreover, C2C12 cells were induced to enable their differentiation into skeletal muscle cells, and muscle factor levels were then detected. Furthermore, changes in muscle factor levels were detected at various glucose concentrations (11 mM, 22 mM, and 44 mM). Results: In vivo, dulaglutide alleviated muscle tissue injury; reduced levels of the inflammatory factors, IL-1ß, IL-6, CCL2, and CXCL1; and reversed the level of FNDC5 in the muscle tissues of db/db mice. In vitro, a C2C12 cell differentiation model was established through the observation of cell morphology and determination of myokine levels. Upon stimulation with high glucose, the differentiation of C2C12 cells was inhibited. Dulaglutide improved this inhibitory state by upregulating the levels of both FNDC5 mRNA and protein. Conclusions: Treatment with the GLP-1RA dulaglutide protects db/db mice against skeletal muscle injury by inhibiting inflammation and regulating the differentiation of myoblasts. High glucose inhibited the differentiation of C2C12 cells and decreased the mRNA and protein levels of myokines. Dulaglutide could reverse the differentiation state induced in C2C12 cells by high glucose.

Screening and validation of plasma cell-derived, purinergic, and calcium signalling-related genetic signature to predict prognosis and PD-L1/PD-1 blockade responses in lung adenocarcinoma.

BACKGROUND: This study aims at  screening and validation of prospective genetic signature for lung adenocarcinoma (LUAD) prognosis and treatment. METHODS: The immune-related genes (IRGs) were obtained from The Cancer Genome Atlas (TCGA) dataset where a total of 535 LUAD and 59 control samples were included. A risk model was then developed for the risk stratification of LUAD patients.  The immune cell infiltration, clinical outcomes, and the therapeutic efficacy of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) blockade were compared between high and low-risk groups. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were used to explore the biological processes and signalling pathways associated with the IRGs. Finally, IRGs mRNA levels were assayed by reverse transcription quantitative real-time PCR (RT-qPCR) in LUAD and relevant cell lines. RESULTS: Two IRGs, P2RX1 (purinergic receptor P2X 1) and PCP4 (Purkinje cell protein 4), were screened from a module that possesses the highest correlation with plasma cells. RT-qPCR verified the expression of the two IRGs in plasmacytoma cell RPMI 8226 but not in LUAD cells. A higher risk score is associated with a lower infiltration of immune cells. Kaplan-Meier and nomogram analysis showed that the high-risk group has a lower survival rate than the low-risk cohort. Furthermore, the high-risk group had a worse response rate to PD-L1/PD-1 blockade. GSVA and GSEA-GO results indicated that a lower risk score is linked to signalling pathways and biological functions promoting immune response and inflammation. In contrast, a higher risk score is associated with signalling cascades promoting tumour growth. CONCLUSION: The immune-related prognostic model based on P2RX1 and PCP4 is conducive to predicting the therapeutic response of PD-L1/PD-1 blockade and clinical outcomes of LUAD.

Molecular determinants of protein evolvability.

The plethora of biological functions that sustain life is rooted in the remarkable evolvability of proteins. An emerging view highlights the importance of a protein's initial state in dictating evolutionary success. A deeper comprehension of the mechanisms that govern the evolvability of these initial states can provide invaluable insights into protein evolution. In this review, we describe several molecular determinants of protein evolvability, unveiled by experimental evolution and ancestral sequence reconstruction studies. We further discuss how genetic variation and epistasis can promote or constrain functional innovation and suggest putative underlying mechanisms. By establishing a clear framework for these determinants, we provide potential indicators enabling the forecast of suitable evolutionary starting points and delineate molecular mechanisms in need of deeper exploration.

Low-Temperature-Tolerant Strain-Sensing Flexible Composite for Soft Body Armor.

Developing soft body armor with sensing characteristics in various application scenarios is a challenge but important for creating a peaceful world and personal safety, whereas existing materials suffer from indefinite protective effects and stimulus response at subzero temperatures in the long term. Herein, an anti-freezing and flexible puncture-resistance composite with strain-sensing ability is developed by compounding a NaCl-soaked poly(vinyl alcohol) (PVA)/sodium alginate (SA)/glycerol (Gly) hydrogel (PSGN hydrogel) with Kevlar fabric. After freezing-thawing treatment once and NaCl immersion for 10 h, the Kevlar/PSGN-10 composite has excellent puncture-resistance properties and linear, rapid response, wide band, and stable strain-sensing behaviors at 25 and -30 °C. The composite's maximum puncturing force and energy dissipation at -30 °C are 53.92 N and 370 mJ, respectively, increased by 285 and 302% compared with neat Kevlar fabric. The flexibility reduction and the mass addition of the Kevlar/PSGN-10 composite are merely 19 and 40%, respectively, showing superior wearable comfortability and protection efficiency. The composites also reveal remarkable strain-sensing abilities at -30 °C (linear strain sensitivity with GF = 0.27 and R2 = 0.981, a wide working frequency range of 0.16-1.3 Hz, and sensing stability for 1500 cycles). Moreover, the composite could respond to multipart body motion directly, including fingers, elbows, wrists, and knees. Consequently, the Kevlar/PSGN composite developed in this paper is promising for intelligent soft body armor at various temperatures.

Tumor-expressed B7-H3 promotes vasculogenic mimicry formation rather than angiogenesis in non-small cell lung cancer.

BACKGROUND: Vasculogenic mimicry (VM), an alternative microvascular circulation independent of angiogenesis, is formed by aggressive cancer cells. Tumor-expressed B7-H3 has been reported to promote VM formation in hepatocellular carcinoma and modulate angiogenesis in breast cancer and colorectal cancer. However, its effects on VM generation and angiogenesis in non-small cell Lung cancer (NSCLC) remained to be elucidated. METHODS: CRISPR/Cas9-mediated B7-H3 knockout (KO) was conducted in NSCLC A549 and H3255 cells. The expression of VM-related proteins, including vascular endothelial (VE)-cadherin and matrix metalloproteinase 14 (MMP14), and the secretion of vascular endothelial growth factor (VEGF) were measured by western blotting and chemiluminescence assay in both B7-H3 KO and mock-edited A549 and H3255 cells. To examine VM formation, a three-dimensional (3D) culture model was used for B7-H3 KO and mock A549 and H3255 cells. For in vivo analysis, xenograft mice models were established using B7-H3 KO and mock-edited A549 cells, and immunohistochemical (CD31) and histochemical (periodic acid-Schiff, PAS) double staining were performed to identify VM and endothelial vessels in tumor tissues. Finally, specific signaling inhibitors were used to analyze B7-H3-induced signaling pathway responsible for VE-cadherin and MMP14 expression and VM generation. RESULTS: Higher expression of B7-H3 was associated with a worse prognosis and more advanced T-category in NSCLC. CRISPR/Cas9-mediated B7-H3 KO in A549 and H3255 cells led to decreased expression of VE-cadherin and MMP14; however, the secretion of VEGF by the two cell lines remained unchanged. In the 3D cell culture model, both B7-H3 KO A549 and H3255 cells showed a significant reduction in the formation of capillary-like tubular structures compared to mock-edited cells. In the in vivo xenograft model, mock-edited A549 cells formed excessive PAS+ CD31- VM channels, while B7-H3 KO restrained VM formation in the xenograft tumors. However, no significant differences were found in CD31+ endothelial vessels between xenografts formed by B7-H3 KO and mock-edited A549 cells. Finally, we analyzed the signaling pathway responsible for B7-H3-induced VM formation and found that selective inhibition of the phosphoinositide 3-kinase(PI3K)/protein kinase B (AKT) hyperactivation by LY294002 was associated with decreased expression of MMP14 and VE-cadherin, and in vitro VM formation by both A549 and H3255 cells. CONCLUSIONS: Tumor-expressed B7-H3 acts via PI3K/AKT signaling pathway to promote VM formation by NSCLC cells while bears no effects on angiogenesis in NSCLC.

Prealbumin as a Predictor of Short-Term Prognosis in Patients with HBV-Related Acute-on-Chronic Liver Failure.

Purpose: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a serious medical condition with a high short-term mortality rate, making accurate prognostic assessment essential for informed clinical decision-making. In this study, we aimed to develop a simple and effective prognostic model for predicting short-term mortality in patients with HBV-ACLF. Patients and Methods: To achieve our objective, we enrolled both a cross-sectional cohort (n = 291) and a retrospective cohort (n = 185) in this study. We collected laboratory and clinical data from these cohorts and performed univariate and multivariate logistic regression analyses to identify independent predictors of short-term mortality. Subsequently, we developed a novel prognostic score for HBV-ACLF, which was validated and assessed using receiver operating characteristic (ROC) curve analysis to determine its performance. Results: Our analysis revealed that the admission prealbumin (PAB) level was a robust independent predictor of 30-day mortality, with an area under the receiver operating characteristic (AUROC) of 0.760. Moreover, we developed the HIAPP score, a prognostic-score model based on PAB. The HIAPP score was significantly lower in survivors compared to non-survivors (-2.80±0.21 vs 0.97±0.41, P < 0.001). The HIAPP score's AUROC value was 0.899, which was found to be superior to the MELD score (AUROC = 0.795) and the CLIF-C ACLF score (AUC =0.781) and comparable to the COSSH-ACLF II score (AUC =0.825) for predicting 30-day mortality. These findings were also validated in a separate cohort, further supporting the utility of the HIAPP score as a prognostic tool for HBV-ACLF patients. Conclusion: Our study identifies the admission PAB level as a simple and valuable predictive index for 30-day mortality in HBV-ACLF patients. Furthermore, the HIAPP score, which incorporates PAB, PLT, INR, HE, and age, is an easy-to-use and pragmatic prognostic score in predicting short-term mortality.

A scalable sparse neural network framework for rare cell type annotation of single-cell transcriptome data.

Automatic cell type annotation methods are increasingly used in single-cell RNA sequencing (scRNA-seq) analysis due to their fast and precise advantages. However, current methods often fail to account for the imbalance of scRNA-seq datasets and ignore information from smaller populations, leading to significant biological analysis errors. Here, we introduce scBalance, an integrated sparse neural network framework that incorporates adaptive weight sampling and dropout techniques for auto-annotation tasks. Using 20 scRNA-seq datasets with varying scales and degrees of imbalance, we demonstrate that scBalance outperforms current methods in both intra- and inter-dataset annotation tasks. Additionally, scBalance displays impressive scalability in identifying rare cell types in million-level datasets, as shown in the bronchoalveolar cell landscape. scBalance is also significantly faster than commonly used tools and comes in a user-friendly format, making it a superior tool for scRNA-seq analysis on the Python-based platform.

Dulaglutide provides protection against sepsis-induced lung injury in mice by inhibiting inflammation and apoptosis.

Sepsis is a dangerous condition with a high mortality rate. In addition to promoting insulin secretion in a glucose-dependent manner, glucagon-like peptide-1 (GLP-1) also exhibits anti-inflammatory properties. Dulaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA). In this study, we investigated the effects and mechanism of action of dulaglutide (Dul) in lipopolysaccharide (LPS) induced lung injury in mice with sepsis. In mice with LPS (15 mg/kg, ip, qd)-induced acute lung injury, the administration of dulaglutide (0.6 mg/kg, ip, qd) improved weight loss, reduced lung injury, reversed the increase in IL-1ß, TNF-α, IL-6, CXCL1, CCL2 and CXCL2 expression in the lung, and reduced the infiltration of neutrophils and macrophages in the lung tissues. The decline in caspase-3, cleaved caspase-3, caspase-8, and Bcl-2/Bax expression and the increase in the number of TUNEL positive cells in the lung were reversed, suggesting that GLP-1RA could play a protective role in the lung by inhibiting inflammation and apoptosis. In addition, GLP-1RA could reduce the expression of P-STAT3 and NLRP3, suggesting that P-STAT3 and NLRP3 may be potential targets against lung injury in sepsis. Collectively, our data demonstrated that GLP-1RA exerts a protective effect against sepsis-induced lung injury through mechanisms related to the inhibition of inflammation, apoptosis, and STAT3 signaling.

Integrated analyzes identify CCT3 as a modulator to shape immunosuppressive tumor microenvironment in lung adenocarcinoma.

BACKGROUND: Chaperonin-containing tailless complex polypeptide 1 (TCP1) subunit 3 (CCT3) has tumor-promoting effects in lung adenocarcinoma (LUAD). This study aims to investigate the molecular mechanisms of CCT3 in LUAD oncogenesis. METHODS: The UALCAN databases, Human Protein Atlas (HPA) and The Cancer Genome Atlas (TCGA) data were used to analyze CCT3 expression in LUAD. Both the Wilcoxon rank-sum test and the regression model were used to investigate the connection between clinicopathologic characteristics of LUAD patients and CCT3 expression. The prognostic value of CCT3 was determined by Cox regression models, the Kaplan-Meier method and Nomogram prediction. Next, we identified the most related genes with CCT3 via GeneMANIA and String databases, and the association between CCT3 and infiltrated immune cells using single-sample Gene Set Enrichment Analysis (ssGSEA). CCT3-related pathway enrichment analysis was investigated by GSEA. Finally, CCT3 roles in cell proliferation and apoptosis of LUAD A549 cells was verified by siRNA (small interfering RNA) mediated CCT3 knockdown. RESULTS: CCT3 was upregulated in LUAD both in mRNA and protein levels. CCT3 overexpression was associated with clinicopathological characteristics including sex, smoking, T- and N-categories, pathological staging, and a poor prognosis of LUAD patients. GeneMANIA and String databases found a set of CCT3-related genes that are connected to the assembly and stability of proteins involved in proteostasis of cytoskeletal filaments, DNA repair and protein methylation. Furthermore, CCT3 was found to be positively correlated with the infiltrating Th2 cells (r = 0.442, p < 0.01) while negatively correlated with mast cells (r = -0.49, p < 0.01) and immature dendritic cells (iDCs, r = -0.401, p < 0.001) according to ssGSEA analyzes. The pathway analysis based on GSEA method showed that the cell cycle pathway, the protein export pathway, the proteasome pathway and the ribosome pathway are enriched in CCT3 high group, whereas the JAK/STAT pathway, B cell receptor pathway, T cell receptor pathway and toll like receptor pathway were enriched in CCT3 low group. Finally, CCT3 knockdown substantially inhibited proliferation while promoted apoptosis of A549 cells. CONCLUSION: Integrated analyzes identify CCT3 as a modulator to shape immunosuppressive tumor microenvironment in LUAD and therefore, a prognostic factor for LUAD.

Enzyme-Triggered Size-Switchable Nanosystem for Deep Tumor Penetration and Hydrogen Therapy.

The poor penetration of nanocarriers within tumor dense extracellular matrices (ECM) greatly restricts the access of anticancer drugs to the deep tumor cells, resulting in low therapeutic efficacy. Moreover, the high toxicity of the traditional chemotherapeutics inevitably causes undesirable side effects. Herein, taking the advantages of biosafe H2 and small-sized nanoparticles in diffusion within tumor ECM, we develop a matrix metalloprotease 2 (MMP-2) responsive size-switchable nanoparticle (UAMSN@Gel-PEG) that is composed of ultrasmall amino-modified mesoporous silica nanoparticles (UAMSN) wrapped within a PEG-conjugated gelatin to deliver H2 to the deep part of tumors for effective gas therapy. Ammonia borane (AB) is chosen as the H2 prodrug that can be effectively loaded into UAMSN by hydrogen-bonding adsorption. Gelatin is used as the substrate of MMP-2 to trigger size change and block AB inside UAMSN during blood circulation. PEG is introduced to further increase the particle size and endow the nanoparticle with long blood circulation to achieve effective tumor accumulation via the EPR effect. After accumulation into the tumor site, MMP-2 promptly digests gelatin to expose UAMSN loading AB for deep tumor penetration. Upon stimulation by the acidic tumor microenvironment, AB decomposes into H2 for further intratumor diffusion to achieve effective hydrogen therapy. Consequently, such a simultaneous deep tumor penetration of nanocarriers and H2 results in an evident suppression on tumor growth in a 4T1 tumor-bearing model without any obvious toxicity on normal tissues. Our synthetic nanosystem provides a promising strategy for the development of nanomedicines with enhanced tumor permeability and good biosafety for efficient tumor treatment.

Noninvasive diagnosis of oral squamous cell carcinoma by multi-level deep residual learning on optical coherence tomography images.

BACKGROUND: Oral Squamous Cell Carcinoma (OSCC) is one of the most severe cancers in the world, and its early detection is crucial for saving patients. There is an inevitable necessity to develop the automatic noninvasive OSCC diagnosis approach to identify the malignant tissues on Optical Coherence Tomography (OCT) images. METHODS: This study presents a novel Multi-Level Deep Residual Learning (MDRL) network to identify malignant and benign(normal) tissues from OCT images and trains the network in 460 OCT images captured from 37 patients. The diagnostic performances are compared with different methods in the image-level and the resected patch-level. RESULTS: The MDRL system achieves the excellent diagnostic performance, with 91.2% sensitivity, 83.6% specificity, 87.5% accuracy, 85.3% PPV, and 90.2% NPV in image-level, with 0.92 AUC value. Besides, it also implements 100% sensitivity, 86.7% specificity, 93.1% accuracy, 87.5% PPV, and 100% NPV in the resected patch-level. CONCLUSION: The developed deep learning system expresses superior performance in noninvasive oral squamous cell carcinoma diagnosis, compared with traditional CNNs and a specialist.

[Shenfu Injection improves chronic heart failure by regulating pyroptosis based on NLRP3/caspase-1 pathway].

This study investigated the mechanisms and targets of Shenfu Injection in the intervention in chronic heart failure(CHF) through the NOD-like receptor thermal protein domain associated protein 3(NLRP3)/caspase-1 signaling pathway. A CHF model was induced in rats by subcutaneous injection of isoproterenol. Model rats were randomly divided into a model group, a Shenfu Injection group, and a MCC950(NLRP3 inhibitor) group, and a blank group was also set up as a control. After 15 days of treatment, echocardiography was performed to measure cardiac function parameters [left ventricular ejection fraction(LVEF) and left ventricular fractional shortening(LVFS)]. Enzyme-linked immunosorbent assay(ELISA) was used to measure serum levels of N-terminal pro-brain natriuretic peptide(NT-proBNP), interleukin(IL)-1ß, and IL-18. Hematoxylin-eosin(HE) and Masson staining were used to observe morphological changes in myocardial tissues, and Western blot was used to measure the expression levels of NLRP3/caspase-1 pathway-related proteins [NLRP3, caspase-1, apoptosis-associated speck-like protein containing a CARD(ASC), gasdermin D(GSDMD), IL-1ß, and IL-18]. The study found that isoproterenol-induced CHF in rats resulted in decreased cardiac function, worsened myocardial fibrosis, increased expression levels of NLRP3, ASC, caspase-1, GSDMD-N, IL-1ß, and IL-18 in myocardial tissues, elevated serum inflammatory factors, and induced myocardial cell pyroptosis. Following Shenfu Injection intervention, the Shenfu Injection group showed significantly improved LVEF and LVFS, a significant decrease in NT-proBNP, a marked downregulation of NLRP3, ASC, caspase-1, GSDMD-N, IL-1ß, and IL-18 protein expression levels, reduced serum inflammatory factors IL-1ß and IL-18 expression in CHF rats, and a decrease in the rate of TUNEL-positive cells. Shenfu Injection can significantly improve cardiac function in CHF, inhibit myocardial fibrosis, and alleviate the progression of myocardial cell pyroptosis through the inhibition of the NLRP3/caspase-1 pathway.