Involvement of microglia-expressed MS4A6A in the onset of glioblastoma.

Glioblastoma multiforme (GBM) represents the deadliest form of brain tumour, characterized by its low survival rate and grim prognosis. Cytokines released from glioma-associated microglia/macrophages are involved in establishing the tumour microenvironment, thereby crucially promoting GBM progression. MS4A6A polymorphism was confirmed to be associated with neurodegenerative and polymorphism disease pathobiology, but whether it participates in the regulation of GBM and the underlying mechanisms is still not elucidated. Here, we found that MS4A6A was significantly upregulated in GBM patient samples. The results from the single-cell RNA-sequencing (scRNA-seq) database and immunostaining demonstrated the specific expression of MS4A6A in microglial cells. In vitro, microglial overexpression of MS4A6A stimulated the proliferation and migration of glioblastoma cells. Moreover, high MS4A6A mRNA expression was related to poor prognosis in GBM patients. Our study highlights the potential of MS4A6A as a promising biomarker for GBM, which may provide novel strategies for its prevention, diagnosis and treatment.

Enhanced Phosphorescence of Carbon Nanodots via Double Confinement for 3D Artworks with Long Emission Lifetimes.

Phosphorescent materials as block elements to build artwork incorporating the time and emission, enable them with spectacular lighting effects. In this work, enhanced phosphorescence of carbon nanodots (CNDs) is demonstrated via double confinement strategy, which silica and epoxy resin are used as the first and the second order confinement layer. The multi-confined CNDs show an enhanced phosphorescence quantum yield up to 16.4%, with enduring emission lifetime up to 1.44 s. Delicately, the plasticity of the epoxy resin enables them easily to be designed for 3D artworks with long emission lifetimes in different shapes. The efficient and eco-friendly phosphorescent CNDs may arouse intense interest both in the academic community and markets.

EGFR-Targeted Liposomes Combined with Ginsenoside Rh2 Inhibit Triple-Negative Breast Cancer Growth and Metastasis.

Triple-negative breast cancer (TNBC) remains the most challenging breast cancer subtype due to its lack of targeted therapies and poor prognosis. In order to treat patients with these tumors, efforts have been made to explore feasible targets. Epidermal growth factor receptor (EGFR)-targeted therapy is currently in clinical trials and regarded to be a promising treatment strategy. In this study, an EGFR-targeting nanoliposome (LTL@Rh2@Lipo-GE11) using ginsenoside Rh2 as a wall material was developed, in which GE11 was used as the EGFR-binding peptide to deliver more ginsenoside Rh2 and luteolin into TNBC. In comparison to non-targeted liposomes (Rh2@Lipo and LTL@Rh2@Lipo), the nanoliposomes LTL@Rh2@Lipo-GE11 demonstrated a high specificity to MDA-MB-231 cells that expressed a high level of EGFR both in vitro and in vivo, contributing to the strong inhibitory effects on the growth and migration of TNBC. These results suggest that LTL@Rh2@Lipo-GE11 is a prospective candidate for targeted therapy of TNBC, with a remarkable capability to inhibit tumor development and metastasis.

Deep learning radiomics of multimodal ultrasound for classifying metastatic cervical lymphadenopathy into primary cancer sites: a feasibility study.

PURPOSE: To investigate the feasibility of deep learning radiomics (DLR) based on multimodal ultrasound to differentiate the primary cancer sites of metastatic cervical lymphadenopathy (CLA). MATERIALS AND METHODS: This study analyzed 280 biopsy-confirmed metastatic CLAs from 280 cancer patients, including 54 from head and neck squamous cell carcinoma (HNSCC), 58 from thyroid cancer (TC), 92 from lung cancer (LC), and 76 from gastrointestinal cancer (GIC). Before biopsy, patients underwent conventional ultrasound (CUS), ultrasound elastography (UE), and contrast-enhanced ultrasound (CEUS). Based on CUS, DLR models using CUS, CUS+UE, CUS+CEUS, and CUS+UE+CEUS data were developed and compared. The best model was integrated with key clinical indicators selected by univariate analysis to achieve the best classification performance. RESULTS: All DLR models achieved similar performance with respect to classifying four primary tumor sites of metastatic CLA (AUC:0.708~0.755). After integrating key clinical indicators (age, sex, and neck level), the US+UE+CEUS+clinical model yielded the best performance with an overall AUC of 0.822 in the validation cohort, but there was no significance compared with the basal CUS+clinical model (P>0.05), both of which identified metastasis from HNSCC, TC, LC, and GIC with 0.869 and 0.911, 0.838 and 0.916, 0.750 and 0.610, and 0.829 and 0.769, respectively. CONCLUSION: The ultrasound-based DLR model can be used to classify the primary cancer sites of metastatic CLA, and the CUS combined with clinical indicators is adequate to provide a high discriminatory performance. The addition of the combination of UE and CEUS data is expected to further improve performance.

Effects of optical and radar satellite observations within Google Earth Engine on soil organic carbon prediction models in Spain.

The modeling and mapping of soil organic carbon (SOC) has advanced through the rapid growth of Earth observation data (e.g., Sentinel) collection and the advent of appropriate tools such as the Google Earth Engine (GEE). However, the effects of differing optical and radar sensors on SOC prediction models remain uncertain. This research aims to investigate the effects of different optical and radar sensors (Sentinel-1/2/3 and ALOS-2) on SOC prediction models based on long-term satellite observations on the GEE platform. We also evaluate the relative impact of four synthetic aperture radar (SAR) acquisition configurations (polarization mode, band frequency, orbital direction and time window) on SOC mapping with multiband SAR data from Spain. Twelve experiments involving different satellite data configurations, combined with 4027 soil samples, were used for building SOC random forest regression models. The results show that the synthesis mode and choice of satellite images, as well as the SAR acquisition configurations, influenced the model accuracy to varying degrees. Models based on SAR data involving cross-polarization, multiple time periods and "ASCENDING" orbits outperformed those involving copolarization, a single time period and "DESCENDING" orbits. Moreover, combining information from different orbital directions and polarization modes improved the soil prediction models. Among the SOC models based on long-term satellite observations, the Sentinel-3-based models (R2 = 0.40) performed the best, while the ALOS-2-based model performed the worst. In addition, the predictive performance of MSI/Sentinel-2 (R2 = 0.35) was comparable with that of SAR/Sentinel-1 (R2 = 0.35); however, the combination (R2 = 0.39) of the two improved the model performance. All the predicted maps involving Sentinel satellites had similar spatial patterns that were higher in northwest Spain and lower in the south. Overall, this study provides insights into the effects of different optical and radar sensors and radar system parameters on soil prediction models and improves our understanding of the potential of Sentinels in developing soil carbon mapping.

Multifunctional Modulation of High-Performance Znx Fe3-x O4 Nanoparticles by Precisely Tuning the Zinc Doping Content.

The possibility to precisely control important properties of nanoparticles (NPs) such as their size, morphology, surface charge, or doping content is crucial for enhancing the performance of existing solutions beyond the state-of-the-art and for enabling novel applications. In this work, custom-tailored Znx Fe3- x O4 NPs are synthesized at different Zn doping concentrations to augment and expand their usefulness for high-performance applications in nanomedicine. By precisely increasing the Zn2+ content in the range of 0 ≤ x ≤ 2.0, the discussed NPs can sequentially acquire valuable properties enabling magnetic resonance imaging, near-infrared (NIR) photothermal effects, NIR photocatalytic and photoelectric effects, depending on the variation of substitution position of the Zn2+ in the magnetite structure and the emergence of a ZnO/ZnFe2 O4 heterostructure at high doping concentrations. The presented work demonstrates and explainsa facile route for the synthesis and modulation of multifunctional nanomaterials with manifold roles in disease diagnostics and therapy, and provides helpful guidance in designing divalent transition metal ion-doped nanomaterials.

Exploring the relationship between autophagy and Gefitinib resistance in NSCLC by silencing PDLIM5 using ultrasound-targeted microbubble destruction technology.

BACKGROUND: Ultrasound-targeted microbubble destruction (UTMD) technology is a new drug and gene delivery strategy. This study investigates novel ultrasound (US) sensitive siRNA-loaded nanobubbles (siRNA-NBs) to explore the relationship between PDLIM5 mediated autophagy and drug resistance development using epidermal growth factor tyrosine kinase inhibitors (EGFR-TKIs) in the treatment of non-small cell lung cancer (NSCLC). METHODS: US sensitive siRNA-NBs were designed to inhibit the expression of PDLIM5 in gefitinib-resistant human NSCLC PC9GR cells in vitro. The expression of autophagy-related proteins (P62 and LC3-II/I) and autophagosomes in PC9GR cells after PDLIM5 gene silencing were explored. RESULTS: US-sensitive PDLIM5-targeted siRNA-NBs were effectively delivered into PC9GR cells, inhibiting PDLIM5 expression, increasing LC3-II/I and p62 expressions and increasing autophagosomes in PC9GR cells in vitro. CONCLUSIONS: Using UTMD, US-sensitive siRNA-NBs have the potential as an ideal delivery vector to mediate highly effective RNA interference for NSCLC cells. Furthermore, PDLIM5 plays a role in the autophagy-mediated resistance in gefitinib-resistant PC9GR cells.

LINC_00355 promotes gastric cancer progression by upregulating PHF19 expression through sponging miR-15a-5p.

BACKGROUND: Long non-coding RNAs exert vital roles in several types of cancer. The objective of this study was to explore the role of LINC_00355 in gastric cancer (GC) progression and its potential mechanism. METHODS: The expression levels of LINC_00355 in GC tissues and cells were detected by quantitative real-time PCR, followed by assessing the effects of LINC_00355 knockdown or overexpression on cell properties. Dual-luciferase reporter assay was utilized to identify the relationship between LINC_00355 and microRNA (miR)-15a-5p and miR-15a-5p and PHD finger protein 19 (PHF19), followed by the rescue experiments. RESULTS: The results showed that LINC_00355 was highly expressed in GC tissues and cells compared with the corresponding control. LINC_00355 knockdown decreased the viability, migration, and invasion and increased the accumulation of GC cells in G1 phase and apoptosis. Meanwhile, LINC_00355 downregulation markedly increased cleaved caspase 3 and cleaved poly (ADP-ribose) polymerase protein levels, whereas decreased cyclin D1, cyclin E, matrix metalloproteinase (MMP) 9, MMP2, and N-cadherin protein levels in GC cells. However, LINC_00355 overexpression had the opposite effects. It was verified that LINC_00355 upregulated the expression of PHF19 through sponging miR-15a-5p. Furthermore, PHF19 overexpression reversed the effect of LINC_00355 knockdown on GC cell properties, including cell viability, migration, invasion, and apoptosis. CONCLUSIONS: Collectively, these results suggest that LINC_00355 promotes GC progression by up-regulating PHF19 through sponging miR-15a-5p. Our findings may provide an important clinical basis for reversing the malignant phenotype of GC.

Efficacy and safety of endoscopic submucosal tunnel dissection for superficial esophageal squamous cell carcinoma: a propensity score matching analysis.

BACKGROUND AND AIMS: Esophageal endoscopic submucosal dissection (ESD) is technically challenging because of the thinner wall and narrow lumen. The tunnel technique was proposed previously. This current retrospective study aimed to evaluate the efficacy of the tunnel technique in ESD of superficial esophageal squamous cell carcinoma (ESCC). METHODS: Patients who underwent ESD for superficial ESCC between October 2013 and September 2015 were included in the study. Propensity score matching was used to compensate for the differences in age, sex, resected specimen size, and pathology. Treatment outcomes were compared with conventional statistic methods between the tunnel ESD group and conventional ESD group after matching. To further explore the potential variables relevant to procedure time, univariate and multivariate logistic regression analyses were applied. RESULTS: A total of 115 lesions were included in the analysis. Propensity score matching analysis created 38 matched pairs. There was no difference on en bloc resection rate, complete resection rate, and curative rate between the 2 groups. The ESD procedure time was 38.0 (range 29.5-46.0) minutes in the tunnel ESD group and 48.0 (35.4-83.3) minutes in the conventional ESD group (P = .006). There was no difference in adverse events including postprocedural bleeding, perforation, and chest pain, but a lower rate of muscular injury (28.9% vs 52.6%; P = .036) and a less-frequent use of coagulation forceps (36.8% vs 65.8%; P = .012) were shown in the tunnel ESD group. In multivariate regression analysis for procedure time, the tunnel ESD technique (odds ratio [OR] 3.42; 95% confidence interval [CI], 1.32-8.85; P = .011) and specimen size <40 mm (OR 8.74; 95% CI, 1.30-58.5; P = .026) were associated with a shorter procedure time. CONCLUSIONS: The endoscopic submucosal tunnel dissection improved the efficacy and safety of the ESD procedure by shortening the procedure time and reducing injury to the muscular layer.

Identification of disulfidptosis- and ferroptosis-related transcripts in periodontitis by bioinformatics analysis and experimental validation.

Background: Disulfidptosis and ferroptosis are forms of programmed cell death that may be associated with the pathogenesis of periodontitis. Our study developed periodontitis-associated biomarkers combining disulfidptosis and ferroptosis, which provides a new perspective on the pathogenesis of periodontitis. Methods: Firstly, we obtained the periodontitis dataset from public databases and found disulfidptosis- and ferroptosis-related differentially expressed transcripts based on the disulfidptosis and ferroptosis transcript sets. After that, transcripts that are tissue biomarkers for periodontitis were found using three machine learning methods. We also generated transcript subclusters from two periodontitis microarray datasets: GSE16134 and GSE23586. Furthermore, three transcripts with the best classification efficiency were further screened. Their expression and classification efficacy were validated using qRT-PCR. Finally, periodontal clinical indicators of 32 clinical patients were collected, and the correlation between three transcripts above and periodontal clinical indicators was analyzed. Results: We identified six transcripts that are tissue biomarkers for periodontitis, the top three transcripts with the best classification, and delineated two expression patterns in periodontitis. Conclusions: Our study found that disulfidptosis and ferroptosis were associated with immune responses and may involve periodontitis genesis.

Moderating effect of negative emotion differentiation in chronic stress and fatigue among Chinese employees.

Introduction: According to the reactivity hypothesis and the diathesis-stress model, repeated activation of the stress system has a negative effect on health, and this effect may differ because of individual characteristics. Thus, the present study explores the effect of chronic stress on fatigue and investigates its mechanism. Methods: A questionnaire survey of 288 participants selected from the northwest part of China was conducted (13.89% females; ages ranged from 18 to 34 years, with M ± SD = 23.14 ± 3.79 years) on chronic stress, fatigue, depression, anxiety, and negative emotion differentiation. SPSS 28.0 was used to process descriptive statistics and correlation analysis and the PROCESS macro was used to analyze the moderated chained multi-mediation. Results: Chronic stress was found to be positively correlated with fatigue, depression, and anxiety; depression and anxiety played a chained multi-mediating role between chronic stress and fatigue, and negative emotion differentiation played a moderating role in the chained multi-mediation model. Discussion: Compared with depression, anxiety plays a more important role in the influence of chronic stress on fatigue. Therefore, it is necessary to pay more attention to anxiety symptoms and take appropriate intervention measures. Negative emotion differentiation plays a moderating role. Improving negative emotion differentiation through mindfulness and adaptive emotion regulation is an effective way to reduce the influence of chronic stress on fatigue.

Clinical efficacy evaluation of the implantation of a diffractive trifocal intraocular lens in high myopia eyes: Two-year follow-up.

PURPOSE: To evaluate the long-term subjective and objective visual quality after implantation of a diffractive trifocal intraocular lens (IOL) in high myopic eyes. METHODS: A total of 53 eyes from 38 patients with high myopia who underwent phacoemulsification and trifocal IOL implantation were investigated. The visual acuity, contrast sensitivity, diopter, defocus curve, and objective visual quality at 1 month, 3 months, 1 year, and 2 years after surgery, as well as the satisfaction questionnaire and VF-14 scale, were statistically analyzed. RESULTS: The average age was 53.14 ± 4.70 years. The average preoperative spherical equivalent was -10.77 ± 3.98 D. Two years after surgery, 94.3% of the patients achieved an uncorrected distance visual acuity of 0.1 (LogMAR), and 84.9% and 94.3% of the patients had SE within ±0.50 D and ±1.0 D, respectively. The defocus curve was smooth and at a high value within the range of 0 D to -2.50 D. In CS or objective visual quality, there was no significant difference at 3 months, 1 year, and 2 years after operation (all P > 0.05). The rate of spectacle independence was 100%. The proportion of patients with moderate or severe glare and halo was 10.5% and 13.2%, respectively. Furthermore, 23.7%, 26.3%, and 18.4% of the patients had difficulties in reading small font, doing delicate tasks, and driving or riding at night, respectively. CONCLUSION: The diffractive trifocal IOL implantation provided good distance, intermediate, and near uncorrected visual acuity for patients with cataracts and high myopia. It was safe, effective, predictable, and stable. It provided long-term good visual quality after surgery, with high spectacle independence and high patient satisfaction.

COSTA: A Multi-center TOF-MRA Dataset and A Style Self-Consistency Network for Cerebrovascular Segmentation.

Time-of-flight magnetic resonance angiography (TOF-MRA) is the least invasive and ionizing radiation-free approach for cerebrovascular imaging, but variations in imaging artifacts across different clinical centers and imaging vendors result in inter-site and inter-vendor heterogeneity, making its accurate and robust cerebrovascular segmentation challenging. Moreover, the limited availability and quality of annotated data pose further challenges for segmentation methods to generalize well to unseen datasets. In this paper, we construct the largest and most diverse TOF-MRA dataset (COSTA) from 8 individual imaging centers, with all the volumes manually annotated. Then we propose a novel network for cerebrovascular segmentation, namely CESAR, with the ability to tackle feature granularity and image style heterogeneity issues. Specifically, a coarse-to-fine architecture is implemented to refine cerebrovascular segmentation in an iterative manner. An automatic feature selection module is proposed to selectively fuse global long-range dependencies and local contextual information of cerebrovascular structures. A style self-consistency loss is then introduced to explicitly align diverse styles of TOF-MRA images to a standardized one. Extensive experimental results on the COSTA dataset demonstrate the effectiveness of our CESAR network against state-of-the-art methods. We have made 6 subsets of COSTA with the source code online available, in order to promote relevant research in the community.

Ferroptosis biomarkers predict tumor mutation burden's impact on prognosis in HER2-positive breast cancer.

BACKGROUND: Ferroptosis has recently been associated with multiple degenerative diseases. Ferroptosis induction in cancer cells is a feasible method for treating neoplastic diseases. However, the association of iron proliferation-related genes with prognosis in HER2+ breast cancer (BC) patients is unclear. AIM: To identify and evaluate fresh ferroptosis-related biomarkers for HER2+ BC. METHODS: First, we obtained the mRNA expression profiles and clinical information of HER2+ BC patients from the TCGA and METABRIC public databases. A four-gene prediction model comprising PROM2, SLC7A11, FANCD2, and FH was subsequently developed in the TCGA cohort and confirmed in the METABRIC cohort. Patients were stratified into high-risk and low-risk groups based on their median risk score, an independent predictor of overall survival (OS). Based on these findings, immune infiltration, mutations, and medication sensitivity were analyzed in various risk groupings. Additionally, we assessed patient prognosis by combining the tumor mutation burden (TMB) with risk score. Finally, we evaluated the expression of critical genes by analyzing single-cell RNA sequencing (scRNA-seq) data from malignant vs normal epithelial cells. RESULTS: We found that the higher the risk score was, the worse the prognosis was (P < 0.05). We also found that the immune cell infiltration, mutation, and drug sensitivity were different between the different risk groups. The high-risk subgroup was associated with lower immune scores and high TMB. Moreover, we found that the combination of the TMB and risk score could stratify patients into three groups with distinct prognoses. HRisk-HTMB patients had the worst prognosis, whereas LRisk-LTMB patients had the best prognosis (P < 0.0001). Analysis of the scRNA-seq data showed that PROM2, SLC7A11, and FANCD2 were significantly differentially expressed, whereas FH was not, suggesting that these genes are expressed mainly in cancer epithelial cells (P < 0.01). CONCLUSION: Our model helps guide the prognosis of HER2+ breast cancer patients, and its combination with the TMB can aid in more accurate assessment of patient prognosis and provide new ideas for further diagnosis and treatment.

Ultrasound-Mediated PLGA-PEI Nanobubbles Carrying STAT6 SiRNA Enhances NSCLC Treatment via Repolarizing Tumor-associated Macrophages from M2 to M1 Phenotypes.

BACKGROUND: Tumor-associated macrophages (TAMs) are crucial for non-small cell lung cancer (NSCLC) development. OBJECTIVE: In this study, polylactic acid-co-glycolic acid (PLGA)-polyethylenimine (PEI) nanobubbles (NBs) carrying STAT6 siRNA were prepared and combined with ultrasound-mediated nanobubbles destruction (UMND) to silence the STAT6 gene, ultimately repolarizing TAMs from the M2 to the M1 phenotype, treating NSCLC in vitro. METHODS: PLGA-PEI NBs-siRNA were prepared and characterised, and their respective ultrasound imaging, biological stabilities and cytotoxicities were detected. Transfection efficiency was evaluated by fluorescence microscopy and flow cytometry. Repolarization of THP-1-derived M2-like macrophages was determined by qPCR and flow cytometry. NSCLC cells (A549) were co-cultured with transfected M2-like macrophages or their associated conditioned medium (CM). Western blotting was used to detect STAT6 gene silencing in M2-like macrophages and markers of epithelial and mesenchymal in A549 cells. The proliferation of A549 cells was detected using CCK-8 and cell colony formation assays. Transwell assays were used to detect the migration and invasion of A549 cells. RESULTS: PLGA-PEI NBs-siRNA had an average size of 223.13±0.92nm and a zeta potential of about -5.59±0.97 mV. PLGA-PEI NBs showed excellent ultrasonic imaging capability in addition to biological stability to protect siRNA from degradation. UMND enhanced PLGA-PEI NBs-STAT6 siRNA transfection in M2-like macrophages, which made M2-like macrophages repolarize to M1-like macrophages and prevented proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) in A549 cells. CONCLUSION: UMND enhanced PLGA-PEI NBs-STAT6 siRNA to repolarize TAMs from the M2 to the M1 phenotype, thus treating NSCLC. These findings provide a promising therapeutic approach for enhancing NSCLC immunotherapy.

The Role of XBP1 in bone metabolism.

Bone is a dynamic organ that, once formed, undergoes a constant remodeling process that includes bone resorption and synthesis. Osteoclasts and osteoblasts are primarily responsible for controlling this process. X-box binding protein 1 (XBP1), a transcription factor, affects the metabolism of bones in various ways. In recent years, numerous studies have revealed that XBP1 plays a vital role in bone metabolism, including osteoclast and osteoblast development, as well as in regulating immune cell differentiation that affects the immune microenvironment of bone remodeling. In this review, we highlight the regulatory mechanisms of XBP1 on osteoclasts and osteoblasts, how XBP1 affects the immune microenvironment of bone remodeling by influencing the differentiation of immune cells, and predict the possible future research directions of XBP1 to provide new insights for the treatment of bone-related metabolic diseases.

Ultrasound-mediated mesoporous silica nanoparticles loaded with PDLIM5 siRNA inhibit gefitinib resistance in NSCLC cells by attenuating EMT.

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKIs) was one of the main drugs in the treatment of non-small cell lung cancer (NSCLC). Previous studies had demonstrated that PDZ and LIM Domain 5 (PDLIM5) played an important role in EGFR TKIs resistance. However, there was no feasible method to eliminate EGFR TKIs resistance by suppressing this gene. Here, we formulated a novel mesoporous silica-loaded PDLIM5 siRNA (Small interfering RNA) nanoplatforms. The results have shown that PDLIM5 siRNA could be effectively bound to the nanoplatforms and had good biocompatibility. Further exploration suggested that the nano-platform combined with ultrasonic irradiation could be very effective for siRNA delivery and ultrasound imaging. Moreover, Epithelial-mesenchymal transformation (EMT) changes occurred in PC-9 Gefitinib resistance (PC-9/GR) cells during the development of drug resistance. When PDLIM5 siRNA entered PC-9/GR cells, the sensitivity of drug-resistant cells to gefitinib could be restored through the transforming growth factor-ß (TGF-ß)/EMT pathway. Therefore, PDLIM5 may be an important reason for the resistance of NSCLC cells to gefitinib, and this nanoplatform may become a novel treatment for EGFR TKIs resistance in NSCLC patients.

cRGD-targeted gold-based nanoparticles overcome EGFR-TKI resistance of NSCLC via low-temperature photothermal therapy combined with sonodynamic therapy.

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is a first-line targeted drug for the treatment of advanced non-small cell lung cancer (NSCLC) in clinical practice, but EGFR-TKI-acquired resistance limits its therapeutic effect. To address this challenge, a novel multifunctional gold-based targeted nanoparticle-based drug delivery system is fabricated. The gold-based nanoparticle is loaded with the EGFR-TKI (gefitinib) and IR780, and the surface-modified gold nanoshell layer has a photothermal effect for thermally triggered drug release. Finally, the unique binding of cyclic arginine-glycine-aspartic acid (cRGD) to the αvß3 receptor ensured that the nanoparticle (cRGD-GIPG) targeted transport into drug-resistant NSCLC cells was functional. Due to the sonodynamic properties of IR780, ultrasound (US) irradiation promoted reactive oxygen species (ROS) generation, while low-temperature photothermal therapy (PTT) not only promoted the release of drug, but also further enhanced the cytotoxic effects of ROS. In turn, it blocked the activation of TGF-ß/PDLIM5/SMAD resistance pathway and induced apoptosis of drug-resistant cells through mitochondrial apoptosis, enabling the treatment of EGFR-TKI-resistant NSCLC. The low-temperature PTT combined with sonodynamic therapy (SDT) by cRGD-GIPG thus shows potent anticancer activity against EGFR-TKI-resistant NSCLC cells in vitro and in vivo. The present work provides a valuable strategy for highly targeted and EGFR-TKI-resistant reversal therapy in NSCLC.

Poly-l-lactide-co-ε-caprolactone (PLCL) and poly-l-lactic acid (PLLA)/gelatin electrospun subacromial spacer improves extracellular matrix (ECM) deposition for the potential treatment of irreparable rotator cuff tears.

Biodegradable subacromial spacer implantation has become practicable for the treatment of irreparable rotator cuff tears (IRCT). However, the relative high degradation rate and inferior tissue regeneration properties of current subacromial spacer may lead to failure regards to long-term survival. It is reported that satisfactory clinical results lie in the surrounding extracellular matrix (ECM) deposition after implantation. This study aims to develop a biological subacromial spacer that would enhance tissue regeneration properties and results in better ECM deposition. Physicochemical properties were characterized on both poly-l-lactide-co-ε-caprolactone (PLCL) dip-coating spacer (monolayer spacer, MS) and PLCL dip-coating + Poly-l-Lactic Acid (PLLA)/Gelatin electrospun spacer (Bilayer Spacer, BS). Cytocompatibility, angiogenesis, and collagen inducibility were evaluated with tendon fibroblasts and endothelial cells. Ultrasonography and histomorphology were used to analyze biodegradability and surrounding ECM deposition after the implantation in vivo. BS was successfully fabricated with the dip-coating and electrospinning technique, based on the human humeral head data. In vitro studies demonstrated that BS showed a greater cytocompatibility, and increased secretion of ECM proteins comparing to MS. In vivo studies indicated that BS promoted ECM deposition and angiogenesis in the surrounding tissue. Our research highlights that BS exhibits better ECM deposition and reveals a potential candidate for the treatment of IRCT in future.