Greatly isolated heterogeneous circulating tumor cells using hybrid engineered cell membrane-camouflaged magnetic nanoparticles.

BACKGROUND: Circulating tumor cells (CTCs) are considered as a useful biomarker for early cancer diagnosis, which play a crucial role in metastatic process. Unfortunately, the tumor heterogeneity and extremely rare occurrence rate of CTCs among billions of interfering leukocytes seriously hamper the sensitivity and purity of CTCs isolation. METHODS: To address these, we firstly used microfluidic chips to detect the broad-spectrum of triple target combination biomarkers in CTCs of 10 types of cancer patients, including EpCAM, EGFR and Her2. Then, we constructed hybrid engineered cell membrane-camouflaged magnetic nanoparticles (HE-CM-MNs) for efficient capture of heterogeneous CTCs with high-purity, which was enabled by inheriting the recognition ability of HE-CM for various CTCs and reducing homologous cell interaction with leukocytes. Compared with single E-CM-MNs, HE-CM-MNs showed a significant improvement in the capture efficiency for a cell mixture, with an efficiency of 90%. And the capture efficiency of HE-CM-MNs toward 12 subpopulations of tumor cells was ranged from 70 to 85%. Furthermore, by using HE-CM-MNs, we successfully isolated heterogeneous CTCs with high purity from clinical blood samples. Finally, the captured CTCs by HE-CM-MNs could be used for gene mutation analysis. CONCLUSIONS: This study demonstrated the promising potential of HE-CM-MNs for heterogeneous CTCs detection and downstream analysis.

Accurate prediction of myopic progression and high myopia by machine learning.

Background: Myopia is a leading cause of visual impairment in Asia and worldwide. However, accurately predicting the progression of myopia and the high risk of myopia remains a challenge. This study aims to develop a predictive model for the development of myopia. Methods: We first retrospectively gathered 612 530 medical records from five independent cohorts, encompassing 227 543 patients ranging from infants to young adults. Subsequently, we developed a multivariate linear regression algorithm model to predict the progression of myopia and the risk of high myopia. Result: The model to predict the progression of myopia achieved an R2 value of 0.964 vs a mean absolute error (MAE) of 0.119D [95% confidence interval (CI): 0.119, 1.146] in the internal validation set. It demonstrated strong generalizability, maintaining consistent performance across external validation sets: R2 = 0.950 vs MAE = 0.119D (95% CI: 0.119, 1.136) in validation study 1, R2 = 0.950 vs MAE = 0.121D (95% CI: 0.121, 1.144) in validation study 2, and R2 = 0.806 vs MAE = -0.066D (95% CI: -0.066, 0.569) in the Shanghai Children Myopia Study. In the Beijing Children Eye Study, the model achieved an R2 of 0.749 vs a MAE of 0.178D (95% CI: 0.178, 1.557). The model to predict the risk of high myopia achieved an area under the curve (AUC) of 0.99 in the internal validation set and consistently high area under the curve values of 0.99, 0.99, 0.96 and 0.99 in the respective external validation sets. Conclusion: Our study demonstrates accurate prediction of myopia progression and risk of high myopia providing valuable insights for tailoring strategies to personalize and optimize the clinical management of myopia in children.

Safety factor diagnostic for tokamak core plasma from three-dimensional reconstruction of pellet ablation trail.

Using a stereo camera system, a new diagnostic for the safety factor of the core plasma based on the pellet ablation trail is applied on the Experimental Advanced Superconducting Tokamak (EAST). In EAST discharge No. 128 874, a shattered pellet injection system is applied to inject a shattered neon pellet into the EAST. Since the strong magnetic field in tokamaks binds the ablated pellet material, the orientation of the pellet ablation trail is the same as the local magnetic field direction. Thus, from the three-dimensional reconstruction result of the pellet ablation trail, the local safety factor q can be obtained. The motional Stark effect (MSE) diagnostic is applied to determine the safety factor q profile in this shot. The determined safety factor q results for this new diagnostic are in quantitative agreement with those from the MSE diagnostic with the mean relative difference of only 6.8%, confirming the effectiveness of this new diagnostic of the safety factor.

Effect of parenting style on the emotional and behavioral problems among Chinese adolescents: the mediating effect of resilience.

BACKGROUND: Although previous studies have found that parenting style significantly predicts emotional and behavioral problems (EBPs) among Chinese adolescents, the mechanism between different parenting styles and EBPs requires in-depth investigation. In our study, we aimed to investigate the mediating effect of resilience, a positive psychological characteristic, between parenting style and EBPs among Chinese adolescents. METHODS: In this cross-sectional study, we used a multistage stratified cluster random sampling method to collect data in Shenyang, Liaoning Province from November to December 2019. Self-developed questionnaires were distributed to 1028 adolescents aged 10-18. Finally, the study consisted of 895 participants. The bootstrap method was used to investigate the role of resilience as a mediator in the relationship between different parenting styles and EBPs from a positive psychology perspective. RESULTS: The mean score of EBPs was 12.71 (SD = 5.77). After controlling for variables such as gender, age, left-behind children, family type and family income, resilience partially played a mediating role in the associations of paternal rejection (a × b = 0.051 BCa95%CI:0.023,0.080), maternal rejection (a × b = 0.055 BCa95%CI: 0.024, 0.086), paternal emotional warmth (a × b = -0.139 BCa95%CI: -0.182, -0.099) and maternal emotional warmth (a × b = -0.140 BCa95%CI: -0.182, -0.102), with EBPs. The effect sizes were11.28%, 11.51%, 40.76%, and 38.78%, respectively. CONCLUSIONS: Resilience could partially mediate the relationship between parenting style and EBPs, highlighting that parents should adopt a positive parenting style and that resilience improvement could be effective in reducing EBPs among Chinese adolescents.

Oncolytic mineralized bacteria as potent locally administered immunotherapeutics.

Oncolytic bacteria can trigger innate immune activity. However, the antitumour efficacy of inactivated bacteria is poor, and attenuated live bacteria pose substantial safety risks. Here we show that intratumourally injected paraformaldehyde-fixed bacteria coated with manganese dioxide potently activate innate immune activity, modulate the immunosuppressive tumour microenvironment and trigger tumour-specific immune responses and abscopal antitumour responses. A single intratumoural administration of mineralized Salmonella typhimurium suppressed the growth of multiple types of subcutaneous and orthotopic tumours in mice, rabbits and tree shrews and protected the cured animals against tumour rechallenge. We also show that mineralized bacteria can be administered via arterial embolization to treat orthotopic liver cancer in rabbits. Our findings support the further translational testing of oncolytic mineralized bacteria as potent and safe antitumour immunotherapeutics.

Comparative analysis of robotically-assisted versus conventional sternotomy approach in left atrial myxoma resection: A single-center retrospective observational study.

BACKGROUND: Minimally invasive surgery has emerged as a favorable alternative to conventional surgery for various cardiac conditions. This study aimed to compare the perioperative outcomes and follow-up results of the robotic approach versus the sternotomy approach for left atrial myxoma (LAM) resection. METHOD: We retrospectively analyzed the perioperative outcomes and follow-up results of 94 patients who underwent left atrial myxoma resection using either the sternotomy approach (n = 64) or the robotic approach (n = 30) at our center between January 2017 and April 2023. Multiple linear regressions were employed to examine the actual impact of the surgical approach on perioperative outcomes while controlling for potential confounding factors. RESULTS: There were no in-hospital deaths or follow-up deaths in the robotic group. Univariate analyses revealed that robotic LAM resection had a longer cardiopulmonary bypass (CPB) time (99.93 ± 22.30 vs. 76.28 ± 24.92, P < 0.001), longer aortic clamping time (57.80 ± 20.27 vs. 47.89 ± 18.10, P = 0.019), reduced postoperative drainage (P < 0.001), shorter mechanical ventilation time (P = 0.005), shorter postoperative bed-stay time (P < 0.001), shorter postoperative hospitalization time (P = 0.040), and higher hospital costs (P = 0.001) compared to the sternotomy group. After adjusting for baseline characteristics in a multiple regression model, a longer CPB time (B = 28.328; CI, 18.609-38.047; P < 0.001), longer aortic clamping time (B = 11.856; CI, 4.069-19.644; P = 0.003), reduced postoperative drainage (B = -200.224; CI, -254.962- -145.486; P < 0.001), shorter mechanical ventilation time (B = -3.429; CI, -6.562- -0.295; P = 0.032), shorter postoperative bed-stay time (B = -2.230; CI, -3.267- -1.193; P < 0.001), shorter postoperative hospitalization time (B = -1.998; CI, -3.747- -0.250; P = 0.026), and higher hospital costs (B = 2096.866, P = 0.002) were found in the robotic group. Furthermore, the robotic group exhibited a faster return to exercise compared to the sternotomy group (Log-Rank χ2 = 34.527, P < 0.001). CONCLUSION: Both the robotic and sternotomy approaches are viable and safe options for LAM resection. However, despite the higher costs, longer CPB time, and longer aortic clamping time associated with robotic LAM resection, this technique was correlated with reduced postoperative drainage and faster postoperative recovery compared to the sternotomy technique.

ACADL-YAP axis activity in non-small cell lung cancer carcinogenicity.

BACKGROUND: The role of Acyl-CoA dehydrogenase long chain (ACADL) in different tumor types had different inhibiting or promoting effect. However, its role in non-small cell lung cancer (NSCLC) carcinogenicity is not clear. METHOD: In this study, we utilized The Cancer Genome Atlas (TCGA) database to analyze ACADL expression in NSCLC and its correlation with overall survival. Furthermore, we investigated the function of ACADL on cellular proliferation, invasion, colony, apoptosis, cell cycle in vitro with NSCLC cells. Mechanistically, we evaluated the regulatory effect of ACADL expression on its downstream factor yes-associated protein (YAP) by assessing YAP phosphorylation levels and its cellular localization. Finally, we verified the tumorigenic effect of ACADL on NSCLC cells through xenograft experiments in vivo. RESULTS: Compared to adjacent non-cancerous samples, ACADL significantly down-regulated in NSCLC. Overexpression of ACADL, effectively reduced the proliferative, colony, and invasive capabilities of NSCLC cells, while promoting apoptosis and inducing cell cycle arrest. Moreover, ACADL overexpression significantly enhanced YAP phosphorylation and hindered its nuclear translocation. However, the inhibitory effect of the overexpression of ACADL in NSCLC cells mentioned above can be partially counteracted by YAP activator XMU-MP-1 application both in vitro and in vivo. CONCLUSION: The findings suggest that ACADL overexpression could suppress NSCLC development by modulating YAP phosphorylation and limiting its nuclear shift. This role of ACADL-YAP axis provided novel insights into NSCLC carcinogenicity and potential therapeutic strategies.

TiO2/Polystyrene Nanocomposite Antibacterial Material as a Hemoperfusion Adsorbent for Efficient Bilirubin Removal and Prevention of Bacterial Infection.

The use of hemoperfusion adsorbents for the removal of bilirubin in patients with liver failure has become a critical treatment. However, the insufficient clearance of bilirubin and the possibility of bacterial infection during hemoperfusion limit the application. In this work, we designed a novel antibacterial bilirubin adsorbent (PSVT) through the suspension polymerization reaction between double-bond functionalized TiO2 nanoparticles and styrene. PSVT showed an excellent bilirubin adsorption ability and antibacterial performance, ensuring efficient clearance of bilirubin in liver failure patients during hemoperfusion and preventing bacterial infection. The experimental results indicated that TiO2 was uniformly dispersed in the microspheres, which improved the mesoporous structure and increased the specific surface area. Composite adsorbent PSVT showed an exceptional bilirubin adsorption capacity, with the maximum adsorption capacity reaching 24.3 mg/g. In addition, the introduction of TiO2 endowed PSVT with excellent antibacterial ability; the ultimate antibacterial rates against Escherichia coli and Staphylococcus aureus reached 97.31 and 96.47%, respectively. In summary, PSVT served as a novel antibacterial bilirubin adsorbent with excellent bilirubin clearance capacity and antibacterial performance, providing excellent application prospects for treating liver failure patients.

Emerging Co-Assembled and Sustained Released Natural Medicinal Nanoparticles for Multitarget Therapy of Choroidal Neovascularization.

Age-related macular degeneration (AMD) disease has become a worldwide senile disease, and frequent intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) is the mainstream treatment in the clinic, which is associated with sight-threatening complications. Herein, nintedanib, an inhibitor of angiogenesis, and lutein, a potent antioxidant, can co-assemble into nanoparticles through multiple noncovalent interactions. Interestingly, the co-assembled lutein/nintedanib nanoparticles (L/N NPs) exhibit significantly improved stability and achieve long-term sustained release of two drugs for at least two months in mice. Interestingly, in rabbit eyeball with a more complete barrier system, the L/N NPs still successfully distribute in the retina and choroid for a month. In the laser-induced mouse choroidal neovascularization model, the L/N NPs after a minimally invasive subconjunctival administration can successfully inhibit angiogenesis and achieve comparable and even better therapeutic results to that of standard intravitreal injection of anti-VEGF. Therefore, the subconjunctival injection of L/N NPs with long-term sustained drug release behavior represents a promising and innovative strategy for AMD treatment. Such minimally invasive administration together with the ability to effectively inhibit angiogenesis reduce inflammation and counteract oxidative stress and holds great potential for improving patient outcomes and quality of life in those suffering from this debilitating eye condition.

Artificial Intelligence in Liver Diseases: Recent Advances.

Liver diseases cause a significant burden on public health worldwide. In spite of great advances during recent years, there are still many challenges in the diagnosis and treatment of liver diseases. During recent years, artificial intelligence (AI) has been widely used for the diagnosis, risk stratification, and prognostic prediction of various diseases based on clinical datasets and medical images. Accumulative studies have shown its performance for diagnosing patients with nonalcoholic fatty liver disease and liver fibrosis and assessing their severity, and for predicting treatment response and recurrence of hepatocellular carcinoma, outcomes of liver transplantation recipients, and risk of drug-induced liver injury. Herein, we aim to comprehensively summarize the current evidence regarding diagnostic, prognostic, and/or therapeutic role of AI in these common liver diseases.

Dissolving microneedle system containing Ag nanoparticle-decorated silk fibroin microspheres and antibiotics for synergistic therapy of bacterial biofilm infection.

Most cases of delayed wound healing are associated with bacterial biofilm infections due to high antibiotic resistance. To improve patient compliance and recovery rates, it is critical to develop minimally invasive and efficient methods to eliminate bacterial biofilms as an alternative to clinical debridement techniques. Herein, we develop a dissolving microneedle system containing Ag nanoparticles (AgNPs)-decorated silk fibroin microspheres (SFM-AgNPs) and antibiotics for synergistic treatment of bacterial biofilm infection. Silk fibroin microspheres (SFM) are controllably prepared in an incompatible system formed by a mixture of protein and carbohydrate solutions by using a mild all-aqueous phase method and serve as biological templates for the synthesis of AgNPs. The SFM-AgNPs exert dose- and time-dependent broad-spectrum antibacterial effects by inducing bacterial adhesion. The combination of SFM-AgNPs with antibiotics breaks the limitation of the antibacterial spectrum and achieves better efficacy with reduced antibiotic dosage. Using hyaluronic acid (HA) as the soluble matrix, the microneedle system containing SFM-AgNPs and anti-Gram-positive coccus drug (Mupirocin) inserts into the bacterial biofilms with sufficient strength, thereby effectively delivering the antibacterial agents and realizing good antibiofilm effect on Staphylococcus aureus-infected wounds. This work demonstrates the great potential for the development of novel therapeutic systems for eradicating bacterial biofilm infections.

Integrated characterization of hepatobiliary tumor organoids provides a potential landscape of pharmacogenomic interactions.

Despite considerable efforts to identify human liver cancer genomic alterations that might unveil druggable targets, the systematic translation of multiomics data remains challenging. Here, we report success in long-term culture of 64 patient-derived hepatobiliary tumor organoids (PDHOs) from a Chinese population. A divergent response to 265 metabolism- and epigenetics-related chemicals and 36 anti-cancer drugs is observed. Integration of the whole genome, transcriptome, chromatin accessibility profiles, and drug sensitivity results of 64 clinically relevant drugs defines over 32,000 genome-drug interactions. RUNX1 promoter mutation is associated with an increase in chromatin accessibility and a concomitant gene expression increase, promoting a cluster of drugs preferentially sensitive in hepatobiliary tumors. These results not only provide an annotated PDHO biobank of human liver cancer but also suggest a systematic approach for obtaining a comprehensive understanding of the gene-regulatory network of liver cancer, advancing the applications of potential personalized medicine.

Polydopamine nanoplatform with near infrared light and pH dual stimuli-responsive for chemo-photothermal cancer therapy.

Photothermal agent accompanying with thermally responsive materials, displays well controlled drug release property, which is well-received as an outstanding design strategy for simultaneous photothermal/chemotherapy in cancer. Cyanine dye, as the prestigious photothermal agent has shown great potential due to its preeminent near-infrared absorbance and excellent thermal conversion efficiency. However, their inherent defect such as inferior photothermal stability, high leakage risk and poor therapy efficacy limit their further application in cancer therapy. Hence, a facile and universal strategy to make up these deficiencies is developed. Chemotherapeutic drug DOX and cyanine dye were loaded into polydopamine (PDA) nanoparticles. The PDA encapsulation dramatically improved the photothermal stability of cyanine dye. Attributed by the PDA structure feature, the thermo-sensitive small molecule glyamine (Gla) is introduced into the PDA surface to lessen leakage. The Gla can form a dense encapsulation layer on the dopamine surface through hydrogen bond. This newly fabricated Cyanine/DOX@PDA-Gla nanopaltform is characterized with NIR light/pH dual-responsive property, high NIR photothermal conversion performance and fluorescence guided chemo-photothermal therapy.

Non-invasive transdermal delivery of biomacromolecules with fluorocarbon-modified chitosan for melanoma immunotherapy and viral vaccines.

Transdermal drug delivery has been regarded as an alternative to oral delivery and subcutaneous injection. However, needleless transdermal delivery of biomacromolecules remains a challenge. Herein, a transdermal delivery platform based on biocompatible fluorocarbon modified chitosan (FCS) is developed to achieve highly efficient non-invasive delivery of biomacromolecules including antibodies and antigens. The formed nanocomplexes exhibits effective transdermal penetration ability via both intercellular and transappendageal routes. Non-invasive transdermal delivery of immune checkpoint blockade antibodies induces stronger immune responses for melanoma in female mice and reduces systemic toxicity compared to intravenous injection. Moreover, transdermal delivery of a SARS-CoV-2 vaccine in female mice results in comparable humoral immunity as well as improved cellular immunity and immune memory compared to that achieved with subcutaneous vaccine injection. Additionally, FCS-based protein delivery systems demonstrate transdermal ability for rabbit and porcine skins. Thus, FCS-based transdermal delivery systems may provide a compelling opportunity to overcome the skin barrier for efficient transdermal delivery of bio-therapeutics.

Gel-mediated recruitment of conventional type 1 dendritic cells potentiates the therapeutic effects of radiotherapy.

The efficacy of radiotherapy has not yet achieved optimal results, partially due to insufficient priming and infiltration of effector immune cells within the tumor microenvironment (TME), which often exhibits suppressive phenotypes. In particular, the infiltration of X-C motif chemokine receptor 1 (XCR1)-expressing conventional type-1 dendritic cells (cDC1s), which are critical in priming CD8+ cytotoxic T cells, within the TME is noticeably restricted. Hence, we present a facile methodology for the efficient fabrication of a calcium phosphate hydrogel loaded with X-C motif chemokine ligand 1 (XCL1) to selectively recruit cDC1s. Manganese phosphate microparticles were also loaded into this hydrogel to reprogram the TME via cGAS-STING activation, thereby facilitating the priming of cDC1s propelled specific CD8+ T cells. They also polarize tumor-associated macrophages towards the M1 phenotype and reduce the proportion of regulatory cells, effectively reversing the immunosuppressive TME into an immune-active one. The yielded XCL1@CaMnP gel exhibits significant efficacy in enhancing the therapeutic outcomes of radiotherapy, particularly when concurrently administered with postoperative radiotherapy, resulting in an impressive 60 % complete response rate. Such XCL1@CaMnP gel, which recruits cDC1s to present tumor antigens generated in situ, holds great potential as a versatile platform for enhanced cancer treatment through modulating the immunosuppressive TME.

Comparative transcriptome analysis of ovaries and testes reveals sex-biased genes and pathways in zebrafish.

Zebrafish (Danio rerio) is a widely recognized and extensively studied model organism in scientific research. The regulatory mechanism of gonadal development and differentiation of this species has aroused considerable attention. Nonetheless, the major sex-biased genes and pathways associated with gonadal development remain elusive. Therefore, to comprehend this intricate process, gonadal transcriptome sequencing was carried out to identify differentially expressed genes (DEGs) between the testes and ovaries of adult zebrafish. The preliminary assessment yielded a total of 23,529,272 and 23,521,368 clean reads from the cDNA libraries of ovaries and testes. Afterward, a comparative analysis of the transcriptome revealed 3,604 upregulated and 11,371 downregulated DEGs in the ovaries compared to the testes. Of these genes, 428 were exclusively expressed in females, while 3,516 were exclusively expressed in males. Additionally, further assessments were conducted to explore the functions associated with these DEGs in various biological processes. The data revealed their involvement in sex-biased pathways, such as progesterone-mediated oocyte maturation, oocyte meiosis, cytokine-cytokine receptor interaction, and cardiac muscle contraction. Finally, the expression levels of 14 sex-biased DEGs (cdc20, ccnb1, ypel3, chn1, bmp15, rspo1, tnfsf10, egfra, acta2, cox8a, gsdf, dmrt1, star, and cyp17a1) associated with the enriched pathways were subjected to further validation through qRT-PCR. The data acquired from these investigations offer valuable resources to support further exploration of the mechanisms governing sexual dimorphism and gonadal development in zebrafish.

Nanomedicine approaches against SARS-CoV-2 and variants.

The world is grappling with the ongoing crisis of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), a global pandemic that continues to have a detrimental impact on public health and economies worldwide. The virus's relentless mutation has led to more transmissible, immune-evasive strains, thereby escalating the incidence of reinfection. This underscores the urgent need for highly effective and safe countermeasures against SARS-CoV-2 and its evolving variants. In the current context, nanomedicine presents an innovative and promising alternative to mitigate the impacts of this pandemic wave. It does so by harnessing the structural and functional properties at a nanoscale in a straightforward and adaptable manner. This review emphasizes the most recent progress in the development of nanovaccines, nanodecoys, and nanodisinfectants to tackle SARS-CoV-2 and its variants. Notably, the insights gained and strategies implemented in managing the ongoing pandemic may also offer invaluable guidance for the development of potent nanomedicines to combat future pandemics.

A parametrized two-domain thermodynamic model explains diverse mutational effects on protein allostery.

New experimental findings continue to challenge our understanding of protein allostery. Recent deep mutational scanning study showed that allosteric hotspots in the tetracycline repressor (TetR) and its homologous transcriptional factors are broadly distributed rather than spanning well-defined structural pathways as often assumed. Moreover, hotspot mutation-induced allostery loss was rescued by distributed additional mutations in a degenerate fashion. Here, we develop a two-domain thermodynamic model for TetR, which readily rationalizes these intriguing observations. The model accurately captures the in vivo activities of various mutants with changes in physically transparent parameters, allowing the data-based quantification of mutational effects using statistical inference. Our analysis reveals the intrinsic connection of intra- and inter-domain properties for allosteric regulation and illustrate epistatic interactions that are consistent with structural features of the protein. The insights gained from this study into the nature of two-domain allostery are expected to have broader implications for other multidomain allosteric proteins.