Identification and validation of cuproptosis-related genes in acetaminophen-induced liver injury using bioinformatics analysis and machine learning.

Background: Acetaminophen (APAP) is commonly used as an antipyretic analgesic. However, acetaminophen overdose may contribute to liver injury and even liver failure. Acetaminophen-induced liver injury (AILI) is closely related to mitochondrial oxidative stress and dysfunction, which play critical roles in cuproptosis. Here, we explored the potential role of cuproptosis-related genes (CRGs) in AILI. Methods: The gene expression profiles were obtained from the Gene Expression Omnibus database. The differential expression of CRGs was determined between the AILI and control samples. Protein protein interaction, correlation, and functional enrichment analyses were performed. Machine learning was used to identify hub genes. Immune infiltration was evaluated. The AILI mouse model was established by intraperitoneal injection of APAP solution. Quantitative real-time PCR and western blotting were used to validate hub gene expression in the AILI mouse model. The copper content in the mouse liver samples and AML12 cells were quantified using a colorimetric assay kit. Ammonium tetrathiomolybdate (ATTM), was administered to mouse models and AML12 cells in order to investigate the effects of copper chelator on AILI. Results: The analysis identified 7,809 differentially expressed genes, 4,245 of which were downregulated and 3,564 of which were upregulated. Four optimal feature genes (OFGs; SDHB, PDHA1, NDUFB2, and NDUFB6) were identified through the intersection of two machine learning algorithms. Further nomogram, decision curve, and calibration curve analyses confirmed the diagnostic predictive efficacy of the four OFGs. Enrichment analysis indicated that the OFGs were involved in multiple pathways, such as IL-17 pathway and chemokine signaling pathway, that are related to AILI progression. Immune infiltration analysis revealed that macrophages were more abundant in AILI than in control samples, whereas eosinophils and endothelial cells were less abundant. Subsequently, the AILI mouse model was successfully established, and histopathological analysis using hematoxylin-eosin staining along with liver function tests revealed a significant induction of liver injury in the APAP group. Consistent with expectations, both mRNA and protein levels of the four OFGs exhibited a substantial decrease. The administration of ATTAM effectively mitigates copper elevation induced by APAP in both mouse model and AML12 cells. However, systemic administration of ATTM did not significantly alleviate AILI in the mouse model. Conclusion: This study first revealed the potential role of CRGs in the pathological process of AILI and offered novel insights into its underlying pathogenesis.

A magnetic-guided nano-antibacterial platform for alternating magnetic field controlled vancomycin release in staphylococcus aureus biofilm eradication.

Bacterial resilience within biofilms, rendering them up to 1000 times more resistant to antibiotic drugs, poses a formidable challenge. This study introduces a targeted biofilm eradication strategy, termed "target-penetration-killing-eradication", implemented through magnetic micro-robotic technology. Specifically, we present the development of a magnetic-guided nano-antibacterial platform designed for alternating magnetic field (AMF) controlled vancomycin release in the eradication of Staphylococcus aureus biofilms. To address the issue of premature vancomycin release in physiological conditions, we employed a temperature-sensitive linking agent, 4,4'-azobis(4-cyano valeric acid), facilitating the conjugation of vancomycin onto Fe3O4/CS nanocomposites, resulting in the novel construct Fe3O4@CS-ACVA-VH. The release mechanism adheres to first-order kinetics and Fickian diffusion, with each 10-min AMF treatment releasing approximately 8.4 ± 1.1% of vancomycin. The potency of vancomycin in the release solution was similar to that of the original drug (MIC: 7.4 ± 3.5 vs. 5.6 µg/mL). Fe3O4@CS-ACVA-VH exhibited sustained antibacterial efficacy, inhibiting bacterial growth for four consecutive days and preventing the formation of bacterial biofilms on its surface. Contact-inhibition bacterial activity of Fe3O4@CS-ACVA-VH against S. aureus was 0.046875 mg/mL. Conceptually validating our approach, we emphasize Fe3O4@CS-ACVA-VH's exceptional ability to penetrate S. aureus biofilms under static magnetic field attraction. Furthermore, the nano-platform offers the unique advantage of on-demand vancomycin release through alternating magnetic field stimulation, effectively clearing a larger biofilm area. This multifunctional nano-platform demonstrates magnetic-guided biofilm penetration followed by controlled vancomycin release, presenting a promising strategy for enhanced biofilm eradication.

Sub-micron pixel polarization-sensitive photodetector based on silicon nanowire.

Silicon nanowire is a potential candidate to be used as polarization-sensitive material, but the relative mechanism of polarization response must be carried out. Herein, a sub-micron metal-single silicon nanowire-metal photodetector exhibits polarization-sensitive characteristics with an anisotropic photocurrent ratio of 1.59 at 780 nm, an excellent responsivity of 24.58 mA/W, and a high detectivity of 8.88 × 109 Jones at 980 nm. The underlying principle of optical anisotropy in silicon nanowire is attributed to resonance enhancement verified by polarizing light microscopy and simulation. Furthermore, Stokes parameter measurements and imaging are all demonstrated by detecting the characteristics of linearly polarized light and imaging the polarizer array, respectively. Given the maturity of silicon processing, the sub-micron linearly polarized light detection proposed in this study lays the groundwork for achieving highly integrated, simplified processes, and cost-effective on-chip polarization-sensitive optical chips in the future.

Thoracic giant cell tumor after two total en bloc spondylectomies including one emergency surgery: A case report.

BACKGROUND: For patients with acute paraplegia caused by spinal giant cell tumor (GCT) who require emergency decompressive surgery, there is still a lack of relevant reports on surgical options. This study is the first to present the case of an acute paraplegic patient with a thoracic spinal GCT who underwent an emergency total en bloc spondylectomy (TES). Despite tumor recurrence, three-level TES was repeated after denosumab therapy. CASE SUMMARY: A 27-year-old female patient who underwent single-level TES in an emergency presented with sudden severe back pain and acute paraplegia due to a thoracic spinal tumor. After emergency TES, the patient's spinal cord function recovered, and permanent paralysis was avoided. The postoperative histopathological examination revealed that the excised neoplasm was a rare GCT. Unfortunately, the tumor recurred 9 months after the first surgery. After 12 months of denosumab therapy, the tumor size was reduced, and tumor calcification. To prevent recurrent tumor progression and provide a possible cure, a three-level TES was performed again. The patient returned to an active lifestyle 1 month after the second surgery, and no recurrence of GCT was found at the last follow-up. CONCLUSION: This patient with acute paraplegia underwent TES twice, including once in an emergency, and achieved good therapeutic results. TES in emergency surgery is feasible and safe when conditions permit; however, it may increase the risk of tumor recurrence.

Decellularized periosteum and sodium alginate-based photoresponsive dressing with copper selenide nanoparticles for infected-wound healing in diabetic mice.

Diabetes-related skin ulcers are of significant clinical concern. Although conventional dressings have been developed, their outcomes have not been adequate, indicating the need to investigate functional dressings for the treatment of diabetic ulcers. Copper selenide nanoparticles (Cu2Se NPs) demonstrate outstanding photoresponsiveness, which is critical to the healing process. However, their limited solubility in water restricts their application. To synthesize the ODT-PMMA@Cu2Se NP-doped decellularized periosteum­sodium alginate functional dressing-ODT-PMMA@Cu2Se/ECM-S (OP@Cu2Se/ECM-S), Cu2Se NPs were modified by n-octadecanethiol (ODT) end-functionalized poly (methacrylic acid) (PMAA) ligands homogeneously dispersed in a decellularized periosteum/sodium alginate matrix. This process improved the water solubility and stability. Moreover, under near-infrared irradiation (NIR), ODT-PMMA@Cu2Se demonstrated robust photo-responsiveness along with photothermal and photodynamic effects, leading to rapid heating and stimulation of reactive oxygen species (ROS) generation. These two processes work in concert to exhibit excellent antibacterial ability; at 20 µg/mL concentration of Cu2Se NPs, the bacterial activities of S. aureus and E. coli were 5.40 % and 0.96 %, respectively. Without the NIR laser irradiation, OP@Cu2Se/ECM-S rapidly increased the vascular endothelial growth factor (VEGF) expression, triggered the phosphatidylinositide 3-kinases (PI3K) and protein kinase B (AKT) signaling pathway, affected the expression of bFGF and CD31, and promoted neovascularization, proliferation, and cell migration. In a diabetic mouse wound model, OP@Cu2Se/ECM-S exhibited good biocompatibility and promoted epidermal regeneration, collagen deposition, and neovascularization. In a mouse model of subcutaneous abscesses, OP@Cu2Se/ECM-S also showed excellent antibacterial activity, in vivo experiments confirmed a decrease in bacterial activity to 1.97 %. Thus, OP@Cu2Se/ECM-S is a potentially useful approach for healing diabetic wounds.

Application of Platysma Myocutaneous Flap in Surgical Repair after T2-3 Glottic Carcinoma Resection.

OBJECTIVE: Numerous methods and materials are available for vertical partial laryngectomy. In this study, the reparative effects of the platysma myocutaneous flap (PMF) and ribbon myocutaneous flap (RMF) on the postoperative voice quality of patients were compared to provide a reference for selecting a method conducive to improving postoperative voice quality. METHODS: A retrospective analysis was performed on patients with unilateral T2-3 glottic carcinoma. Following vertical partial laryngectomy, the defect was repaired with a PMF or simple RMF. Twelve months after surgery, voice quality was assessed according to voice acoustics, aerodynamics, and subjective perceptual evaluation, and glottic morphology was recorded using a laryngeal stroboscopy. RESULTS: A total of 70 patients were identified, including 54 in the PMF group and 16 in the RMF group. The PMF group was superior to the RMF group in terms of voice quality assessed by voice acoustics, aerodynamics, and subjective perceptual evaluation. In the PMF group, 72.2% of patients performed phonation with their vocal cords, and approximately 27.8% of patients were affected by supraglottic compression. In the RMF group, 81.3% of patients were affected by supraglottic compression. No significant difference was found in the 5-year survival rate between the two groups. CONCLUSION: For defect repair following vertical partial laryngectomy, a PMF can allow better postoperative voice quality to be achieved than an RMF because a PMF can provide more tissue (including strap muscle under the flap) for padding, which enables the glottic portion corresponding to the vocal cord to close well. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:3181-3186, 2024.

A biodegradable PVA coating constructed on the surface of the implant for preventing bacterial colonization and biofilm formation.

BACKGROUND: Bone implant infections pose a critical challenge in orthopedic surgery, often leading to implant failure. The potential of implant coatings to deter infections by hindering biofilm formation is promising. However, a shortage of cost-effective, efficient, and clinically suitable coatings persists. Polyvinyl alcohol (PVA), a prevalent biomaterial, possesses inherent hydrophilicity, offering potential antibacterial properties. METHODS: This study investigates the PVA solution's capacity to shield implants from bacterial adhesion, suppress bacterial proliferation, and thwart biofilm development. PVA solutions at concentrations of 5%, 10%, 15%, and 20% were prepared. In vitro assessments evaluated PVA's ability to impede bacterial growth and biofilm formation. The interaction between PVA and mCherry-labeled Escherichia coli (E. coli) was scrutinized, along with PVA's therapeutic effects in a rat osteomyelitis model. RESULTS: The PVA solution effectively restrained bacterial proliferation and biofilm formation on titanium implants. PVA solution had no substantial impact on the activity or osteogenic potential of MC3T3-E1 cells. Post-operatively, the PVA solution markedly reduced the number of Staphylococcus aureus and E. coli colonies surrounding the implant. Imaging and histological scores exhibited significant improvements 2 weeks post-operation. Additionally, no abnormalities were detected in the internal organs of PVA-treated rats. CONCLUSIONS: PVA solution emerges as an economical, uncomplicated, and effective coating material for inhibiting bacterial replication and biofilm formation on implant surfaces, even in high-contamination surgical environments.

Inhibition of HOXD11 promotes cartilage degradation and induces osteoarthritis development.

The 5'-HOXD genes are important for chondrogenesis in vertebrates, but their roles in osteoarthritis (OA) are still ambiguous. In our study, 5'-HOXD genes involvement contributing to cartilage degradation and OA was investigated. In bioinformatics analysis of 5'-HOXD genes, we obtained the GSE169077 data set related to OA in the GEO and analyzed DEGs using the GEO2R tool attached to the GEO. Then, we screened the mRNA levels of 5'-HOXD genes by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). We discovered that OA chondrocyte proliferation was inhibited, and apoptosis was increased. Moreover, it was discovered that SOX9 and COL2A1 were downregulated at mRNA and protein levels, while matrix metalloproteinases (MMPs) and a disintegrin-like and metalloproteinase with thrombospondin motifs (ADAMTSs) were upregulated. According to the results of differentially expressed genes (DEGs) and qRT-PCR, we evaluated the protein level of HOXD11 and found that the expression of HOXD11 was downregulated, reversed to MMPs and ADAMTSs but consistent with the cartilage-specific factors, SOX9 and COL2A1. In the lentivirus transfection experiments, HOXD11 overexpression reversed the effects in OA chondrocytes. In human OA articular cartilage, aberrant subchondral bone was formed in hematoxylin-eosin (H&E) and Safranin O and fast green (SOFG) staining results. Furthermore, according to immunohistochemistry findings, SOX9 and HOXD11 expression was inhibited. The results of this study established that HOXD11 was downregulated in OA cartilage and that overexpression of HOXD11 could prevent cartilage degradation in OA.

Single-Component Dual-Functional Autoboost Strategy by Dual Photodynamic and Cyclooxygenase-2 Inhibition for Lung Cancer and Spinal Metastasis.

Coloading adjuvant drugs or biomacromolecules with photosensitizers into nanoparticles to enhance the efficiency of photodynamic therapy (PDT) is a common strategy. However, it is difficult to load positively charged photosensitizers and negatively charged adjuvants into the same nanomaterial and further regulate drug release simultaneously. Herein, a single-component dual-functional prodrug strategy is reported for tumor treatment specifically activated by tumor microenvironment (TME)-generated HOCl. A representative prodrug (DHU-CBA2) is constructed using indomethacin grafted with methylene blue (MB). DHU-CBA2 exhibited high sensitivity toward HOCl and achieved simultaneous release of dual drugs in vitro and in vivo. DHU-CBA2 shows effective antitumor activity against lung cancer and spinal metastases via PDT and cyclooxygenase-2 (COX-2) inhibition. Mechanistically, PDT induces immunogenic cell death but stimulates the gene encoding COX-2. Downstream prostaglandins E2 and Indoleamine 2,3 dioxygenase 1 (IDO1) mediate immune escape in the TME, which is rescued by the simultaneous release of indomethacin. DHU-CBA2 promotes infiltration and function of CD8+ T cells, thus inducing a robust antitumor immune response. This work provides an autoboost strategy for a single-component dual-functional prodrug activated by TME-specific HOCl, thereby achieving favorable tumor treatment via the synergistic therapy of PDT and a COX-2 inhibitor.

Prediction and simulation of a potential barrier block in Van der Waals heterojunction photodetectors.

The pBp structure can effectively suppress the dark current of a photodetector by blocking the majority of carriers. However, it is a big challenge to carry out large-scale simulation optimization for two-dimensional (2D) pBp heterojunction photodetectors due to a lack of the device models. Here, a numerical simulation model of the 2D pBp heterojunction was established based on the finite element method to solve this problem. Using this model, the spatial distribution of the energy band is clarified for each layer. The concentration of nonuniformly distributed electrons, induced by the incident light and bias voltage, is obtained by solving the diffusion and drift equations. The characteristics of the photocurrent and the dark current could be presented and the quantum efficiency could be calculated by counting the ratio of the number of carriers collected at the terminals and the carriers photogenerated. The material parameters could be modified for the optimization of the simulation and prediction. In using our model, a B P/M o S 2/graphene photodetector was constructed, and the simulation results show that it works effectively under a reverse bias ranging from -0.3 to 0 V. The external quantum efficiency is 18%, while the internal efficiency approaches 85%. The doping in the barrier region definitely does not affect the dark current and the photocurrent. These results are similar to experimental results published earlier. In addition, with the BP bandgap width of 0.8 eV and incident wavelength of 1.7 µm, the dark current density predicted by the model could reach 3.3×10-8 A/c m 2, which is two orders lower than the reported 2D photodetectors at room temperature. This proposed model provides a way to design 2D pBp heterojunction photodetectors.

Nuclear-Targeted Nanostrategy Regulates Spatiotemporal Communication for Dual Antitumor Immunity.

Intercellular communication between tumor cells and immune cells regulates tumor progression including positive communication with immune activation and negative communication with immune escape. An increasing number of methods are employed to suppress the dominant negative communication in tumors such as PD-L1/PD-1. However, how to effectively improve positive communication is still a challenge. In this study, a nuclear-targeted photodynamic nanostrategy is developed to establish positive spatiotemporal communication, further activating dual antitumor immunity, namely innate and adaptative immunity. The mSiO2 -Ion@Ce6-NLS nanoparticles (NPs) are designed, whose surface is modified by ionic liquid silicon (Ion) and nuclear localization signal peptide (NLS: PKKKRKV), and their pores are loaded with the photosensitizer hydrogen chloride e6 (Ce6). Ion-modified NPs enhance intratumoral enrichment, and NLS-modified NPs exhibit nuclear-targeted characteristics to achieve nuclear-targeted photodynamic therapy (nPDT). mSiO2 -Ion@Ce6-NLS with nPDT facilitate the release of damaged double-stranded DNA from tumor cells to activate macrophages via stimulator of interferon gene signaling and induce the immunogenic cell death of tumor cells to activate dendritic cells via "eat me" signals, ultimately leading to the recruitment of CD8+ T-cells. This therapy effectively strengthens positive communication to reshape the dual antitumor immune microenvironment, further inducing long-term immune memory, and eventually inhibiting tumor growth and recurrence.

Golgi Apparatus-Targeted Photodynamic Therapy for Enhancing Tumor Immunogenicity by Eliciting NLRP3 Protein-Dependent Pyroptosis.

Innate and adaptive immunity is important for initiating and maintaining immune function. The nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome serves as a checkpoint in innate and adaptive immunity, promoting the secretion of pro-inflammatory cytokines and gasdermin D-mediated pyroptosis. As a highly inflammatory form of cell death distinct from apoptosis, pyroptosis can trigger immunogenic cell death and promote systemic immune responses in solid tumors. Previous studies proposed that NLRP3 was activated by translocation to the mitochondria. However, a recent authoritative study has challenged this model and proved that the Golgi apparatus might be a prerequisite for the activation of NLRP3. In this study, we first developed a Golgi apparatus-targeted photodynamic strategy to induce the activation of NLRP3 by precisely locating organelles. We found that Golgi apparatus-targeted photodynamic therapy could significantly upregulate NLRP3 expression to promote the subsequent release of intracellular proinflammatory contents such as IL-1ß or IL-18, creating an inflammatory storm to enhance innate immunity. Moreover, this acute NLRP3 upregulation also activated its downstream classical caspase-1-dependent pyroptosis to enhance tumor immunogenicity, triggering adaptive immunity. Pyroptosis eventually led to immunogenic cell death, promoted the maturation of dendritic cells, and effectively activated antitumor immunity and long-lived immune memory. Overall, this Golgi apparatus-targeted strategy provided molecular insights into the occurrence of immunogenic pyroptosis and offered a platform to remodel the tumor microenvironment.

Biomimetic Structural Protein Based Magnetic Responsive Scaffold for Enhancing Bone Regeneration by Physical Stimulation on Intracellular Calcium Homeostasis.

The bone matrix has distinct architecture and biochemistry which present a barrier to synthesizing bone-mimetic regenerative scaffolds. To mimic the natural structures and components of bone, biomimetic structural decellularized extracellular matrix (ECM)/regenerated silk fibroin (RSF) scaffolds incorporated with magnetic nanoparticles (MNP) are prepared using a facile synthetic methodology. The ECM/RSF/MNP scaffold is a hierarchically organized and interconnected porous structure with silk fibroin twined on the collagen nanofibers. The scaffold demonstrates saturation magnetization due to the presence of MNP, along with good cytocompatibility. Moreover, the ß-sheet crystalline domain of RSF and the chelated MNP could mimic the deposition of hydroxyapatite and enhance compressive modulus of the scaffold by ≈20%. The results indicate that an external static magnetic field (SMF) with a magnetic responsive scaffold effectively promotes cell migration, osteogenic differentiation, neogenesis of endotheliocytes in vitro, and new bone formation in a critical-size femur defect rat model. RNA sequencing reveals that the molecular mechanisms underlying this osteogenic effect involve calsequestrin-2-mediated Ca2+ release from the endoplasmic reticulum to activate Ca2+ /calmodulin/calmodulin-dependent kinase II signaling axis. Collectively, bionic magnetic scaffolds with SMF stimulation provide a potent strategy for bone regeneration through internal structural cues, biochemical composition, and external physical stimulation on intracellular Ca2+ homeostasis.

Management of anticoagulation in patients with infective endocarditis.

Infective endocarditis (IE) carries a high risk of vascular complications (e.g., cerebral embolism, intracerebral hemorrhage, and renal infarction), which are correlated with increased early and late mortality. Although anticoagulation is the cornerstone for management of thromboembolic complications, it remains controversial and challenging in patients with IE. An appropriate anticoagulation strategy is crucial to improving outcomes and requires a good understanding of the indication, timing, and regimen of anticoagulation in the setting of IE. Observational studies have shown that anticoagulant treatment failed to reduce the risk of ischemic stroke in patents with IE, supporting that IE alone is not an indication for anticoagulation. In the absence of randomized controlled trials and high-quality meta-analyses, however, current guidelines on IE were based largely on observational data and expert opinion, providing few specific recommendations on anticoagulation. A multidisciplinary approach and patient engagement are required to determine the timing and regimen of anticoagulation in patients with IE, especially in specific situations (e.g., receiving warfarin anticoagulation at the time of IE diagnosis, cerebral embolism or ischemic stroke, intracerebral hemorrhage, or urgent surgery). Collectively, individualized strategies on anticoagulation management of IE should be based on clinical evaluation, available evidence, and patient engagement, and ultimately be developed by the multidisciplinary team.

Harmine loaded Au@MSNs@PEG@Asp6 nano-composites for treatment of spinal metastasis from lung adenocarcinoma by targeting ANXA9 in vivo experiment.

Background: Annexin A9 (ANXA9) has been proved to be concerned with cancer development. However, to explore the clinical consequences of ANXA9 in lung adenocarcinoma (LUAD), especially its correlation to spinal metastasis (SM) has no in-depth study. The study was expected to elucidate the mechanism of ANXA9 in regulating SM of LUAD and create a productive nano-composites delivery system targeting this gene for treatment of SM. Methods: Harmine (HM), a ß-carboline extracted from the traditional Chinese herb Peganum harmala, loaded Au@MSNs@PEG@Asp6 (NPS) nano-composites were synthesized. Bioinformatics analysis and clinical specimens' tests were used to verify the association between ANXA9 and prognosis of LUAD with SM. The immunohistochemistry (IHC) was employed to detect the expression levels of the ANXA9 protein in LUAD tissues with or without SM, and its significance in clinic was also explored. ANXA9­siRNA was applied to investigate the molecular mechanism of ANXA9 in tumor behaviors. The HM release kinetics was detected by high performance liquid chromatography (HPLC) method. The cellular uptake efficiency of nanoparticles by A549 cells was observed by fluorescence microscope. Antitumor effects of nanoparticles were assessed in the nude mouse model of SM. Results: The genomic amplification of ANXA9 was prevalent in LUAD tissues and closely associated with poor outcome and SM (P<0.01). The experimental result manifested that high expression of ANXA9 could lead to wretched prognosis and ANXA9 was an independent risk factor for survival (P<0.05). After impeding expression of ANXA9, the proliferation and metastatic ability of tumor cells obviously decreased, and expression of matrix metallopeptidase 2 (MMP-2) and matrix metallopeptidase 9 (MMP-9) were considerably downregulated, while the expression of associated oncogene pathway were downregulated (P<0.01) as well. The synthesized HM-loaded NPS nano-composites could target to cancer and response to reactive oxygen species (ROS) to release HM slowly. Notably, in comparison to free HM, the nano-composites showed excellent targeting and anti-tumor effects in the A549 cell-bearing mouse model. Conclusions: ANXA9 may serve as a novel biomarker for predicting poor prognosis in LUAD, and we provided an efficient and targeting drug delivery nano-composites system for precise treatment of SM from LUAD.

Preparation of Melatonin-Loaded Nanoparticles with Targeting and Sustained Release Function and Their Application in Osteoarthritis.

(1) The vicious cycle of innate immune response and reactive oxygen species (ROS) generation is an important pathological process of osteoarthritis (OA). Melatonin may be a new hope for the treatment of OA because of its antioxidant capacity. However, the mechanism of melatonin in the treatment of OA is still not completely clear, and the physiological characteristics of articular cartilage make melatonin unable to play a long-term role in OA. (2) The effects of melatonin on ROS and the innate immune response system in OA chondrocytes and the therapeutic effect in vivo were evaluated. Then, a melatonin-loaded nano-delivery system (MT@PLGA-COLBP) was prepared and characterized. Finally, the behavior of MT@PLGA-COLPB in cartilage and the therapeutic effect in OA mice were evaluated. (3) Melatonin can inhibit the activation of the innate immune system by inhibiting the TLR2/4-MyD88-NFκB signal pathway and scavenging ROS, thus improving cartilage matrix metabolism and delaying the progression of OA in vivo. MT@PLGA-COLBP can reach the interior of cartilage and complete the accumulation in OA knee joints. At the same time, it can reduce the number of intra-articular injections and improve the utilization rate of melatonin in vivo. (4) This work provides a new idea for the treatment of osteoarthritis, updates the mechanism of melatonin in the treatment of osteoarthritis, and highlights the application prospect of PLGA@MT-COLBP nanoparticles in preventing OA.

Precise manipulation of circadian clock using MnO2 nanocapsules to amplify photodynamic therapy for osteosarcoma.

Circadian rhythm (CR) disruption contributes to tumor initiation and progression, however the pharmacological targeting of circadian regulators reversely inhibits tumor growth. Precisely controlling CR in tumor cells is urgently required to investigate the exact role of CR interruption in tumor therapy. Herein, based on KL001, a small molecule that specifically interacts with the clock gene cryptochrome (CRY) functioning at disruption of CR, we fabricated a hollow MnO2 nanocapsule carrying KL001 and photosensitizer BODIPY with the modification of alendronate (ALD) on the surface (H-MnSiO/K&B-ALD) for osteosarcoma (OS) targeting. The H-MnSiO/K&B-ALD nanoparticles reduced the CR amplitude in OS cells without affecting cell proliferation. Furthermore, nanoparticles-controlled oxygen consumption by inhibiting mitochondrial respiration via CR disruption, thus partially overcoming the hypoxia limitation for photodynamic therapy (PDT) and significantly promoting PDT efficacy. An orthotopic OS model demonstrated that KL001 significantly enhanced the inhibitory effect of H-MnSiO/K&B-ALD nanoparticles on tumor growth after laser irradiation. CR disruption and oxygen level enhancement induced by H-MnSiO/K&B-ALD nanoparticles under laser irradiation were also confirmed in vivo. This discovery first demonstrated the potential of CR controlling for tumor PDT ablation and provided a promising strategy for overcoming tumor hypoxia.

Deep learning of bone metastasis in small cell lung cancer: A large sample-based study.

Introduction: Bone is a common metastatic site for small cell lung cancer (SCLC). Bone metastasis (BM) in patients have are known to show poor prognostic outcomes. We explored the epidemiological characteristics of BM in SCLC patients and create a new deep learning model to predict outcomes for cancer-specific survival (CSS) and overall survival (OS). Materials and Methods: Data for SCLC patients diagnosed with or without BM from 2010 to 2016 were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox proportional hazards regression models were used to evaluate the effects of prognostic variables on OS and CSS. Through integration of these variables, nomograms were created for the prediction of CSS and OS rates at 3-month,6- month,and 12-month. Harrell's coordination index, calibration curves,and time- dependent ROC curves were used to assess the nomograms' accuracy. Decision tree analysis was used to evaluate the clinical application value of the established nomogram. Results: In this study, 4201 patients were enrolled. Male sex, tumor size 25 but <10, brain and liver metastases, as well as chemotherapy were associated with a high risk for BM. Tumor size, Age, N stage, gender, liver metastasis, radiotherapy as well as chemotherapy were shown to be prognostic variables for OS, and the prognostic variables for CSS were added to the tumor number in addition. Based on these results, nomograms for CSS and OS were established separately. Internal as well as external validation showed that the C-index, calibration cuurve and DCA had good constructive correction effect and clinical application value. Decision tree analysis further confirmed the prognostic factors of OS and CSS. Discussion: The nomogram and decision tree models developed in this study effectively guided treatment decisions for SCLC patients with BM. The creation of prediction models for BM SCLC patients may be facilitated by deep learning models.

Follicle-like tertiary lymphoid structures: A potential biomarker for prognosis and immunotherapy response in patients with laryngeal squamous cell carcinoma.

Background: The maturity and spatial distribution of tertiary lymphoid structures (TLSs) vary dynamically within and between cancers, leading to a controversial role in cancer. We aimed to develop a simple morphology-based approach to identify the maturity of TLSs in laryngeal squamous cell carcinoma and examine their clinically relevant functional role. Methods: TLSs were identified based on morphological features via hematoxylin and eosin (H&E) staining, and the accuracy was verified by multi-immunohistochemical analysis. The density, maturity, spatial distribution and prognostic value of TLSs were separately analyzed in two human laryngeal cancer cohorts. The TLS profile was linked to RNA-seq data from the TCGA database to perform bioinformatics analysis. Results: TLSs can be classified as early TLSs (E-TLSs), primary follicle-like TLSs (PFL-TLSs) and secondary follicle-like TLSs (SFL-TLSs). The three types of TLSs showed higher infiltration in the extratumoral region. XCL2 is a vital chemokine in the maturation and infiltration of TLSs. FL-TLS was an independent positive prognostic indicator in laryngeal cancer. The FL-TLS group had more abundant immune cell infiltration and a better response to immunotherapies than the non-FL-TLS group. Functional analysis showed that the non-FL-TLS group was enriched in tumor invasion, metastasis and immunosuppression pathways. Conclusion: The maturity of TLSs can be accurately classified by H&E staining. FL-TLS is a potential mediator of antitumor immunity in human laryngeal cancer.

EEG-based driver states discrimination by noise fraction analysis and novel clustering algorithm.

Driver states are reported as one of the principal factors in driving safety. Distinguishing the driving driver state based on the artifact-free electroencephalogram (EEG) signal is an effective means, but redundant information and noise will inevitably reduce the signal-to-noise ratio of the EEG signal. This study proposes a method to automatically remove electrooculography (EOG) artifacts by noise fraction analysis. Specifically, multi-channel EEG recordings are collected after the driver experiences a long time driving and after a certain period of rest respectively. Noise fraction analysis is then applied to remove EOG artifacts by separating the multichannel EEG into components by optimizing the signal-to-noise quotient. The representation of data characteristics of the EEG after denoising is found in the Fisher ratio space. Additionally, a novel clustering algorithm is designed to identify denoising EEG by combining cluster ensemble and probability mixture model (CEPM). The EEG mapping plot is used to illustrate the effectiveness and efficiency of noise fraction analysis on the denoising of EEG signals. Adjusted rand index (ARI) and accuracy (ACC) are used to demonstrate clustering performance and precision. The results showed that the noise artifacts in the EEG were removed and the clustering accuracy of all participants was above 90%, resulting in a high driver fatigue recognition rate.