Individualized prediction of non-sentinel lymph node metastasis in Chinese breast cancer patients with ≥ 3 positive sentinel lymph nodes based on machine-learning algorithms.

BACKGROUND: Axillary lymph node dissection (ALND) is a standard procedure for early-stage breast cancer (BC) patients with three or more positive sentinel lymph nodes (SLNs). However, ALND can lead to significant postoperative complications without always providing additional clinical benefits. This study aims to develop machine-learning (ML) models to predict non-sentinel lymph node (non-SLN) metastasis in Chinese BC patients with three or more positive SLNs, potentially allowing the omission of ALND. METHODS: Data from 2217 BC patients who underwent SLN biopsy at Shantou University Medical College were analyzed, with 634 having positive SLNs. Patients were categorized into those with ≤ 2 positive SLNs and those with ≥ 3 positive SLNs. We applied nine ML algorithms to predict non-SLN metastasis. Model performance was evaluated using ROC curves, precision-recall curves, and calibration curves. Decision Curve Analysis (DCA) assessed the clinical utility of the models. RESULTS: The RF model showed superior predictive performance, achieving an AUC of 0.987 in the training set and 0.828 in the validation set. Key predictive features included size of positive SLNs, tumor size, number of SLNs, and ER status. In external validation, the RF model achieved an AUC of 0.870, demonstrating robust predictive capabilities. CONCLUSION: The developed RF model accurately predicts non-SLN metastasis in BC patients with ≥ 3 positive SLNs, suggesting that ALND might be avoided in selected patients by applying additional axillary radiotherapy. This approach could reduce the incidence of postoperative complications and improve patient quality of life. Further validation in prospective clinical trials is warranted.

Noninvasive prediction of BRAF V600E mutation status of pleomorphic xanthoastrocytomas with MRI morphologic features and diffusion-weighted imaging.

OBJECTIVES: Seeking a noninvasive predictor for BRAF V600E mutation status of pleomorphic xanthoastrocytomas (PXAs) is essential for their prognoses and therapeutic use of BRAF inhibitors. We aimed to noninvasively diagnose BRAF V600E-mutated PXAs using MRI morphologic, DWI and clinical parameters. METHODS: The clinical findings, anatomical MRI characteristics, and diffusion parameters of 36 pathologically confirmed PXAs were retrospectively analyzed, and BRAF V600E-mutated (n = 16) and wild-type (n = 20) groups were compared. A binary logistic-regression analysis was performed, and a ROC curve was calculated to determine the independent predictors of BRAF V600E mutation status, diagnostic accuracy, and optimal cut-off value. RESULTS: A comparison of findings between groups showed that BRAF V600E-mutated PXAs were more frequent in children and young adults (≤ 35 years; P = 0.042) who often had histories of seizures (P = 0.004). Furthermore, BRAF V600E-mutated PXAs generally presented as solitary masses (P = 0.024), superficial locations with meningeal attachment (P < 0.001), predominantly cystic with mural nodules (P = 0.005), and had greater minimal ADC ratio (ADCratio) values of the tumor and peritumoral edema (P < 0.001). Binary logistic regression showed that age ≤ 35 years, solitary mass, superficial locations with meningeal attachment, and a greater minimal ADCratio of the tumor were independent predictors of BRAF V600E-mutated PXAs. The combination of all four independent predictors resulted in the highest sensitivity (100%) and specificity (90%), with AUC = 0.984. CONCLUSION: The BRAF V600E mutation status of PXAs could be noninvasively predicted using clinical and MRI characteristics. CRITICAL RELEVANCE STATEMENT: The noninvasive diagnostic criteria for BRAF V600E-mutated PXAs could offer guidance for the administration of BRAF V600E mutation inhibitors in the future.

Activation of the IL-17/TRAF6/NF-κB pathway is implicated in Aß-induced neurotoxicity.

BACKGROUND: Neuroinflammation plays a critical role in Amyloid-ß (Aß) pathophysiology. The cytokine, interleukin-17A (IL-17) is involved in the learning and memory process in the central nervous system and its level was reported to be increased in Alzheimer's disease (AD) brain, while the effect of IL-17 on the course of Aß has not been well defined. METHODS: Here, we used APP/PS1 mice to detect the IL-17 expression level. Primary hippocampal neurons were treated with IL-17, and immunofluorescence was used to investigate whether IL-17 induced neuron damage. At the same time, male C57BL/6 mice were injected with Aß42 to mimic the Aß model. Then IL-17 neutralizing antibody (IL-17Ab) was used to inject into the lateral ventricle, and the Open field test, Novel Objective Recognition test, Fear condition test were used to detect cognitive function. LTP was used to assess synaptic plasticity, molecular biology technology was used to assess the IL-17/TRAF6/NF-κB pathway, and ELISA was used to detect inflammatory factors. RESULTS: Altogether, we here found that IL-17 was increased in APP/PS1 mice, and it induced neural damage by the administration to primary hippocampal neurons. Interestingly, Using Aß42 mice, the results showed that the level of IL-17 was increased in Aß42 model mice, and IL-17Ab could ameliorate Aß-induced neurotoxicity and cognitive decline in C57BL/6 mice by downregulation the TRAF6/NF-κB pathway. CONCLUSION: These findings highlight the pathogenic role of IL-17 in Aß induced-synaptic dysfunction and cognitive deficits. Inhibition of IL-17 could ameliorate Aß-induced neurotoxicity and cognitive decline in C57BL/6 mice by downregulation of the TRAF6/NF-κB pathway, which provides new clues for the mechanism of Aß-induced cognitive impairments, and a basis for therapeutic intervention.

Antibacterial-Antioxidative Thiolated Gelatin/Methacrylated Silk Fibroin Hydrogels with Nitric Oxide Release Catalyzed by Metal-Polyphenol Nanoparticles for MRSA-Infected Wound Healing.

Chronic wound infection often leads to irregular tissue closure and accompanies delayed healing and economy issues. Developing an ideal wound dressing that can control the occurrence of antibacterial infections and biological responses is highly desirable. In this study, a multifunctional hybrid hydrogel (GS@EG-Cu-CA NPs) containing synthesized thiolated gelatin, methacrylated silk fibroin, and (-)-epigallocatechin gallate-copper ionic-carrageenan nanoparticles (EG-Cu-CA NPs) was engineered by a thio-ene click reaction. The metal-polyphenol EG-Cu-CA NPs were encapsulated with kappa-carrageenan to enhance its aqueous-soluble, mechanical, and bioactive properties and endowed the hydrogel dressing with fascinating antibacterial, antioxidation, and nitric oxide (NO) generation by catalyzing. The hybrid hydrogels also illustrated a favorable cytocompatibility. Benefiting from the thio-ene click reaction, the hybrid hydrogels were injected and photocured rapidly in situ to cover an irregular wound. In an SD rat full-thickness skin-wound-infected model, the methicillin-resistant Staphylococcus aureus-infected wound covered with GS@EG-Cu-CA NPs was almost completely healed after 10 days. This study presents a facile design of hydrogel dressing incorporating metal-polyphenol nanoparticles, which demonstrates a promising potential way for dealing with effective wound infection management and other complicated wound healings.

Enhancing Idiopathic Scoliosis Patients' Outcomes Through Functional Rehabilitation Training in Combination with Orthosis.

Objective: This study aims to provide clinical evidence for the treatment of idiopathic scoliosis (IS) by assessing the therapeutic effectiveness of combining functional rehabilitation training with orthosis. Methods: We enrolled a total of 94 IS patients who were admitted to our hospital from April 2020 to February 2022. These patients were randomly assigned into two groups: a research group (RG; n=47) receiving functional rehabilitation training combined with orthosis and a control group (CG; n=47) receiving orthosis treatment alone. Clinical outcomes were evaluated one year after treatment. We also measured the Cobb angle, apical vertebral rotation (AVR), and the distance between the vertical line of the sacrum and the spinous process of the scoliosis parietal vertebra before and after treatment to determine apical vertebral translation (AVT) from the sacral midline and lumbar range of motion (ROM). Patient quality of life was assessed using the Short-Form 36 Item Health Survey (SF-36). Results: After treatment, the research group exhibited significantly lower Cobb angles, AVR, and AVT, along with a higher overall response rate and greater lumbar ROM compared to the control group (P < .05). Post-treatment SF-36 scores increased in both groups, with notably higher scores in the research group (P < .05). Conclusions: Combining functional rehabilitation training with orthosis is an effective approach for the treatment of IS and holds substantial clinical significance.

Comparison of Different Competitive Proteome Profiling Approaches in Target Identification of Covalent Inhibitors.

Competitive proteome profiling is a powerful approach for the identification of targets of small molecules. This approach usually employs an inhibitor-derived probe or a cysteine-reactive probe such as an IA-alkyne in a comparison between inhibitor-treated and untreated samples, thus enabling distinction between genuine targets and nonspecific labeling. We have developed an active probe derived from an EGFR inhibitor, afatinib, and a cysteine reactive probe, an alkyne-containing α,ß-unsaturated amide, to compare their characterization of cellular targets. In both approaches, myosin heavy chain 9 (MYH9) was identified as an off-target. Subsequent functional validation experiments suggested that MYH9 might be involved in the function of afatinib.

Mxene Reinforced Supramolecular Hydrogels with High Strength, Stretchability, and Reliable Conductivity for Sensitive Strain Sensors.

Conductive hydrogels used as electronics have received much attention due to their great flexibility and stretchability. However, the fabrication of ideal conductive hydrogels fulfilling the excellent mechanical properties and outstanding sensitivity remains a great challenge until now. Moreover, high sensitivity and broad linearity range are pivotal for the feasibility and accuracy of hydrogel sensors. In this study, a conductive supramolecular hydrogel is engineered by directly mixing the aqueous dispersion of MXene with the precursor of N-acryloyl glycinamide (NAGA) monomer and then rapidly photo cross-linked by UV irradiation. The resultant PNAGA/MXene hydrogel-sensors exhibit high mechanical strength (4.8 MPa), great stretchability (630%), and excellent durability. The conductive hydrogel-based sensor presents excellent conductivity (17.3 S m-1 ) and a wide scope of linear dependence of sensitivity on strain (0%-125%, gauge factor = 2.05). It displays reliable detection of various motions, including repeated subtle movements and large strain. It also shows good degradation in vitro and antifouling capability. This work may provide a simple and promising platform for engineering conductive supramolecular hydrogels with integrated high performance aiming for smart wearable electronics, electronic skin, soft robots, and human-machine interfacing.

Metformin attenuates sepsis-induced neuronal injury and cognitive impairment.

BACKGROUND: Sepsis is considered to be a high-risk factor for cognitive impairment in the brain. The purpose of our study is to explore whether sepsis causes cognitive impairment and try to evaluate the underlying mechanisms and intervention measures. METHODS: Here, we used cecum ligation and puncture (CLP) to simulate sepsis. Open field, Novel Objective Recognition, and Morris Water Maze Test were used to detect cognitive function, long-term potentiation was used to assess of synaptic plasticity, and molecular biological technics were used to assess synaptic proteins, ELISA kits were used to detect inflammatory factors. Metformin was injected into the lateral ventricle of SD rats, and we evaluated whether metformin alleviated CLP-mediated cognitive impairment using behavioral, electrophysiological and molecular biological technology experiments. RESULTS: Here we report hippocampal-dependent cognitive deficits and synaptic dysfunction induced by the CLP, accompanied by a significant increase in inflammatory factors. At the same time, metformin was able to improve cognitive impairment induced by CLP in adult male rats. CONCLUSION: These findings highlight a novel pathogenic mechanism of sepsis-related cognitive impairment through activation of inflammatory factors, and these are blocked by metformin to attenuate sepsis-induced neuronal injury and cognitive impairment.

Metformin attenuates LPS-induced neuronal injury and cognitive impairments by blocking NF-κB pathway.

BACKGROUND: Neuroinflammatory response is considered to be a high-risk factor for cognitive impairments in the brain. Lipopolysaccharides (LPS) is an endotoxin that induces acute inflammatory responses in injected bodies. However, the molecular mechanisms underlying LPS-associated cognitive impairments still remain unclear. METHODS: Here, primary hippocampal neurons were treated with LPS, and western blotting and immunofluorescence were used to investigate whether LPS induces neurons damage. At the same time, SD rats were injected with LPS (830 µg/Kg) intraperitoneally, and Open field test, Novel Objective Recognition test, Fear condition test were used to detect cognitive function. LTP was used to assess synaptic plasticity, and molecular biology technology was used to assess the NF-κB pathway, while ELISA was used to detect inflammatory factors. In addition, metformin was used to treat primary hippocampal neurons, and intraventricularly administered to SD rats. The same molecular technics, behavioral and electrophysiological tests were used to examine whether metformin could alleviate the LPS-associated neuronal damage, as well as synaptic plasticity, and behavioral alterations in SD rats. RESULTS: Altogether, neuronal damage were observed in primary hippocampal neurons after LPS intervention, which were alleviated by metformin treatment. At the same time, LPS injection in rat triggers cognitive impairment through activation of NF-κB signaling pathway, and metformin administration alleviates the LPS-induced memory dysfunction and improves synaptic plasticity. CONCLUSION: These findings highlight a novel pathogenic mechanism of LPS-related cognitive impairments through activation of NF-κB signaling pathway, and accumulation of inflammatory mediators, which induces neuronal pathologic changes and cognitive impairments. However, metformin attenuates LPS-induced neuronal injury and cognitive impairments by blocking NF-κB pathway.

Recombinant Tissue-Type Plasminogen Activator Study of Wake-Up Ischemic Strokes Guided by Rapid MRI.

BACKGROUND: rt-PA intravenous thrombolytic therapy and its efficacy have been widely recognized and proved for strokes. However, for patients with wake-up ischemic stroke (WUIS), they lose the opportunity to receive rt-PA intravenous thrombolytic therapy because of the difficulty of determining the onset time window. AIM: This study is aimed at investigating the intravenous thrombolytic therapy of WUIS guided by rapid MRI. METHODS: Data were collected from patients with acute ischemic stroke within 4.5 h and from WUIS patients with uncertain onset time window, who received the treatment of rt-PA intravenous thrombolytic therapy in our hospital from November 2006 to April 2018. The improved Rankin scale was used to evaluate neurological function recovery. According to the Rankin scale score, patients were divided into two groups: those with good prognosis (modified Rankin scale [mRS] score 0-1) and those with poor prognosis (mRS score 2-6). RESULTS: A total of 253 patients received rt-PA intravenous thrombolysis after head MRI evaluation; this included 177 cases of acute ischemic stroke and 76 cases of WUIS (which contains 2 death cases, 0.8% mortality; 3 cases of symptomatic bleeding, 1.2% bleeding rate; and 5 cases of aggravation, 2.0% aggravation rate). There was no statistical difference between the baseline data from the acute ischemic stroke patients with 4.5 h onset time window and the baseline data from the WUIS patients with undetermined onset time window, when the treatment was guided by rapid MRI. There were also no significant statistical differences in National Institutes of Health Stroke Scale score, Rankin scale score, symptomatic bleeding, death and aggravation of the disease between the 2 groups at 24 h, 3 days, and 7 days after admission (p < 0.05). CONCLUSION: According to the characteristic of undetermined onset time window of WUIS, more WUIS patients would be benefited from the rt-PA intravenous thrombolytic treatment when it is conducted under the guidance of rapid MRI.

Gardenamide A Protects RGC-5 Cells from H2O2-Induced Oxidative Stress Insults by Activating PI3K/Akt/eNOS Signaling Pathway.

Gardenamide A (GA) protects the rat retinal ganglion (RGC-5) cells against cell apoptosis induced by H2O2. The protective effect of GA was completely abrogated by the specific phosphoinositide 3-kinase (PI3K) inhibitor LY294002, and the specific protein kinase B (Akt) inhibitor Akt VIII respectively, indicating that the protective mechanism of GA is mediated by the PI3K/Akt signaling pathway. The specific extracellular signal-regulated kinase (ERK1/2) inhibitor PD98059 could not block the neuroprotection of GA. GA attenuated the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) induced by H2O2. Western blotting showed that GA promoted the phosphorylation of ERK1/2, Akt and endothelial nitric oxide synthase (eNOS), respectively, and effectively reversed the H2O2-inhibited phosphorylation of these three proteins. LY294002 completely inhibited the GA-activated phosphorylation of Akt, while only partially inhibiting eNOS. This evidence implies that eNOS may be activated directly by GA. PD98059 attenuated only partially the GA-induced phosphorylation of ERK1/2 with/without the presence of H2O2, indicating that GA may activate ERK1/2 directly. All these results put together confirm that GA protects RGC-5 cells from H2O2 insults via the activation of PI3K/Akt/eNOS signaling pathway. Whether the ERK1/2 signaling pathway is involved requires further investigations.

[Different ratio of hormone effects on Fritillaria cirrhosa bulb induction].

OBJECTIVE: To study the effects of different hormone induced bulb of Fritillaria cirrhosa seedling leaves, in order to provide an effective way to expant Fritillaria cirrhosa source. METHODS: Fritillaria cirrhosa seedling leaves were used as explants, orthogonal test was carried out to study the medium consisting of 6-BA, NAA, 2, 4-D and KT, and proliferation induced by direct bulb. Induction rate and average number of bulb producing was treated as the assessment indices, and the content of alkaloid of bulb was determined. RESULTS: The best medium formula for Fritillaria cirrhosa tissue culture seedling was MS+6-BA 2.0 mg/L +NAA 1.0mg/L +KT 1.0mg/L, the bulb induction rate was 83.37% and the average number of bulb was 17.27. The alkaloid content of induced bulb was 0.389%, which was 1.64 times that of wild Fritillaria cirrhosa bulb. CONCLUSION: This study provides a simple and rapid mehod for the production of tissue culture of Fritillaria cirrhosa bulb. It is useful for reasonable development and utilization of Fritillaria cirrhosa resources, as well as improvement of the quality of medicinal materials.

Clinical significance and immune characteristics analysis of miR-221-3p and its key target genes related to epithelial-mesenchymal transition in breast cancer.

BACKGROUND: MicroRNA-221-3p (miR-221-3p) facilitates the advancement of breast cancer (BC) through the induction of epithelial-mesenchymal transition (EMT). Our research aimed to utilize bioinformatics to discover possible EMT-related target genes (ETGs) of miR-221-3p and examine their roles in breast cancer. METHODS: We employed bioinformatics techniques to identify ten key ETGs of miR-221-3p. Subsequently, we conducted an extensive analysis of both miR-221-3p and the ten ETGs, including clinical significance and immune characteristics. RESULTS: The expression of miR-221-3p was notably higher in Basal-like BC compared to other subtypes and adjacent normal tissue. Our pathway analysis suggested that miR-221-3p might regulate EMT through the MAPK signaling pathway by targeting its ETGs. Among the ETGs, seven core genes (EGFR, IGF1, KDR, FGF2, KIT, FGFR1, and FGF1) exhibited downregulation in BC. Conversely, ERBB2, SDC1, and MMP14 showed upregulation in BC and displayed potential diagnostic value. The analysis of prognostication indicated that increased levels of SDC1 and MMP14 were correlated with an unfavorable prognosis, whereas elevated expression of KIT was associated with a more favorable prognosis. The infiltration of various immune cells and the expression of immune checkpoint genes (ICGs) exhibited positive correlations with most ETGs and miR-221-3p. SDC1 exhibited a greater tumor mutational burden (TMB) score, while ERBB2, KDR, FGF2, KIT, FGFR1, and FGF1 showed lower TMB scores. Furthermore, decreased ERBB2 and KDR expression levels were correlated with elevated microsatellite instability (MSI) scores. Elevated expression of ETGs was linked to decreased mRNA stemness indices (mRNAsi), whereas miR-221-3p displayed the opposite pattern. Most ETGs and miR-221-3p expression exhibited a negative correlation with IC50 values for drugs. Among the ETGs, amplification was the most significant genetic alteration, except for IGF1. CONCLUSION: In conclusion, miR-221-3p acts as a unique indicator for Basal-like BC. The examination revealed ten essential ETGs of miR-221-3p, some of which show potential as diagnostic and prognostic markers. The in-depth examination of these ten ETGs and miR-221-3p indicates their participation in the development of BC, emphasizing their promise as innovative targets for therapy in BC patients.

Guanidinylated bioactive chitosan-based injectable hydrogels with pro-angiogenic and mechanical properties for accelerated wound closure.

Wound healing is a complex process involving the concerted action of many genes and signaling pathways, with angiogenesis being crucial for expediting wound closure. Dressings that possess pro-angiogenic properties are increasingly recognized as attractive candidates for wound care. Drawing inspiration from the active closure of wounds in embryos, we have developed a thermo-responsive hydrogel with mechanoactive properties, combining vascular regeneration and skin wound contraction to accelerate healing. The significant improvement in vascular reconstruction is attributed to the synergistic effect of arginine and deferoxamine (DFO) released from the hydrogels. Additionally, the contraction force of the hydrogel actively promotes skin closure in wounds. Remarkably, groups treated with hydroxybutyl chitosan methacrylate combined with arginine (HBC_m_Arg/DFO) exhibited increased vascularization, and greater wound maturity, leading to enhanced healing. These results highlight the synergistic impact of pro-angiogenic and mechanical properties of the HBC_m_Arg/DFO hydrogel in accelerating wound healing in rats.

Mitochondrial-related genes as prognostic and metastatic markers in breast cancer: insights from comprehensive analysis and clinical models.

Background: Breast cancer (BC) constitutes a significant peril to global women's health. Contemporary research progressively suggests that mitochondrial dysfunction plays a pivotal role in both the inception and advancement of BC. However, investigations delving into the correlation between mitochondrial-related genes (MRGs) and the prognosis and metastasis of BC are still infrequent. Methods: Utilizing data from the TCGA database, we employed the "limma" R package for differential expression analysis. Subsequently, both univariate and multivariate Cox regression analyses were executed, alongside LASSO Cox regression analysis, to pinpoint prognostic MRGs and to further develop the prognostic model. External validation (GSE88770 merged GSE425680) and internal validation were further conducted. Our investigation delved into a broad spectrum of analyses that included functional enrichment, metabolic and immune characteristics, immunotherapy response prediction, intratumor heterogeneity (ITH), mutation, tumor mutational burden (TMB), microsatellite instability (MSI), cellular stemness, single-cell, and drug sensitivity analysis. We validated the protein and mRNA expressions of prognostic MRGs in tissues and cell lines through immunohistochemistry and qRT-PCR. Moreover, leveraging the GSE102484 dataset, we conducted differential gene expression analysis to identify MRGs related to metastasis, subsequently developing metastasis models via 10 distinct machine-learning algorithms and then selecting the best-performing model. The division between training and validation cohorts was set at 70% and 30%, respectively. Results: A prognostic model was constructed by 9 prognostic MRGs, which were DCTPP1, FEZ1, KMO, NME3, CCR7, ISOC2, STAR, COMTD1, and ESR2. Patients within the high-risk group experienced more adverse outcomes than their counterparts in the low-risk group. The ROC curves and constructed nomogram showed that the model exhibited an excellent ability to predict overall survival (OS) for patients and the risk score was identified as an independent prognostic factor. The functional enrichment analysis showed a strong correlation between metabolic progression and MRGs. Additional research revealed that the discrepancies in outcomes between the two risk categories may be attributed to a variety of metabolic and immune characteristics, as well as differences in intratumor heterogeneity (ITH), tumor mutational burden (TMB), and cancer stemness indices. ITH, TIDE, and IPS analyses suggested that patients possessing a low-risk score may exhibit enhanced responsiveness to immunotherapy. Additionally, distant metastasis models were established by PDK4, NRF1, DCAF8, CHPT1, MARS2 and NAMPT. Among these, the XGBoost model showed the best predicting ability. Conclusion: In conclusion, MRGs significantly influence the prognosis and metastasis of BC. The development of dual clinical prediction models offers crucial insights for tailored and precise therapeutic strategies, and paves the way for exploring new avenues in understanding the pathogenesis of BC.

Prognostic implication of novel immune-related signature in breast cancer.

Checkpoint inhibitor therapy has become increasingly important and has been endorsed as a treatment regimen in breast cancer. But benefits were limited to a small proportion of patients. We aimed to develop an improved signature on the basis of immune genes for detection of potential benefit from immunotherapy. Gene expression data of patients with breast cancer initially extracted from The Cancer Genome Atlas were analyzed. Ten genes were selected from the interaction of differentially expressed genes as well as immune-related genes to develop a survival signature. We compared the high-risk and low-risk groups by gene set enrichment analysis, immune infiltration, checkpoint molecule expression and immunophenoscore. Ten genes were extracted from interactions of differentially expressed and immune-related genes. The immune risk score was determined on the basis of the Cox regression coefficient of hub genes and validated with the GSE96058 dataset. Immune cell infiltrates, including CD8 + T cells, plasma cells, follicular helper T cells, CD4 + memory T cells, M1 macrophages, regulatory T cells and resting NK cells, were more highly infiltrated in the high-risk group as compared to the low-risk group. Checkpoint molecules, including CTLA-4, PD-L1, TIM-3, VISTA, ICOS, PD-1, and PD-L2, were expressed at markedly lower levels in the high-risk group as compared to the low-risk group. Immunophenoscores, as a surrogate of response to immune checkpoint therapy, was observed significant lower in the high-risk group. The 10-gene prognostic signature could identify patients' survival and was correlated with the biomarkers of immune checkpoint inhibitor therapy, which may guide precise therapeutic decisions in clinical practice.

Modulation of macrophage polarization by secondary cross-linked hyaluronan-dopamine hydrogels.

The inflammatory response plays a critical role in standard tissue repair processes, wherein active modulation of macrophage polarization is necessary for wound healing. Dopamine, a mussel-inspired bioactive material, is widely involved in wound healing, neural/bone/myocardial regeneration, and more. Recent studies indicated that dopamine-modified biomaterials can potentially alter macrophages polarization towards a pro-healing phenotype, thereby enhancing tissue regeneration. Nevertheless the immunoregulatory activity of dopamine on macrophage polarization remains unclear. This study introduces a novel interpenetrating hydrogel to bridge this research gap. The hydrogel, combining varying concentrations of oxidized dopamine with hyaluronic acid hydrogel, allows precise regulation of mechanical properties, antioxidant bioactivity, and biocompatibility. Surprisingly, both in vivo and in vitro outcomes demonstrated that dopamine concentration modulates macrophage polarization, but not linearly. Lower concentration (2 mg/mL) potentially decrease inflammation and facilitate M2 type macrophage polarization. In contrast, higher concentration (10 mg/mL) exhibited a pro-inflammatory tendency in the late stages of implantation. RNA-seq analysis revealed that lower dopamine concentrations induced the M1/M2 transition of macrophages by modulating the NF-κB signaling pathway. Collectively, this research offers valuable insights into the immunoregulation effects of dopamine-integrated biomaterials in tissue repair and regeneration.

Injectable hydrogel microsphere-bomb for MRSA-infected chronic osteomyelitis.

Biofilm and bone tissue defect induced by the bacterial infection severely impede chronic osteomyelitis treatment. It is critical to break though the densely and obstinate biofilm so that the target drugs can deliver to the infected bone more effectively. Herein, an acoustically responsive multifunctional hydrogel microsphere-bomb (EMgel) was designed and prepared by microfluidic technology, which could be injected to the focus of bone infection, and blasted into the nidus deeply to destroy the bacterial biofilm matrix barrier under penetrating ultrasound, so the encapsulated natural polyphenolic EGCG and bioactive MoS2 released to repair the damaged bone. The results proved the hydrogel microsphere-bomb exhibited controlling drug release, favorable antibacterial (as high as 99 %), high biofilm resistance, fascinating antioxidation, good cytocompatibility, and osteogenic differentiation. The acoustically responsive microsphere-bomb further proved their fantastic ability to eradicate biofilm and promote bone regeneration in the Methicillin-resistant Staphylococcus aureus (MRSA) infected chronic osteomyelitis model due to the synergy effects of EGCG and bioactive MoS2. Especially, immunohistochemical staining showed lower inflammatory reaction and higher expression of OCN in EMgel group treated with ultrasound wave. This study presents a new design of hydrogel microsphere-based intelligence drug delivery for osteomyelitis treatment, which exhibit great promising potential for dealing with chronic orthopedic infections, drug delivery system and tissue engineering.

Intraoperative evaluation of tumor margins using a TROP2 near-infrared imaging probe to enable human breast-conserving surgery.

Intraoperative surgical margin assessment remains a challenge during breast-conserving surgery. Here, we report a combined strategy of immuno-positron emission tomography (PET) for preoperative detection of breast cancer and guided assessment of margins in breast-conserving surgery through second near-infrared (NIR-II) fluorescence imaging of trophoblastic cell surface antigen 2 (TROP2). We demonstrated that the intensity of PET signals in the tumors was nearly five times higher than in normal breast tissue with a zirconium-89 tracer conjugated to sacituzumab govitecan (SG) in a mouse spontaneous breast cancer model, enabling the identification of tumors. We further generated a NIR-II probe of indocyanine green conjugated to SG (ICG-SG) and developed a rapid incubation imaging method for intraoperative margin assessment in a relevant time window for the operation workflow. The ICG-SG NIR-II fluorescence image guidance was first verified to remove tumors completely and accurately in mouse breast cancer models. Moreover, the rapid incubation imaging method was applied to distinguish benign and malignant breast lesions in samples from 26 patients with breast cancer. Therefore, we have developed both nuclide and optical probes targeting TROP2 for rapid and precise identification of tumor margins during breast-conserving surgery in humans.