Enzyme Core Spherical Nucleic Acid That Enables Enhanced Cuproptosis and Antitumor Immune Response through Alleviating Tumor Hypoxia.

Cuproptosis, a copper-dependent cell death process, has been confirmed to further activate the immune response and mediate the immune resistance. However, hypoxic tumor microenvironment hampers cuproptosis sensitivity and suppresses the body's antitumor immune response. Herein, we have successfully immobilized and functionalized catalase (CAT) with long single-stranded DNA containing polyvalent CpG sequences through rolling circle amplification (RCA) techniques, obtaining an enzyme-cored spherical nucleic acid nanoplatform (CAT-ecSNA-Cu) to deliver copper ions for cuproptosis. The presence of long-stranded DNA-protected CAT enhances mitochondrial respiration by catalyzing the conversion of H2O2 to O2, thereby sensitizing cuproptosis. Meanwhile, increased tumor oxygenation suppresses the expression of the hypoxia-inducible factor-1 (HIF-1) protein, resulting in the alleviation of the immunosuppressive tumor microenvironment. Of note, cuproptosis induces immunogenic cell death (ICD), which facilitates dendritic cell (DC) maturation and enhances antigen presentation through polyCpG-supported Toll-like receptor 9 (TLR9) activation. Furthermore, cuproptosis-induced PD-L1 upregulation in tumor cells complements checkpoint blockers (αPD-L1), enhancing antitumor immunity. The strategy of enhancing cuproptosis-mediated antitumor immune responses by alleviating hypoxia effectively promotes the activation and proliferation of effector T cells, ultimately leading to long-term immunity against cancer.

Iron-Single-Atom Nanozyme with NIR Enhanced Catalytic Activities for Facilitating MRSA-Infected Wound Therapy.

Patients with methicillin-resistant Staphylococcus aureus (MRSA) infections may have higher death rates than those with non-drug-resistant infections. Nanozymes offer a promising approach to eliminating bacteria by producing reactive oxygen species. However, most of the conventional nanozyme technologies encounter significant challenges with respect to size, composition, and a naturally low number of active sites. The present study synthesizes a iron-single-atom structure (Fe-SAC) via nitrogen doped-carbon, a Fe-N5 catalyst (Fe-SAC) with a high metal loading (4.3 wt.%). This catalyst permits the development of nanozymes consisting of single-atom structures with active sites resembling enzymes, embedded within nanomaterials. Fe-SAC displays peroxidase-like activities upon exposure to H2O2. This structure facilitates the production of hydroxyl radicals, well-known for their strong bactericidal effects. Furthermore, the photothermal properties augment the bactericidal efficacy of Fe-SAC. The findings reveal that Fe-SAC disrupts the bacterial cell membranes and the biofilms, contributing to their antibacterial effects. The bactericidal properties of Fe-SAC are harnessed, which eradicates the MRSA infections in wounds and improves wound healing. Taken together, these findings suggest that single Fe atom nanozymes offer a novel perspective on the catalytic mechanism and design, holding immense potential as next-generation nanozymes.

Risk factors for perioperative blood transfusion in patients undergoing total laparoscopic hysterectomy.

PURPOSE: The goal is to identify risk factors associated with receiving a blood transfusion during the perioperative period in patients who undergo total laparoscopic hysterectomy (TLH) using a large-scale national database. METHODS: In this retrospective analysis, data from the Nationwide Inpatient Sample (NIS) was utilized to review the medical records of all patients who underwent TLH from 2010 to 2019. The researchers identified patients who had received a blood transfusion during the perioperative period and compared with those who had not. The subsequent factors associated with blood transfusion were examined: hospital characteristics (type of admission and payer, patient demographics (age and race), bed size, teaching status, location, and region of hospital), length of stay (LOS), total charges during hospitalization, in-hospital mortality, comorbidities, and perioperative complications. The data was analyzed using descriptive statistics. The independent risk factors of perioperative blood transfusion after TLH was identified by performing multivariate logistic regression. RESULTS: A total of 79,933 TLH were captured from the NIS database, among which 3433 (4.40%) patients received a perioperative blood transfusion. TLH patients affected by blood transfusion were 2 days longer hospital stays (P < 0.001), higher overall costs (P < 0.001), the patients who received a transfusion after a long-term hospitalization had a significantly higher rate of mortality (0.5% vs. 0.1%; P < 0.001). Perioperative blood transfusion after TLH was associated with chronic blood loss anemia, deficiency anemia, coagulopathy, congestive heart failure, fluid and electrolyte disorders, renal failure, metastatic cancer, sepsis, weight loss, deep vein thrombosis, gastrointestinal hemorrhage, shock, acute myocardial infarction, and pneumonia, stroke, hemorrhage, pulmonary embolism, and disease of the genitourinary system. CONCLUSION: Studying the risk factors of perioperative blood transfusion after TLH is advantageous in order to ensure proper management and optimize outcomes.

A Cardiac-Targeted Nanozyme Interrupts the Inflammation-Free Radical Cycle in Myocardial Infarction.

Severe systemic inflammation following myocardial infarction (MI) is a major cause of patient mortality. MI-induced inflammation can trigger the production of free radicals, which in turn ultimately leads to increased inflammation in cardiac lesions (i.e., inflammation-free radicals cycle), resulting in heart failure and patient death. However, currently available anti-inflammatory drugs have limited efficacy due to their weak anti-inflammatory effect and poor accumulation at the cardiac site. Herein, a novel Fe-Cur@TA nanozyme is developed for targeted therapy of MI, which is generated by coordinating Fe3+ and anti-inflammatory drug curcumin (Cur) with further modification of tannic acid (TA). Such Fe-Cur@TA nanozyme exhibits excellent free radicals scavenging and anti-inflammatory properties by reducing immune cell infiltration, promoting macrophage polarization toward the M2-like phenotype, suppressing inflammatory cytokine secretion, and blocking the inflammatory free radicals cycle. Furthermore, due to the high affinity of TA for cardiac tissue, Fe-Cur@TA shows an almost tenfold greater in cardiac retention and uptake than Fe-Cur. In mouse and preclinical beagle dog MI models, Fe-Cur@TA nanozyme preserves cardiac function and reduces scar size, suggesting promising potential for clinical translation in cardiovascular disease.

Smartphone-Based Fluorescent Profiling of Quaternary MicroRNAs in Urine for Rapid Diagnosis of Urological Cancers Using a Multiplexed Isothermal Exponential Amplification Reaction.

Urological cancers such as bladder or prostate cancer represent one of the most malignant tumors that accounts for an extremely high mortality. However, conventionally standard diagnostics for urological cancers are hardly available in low-resource settings. We developed herein a hand-held fluorescent imaging platform by integrating a multiplexed isothermal exponential amplification reaction (EXPAR) with a microgel-enriched methodology for sensitive profiling of quaternary microRNAs (miRNAs) in urine and quick diagnosis of urological cancers at the early stage. The target miRNA mixtures in the urine underwent four parallel EXPARs without cross-reactivity, followed by surface concentration and hybridization by the encoded polyacrylamide microgels. This mix-and-read strategy allowed for one-pot analysis of several key miRNAs simultaneously and provided 5-fold enhancement in fluorescent detection sensitivities compared to the individual EXPAR-based assays. Four urinary miRNAs (let-7a, miRNA-155, -223, and -143) could be quantitatively determined in a wide linear range from 50 fM to 30 nM, with the limits of detection at femtomolar levels. Using a smartphone-based imaging microreader, healthy and cancerous cohorts with prostate, bladder, and renal cell cancers could be discriminated in 30 min with the accuracy >83% using linear discriminant analysis. The developed detection platform has proven to be a portable, noninvasive, and useful complement to the toolbox for miRNA-based liquid biopsies, which holds immense potential and advantage for regular and large-scale applications in early cancer diagnosis.

An Intelligent DNA Nanoreactor for Easy-to-Read In Vivo Tumor Imaging and Precise Therapy.

Nanomaterial-based in vivo tumor imaging and therapy have attracted extensive attention; however, they suffer from the unintelligent "always ON" or single-parameter responsive signal output, substantial off-target effects, and high cost. Therefore, achieving in vivo easy-to-read tumor imaging and precise therapy in a multi-parameter responsive and intelligent manner remains challenging. Herein, an intelligent DNA nanoreactor (iDNR) was constructed following the "AND" Boolean logic algorithm to address these issues. iDNR-mediated in situ deposition of photothermal substance polydopamine (PDA) can only be satisfied in tumor tissues with abundant membrane protein biomarkers "AND" hydrogen peroxide (H2 O2 ). Therefore, intelligent temperature-based in vivo easy-to-read tumor imaging is realized without expensive instrumentation, and its diagnostic performance matches with that of flow cytometry, and photoacoustic imaging. Moreover, precise photothermal therapy (PTT) of tumors could be achieved via intelligent heating of tumor tissues. The precise PTT of primary tumors in combination with immune checkpoint blockade (ICB) therapy suppresses the growth of distant tumors and inhibits tumor recurrence. Therefore, highly programmable iDNR is a powerful tool for intelligent biomedical applications.

Advances of hafnium based nanomaterials for cancer theranostics.

Hafnium-based nanomaterials (Hf-NMs) have attracted the interest of numerous biomedical researchers by their unique properties. Recent years have witnessed significant advancements in the field of Hafnium-based nanomaterials, particularly in the context of cancer diagnosis and treatment. However, research in this area, especially concerning the clinical application of Hafnium-based nanomaterials, has not been thoroughly reviewed. This review will cover: 1) Classification and synthesis of Hafnium-based nanomaterials including Hafnium oxide nanomaterials, Hafnium Metal-Organic Frameworks/nanoscale coordination polymers (MOFs/NCPs); 2) Hafnium-based nanomaterials act as contrast enhancement agent for cancer imaging, and hafnium-based nanomaterials used for diagnosis in cancer liquid biopsy; 3) hafnium-based nanomaterials for cancer therapy, including hafnium-based nanomaterials for radiotherapy, hafnium-based nanomaterials for photodynamic therapy, hafnium-based nanomaterials for various combined therapy; and 4) Translation, toxicity, and safety for Hf-NMs in human and preclinical animal models. More attention will be given to the clinical translation of Hf-NMs in cancer.

Small breast epithelial mucin as a useful prognostic marker for breast cancer patients.

This study aimed to evaluate the clinical utility of small breast epithelial mucin (SBEM) as a prognostic biomarker in an independent patient cohort. The paraffin-embedded tissues and clinicopathological data of 105 patients with breast cancer were collected, and the expression of SBEM in breast cancer samples was detected by immunohistochemical staining. The correlations between clinicopathological variables and the expression of SBEM were analyzed, and its significance as a prognostic indicator for breast cancer patients was determined. Immunohistochemical staining revealed that SBEM was expressed mostly in the cytomembrane and cytoplasm, with markedly increased SBEM expression (≥4 points on staining intensity) observed in 34 of 105 breast cancer tissues (32.4%). Elevated expression of SBEM was found to be significantly associated with larger tumor size (P = 0.002), more frequent lymph node metastasis (P = 0.029), advanced tumor node metastasis stage (P = 0.005), reduced expression of the progesterone receptor (PR) (P = 0.002), and a higher Ki-67 index (P = 0.006). Survival analysis indicated that patients with elevated SBEM expression had worse overall survival (OS) (5-year OS rate: 50.5 vs 93.9% for high and low SBEM expression, respectively, P < 0.001) and disease-free survival (DFS) (5-year DFS rate: 52.8 vs 81.7% for high and low SBEM expression, respectively, P = 0.001) rates than those with low expression of SBEM. Univariate and multivariate Cox analyses demonstrated that elevated expression of SBEM (hazard ratio [HR] = 1.994, 95% confidence interval [CI]: 1.008-3.945, P = 0.047), tumor size (HR = 2.318, 95% CI: 1.071-5.017, P = 0.033), and PR status (HR = 0.195, 95% CI: 0.055-0.694, P = 0.012) were independent predictors of OS in breast cancer patients. Elevated expression of SBEM was associated with both aggressive tumor characteristics and poor survival, indicating its potential as a useful prognostic biomarker for breast cancer patients.

Metal-DNA Nanocomplexes Enhance Chemo-dynamic Therapy by Inhibiting Autophagy-Mediated Resistance.

Chemo-dynamic therapy (CDT) based on the Fenton or Fenton-like reaction has emerged as a promising approach for cancer treatment. However, autophagy-mediated self-protection mechanisms of cancer cells pose a significant challenge to the efficacy of CDT. Herein, we developed metal-DNA nanocomplexes (DACs-Mn) to enhance CDT via DNAzyme inhibition of autophagy. Specifically, Mn-based catalyst in DACs-Mn was used to generate highly hydroxyl radicals (⋅OH) that kill cancer cells, while the ATG5 DNAzyme incorporated into DACs-Mn inhibited the expression of autophagy-associated proteins, thereby improving the efficacy of CDT. By disrupting the self-protective pathway of cells under severe oxidative stress, this novel approach of DACs-Mn was found to synergistically enhance CDT in both in vitro and in vivo models, effectively amplifying tumor-specific oxidative damage. Notably, the Metal-DNA nanocomplexes can also induce immunogenic cell death (ICD), thereby inhibiting tumor metastasis. Specifically, in a bilateral tumor model in mice, the combined approach of CDT and autophagy inhibition followed by immune checkpoint blockade therapy shown significant potential as a novel and effective treatment modality for primary and metastatic tumors.

Covalent LYTAC Enabled by DNA Aptamers for Immune Checkpoint Degradation Therapy.

Immune checkpoint blockade (ICB) therapy, while achieving tremendous clinical successes, still suffers from a low objective response rate in clinical cancer treatment. As a proof-of-concept study, we propose a new immune checkpoint degradation (ICD) therapy relying on lysosome-targeting chimera (LYTAC) to deplete immune checkpoint programmed death ligand-1 (PD-L1) on the tumor cell surface. Our designed chimeric aptamer on one side targets lysosome-trafficking receptor, and on the other side allows biorthogonal covalent-conjugation-reinforced specific binding of PD-L1. This covalent LYTAC is able to hijack PD-L1 for lysosomal degradation with greatly improved efficiency over its noncovalent counterpart in complex in vivo environment. Beyond abolishing the PD-1/PD-L1 axis associated immune resistance, we demonstrate for the first time that LYTAC-triggered PD-L1 degradation could directly cause immunogenic apoptosis of tumor cells to elicit tumor-specific immune responses, offering unparalleled advantages over ICB antibody therapy. Remarkably, ICD therapy with covalent LYTAC achieves comparable or higher antitumor efficacy while causing significantly less inflammatory injury compared to antibody-based ICB therapy. Moreover, covalent LYTAC can serve as a general platform for specifically degrading other membrane-associated proteins, making it a promising tool for future applications. Our work presents a novel molecular tool for effective LYTAC in complex environments, offering valuable insights in pushing DNA-based LYTAC drugs toward in vivo and clinical applications.

Rapid Diagnosis of Urinary Tract Cancers on a LEGO-Inspired Detection Platform via Chemiresistive Profiling of Volatile Metabolites.

Rapid and in situ profiling of volatile metabolites from body fluids represents a new trend in cancer diagnosis and classification in the early stages. We report herein an on-chip strategy that combines an array of conductive nanosensors with a chaotic gas micromixer for real-time monitoring of volatiles from urine and for accurate diagnosis and classification of urinary tract cancers. By integrating a class of LEGO-inspired microchambers immobilized with MXene-based sensing nanofilms and zigzag microfluidic gas channels, it enables the intensive intermingling of volatile organic chemicals with sensor elements that tremendously facilitate their ion-dipole interactions for molecular recognition. Aided with an all-in-one, point-of-care platform and an effective machine-learning algorithm, healthy or diseased samples from subpopulations (i.e., tumor subtypes, staging, lymph node metastasis, and distant metastasis) of urinary tract cancers can be reliably fingerprinted in a few minutes with high sensitivity and specificity. The developed detection platform has proven to be a noninvasive supplement to the liquid biopsies available for facile screening of urinary tract cancers, which holds great potential for large-scale personalized healthcare in low-resource areas.

Comprehensive Analysis of the Expression and Prognostic Significance of the CENP Family in Breast Cancer.

Background: Centromere proteins (CENPs) are a set of protein-coding genes involved in the transient assembly of the kinetochore which occurs during mitosis. This study intended to clarify the expression patterns, prognosis and potential mechanisms of CENPs in breast cancer (BC). Methods: Coexpedia was used to screen GEO datasets and PubMed articles related to CENPs and BC. CENPs expressions, prognosis and alteration were analyzed by Oncomine, Ualcan and Kaplan Meier plotter and cBioPortal. The correlation and interaction of CENPs was performed by Breast Cancer Gene-Expression Miner, GeneMANIA and STRING portal. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were conducted to clarify the functional roles of CENPs. CENPF, E, U, A, N, I, K, W, M, L were selected for further analysis. Results: All CENPs were highly expressed in BC compared to normal tissue. High expression of CENPF, E, U, A, N, I, W, M, L and CENPF, E, U, A, N, I, M correlated with worse relapse free survival (RFS) and worse overall survival (OS), respectively. All of 10 CENPs indicated positive correlations and complex interactions between each other at mRNA expression and protein level. CENPs were enriched GO terms mainly in centromere complex assembly and KEGG terms in progesterone-mediated oocyte maturation, cell cycle and oocyte meiosis. Conclusion: The 10 CENPs could be diagnostic biomarkers and all of them except CENPK can be used as prognosis biomarkers in BC. CENPs play an oncogenic role and may be the potential therapy targets of treatment for BC patients.

[WITHDRAWN] miR-144-3p Functions as a Tumor Suppressor in Endometrial Cancer by Targeting PRR11.

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

Light-Triggered Efficient Sequential Drug Delivery of Biomimetic Nanosystem for Multimodal Chemo-, Antiangiogenic, and Anti-MDSC Therapy in Melanoma.

In view of the multiple pathological hallmarks of tumors, nanosystems for the sequential delivery of various drugs whose targets are separately located inside and outside tumor cells are desired for improved cancer therapy. However, current sequential delivery is mainly achieved through enzyme- or acid-dependent degradation of the nanocarrier, which would be influenced by the heterogeneous tumor microenvironment, and unloading efficiency of the drug acting on the target outside tumor cells is usually unsatisfactory. Here, a light-triggered sequential delivery strategy based on a liposomal formulation of doxorubicin (DOX)-loaded small-sized polymeric nanoparticles (DOX-NP) and free sunitinib in the aqueous cavity, is developed. The liposomal membrane is doped with photosensitizer porphyrin-phospholipid (PoP) and hybridized with red blood cell membrane to confer biomimetic features. Near-infrared light-induced membrane permeabilization triggers the "ultrafast" and "thorough" release of sunitinib (100% release in 5 min) for antiangiogenic therapy and also myeloid-derived suppressor cell (MDSC) inhibition to reverse the immunosuppressive tumor environment. Subsequently, the small-sized DOX-NP liberated from the liposomes is more easily uptaken by tumor cells for improved immunogenic chemotherapy. RNA sequencing and immune-related assay indicates therapeutic immune enhancement. This light-triggered sequential delivery strategy demonstrates the potency in cancer multimodal therapy against multiple targets in different spatial positions in tumor microenvironment.

The Two-Steps Reaction Fluorescent Probe for the Selective Detection of Cysteine and Its Applications.

We reported the specific fluorescent probe (MC-BOD-XDS) with two-steps reaction based on monosulfanyl-coumarin-BODIPY for selective detection of cysteine, high activity sulfanyl-coumarin as the multiple reaction group instead of a group internal standard fluorophore. The reaction mechanism of MC-BOD-XDS for detecting cysteine was different from the reported probes about the nucleophilic aromatic substitution reaction (SNAr) of chlorinated BODIPY. The fluorescent color of MC-BOD-XDS changed from yellow to red, and then to orange. The linear calibration diagram showed that it can potentially be used for quantitatively detection of Cys. Its potential applications were demonstrated by employing it for detection of Cys in artificial urine and in fluorescent imaging in HeLa cells.

Saikosaponin A, a Triterpene Saponin, Suppresses Angiogenesis and Tumor Growth by Blocking VEGFR2-Mediated Signaling Pathway.

Saikosaponin A (SSA), a main triterpenoid saponin component from Radix Bupleurum, has been revealed to have a variety of pharmacological activities. However, whether SSA can inhibit angiogenesis, a key step in solid tumor progression, remains unknown. In this study, we demonstrated that SSA could powerfully suppress the proliferation, migration, and tube formation of human umbilical vein endothelial cells. SSA also significantly inhibited angiogenesis in the models of the chick embryo chorioallantoic membrane and Matrigel plugs. Moreover, SSA was found to inhibit tumor growth in both orthotopic 4T1 breast cancer and subcutaneous HCT-15 colorectal tumor by the inhibition of tumor angiogenesis. Western blot assay indicated the antiangiogenic mechanism of SSA in the suppression of the protein phosphorylation of VEGFR2 and the downstream protein kinase including PLCγ1, FAK, Src, and Akt. In summary, SSA can suppress angiogenesis and tumor growth by blocking the VEGFR2-mediated signaling pathway.

The Innate Immune DNA Sensing cGAS-STING Signaling Pathway Mediates Anti-PRRSV Function.

Porcine reproductive and respiratory syndrome virus (PRRSV) modulates host innate immunity which plays a key role against PRRSV infection. As a RNA virus, PRRSV is mainly sensed by innate immune RNA receptors, whereas the role of innate immune DNA sensors in the PRRSV infection has not been elucidated. Here, we investigated the roles of DNA sensing cGAS-STING pathway in both PRRSV infected Marc-145 cells and porcine macrophages. The results show that in Marc-145 cells, the stable expression of STING with or without stimulations exhibited anti-PRRSV activity, and STING knockout heightened PRRSV infection. In CD163-3D4/21 porcine macrophages, either expression of STING or stimulation of cGAS-STING signaling obviously suppressed PRRSV infection, whereas in STING knockdown macrophages, the PRRSV infection was upregulated. Our results clearly demonstrate that the host cGAS-STING signal exerts an important antiviral role in PRRSV infection.

Metal Phenolic Network-Integrated Multistage Nanosystem for Enhanced Drug Delivery to Solid Tumors.

Metal-phenolic networks (MPNs) are an emerging class of supramolecular surface modifiers with potential use in various fields including drug delivery. Here, the development of a unique MPN-integrated core-satellite nanosystem (CS-NS) is reported. The "core" component of CS-NS comprises a liposome loaded with EDTA (a metal ion chelator) in the aqueous core and DiR (a near-infrared photothermal transducer) in the bilayer. The "satellite" component comprises mesoporous silica nanoparticles (MSNs) encapsulating doxorubicin and is coated with a Cu2+ -tannic acid MPN. Liposomes and MSNs self-assemble into the CS-NS through adhesion mediated by the MPN. When irradiated with an 808 nm laser, CS-NS liberated the entrapped EDTA, leading to Cu2+ chelation and subsequent disassembly of the core-satellite nanostructure. Photo-conversion from the large assembly to the small constituent particles proceeded within 5 min. Light-triggered CS-NS disassembly enhanced the carrier and cargo penetration and accumulation in tumor spheroids in vitro and in orthotopic murine mammary tumors in vivo. CS-NS is long circulating in the blood and conferred improved survival outcomes to tumor-bearing mice treated with light, compared to controls. These results demonstrate an MPN-integrated multistage nanosystem for improved solid tumor treatment.

Analysis of Porcine RIG-I Like Receptors Revealed the Positive Regulation of RIG-I and MDA5 by LGP2.

The RLRs play critical roles in sensing and fighting viral infections especially RNA virus infections. Despite the extensive studies on RLRs in humans and mice, there is a lack of systemic investigation of livestock animal RLRs. In this study, we characterized the porcine RLR members RIG-I, MDA5 and LGP2. Compared with their human counterparts, porcine RIG-I and MDA5 exhibited similar signaling activity to distinct dsRNA and viruses, via similar and cooperative recognitions. Porcine LGP2, without signaling activity, was found to positively regulate porcine RIG-I and MDA5 in transfected porcine alveolar macrophages (PAMs), gene knockout PAMs and PK-15 cells. Mechanistically, LGP2 interacts with RIG-I and MDA5 upon cell activation, and promotes the binding of dsRNA ligand by MDA5 as well as RIG-I. Accordingly, porcine LGP2 exerted broad antiviral functions. Intriguingly, we found that porcine LGP2 mutants with defects in ATPase and/or dsRNA binding present constitutive activity which are likely through RIG-I and MDA5. Our work provided significant insights into porcine innate immunity, species specificity and immune biology.