Association of ADAMTS13 activity with cerebral deep medullary vein: A community-based cross-sectional study.

Objectives: This study aims to investigate whether circulating ADAMTS13 activity can offer insights into the mechanism of pathophysiological changes in deep medullary veins (DMVs). Methods: This study was conducted on a community cohort of elderly individuals in Shanghai. Plasma von Willebrand factor (VWF) levels and ADAMTS13 activity were measured. A validated DMV score described the overall burden of DMV on the brain. Through ordinal regression models, we investigated the correlation between VWF levels, ADAMTS13 activity, and increasing severity of DMV score while adjusting for demographics and cardiovascular risk factors. Results: The study enrolled 262 subjects according to the inclusion criteria. The mean VWF level (1.35 ± 0.25) was higher in the DMV group than in the group without DMV (1.25 ± 0.30) (p = 0.025), and ADAMTS13 activity (83.76 ± 7.96) was relatively lower. After adjusting for age, sex, alcohol consumption, smoking, hypertension, and diabetes, reduced ADAMTS13 activity [ß = -7.78; 95 % CI (-10.21, -5.35) p < 0.01] was associated with DMV. Moreover, correlation analysis indicated that ADAMTS13 activity was negatively correlated with the DMV score (Kendall's tau-b = -0.53, p < 0.001). Discussion: In summary, there was an inverse correlation observed between ADAMTS13 activity and the DMV score, which may provide some clinical clues for exploring the potential pathogenesis of DMV.

Quantifying H&E staining results, grading and predicting IDH mutation status of gliomas using hybrid multi-dimensional MRI.

OBJECTIVE: To assess the performance of hybrid multi-dimensional magnetic resonance imaging (HM-MRI) in quantifying hematoxylin and eosin (H&E) staining results, grading and predicting isocitrate dehydrogenase (IDH) mutation status of gliomas. MATERIALS AND METHODS: Included were 71 glioma patients (mean age, 50.17 ± 13.38 years; 35 men). HM-MRI images were collected at five different echo times (80-200 ms) with seven b-values (0-3000 s/mm2). A modified three-compartment model with very-slow, slow and fast diffusion components was applied to calculate HM-MRI metrics, including fractions, diffusion coefficients and T2 values of each component. Pearson correlation analysis was performed between HM-MRI derived fractions and H&E staining derived percentages. HM-MRI metrics were compared between high-grade and low-grade gliomas, and between IDH-wild and IDH-mutant gliomas. Using receiver operational characteristic (ROC) analysis, the diagnostic performance of HM-MRI in grading and genotyping was compared with mono-exponential models. RESULTS: HM-MRI metrics FDvery-slow and FDslow demonstrated a significant correlation with the H&E staining results (p < .05). Besides, FDvery-slow showed the highest area under ROC curve (AUC = 0.854) for grading, while Dslow showed the highest AUC (0.845) for genotyping. Furthermore, a combination of HM-MRI metrics FDvery-slow and T2Dslow improved the diagnostic performance for grading (AUC = 0.876). DISCUSSION: HM-MRI can aid in non-invasive diagnosis of gliomas.

Bicomponent core/sheath melt-blown fibers for air filtration with ultra-low resistance.

With the escalating air pollution and frequent outbreaks of airborne diseases, there is a growing demand for personal protective filtration media. Melt-blown nonwovens have proven to be highly effective in capturing tiny particles, but their tightly packed fiber assemblages are more resistant to airflow and less comfortable to breathe. Here, we present a one-step melt-blown spinning process for the production of bicomponent core/sheath (BCS) crimped fibers and their application in high-efficiency, low-resistance air filtration. Fiber curl is caused by unbalanced internal stresses resulting from differences in the structure components, resulting in uneven shrinkage inside and outside the fibers. The resulting CM@S-2 filtration media features a uniform fiber curl and a porous fiber mesh structure, which reduces air filtration resistance. Under the same filtration conditions, the filtration efficiency of CM@S-2 (96.58% vs. 95.58%), filtration resistance (56.1 Pa vs. 108.0 Pa), quality factor (0.061 Pa-1vs. 0.029 Pa-1), and dust holding capacity (10.60 g m-2vs. 9.10 g m-2) were comparable to those of the single-component polypropylene filters. The filtration efficiency of the CM@S-2 remained above 94.0% after 30 days of indoor storage. Computational Fluid Dynamics (CFD) simulation demonstrated that crimped fibers effectively reduce pressure surges on the filter media caused by fiber accumulation. In comparative tests with commercial masks, the CM@S-2 cartridge masks demonstrated superior air permeability compared to commercial masks under similar filtration conditions. In conclusion, the bicomponent core/sheath melt-blown fibers significantly reduce air resistance and show excellent potential for application in protective masks.

The feasibility of half-dose contrast-enhanced scanning of brain tumours at 5.0 T: a preliminary study.

PURPOSE: This study investigated and compared the effects of Gd enhancement on brain tumours with a half-dose of contrast medium at 5.0 T and with a full dose at 3.0 T. METHODS: Twelve subjects diagnosed with brain tumours were included in this study and underwent MRI after contrast agent injection at 3.0 T (full dose) or 5.0 T (half dose) with a 3D T1-weighted gradient echo sequence. The postcontrast images were compared by two independent neuroradiologists in terms of the signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR) and subjective image quality score on a ten-point Likert scale. Quantitative indices and subjective quality ratings were compared with paired Student's t tests, and interreader agreement was assessed with the intraclass correlation coefficient (ICC). RESULTS: A total of 16 enhanced tumour lesions were detected. The SNR was significantly greater at 5.0 T than at 3.0 T in grey matter, white matter and enhanced lesions (p < 0.001). The CNR was also significantly greater at 5.0 T than at 3.0 T for grey matter/tumour lesions, white matter/tumour lesions, and grey matter/white matter (p < 0.001). Subjective evaluation revealed that the internal structure and outline of the tumour lesions were more clearly displayed with a half-dose at 5.0 T (Likert scale 8.1 ± 0.3 at 3.0 T, 8.9 ± 0.3 at 5.0 T, p < 0.001), and the effects of enhancement in the lesions were comparable to those with a full dose at 3.0 T (7.8 ± 0.3 at 3.0 T, 8.7 ± 0.4 at 5.0 T, p < 0.001). All subjective scores were good to excellent at both 5.0 T and 3.0 T. CONCLUSION: Both quantitative and subjective evaluation parameters suggested that half-dose enhanced scanning via 5.0 T MRI might be feasible for meeting clinical diagnostic requirements, as the image quality remains optimal. Enhanced scanning at 5.0 T with a half-dose of contrast agents might benefit patients with conditions that require less intravenous contrast agent, such as renal dysfunction.

Improved Detection of Target Metabolites in Brain Tumors with Intermediate TE, High SNR, and High Bandwidth Spin-Echo Sequence at 5T.

BACKGROUND AND PURPOSE: Due to high chemical shift displacement, challenges emerge at ultra-high fields when measuring metabolites using 1H-MRS. Our goal was to investigate how well the high SNR and high bandwidth spin-echo (HISE) technique perform at 5T for detecting target metabolites in brain tumors. MATERIALS AND METHODS: Twenty-six subjects suspected of having brain tumors were enrolled. HISE and point-resolved spectroscopy (PRESS) single-voxel spectroscopy scans were collected with a 5T clinical scanner with an intermediate TE (TE = 144 ms). The main metabolites, including total NAA, Cr, and total Cho, were accessed and compared between HISE and PRESS using a paired Student t test, with full width at half maximum and SNR as covariates. The detection rate of specific metabolites, including lactate, alanine, and lipid, and subjective spectral quality were accessed and compared between HISE and PRESS. RESULTS: Twenty-three pathologically confirmed brain tumors were included. Only the full width at half maximum for total NAA was significantly lower with HISE than with PRESS (P < .05). HISE showed a significantly higher SNR for total NAA, Cr, and total Cho compared with PRESS (P < .05). Lactate was detected in 21 of the 23 cases using HISE, but in only 4 cases using PRESS. HISE detected alanine in 8 of 9 meningiomas, whereas PRESS detected alanine in just 3 meningiomas. PRESS found lipid in more cases than HISE, while HISE outperformed PRESS in terms of subjective spectral quality. CONCLUSIONS: HISE outperformed the clinical standard PRESS technique in detecting target metabolites of brain tumors at 5T, particularly lactate and alanine.

Metabolism/Immunity Dual-Regulation Thermogels Potentiating Immunotherapy of Glioblastoma Through Lactate-Excretion Inhibition and PD-1/PD-L1 Blockade.

Intrinsic immunosuppressive tumor microenvironment (ITM) and insufficient tumor infiltration of T cells severely impede the progress of glioblastoma (GBM) immunotherapy. In this study, it is identify that inhibiting the expression of glucose transporter 1 (GLUT1) can facilitate the prevention of lactate excretion from tumor glycolysis, which significantly alleviates the lactate-driven ITM by reducing immunosuppressive tumor-associated macrophages (TAMs) and regulatory T cells (Tregs). Simultaneously, the findings show that the generated inflammatory cytokine IFN-γ during immune activation aggravates the immune escape by upregulating immune checkpoint programmed death-ligand 1 (PD-L1) in tumor cells and TAMs. Therefore, an injectable thermogel loaded with a GLUT1 inhibitor BAY-876 and a PD-1/PD-L1 blocker BMS-1 (Gel@B-B) for dual-regulation of metabolism and immunity of GBM is developed. Consequently, in situ injection of Gel@B-B significantly delays tumor growth and prolongs the survival of the orthotopic GBM mouse model. By actively exposing tumor antigens to antigen-presenting cells, the GBM vaccine combined with Gel@B-B is found to significantly increase the fraction of effector T cells (Th1/CTLs) in the tumor microenvironment, thereby remarkably mitigating tumor recurrence long-term. This study may provide a promising strategy for GBM immunotherapy.

A cascade nanoplatform for intelligent response to tumor microenvironment and collaborative cancer therapy.

Disulfiram (DSF), a new potential anticancer drug, has been shown to exhibit anticancer activity dependent on the formation of CuET, the chelation product of DSF with Cu2+. However, the poor stability of DSF and insufficient physiological concentration of Cu2+ hinder its practical application. To achieve the co-delivery of DSF and Cu2+ while overcoming the inefficiency of single chemotherapy, in this study, a cascade nanoplatform, DSF/Ce6@ZIF-8@CuO2, was constructed by encapsulating DSF and chlorin e6 (Ce6, a photosensitizer) in zeolite imidazole framework-8 (ZIF-8, a nanocarrier) and then loading CuO2, which self-supplied H2O2/O2, onto DSF/Ce6@ZIF-8. By triggering the response of DSF/Ce6@ZIF-8@CuO2 to the acidic tumor microenvironment, encapsulated DSF, Ce6 and CuO2 were released to achieve multimodal synergistic treatment with enhanced DSF chemotherapy and chemodynamic/photodynamic therapy (CDT/PDT). In vitro and animal studies indicated that the designed DSF/Ce6@ZIF-8@CuO2 has strong tumor-inhibitory effects and provides a promising paradigm for designing smart nanoplatforms.

FOXO3a-regulated arginine metabolic plasticity adaptively promotes esophageal cancer proliferation and metastasis.

Esophageal squamous cell carcinoma (ESCC) is a common malignant tumor with a poor prognosis due to a lack of early detection. Indeed, the mechanisms underlying ESCC progression remain unclear. Here, we discovered that abnormal arginine metabolism contributes to ESCC progression. Based on transcriptomic and metabolomic analyses, we found that argininosuccinate synthetase 1 (ASS1) and argininosuccinate lyase (ASL) levels were increased in primary tumor tissues but decreased in lymph-metastatic tumor tissues. Intriguingly, FOXO3a was inversely correlated with ASS1 and ASL in primary and metastatic tumor tissues, suggesting that FOXO3a dissimilarly regulates ASS1 and ASL at different stages of ESCC. Silencing ASS1/ASL inhibited primary tumor growth and promoted metastasis. Conversely, overexpression of ASS1/ASL or increased arginine supply promoted tumor proliferation but suppressed metastasis. In addition, FOXO3a activation inhibited primary tumor growth by repressing ASS1 and ASL transcription, whereas inactivation of FOXO3a impeded metastasis by releasing ASS1 and ASL transcription. Together, the finding sheds light on metastatic reprogramming in ESCC.

Prostate cancer cell-derived exosomal IL-8 fosters immune evasion by disturbing glucolipid metabolism of CD8+ T cell.

Depletion of CD8+ T cells is a major obstacle in immunotherapy; however, the relevant mechanisms remain largely unknown. Here, we showed that prostate cancer (PCa) cell-derived exosomes hamper CD8+ T cell function by transporting interleukin-8 (IL-8). Compared to the low IL-8 levels detected in immune cells, PCa cells secreted the abundance of IL-8 and further accumulated in exosomes. The delivery of PCa cell-derived exosomes into CD8+ T cells exhausted the cells through enhanced starvation. Mechanistically, exosomal IL-8 overactivated PPARα in recipient cells, thereby decreasing glucose utilization by downregulating GLUT1 and HK2 but increasing fatty acid catabolism via upregulation of CPT1A and ACOX1. PPARα further activates uncoupling protein 1 (UCP1), leading to fatty acid catabolism for thermogenesis rather than ATP synthesis. Consequently, inhibition of PPARα and UCP1 restores CD8+ T cell proliferation by counteracting the effect of exosomal IL-8. This study revealed that the tumor exosome-activated IL-8-PPARα-UCP1 axis harms tumor-infiltrating CD8+ T cells by interfering with energy metabolism.

RelB-activated GPX4 inhibits ferroptosis and confers tamoxifen resistance in breast cancer.

Tamoxifen (TAM) resistance remains a major obstacle in the treatment of advanced breast cancer (BCa). In addition to the competitive inhibition of the estrogen receptor (ER) signaling pathway, damping of mitochondrial function by increasing reactive oxygen species (ROS) is critical for enhancing TAM pharmacodynamics. Here, we showed that RelB contributes to TAM resistance by inhibiting TAM-provoked ferroptosis. TAM-induced ROS level promoted ferroptosis in TAM-sensitive cells, but the effect was alleviated in TAM-resistant cells with high constitutive levels of RelB. Mechanistically, RelB inhibited ferroptosis by transcriptional upregulating glutathione peroxidase 4 (GPX4). Consequently, elevating RelB and GPX4 in sensitive cells increased TAM resistance, and conversely, depriving RelB and GPX4 in resistant cells decreased TAM resistance. Furthermore, suppression of RelB transcriptional activation resensitized TAM-resistant cells by enhancing ferroptosis in vitro and in vivo. The inactivation of GPX4 in TAM-resistant cells consistently resensitized TAM by increasing ferroptosis-mediated cell death. Together, this study uncovered that inhibition of ferroptosis contributes to TAM resistance of BCa via RelB-upregulated GPX4.

Near-Infrared Light-Enhanced Generation of Hydroxyl Radical for Cancer Immunotherapy.

Hydroxyl radical (• OH) as a highly oxidizing reactive oxygen species can induce immunogenic cell death (ICD) in cancer treatment. However, high-efficiency cancer immunotherapy is still a huge challenge due to the low • OH generation efficiency in the tumor microenvironment, resulting in insufficient immunogenicity and the poor immune response. Here, a near-infrared (NIR) light-enhanced • OH generation strategy is developed for cancer immunotherapy by using a copper-based metal-organic framework (Cu-DBC) nanoplatform. With this strategy, the generation efficiency of • OH under NIR irradiation is increased 7.34 times than that without NIR irradiation, which induces robust ICD and immune response, thus leading to primary tumor elimination and the inhibition of distant tumor growth and tumor lung metastasis. Experimental results show that Cu-DBC can induce • OH boosting through photothermal (PT)-enhanced Cu-catalytic Fenton-like reaction and photocatalytic electron transfer under NIR light irradiation to amplify tumor ICD for immunotherapy.

Stromal cell-derived small extracellular vesicles enhance radioresistance of prostate cancer cells via interleukin-8-induced autophagy.

Radiation is a curative treatment for localized prostate cancer (PCa). Unfortunately, radiotherapeutic efficacy is often diminished when patients develop more aggressive or metastatic phenotypes. Recent studies have demonstrated that extracellular vesicles participate in cancer therapeutic resistance by delivering small bioactive molecules, such as small non-coding RNAs. Here, we show that stromal cell-derived small extracellular vesicles (sEVs) facilitate the radioresistance of PCa cells by transporting interleukin-8 (IL-8). Indeed, prostatic stromal cells secrete more IL-8 than AR-positive PCa cells, which can be accumulated in sEVs. Intriguingly, the uptake of stromal cells-derived sEVs by radiosensitive PCa cells enhanced their radioresistance, which could be attenuated by silencing CXCL8 in stromal cells or inhibiting its receptor CXCR2 in PCa cells. sEV-mediated radioresistance has been validated in zebrafish and mouse xenograft tumours. Mechanistically, the uptake of stromal sEVs triggers the AMPK-activated autophagy pathway in PCa cells under the irradiation condition. Consequently, inactivating AMPK efficiently resensitized radiotherapy either by utilizing an AMPK inhibitor or silencing AMPKα in PCa cells. Furthermore, chloroquine (CQ), a lysosomal inhibitor, sufficiently resensitized radiotherapy via blockade of autophagolysosome fusion, leading to autophagosome accumulation in PC cells. Collectively, these results suggest that stromal cells enhance the radioresistance of PCa cells mainly through sEVs that deliver IL-8.

Calcination-controlled performance optimization of iron-vanadium bimetallic oxide nanoparticles for synergistic tumor therapy.

Calcination has been widely demonstrated as a favorable protocol for producing various inorganic nanomaterials for tumor therapy. However, little attention has been paid to its effect on the biotherapeutic efficacy of inorganic nanomaterials. Herein, we compare the effects of different calcination atmospheres on the therapeutic efficacy of Fe-V-O (FVO) nanomaterials. We find that compared with FVO nanomaterials synthesized by calcination in air, those prepared by argon calcination have a lower metallic valence state and a higher near-infrared light absorption capacity, hence resulting in significantly better biosafety and higher chemodynamic therapy (CDT)/photothermal therapy (PTT) efficacy. This study demonstrates that the therapeutic efficacy of inorganic nanomaterials can be optimized by employing different thermal treatment atmospheres, which provides new insights into the development of efficient anti-tumor agents.

A clinical decision support system for AI-assisted decision-making in response-adaptive radiotherapy (ARCliDS).

Involvement of many variables, uncertainty in treatment response, and inter-patient heterogeneity challenge objective decision-making in dynamic treatment regime (DTR) in oncology. Advanced machine learning analytics in conjunction with information-rich dense multi-omics data have the ability to overcome such challenges. We have developed a comprehensive artificial intelligence (AI)-based optimal decision-making framework for assisting oncologists in DTR. In this work, we demonstrate the proposed framework to Knowledge Based Response-Adaptive Radiotherapy (KBR-ART) applications by developing an interactive software tool entitled Adaptive Radiotherapy Clinical Decision Support (ARCliDS). ARCliDS is composed of two main components: Artifcial RT Environment (ARTE) and Optimal Decision Maker (ODM). ARTE is designed as a Markov decision process and modeled via supervised learning. Given a patient's pre- and during-treatment information, ARTE can estimate treatment outcomes for a selected daily dosage value (radiation fraction size). ODM is formulated using reinforcement learning and is trained on ARTE. ODM can recommend optimal daily dosage adjustments to maximize the tumor local control probability and minimize the side effects. Graph Neural Networks (GNN) are applied to exploit the inter-feature relationships for improved modeling performance and a novel double GNN architecture is designed to avoid nonphysical treatment response. Datasets of size 117 and 292 were available from two clinical trials on adaptive RT in non-small cell lung cancer (NSCLC) patients and adaptive stereotactic body RT (SBRT) in hepatocellular carcinoma (HCC) patients, respectively. For training and validation, dense data with 297 features were available for 67 NSCLC patients and 110 features for 71 HCC patients. To increase the sample size for ODM training, we applied Generative Adversarial Networks to generate 10,000 synthetic patients. The ODM was trained on the synthetic patients and validated on the original dataset. We found that, Double GNN architecture was able to correct the nonphysical dose-response trend and improve ARCliDS recommendation. The average root mean squared difference (RMSD) between ARCliDS recommendation and reported clinical decisions using double GNNs were 0.61 [0.03] Gy/frac (mean [sem]) for adaptive RT in NSCLC patients and 2.96 [0.42] Gy/frac for adaptive SBRT HCC compared to the single GNN's RMSDs of 0.97 [0.12] Gy/frac and 4.75 [0.16] Gy/frac, respectively. Overall, For NSCLC and HCC, ARCliDS with double GNNs was able to reproduce 36% and 50% of the good clinical decisions (local control and no side effects) and improve 74% and 30% of the bad clinical decisions, respectively. In conclusion, ARCliDS is the first web-based software dedicated to assist KBR-ART with multi-omics data. ARCliDS can learn from the reported clinical decisions and facilitate AI-assisted clinical decision-making for improving the outcomes in DTR.

Protocol for colitis-associated colorectal cancer murine model induced by AOM and DSS.

Inflammatory bowel diseases (IBDs) contribute to the tumorigenesis of colorectal cancer (CRC). Here, we describe a step-by-step protocol for the construction of colitis-associated CRC murine model by sequential utilization of azoxymethane and dextran sulfate sodium. We also detail steps to determine the degree of murine intestinal inflammation and to generate colorectum Swiss roll for further histopathological analyses. This is a convenient and reproducible protocol for colitis-associated CRC murine model by the induction of general chemical reagents. For complete details on the use and execution of this protocol, please refer to Yang et al. (2022).1.

Engineering a synergistic antioxidant inhibition nanoplatform to enhance oxidative damage in tumor treatment.

The antioxidant system of tumor cells severely impairs reactive oxygen species (ROS)-mediated tumor therapy. Despite extensive attempts to attenuate the antioxidant capacity by eliminating ROS scavengers such as glutathione (GSH), nicotinamide adenine dinucleotide phosphate (NADPH) over-expressed in the tumor microenvironment can regenerate GSH from glutathione disulfide (GSSG), hence weakening ROS-induced oxidative damage. Therefore, engineering a nanoplatform capable of depleting both NADPH and GSH is extremely significant for improving ROS-mediated tumor treatment. Herein, a synergetic antioxidant inhibition strategy is proposed to attenuate intracellular antioxidant capacity for hypoxic tumor therapy. In this context, both porous Prussian blue nanoparticles (PPB NPs) and cisplatin prodrug [cis-Pt (IV)] in the nanoplatform can oxidize GSH to directly reduce GSH levels, while PPB NPs also enable NADPH depletion by peroxidase-mimicking to impair GSH regeneration. Furthermore, PPB NPs with catalase-mimicking activity catalyze H2O2 decomposition to alleviate tumor hypoxia, thus reducing the generation of GSH and boosting singlet oxygen (1O2) production by Chlorin e6 (Ce6) for enhancing oxidative damage. Experimental results prove that the nanoplatform, denoted as PPB-Ce6-Pt, can induce remarkable tumor cells apoptosis and ferroptosis. Importantly, a simple loading method and the use of Food Drug Administration (FDA)-approved materials make PPB-Ce6-Pt have great potential for practical applications. STATEMENT OF SIGNIFICANCE: The antioxidant system in tumor cells disables ROS-mediated tumor therapy. Besides, extensive attempts aim at depleting GSH without considering their regeneration. Therefore, we developed a synergetic strategy to attenuate intracellular antioxidant capacity for hypoxic tumor therapy. PPB-Ce6-Pt nanoplatform could not only directly reduce GSH levels but also deplete NADPH by peroxidase-mimicking to impair GSH regeneration. In addition, PPB-Ce6-Pt nanoplatform could catalyze H2O2 decomposition to alleviate tumor hypoxia, thus reducing the generation of GSH and boosting 1O2 production by Chlorin e6 (Ce6) for increasing oxidative damage. Then, intracellular ROS boost and redox dyshomeostasis induced remarkable tumor cells apoptosis and ferroptosis. Importantly, a simple loading method and the use of biosafety materials made the nanoplatform have great potential for practical applications.

Clinical significance of SPOCK2 expression signature for high-grade serous ovarian cancer patients.

Background: SPOCK2 is a member of the SPOCK family, a 424-amino acid protein that binds to glycosaminoglycans to form proteoglycans. The purpose of this study was to explore expression profile of SPOCK2, and evaluate prognostic potential and its correlation with immune infiltration in high-grade serous ovarian cancer (HGSOC). Methods: Expression of SPOCK2 mRNA and protein between normal and tumor tissues were analyzed using the Cancer Genome Atlas database (TCGA), Gene Expression Omnibus (GEO), Clinical Proteomic Tumor Analysis Consortium (CPTAC), and the Human Protein Atlas (HPA) databases. Receiver operating characteristic (ROC) curve was used to evaluate diagnostic performance of SPOCK2. Kaplan-Meier method and Cox regression analysis were conducted to assess the effect of SPOCK2 on survival. Nomogram was used to predict the impact of SPOCK2 on prognosis. LinkedOmics were used to find correlated genes and perform functional enrichment analyses. The relationships between SPOCK2 and tumor infiltrating lymphocytes (TILs) were determined by tumor-immune system interaction database (TISIDB) and GSVA package (V1.34.0). Results: SPOCK2 was highly expressed in HGSOC tissue compared to normal tissue at both mRNA (p < 0.001) and protein (p = 0.03) levels. The area under the curve (AUC) is 0.894 (CI: 0.865-0.923). Kaplan-Meier analysis showed that HGSOC patients with high-level SPOCK2 mRNA expression had a worse overall survival (OS) than those with a low expression (HR = 1.45, p = 0.005). Univariate logistic regression analysis found that age, primary therapy outcome, tumor status, tumor residual, and SPOCK2 expression level were significantly associated with OS (p < 0.05). The nomogram model indicated an effective predictive performance of SPOCK2. Kyoto encyclopedia of genes and genomes (KEGG) and gene ontology (GO) term analyses showed that SPOCK2 were mainly involved in regulating extracellular matrix. Immune infiltration analysis showed that SPOCK2 may correlate with abundance of TILs. Conclusion: SPOCK2 has potentials to estimate diagnosis and prognosis for HGSOC and is involved in regulating extracellular matrix and immune cell infiltration.

Enzyme-like copper-encapsulating magnetic nanoassemblies for switchable T1-weighted MRI and potentiating chemo-/photo-dynamic therapy.

Photodynamic therapy (PDT) has become a promising cancer treatment due to in situ generation of cytotoxic reactive oxygen (ROS); however, it remains limited by the hypoxia of tumor microenvironment (TME) and penetration depth of laser. Herein, we developed a kind of GSH-/H2O2-responsive copper-encapsulating magnetic nanoassemblies (MNSs) for switchable T1-weighted magnetic resonance imaging (MRI) and enzyme-like activity potentiating PDT of cancer. MNSs were rationally constructed using the chelation effect of copper ions (Cu2+) with polyacrylic acid-coated ultrasmall iron oxide nanoparticles (UIONPs). After uptake by tumor cells, the incorporated Cu2+ of MNSs was reduced to Cu+ through the intracellular GSH, which resulted in the disassembly of MNSs accompanied by the "silenced" MR signal shifting to a positive state. Sequentially, the generated Cu+ manifested peroxidase-like activity, catalyzing local H2O2 in TME to cytotoxic ·OH for chemodynamic therapy. Furthermore, Cu2+ and UIONPs could decompose H2O2 to O2, thus providing extra oxygen necessary for enhancing the PDT effect of photosensitizer IR-780. Finally, IR-780-loading MNSs (MNSs@IR-780) under laser irradiation significantly inhibited tumor growth and prolonged the survival of gastric MGC-803 tumor-bearing mice. Therefore, this study provides a versatile nanoplatform as a tumor-responsive theragnostic agent. STATEMENT OF SIGNIFICANCE: Tumor hypoxia and penetration depth of laser severely hindered the PDT of cancer. Valence-convertible metal ions (VCMI, e.g., Cu2+/Cu+, Fe3+/Fe2+) have been reported as Fenton-like agents disintegrating H2O2 to O2 to enhance PDT. Tumor-delivery of VCMI is of essential importance for in situ triggering of a Fenton-like reaction. We thereby developed magnetic nanoassemblies (MNSs) to encapsulate Cu2+ and load photosensitizer (IR-780). Stimulated by GSH and H2O2, MNSs performed catalase/peroxidase-like activity that provided extra O2 for PDT and catalyzed H2O2 to ·OH for CDT. Consequently, IR-780-loading MNSs under laser irradiation significantly inhibit the tumor growth due to effective tumor delivery of Cu2+ and IR-780. This study might offer a feasible nanoplatform for tumor-delivery of metal ions and drugs.

Precision radiotherapy via information integration of expert human knowledge and AI recommendation to optimize clinical decision making.

In the precision medicine era, there is a growing need for precision radiotherapy where the planned radiation dose needs to be optimally determined by considering a myriad of patient-specific information in order to ensure treatment efficacy. Existing artificial-intelligence (AI) methods can recommend radiation dose prescriptions within the scope of this available information. However, treating physicians may not fully entrust the AI's recommended prescriptions due to known limitations or at instances when the AI recommendation may go beyond physicians' current knowledge. This paper lays out a systematic method to integrate expert human knowledge with AI recommendations for optimizing clinical decision making. Towards this goal, Gaussian process (GP) models are integrated with deep neural networks (DNNs) to quantify the uncertainty of the treatment outcomes given by physicians and AI recommendations, respectively, which are further used as a guideline to educate clinical physicians and improve AI models performance. The proposed method is demonstrated in a comprehensive dataset where patient-specific information and treatment outcomes are prospectively collected during radiotherapy of 67 non-small cell lung cancer (NSCLC) patients and are retrospectively analyzed.

Dual-responsive nano-prodrug micelles for MRI-guided tumor PDT and immune synergistic therapy.

Micelles as nanocarriers not only offer new opportunities for early diagnosis and treatment of malignant cancers but also encounter numerous barriers in the path of efficient delivery of drugs to diseased areas in the body. To address these issues, we developed a pH/GSH responsive nano-prodrug micelle (NLG919/PGA-Cys-PPA@Gd) with a high drug-loading ratio and controlled drug release performance for MRI-guided tumor photodynamic therapy (PDT) and immune synergistic therapy. Under normal conditions, theranostic nanomicelles remained stable and in a photo-quenched state. Upon accumulation in the tumor site, however, the micelles demonstrated tumor microenvironment (TME) triggered photoactive formed-PPA (a photosensitizer) and NLG919 (an indoleamine 2,3-dioxygenase (IDO) inhibitor) release because the amide bonds of PGA-Cys-PPA and the disulfide linkage of Cys were sensitive to pH and GSH, respectively. More importantly, these micelles could avoid the undesired PPA leakage in blood circulation due to the conjugation between PPA and polymers. Furthermore, the obtained micelles could also enhance the contrast of T1-weighted MRI of tumors by virtue of their high relaxivity (r1 = 29.85 mM-1 s-1). In vitro and in vivo results illustrated that the micelles had good biocompatibility and biosafety. On the basis of the efficient drug delivery strategies in PDT and IDO pathway inhibition, this intelligent dual-drug delivery system could serve as an effective approach for MRI guided combination therapy of cancer.