Nitric oxide nano-reactor DNMF/PLGA enables tumor vascular microenvironment and chemo-hyperthermia synergetic therapy.

BACKGROUND: Breast cancer ranks first among malignant tumors, of which triple-negative breast cancer (TNBC) is characterized by its highly invasive behavior and the worst prognosis. Timely diagnosis and precise treatment of TNBC are substantially challenging. Abnormal tumor vessels play a crucial role in TNBC progression and treatment. Nitric oxide (NO) regulates angiogenesis and maintains vascular homeostasis, while effective NO delivery can normalize the tumor vasculature. Accordingly, we have proposed here a tumor vascular microenvironment remodeling strategy based on NO-induced vessel normalization and extracellular matrix collagen degradation with multimodality imaging-guided nanoparticles against TNBC called DNMF/PLGA. RESULTS: Nanoparticles were synthesized using a chemotherapeutic agent doxorubicin (DOX), a NO donor L-arginine (L-Arg), ultrasmall spinel ferrites (MnFe2O4), and a poly (lactic-co-glycolic acid) (PLGA) shell. Nanoparticle distribution in the tumor was accurately monitored in real-time through highly enhanced magnetic resonance imaging and photoacoustic imaging. Near-infrared irradiation of tumor cells revealed that MnFe2O4 catalyzes the production of a large amount of reactive oxygen species (ROS) from H2O2, resulting in a cascade catalysis of L-Arg to trigger NO production in the presence of ROS. In addition, DOX activates niacinamide adenine dinucleotide phosphate oxidase to generate and supply H2O2. The generated NO improves the vascular endothelial cell integrity and pericellular contractility to promote vessel normalization and induces the activation of endogenous matrix metalloproteinases (mainly MMP-1 and MMP-2) so as to promote extravascular collagen degradation, thereby providing an auxiliary mechanism for efficient nanoparticle delivery and DOX penetration. Moreover, the chemotherapeutic effect of DOX and the photothermal effect of MnFe2O4 served as a chemo-hyperthermia synergistic therapy against TNBC. CONCLUSION: The two therapeutic mechanisms, along with an auxiliary mechanism, were perfectly combined to enhance the therapeutic effects. Briefly, multimodality image-guided nanoparticles provide a reliable strategy for the potential application in the fight against TNBC.

A hybrid nanopharmaceutical for specific-amplifying oxidative stress to initiate a cascade of catalytic therapy for pancreatic cancer.

BACKGROUND: Oxidative stress (OS) induced by an imbalance of oxidants and antioxidants is an important aspect in anticancer therapy, however, as an adaptive response, excessive glutathione (GSH) in the tumor microenvironment (TME) acts as an antioxidant against high reactive oxygen species (ROS) levels and prevents OS damage to maintain redox homoeostasis, suppressing the clinical efficacy of OS-induced anticancer therapies. RESULTS: A naturally occurring ROS-activating drug, galangin (GAL), is introduced into a Fenton-like catalyst (SiO2@MnO2) to form a TME stimulus-responsive hybrid nanopharmaceutical (SiO2-GAL@MnO2, denoted SG@M) for enhancing oxidative stress. Once exposed to TME, as MnO2 responds and consumes GSH, the released Mn2+ converts endogenous hydrogen peroxide (H2O2) into hydroxyl radicals (·OH), which together with the subsequent release of GAL from SiO2 increases ROS. The "overwhelming" ROS cause OS-mediated mitochondrial malfunction with a decrease in mitochondrial membrane potential (MMP), which releases cytochrome c from mitochondria, activates the Caspase 9/Caspase 3 apoptotic cascade pathway. Downregulation of JAK2 and STAT3 phosphorylation levels blocks the JAK2/STAT3 cell proliferation pathway, whereas downregulation of Cyclin B1 protein levels arrest the cell cycle in the G2/M phase. During 18 days of in vivo treatment observation, tumor growth inhibition was found to be 62.7%, inhibiting the progression of pancreatic cancer. Additionally, the O2 and Mn2+ released during this cascade catalytic effect improve ultrasound imaging (USI) and magnetic resonance imaging (MRI), respectively. CONCLUSION: This hybrid nanopharmaceutical based on oxidative stress amplification provides a strategy for multifunctional integrated therapy of malignant tumors and image-visualized pharmaceutical delivery.

Nomogram models for stratified prediction of axillary lymph node metastasis in breast cancer patients (cN0).

Objectives: To determine the predictors of axillary lymph node metastasis (ALNM), two nomogram models were constructed to accurately predict the status of axillary lymph nodes (ALNs), mainly high nodal tumour burden (HNTB, > 2 positive lymph nodes), low nodal tumour burden (LNTB, 1-2 positive lymph nodes) and negative ALNM (N0). Accordingly, more appropriate treatment strategies for breast cancer patients without clinical ALNM (cN0) could be selected. Methods: From 2010 to 2015, a total of 6314 patients with invasive breast cancer (cN0) were diagnosed in the Surveillance, Epidemiology, and End Results (SEER) database and randomly assigned to the training and internal validation groups at a ratio of 3:1. As the external validation group, data from 503 breast cancer patients (cN0) who underwent axillary lymph node dissection (ALND) at the Second Affiliated Hospital of Chongqing Medical University between January 2011 and December 2020 were collected. The predictive factors determined by univariate and multivariate logistic regression analyses were used to construct the nomograms. Receiver operating characteristic (ROC) curves and calibration plots were used to assess the prediction models' discrimination and calibration. Results: Univariate analysis and multivariate logistic regression analyses showed that tumour size, primary site, molecular subtype and grade were independent predictors of both ALNM and HNTB. Moreover, histologic type and age were independent predictors of ALNM and HNTB, respectively. Integrating these independent predictors, two nomograms were successfully developed to accurately predict the status of ALN. For nomogram 1 (prediction of ALNM), the areas under the receiver operating characteristic (ROC) curve in the training, internal validation and external validation groups were 0.715, 0.688 and 0.876, respectively. For nomogram 2 (prediction of HNTB), the areas under the ROC curve in the training, internal validation and external validation groups were 0.842, 0.823 and 0.862. The above results showed a satisfactory performance. Conclusion: We established two nomogram models to predict the status of ALNs (N0, 1-2 positive ALNs or >2 positive ALNs) for breast cancer patients (cN0). They were well verified in further internal and external groups. The nomograms can help doctors make more accurate treatment plans, and avoid unnecessary surgical trauma.

A novel targeted multifunctional nanoplatform for visual chemo-hyperthermia synergy therapy on metastatic lymph nodes via lymphatic delivery.

BACKGROUND: Distant metastasis to vital organs is the major contributor to breast cancer mortality, and regional lymph node metastasis is an important facilitator of distant metastasis and recurrence in this cancer. The early diagnosis and precise treatment of lymph node metastasis are crucial for staging and prognosis in breast cancer. Herein, we report a visualized precision medicine nanoplatform of metastatic lymph nodes for ultrasonic/photoacoustic (US/PA) dual modal imaging-guided in situ targeted hyperthermia-combined chemotherapy. RESULTS: Carbon nanoparticles (CNs), approved by the China Food and Drug Administration, were loaded with docetaxel and rationally combined with anti-hypoxia-inducible factor 1α antibody-modified poly (lactic-co-glycolic acid) (PLGA) nanoparticles to achieve the combination of passive targeting at the lymph nodes and intracellular targeting at HIF 1α factor. The accumulation and retention of nanoparticles in metastatic lymph nodes via lymphatic delivery were enhanced. Docetaxel could be effectively offloaded by CNs that have active carbon nanoparticles, and the PLGA membrane prevented drug leakage. The nanoparticles exhibited excellent photothermal performance with a photothermal conversion efficiency of 28.9%, killing tumor cells in metastatic lymph nodes through hyperthermia. In vitro and in vivo systematic evaluations revealed that hyperpyrexia triggered the rupture of nanoparticles caused by the phase transition of perfluorohexane, resulting in docetaxel release for achieving in situ hyperthermia-combined chemotherapy. CONCLUSIONS: The laser-triggered highly efficient in situ chemotherapy nanosystem achieves targeted synergistic chemo-hyperthermia treatment of metastatic lymph nodes, and lymphatic delivery represents a strategy to avoid additional injury caused by drugs entering the blood circulation.

Neural electrophysiological mechanism of joint hierarchical rule shifting: an event-related potential study.

Although previous studies have explored the brain mechanism by which an individual independently accomplishes task switching or rule shifting with different hierarchical structures, electrophysiological evidence indicating that two actors cooperate to complete the hierarchical rule shift remains unclear. This study adopts a modified joint hierarchical rule shifting paradigm in which one actor judged the parity task and the other decided the magnitude task. Results demonstrated that cues in high- and low-shift conditions elicited larger P2 amplitudes and that low-shift had a larger P3 amplitude than high-shift. Results further indicated that participants required more attention resources to ascertain who would make a judgment for the current trial and that low hierarchical features were superior in reconfiguring changed rules. Regarding the target, the high-shift condition evoked smaller P2 and larger N2 amplitudes when compared to low-shift and repeat conditions, whereas when compared to high- and low-shifts, the repeat condition elicited a larger P3 amplitude. The findings revealed that participants required more control resources to process the varied features and that repeat condition required the least cognitive resources to update rules. Thus, participants had different process patterns between cues and targets when cooperating with their co-actors.

Predictors and a Prediction Model for Central Cervical Lymph Node Metastasis in Papillary Thyroid Carcinoma (cN0).

Objectives: To screen out the predictors of central cervical lymph node metastasis (CLNM) for papillary thyroid carcinoma (PTC) and establish a prediction model to guide the operation of PTC patients (cN0). Methods: Data from 296 PTC patients (cN0) who underwent thyroid operation at the Second Affiliated Hospital of Chongqing Medical University were collected and retrospectively analyzed. They were divided into two groups in accordance with central CLNM or not. Their information, including ultrasound (US) features, BRAFV600E status, and other characteristics of the two groups, was analyzed and compared using univariate and multivariate logistic regression analyses, and the independent predictors were selected to construct a nomogram. The calibration plot, C-index, and decision curve analysis were used to assess the prediction model's calibration, discrimination, and clinical usefulness. Results: A total of 37.8% (112/296) of PTC patients had central CLNM, and 62.2% (184/296) did not. The two groups were compared using a univariate logistic regression analysis, and there were no significant differences between the two groups in sex, aspect ratio, boundary, morphology, hypoechoic nodule, thyroid peroxidase antibody, or tumor location (P>0.05), and there were significant differences between age, tumor size, capsule contact, microcalcifications, blood flow signal, thyroglobulin antibodies (TgAb), and BRAF gene status (P<0.05). A multivariate logistic regression analysis was performed to further clarify the correlation of these indices. However, only tumor size (OR=2.814, 95% Cl=1.634~4.848, P<0.001), microcalcifications (OR=2.839, 95% Cl=1,684~4.787, P<0.001) and TgAb (OR=1.964, 95% Cl=1.039~3,711, P=0.038) were independent predictors of central CLNM and were incorporated and used to construct the prediction nomogram. The model had good discrimination with a C-index of 0.715. An ROC curve analysis was performed to evaluate the accuracy of this model. The decision curve analysis showed that the model was clinically useful when intervention was decided in the threshold range of 16% to 80%. Conclusion: In conclusion, three independent predictors of central CLNM, including tumor size (> 1.0 cm), US features (microcalcifications), and TgAb (positive), were screened out. A visualized nomogram model was established based on the three predictors in this study, which could be used as a basis of central cervical lymph node dissection (CLND) for PTC patients (cN0).