A Multifunctional Nanoreactor-Induced Dual Inhibition of HSP70 Strategy for Enhancing Mild Photothermal/Chemodynamic Synergistic Tumor Therapy.

Mild photothermal therapy (PTT) is a spatiotemporally controllable method that utilizes the photothermal effect at relatively low temperatures (40-45 °C) to especially eliminate tumor tissues with negligible side effects on the surrounding normal tissues. However, the overexpression of heat shock protein 70 (HSP70) and limited effect of single treatment drastically impede the therapeutic efficacy. Herein, the constructed multifunctional core-shell structured Ag-Cu@SiO2-PDA/GOx nanoreactors (APG NRs) that provide a dual inhibition of HSP70 strategy for the second near-infrared photoacoustic (NIR-II PA) imaging-guided combined mild PTT/chemodynamic therapy (CDT). The Ag-Cu cores can convert endogenous H2O2 to hydroxyl radical (•OH), which can induce lipid peroxidation (LPO) and further degrade HSP70. The polydopamine (PDA)/glucose oxidase (GOx) shells are utilized as the NIR-II photothermal agent to generate low temperature, and the GOx can reduce the energy supplies and inhibit energy-dependent HSP70 expression. Furthermore, both the generation of •OH and GOx-mediated energy shortage can reduce HSP70 expression to sensitize mild PTT under 1064 nm laser, and in turn, GOx and laser self-amplify the catalytic reactions of APG NRs for more production of •OH. The multifunctional nanoreactors will provide more potential possibilities for the clinical employment of mild PTT and the advancement of tumor combination therapies.

HCC portal hypertension imaging score derived from CT predicts re-bleeding and mortality after acute variceal bleeding.

BACKGROUND/PURPOSE: Risk factors for re-bleeding and death after acute variceal bleeding (AVB) in cirrhotic HCC patients are not fully understood.We aimed to (1) explore how the combination of high-risk esophageal varices, HCC status, and portal vein tumor thrombus (i.e., HCC Portal Hypertension Imaging Score [HCCPHTIS]) helps predict increased risk of variceal re-bleeding and mortality; (2) assess predictability and reproducibility of the identified variceal re-bleeding rules. METHODS: This prospective study included 195 HCC patients with first-time AVB and liver cirrhosis, and conducted multivariable Cox regression analysis and Kaplan-Meier analysis. Receiver operating characteristic curve analysis was calculated to find the optimal sensitivity, specificity, and cutoff values of the variables. The reproducibility of the results obtained was verified in a different but related group of patients. RESULTS: 56 patients (28.7%) had re-bleeding within 6 weeks; HCCPHTIS was an independent risk factor for variceal re-bleeding after AVB (Odd ratio, 2.330; 95% confidence interval: 1.728-3.142, p < 0.001). The positive predictive value of HCCPHTIS cut off value > 3 was 66.2%, sensitivity 83.9%, and specificity 82.3%. HCCPHTIS area under the curve was higher than Child-Pugh score (89% vs. 75%, p < 0.001). 74(37.9%) death occurred within 6 weeks; HCCPHTIS > 4 was associated with increased risk of death within 6 weeks after AVB (p < 0.001). CONCLUSION: HCCPHTIS > 3 is a strong predictor of variceal re-bleeding within the first 6 weeks. However, patients with HCCPHTIS > 4 were at increased risk of death within 6 weeks.

The cellular composition of the tumor microenvironment is an important marker for predicting therapeutic efficacy in breast cancer.

At present, the incidence rate of breast cancer ranks first among new-onset malignant tumors in women. The tumor microenvironment is a hot topic in tumor research. There are abundant cells in the tumor microenvironment that play a protumor or antitumor role in breast cancer. During the treatment of breast cancer, different cells have different influences on the therapeutic response. And after treatment, the cellular composition in the tumor microenvironment will change too. In this review, we summarize the interactions between different cell compositions (such as immune cells, fibroblasts, endothelial cells, and adipocytes) in the tumor microenvironment and the treatment mechanism of breast cancer. We believe that detecting the cellular composition of the tumor microenvironment is able to predict the therapeutic efficacy of treatments for breast cancer and benefit to combination administration of breast cancer.

A Single NIR-II Laser-Triggered Self-Enhancing Photo/Enzyme-coupled Three-in-One Nanosystems for Breast Cancer Phototheranostics.

Multifunctional phototheranostics, employing precise and non-invasive techniques, is widely developed to enhance theranostic efficiency of breast cancer (BC), reduce side-effects, and improve quality of life. Integrating all phototheranostic modalities into a single photosensitizer for highly effective BC treatment is particularly challenging due to the potential inefficiency and time consumption associated with repeated switching of multiple-wavelength lasers. Herein, a novel single NIR-II laser-triggered three-in-one nanosystem(PdCu NY) is rationally designed, which enables dual-modal (NIR-II FL/NIR-II PA) imaging-guided self-enhancing photothermal-photodynamic therapy (PTT-PDT) in NIR-II window. The PdCu NY based on optimal Pd/Cu molar-ratio(1:11) can be easily fabricated and large-scale production for simultaneous PTT-PDT against BC under a single 1064nm laser irradiation. Significantly, the PdCu NY acted as a promising photocatalyst for decomposition of H2O into O2 upon the same laser irradiation. In addition, the inherent catalase (CAT)-like activity of PdCu NYs enables photo-enzyme dual-catalytic O2 supply to effectively alleviate hypoxia, achieving self-enhanced PDT efficiency. These PTT-PDT self-enhanced nanosystems demonstrate precise lesion localization and complete tumor ablation using a single 1064nm laser source by "one-laser, multi-functions" strategy. More importantly, this study not only reports a three-in-one PdCu-based phototheranostic agent, but also sheds light on the exploration of versatile biosafety nanosystems for clinical applications.

Radiomics nomogram for predicting axillary lymph node metastasis in breast cancer based on DCE-MRI: A multicenter study.

OBJECTIVES: This study aims to develop and validate a radiomics nomogram based on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to noninvasively predict axillary lymph node (ALN) metastasis in breast cancer. METHODS: This retrospective study included 263 patients with histologically proven invasive breast cancer and who underwent DCE-MRI examination before surgery in two hospitals. All patients had a defined ALN status based on pathological examination results. Regions of interest (ROIs) of the primary tumor and ipsilateral ALN were manually drawn. A total of 1,409 radiomics features were initially computed from each ROI. Next, the low variance threshold, SelectKBest, and least absolute shrinkage and selection operator (LASSO) algorithms were used to extract the radiomics features. The selected radiomics features were used to establish the radiomics signature of the primary tumor and ALN. A radiomics nomogram model, including the radiomics signature and the independent clinical risk factors, was then constructed. The predictive performance was evaluated by the receiver operating characteristic (ROC) curves, calibration curve, and decision curve analysis (DCA) by using the training and testing sets. RESULTS: ALNM rates of the training, internal testing, and external testing sets were 43.6%, 44.3% and 32.3%, respectively. The nomogram, including clinical risk factors (tumor diameter) and radiomics signature of the primary tumor and ALN, showed good calibration and discrimination with areas under the ROC curves of 0.884, 0.822, and 0.813 in the training, internal and external testing sets, respectively. DCA also showed that radiomics nomogram displayed better clinical predictive usefulness than the clinical or radiomics signature alone. CONCLUSIONS: The radiomics nomogram combined with clinical risk factors and DCE-MRI-based radiomics signature may be used to predict ALN metastasis in a noninvasive manner.

Impact of Yiqi Huoxue Decoction on the Relationship between Remodeling of Cardiac Nerves and Macrophages after Myocardial Infarction in Rats.

Sympathetic nerve remodeling after myocardial infarction (MI) has an indispensable role in cardiac remodeling. Numerous works have shown that sympathetic nerve remodeling can be delayed by inhibition of inflammatory response. Earlier studies have shown improvement in ventricular remodeling and inhibited chronic stage neural remodeling by Yiqi Huoxue decoction (YQHX). Therefore, the current study looked at the inhibitory effect of YQHX prescription on proinflammatory mediators and macrophages and the effect on neural remodeling at 3 and 7 days after MI. YQHX inhibited the expression of Toll-like receptor 4 (TLR4) and nuclear factor kappa B (NF-κB) proteins and macrophage infiltration within 7 days after myocardial infarction. YQHX could decrease Th-positive nerve fiber density in the area around infarction and reduce the expression of growth-associated protein 43 (GAP43), nerve growth factor (NGF), and tyrosine hydroxylase (TH) proteins, which was associated with the remodeling of sympathetic nerves. Thus, the nerve remodeling inhibition after MI due to YQHX may be through its anti-inflammatory action. These data provide direct evidence for the potential application of traditional Chinese medicine (TCM) in the remodeling of sympathetic nerves after MI.

Effects of Yiqi Huoxue Decoction on Post-Myocardial Infarction Cardiac Nerve Remodeling and Cardiomyocyte Hypertrophy in Rats.

Myocardial infarction can lead to ventricular remodeling and arrhythmia, which is closely related to nerve remodeling. Our previous study found that Yiqi Huoxue decoction (YQHX) can improve ventricular remodeling and reduce myocardial damage. Therefore, in this study, we observed the effect of YQHX on cardiac neural remodeling and cardiomyocyte hypertrophy and its possible mechanism. This research is composed of two parts: animal and H9c2 cells experiments. The animal model of acute myocardial infarction was established by ligating the left anterior descending coronary artery in Sprague Dawley (SD) rats. H9c2 cells were placed in 94% N2, 5% CO2, and 1% O2 hypoxic environment for 12 hours to replicate the hypoglycemic hypoxia model. The experimental results showed that, compared with the MI group, YQHX can significantly improve heart function after myocardial infarction and reduce nerve remodeling and myocardial hypertrophy. Pathological structure observation demonstrated reducing myocardial tissue damage and decreasing of cell cross-sectional area, diameter, and circumference. The positive rate of TH declined apparently, and the sympathetic nerve density was lower than that of the MI group. After YQHX was given for 28 days, the proneural remodeling factors TH, NGF, and GAP43 in the marginal zone of infarction and stellate ganglion decreased obviously while the inhibitory nerve remodeling factor Sema-3A increased. The myocardial hypertrophic protein ANP and ß-MHC were also significantly inhibited with p-ERK1/2 protein expression level prominently reduced. There was no difference between the YQHX group and the Meto group. After myocardial infarction, nerve remodeling was seen in the marginal area of infarction and stellate ganglion, and the neuropeptides released by which promoted myocardial hypertrophy. The mechanism may be related to the ERK1/2 signaling pathway. YQHX could regulate the ERK1/2 signaling pathway, inhibit the release of nerve remodeling factors and myocardial hypertrophy protein to reduce nerve remodeling, and relieve myocardial hypertrophy.

The clinical efficacy and safety of the Chinese herbal medicine Astragalus (Huangqi) preparation for the treatment of acute myocardial infarction: A systematic review of randomized controlled trials.

BACKGROUND: In recent years, with the enormous advances in the field of cardiac intervention technology, the survival rate of patients with acute myocardial infarction (AMI) has been improved significantly. However, the risk of arrhythmias and heart failure remains very high in AMI patients for long-term prognosis. Chinese herbal medicine (CHM) is more and more used in the treatment of AMI because of its good curative effect and less side effects. The target of this research is to analyze the efficacy and safety of Astragalus (Huangqi) preparation in the treatment of AMI by meta-analysis and also to provide a better evidence for clinical practice. METHODS: Seven databases will be searched in this study: The Cochrane Library, PubMed, Web of Science, the Chinese National Knowledge Infrastructure (CNKI), the Chinese Scientific Journal Database (CSJD), the Chinese Biomedical Literature Database (CBM), and Wanfang DATA. The following search terms will be used: (Huangqi OR Huang Qi OR Astragalus OR radix astragali) AND (acute myocardial infaction OR myocardial infaction OR AMI) AND (randomized controlled trial OR RCT OR randomized). No language limitations and the searches will be conducted up to March, 2019. INCLUSION CRITERIA: randomized controlled trial (RCT) of Astragalus (Huangqi) preparation in patients with AMI. Main outcome measures will be left ventricular end systolic volume (LVESV), left ventricular end diastolic volume (LVEDV), left ventricular ejection fraction (LVEF), left ventricular mass index (LVMI), recanalization rate, mortality rate, incidence of reperfusion arrhythmias, postinfarction angina pectoris, and re-infarction rate. Secondary outcome indicators were the incidence of adverse reactions and the effective rate of traditional Chinese medicine (TCM) treatment. Two independent reviewers will filter the literature and extract data which based to the Cochrane manual. The relevant data, including bias risk assessment, data synthesis, subgroup analysis, meta-analysis, and final meta-analysis, will be analyzed with RevMan 5.3 software. The funnel diagram will be used to evaluate the reported deviation, and the Egger test will be used to evaluate the symmetry of the funnel graph. RESULTS: This systematic review study will provide a clear basis for evaluating the efficacy and safety of Astragalus (Huangqi) preparation with the treatment of AMI. CONCLUSION: This study will provide an up-to-date evidence for evaluating the efficacy and safety of Astragalus (Huangqi) preparation. PROSPERO REGISTRATION NUMBER: CRD42019124843.

Yiqihuoxue decoction protects against post-myocardial infarction injury via activation of cardiomyocytes PGC-1α expression.

BACKGROUND: Mitochondrial dysfunction has been implicated in the pathogenesis of ischemic heart disease, exacerbating cardiomyocytes injury in myocardial infarction (MI). Peroxisome proliferator-activated receptor gamma co-activator (PGC-1α) has been recognized as the key regulator of mitochondrial biogenesis and energy metabolism. Yiqihuoxue decoction (YQHX), a Traditional Chinese Medicine (TCM) prescription, can prevent and treat ischemic heart disease. However, the mechanisms of YQHX on PGC-1α expression in the ischemic heart have remained unclear. METHODS: Myocardial ischemia rat model and ischemia/hypoxia injury model in the cardiomyocytes were used to minic human cardiovascular disease. Rats were randomly assigned into 4 groups: Sham, Model, YQHX (8.2 g/kg) and Trimetazidine (10 mg/kg) group. 28 days after MI, cardiac functions and morphology were detected by echocardiography and HE staining, respectively. In vitro, the effects of YQHX on H9c2 cell viability, LDH and ROS were detected, respectively. PGC-1α relevant proteins were evaluated by Western blotting. RESULTS: In vivo, echocardiography and HE staining results showed that YQHX improved cardiac functions and modified pathological changes. YQHX enhanced PGC-1α expression and improved the mitochondrial ultrastructure and functions in rats MI model for 4 weeks. Further, we explored its potential mechanisms in cardiomyocytes. In vitro, YQHX significantly enhanced cell viability and reduced LDH release and ROS production induced by hypoxia in cardiomyocytes. Interestingly, exposure of cardiomyocytes to hypoxic conditions for 12 h induced the downregulation of PGC-1α expression, but the expression levels nearly returned to the normal state after hypoxia for 24 h. YQHX significantly enhanced PGC-1α expression between 12 h and 24 h induced by hypoxia through a mechanism associated with the activation of AMPK phosphorylation in H9c2 cells. In addition, YQHX upregulated the expression of Tfam and NRF-1, while NRF-1 expression was completely blocked by an AMPK inhibitor. YQHX largely restored the mitochondrial morphology and increased mitochondrial membrane potential in hypoxia-induced injury. Furthermore, the UHPLC-LTQ-Orbitrap-MSn analysis found that there were 87 chemical constituents in YQHX. CONCLUSIONS: These results suggest that the protective effect of YQHX on cardiomyocytes against hypoxia-induced injury may be attributed to activation of PGC-1α and maintenance of mitochondrial functions through a mechanism involving the activation of AMPK phosphorylation.

[Screening, resistance and growth-promoting effect of endophytic bacteria with ACC deaminase activity isolated from soybean nodules].

Objective: We screened endophytic bacteria containing ACC (1-aminocyclopropane-1-carboxylate) deaminase from soybean nodules, and evaluated salt-alkaline resistance, phylogenetic status and the growthpromoting of representative strain. Methods: The features of strains producing ACC deaminase were determined by using the ACC as a sole nitrogen source, adopting standard curve method, colorimetric method, solid medium screening method, bacterial morphology, physio-biochemical characteristics, similarity analysis of 16S rRNA gene, inoculation tests. Results: Eight endophytic bacteria containing ACC deaminase were screened from soybean nodules collected from 36 points of 13 cities (regions)in Henan province. Enzymaticactivity of DD132 was the highest (15.712 U/mg). Screened strain tolerated to medium of 4%-6% NaCl concentration. Among of them, DD165 and DD132 could tolerate 9% NaCl concentration. Five bacteria growing well under pH 11, showing that these strains had stronger alkali resistance. Eight strains containing ACC deaminase activity were affiliated to four genera: Bacillus, Enterobacter, Stenotrophomonas and Pantoea. Inoculation test showed that DD132 had a significant growthpromoting effect on wheat seedlings. Conclusions: Endophytic bacteria containing high ACC deaminase activity from soybean nodules have stronger salt-alkaline resistance. DD132 has obvious growth-promoting effect on wheat seedlings.