Research Progress on Structure-Activity Relationship of 1,8-Naphthalimide DNA Chimeras Against Tumor.

The development of 1,8-naphthalimide derivatives as cell probes, DNA targeting agents, and anti-tumor drugs is one of the research hotspots in the field of medicine. Naphthalimide compounds are a kind of DNA embedder, which can change the topological structure of DNA by embedding in the middle of DNA base pairs, and then affect the recognition and action of topoisomerase on DNA. Aminofide and mitonafide are the first 2 drugs to undergo clinical trials. They have good DNA insertion ability, can embed DNA double-stranded structure, and induce topoisomerase II to cut part of pBR322DNA, but not yet entered the market due to their toxicity. In this paper, the design and structure-activity relationship of mononaphthalimide and bisaphthalimide compounds were studied, and the relationship between the structure of naphthalimide and anti-tumor activity was analyzed and discussed. It was found that a variety of structural modifications were significant in improving anti-tumor activity and reducing toxicity.

A knowledge graph-based analytical model for mining clinical value of drug stress echocardiography for diagnosis, risk stratification and prognostic evaluation of coronary artery disease.

The three major techniques for clinically diagnosing coronary heart disease, including angina associated with myocardial ischemia, are coronary angiography, myocardial perfusion imaging, and drug stress echocardiography. Compared to the first two methods, which are invasive or involve the use of radionuclides, drug stress echocardiography is increasingly used in clinical practice due to its non-invasive, low-risk, and controllable nature, and wide applicability. We developed a novel methodology to demonstrate knowledge graph-based efficacy analysis of drug stress echocardiography as a complement to traditional meta-analysis. By measuring coronary flow reserve (CFR), we discovered that regional ventricular wall abnormalities (RVWA) and drug-loaded cardiac ultrasound can be used to detect coronary artery disease. Additionally, drug-loaded cardiac ultrasound can be used to identify areas of cardiac ischemia, stratify risks, and determine prognosis. Furthermore, adenosine stress echocardiography(ASE) can determine atypical symptoms of coronary heart disease with associated cardiac events through CFR and related quantitative indices for risk stratification. Using a knowledge graph-based approach, we investigated the positive and negative effects of three drugs - Dipyridamole, Dobutamine, and Adenosine - for coronary artery disease analysis. Our findings show that Adenosine has the highest positive effect and the lowest negative effect among the three drugs. Due to its minimal and controlled side effects, and high sensitivity for diagnosing coronary microcirculation disorders and multiple lesions, adenosine is frequently used in clinical practice.

Prognostic Significance of Tumor-Infiltrating Lymphocytes Determined Using LinkNet on Colorectal Cancer Pathology Images.

PURPOSE: Tumor-infiltrating lymphocytes (TILs) have a significant prognostic value in cancers. However, very few automated, deep learning-based TIL scoring algorithms have been developed for colorectal cancer (CRC). MATERIALS AND METHODS: We developed an automated, multiscale LinkNet workflow for quantifying TILs at the cellular level in CRC tumors using H&E-stained images from the Lizard data set with annotations of lymphocytes. The predictive performance of the automatic TIL scores (TILsLink) for disease progression and overall survival (OS) was evaluated using two international data sets, including 554 patients with CRC from The Cancer Genome Atlas (TCGA) and 1,130 patients with CRC from Molecular and Cellular Oncology (MCO). RESULTS: The LinkNet model provided outstanding precision (0.9508), recall (0.9185), and overall F1 score (0.9347). Clear continuous TIL-hazard relationships were observed between TILsLink and the risk of disease progression or death in both TCGA and MCO cohorts. Both univariate and multivariate Cox regression analyses for the TCGA data demonstrated that patients with high TIL abundance had a significant (approximately 75%) reduction in risk for disease progression. In both the MCO and TCGA cohorts, the TIL-high group was significantly associated with improved OS in univariate analysis (30% and 54% reduction in risk, respectively). The favorable effects of high TIL levels were consistently observed in different subgroups (classified according to known risk factors). CONCLUSION: The proposed deep-learning workflow for automatic TIL quantification on the basis of LinkNet can be a useful tool for CRC. TILsLink is likely an independent risk factor for disease progression and carries predictive information of disease progression beyond the current clinical risk factors and biomarkers. The prognostic significance of TILsLink for OS is also evident.

Regulation of PD-L1 through direct binding of cholesterol to CRAC motifs.

Cholesterol, an essential molecule for cell structure, function, and viability, plays crucial roles in the development, progression, and survival of cancer cells. Earlier studies have shown that cholesterol-lowering drugs can inhibit the high expression of programmed-death ligand 1 (PD-L1) that contributes to immunoevasion in cancer cells. However, the regulatory mechanism of cell surface PD-L1 abundance by cholesterol is still controversial. Here, using nuclear magnetic resonance and biochemical techniques, we demonstrated that cholesterol can directly bind to the transmembrane domain of PD-L1 through two cholesterol-recognition amino acid consensus (CRAC) motifs, forming a sandwich-like architecture and stabilizing PD-L1 to prevent downstream degradation. Mutations at key binding residues prohibit PD-L1-cholesterol interactions, decreasing the cellular abundance of PD-L1. Our results reveal a unique regulatory mechanism that controls the stability of PD-L1 in cancer cells, providing an alternative method to overcome PD-L1-mediated immunoevasion in cancers.

How does bivalve size influence microplastics accumulation?

Microplastics (wasted plastic particles < 5 mm in diameter) are ubiquitously distributed in the marine environment. Filter-feeding and low trophic level bivalves are vulnerable to microplastics accumulation from the surrounding depositional environment, thereby threatening both ecological health and human food safety. Microplastics had been detected in lots of coastal Bivalvia species. However, the influence of biological morphology on the mechanism of microplastics accumulation is not clear. There is also a knowledge gap of which species are preferred for commercial consumption, which creates loopholes in risk identification for food safety. A survey on a commercial popular eaten but under-researched hard clam (Meretrix meretrix; Linnaeus, 1758) from a famous fishery port city in southern China was carried out to comprehensively analyze shell size influence on microplastics accumulation in bivalves and consequently, human intake risk via bivalve consumption. Detected microplastics count in per individual (MCI) was 24.64 ± 19.11 items · individual-1, and microplastics count per gram (MCG; wet weight with shell) was 0.66 ± 0.54 items · g-1. When the shell width grew by 1 mm, MCI increased by 1.01 times, but MCG decreased by 0.97 times. Dominant microplastics characteristics found in this study was fiber and fragment. Sizes ranged from 25 to 150 µm, and dark colors (black, red, and blue) were found. The mostly common polymers were polyethene (PE, 40%), polyethylene terephthalate (PET, 23%), and polypropylene (PP, 18%). Estimated annual intake (EAI) risk of microplastics via hard clam consumption by residents was 6652.26 ± 5327.28 items · year -1 · person -1. The microplastics in bivalves and EAI was relatively high. When shell width grew by 1 mm, EAI decreased by 0.97 times. Therefore, eating a fixed amount of larger hard clams with a relatively low amount of microplastics can reduce EAI risk for consumers. A systematic investigation of emission sources along main coast, where bivalve production is prominent will be useful for food safety control in this region.

TCF12 activates MAGT1 expression to regulate the malignant progression of pancreatic carcinoma cells.

As a highly malignant gastrointestinal tumor, pancreatic carcinoma (PC) has poor prognosis due to its low early diagnosis rate, advanced tumor resection and chemotherapy resistance. Magnesium transporter 1 (MAGT1) is a magnesium ion transporter located on the cell membrane, which shows promotive effects on biological behaviors of multiple tumor cells. The aim of the present study was to investigate the role of MAGT1 in the progression of PC and its potential molecular mechanism. Based on the Gene Expression Profiling Interactive Analysis website, MAGT1 was highly expressed in tissues from patients with PC and was associated with poor prognosis. In functional experiments, MAGT1 was highly expressed in PC cell lines. The Cell Counting Kit-8, gap closure and Transwell assays, and western blot analysis, were used to investigate the effects of MAGT1 overexpression or knockdown on the biological behaviors of PC cells. It was found that MAGT1 promoted the proliferation, migration and invasion of PC cells in vitro. According to the Encyclopedia of RNA Interactomes website, transcription factor 12 (TCF12) mRNA expression level was positively correlated with MAGT1 expression level in the tissues from patients with PC. Positive targeting regulation of MAGT1 by TCF12 was also confirmed using a dual-luciferase gene reporter assay and chromatin immunoprecipitation. In addition, knockdown of TCF12 expression inhibited the proliferation and migration of PC cells, but overexpression of MAGT1 expression partly reversed this. These results suggested that TCF12 could promote the proliferation, migration and invasion of PC cells by activating MAGT1 expression, which was associated with poor prognosis. These findings suggest that MAGT1 could be a promising biomarker for the occurrence, progression and prognosis of PC.

Analysis of risk factors for early stent thrombosis in the Chinese population: A multicenter restrospective study.

BACKGROUND: The predictive scoring systems for early stent thrombosis (EST) remains blank in China. The study aims to evaluate the risk factors and conduct a prediction model of EST in the Chinese population. METHODS: EST was defined as thrombosis that occurs within the first 30 days after primary percutaneous coronary intervention (PCI). Patients from ten Chinese hospitals diagnosed as stent thrombosis (ST) from January 2010 to December 2016 were retrospectively included as the study group. A control group (1 case:2 controls) was created by including patients without ST, major adverse cardiovascular events, or cerebrovascular events during follow-up. The present study evaluated 426 patients with single-vessel lesions and ultimately included 40 patients with EST and 80 control patients, who were included to identify factors that predicted EST and to develop a prediction scoring system. The other 171 patients without integrated 1:2 pair were used for external validation. RESULTS: EST was independently associated with a low hemoglobin concentration (adjusted odds ratio [OR] 0.946, 95% confidence interval [95% CI] 0.901-0.993, P=0.026), a high pre-PCI Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) score (OR 1.166, 95% CI 1.049-1.297, P=0.004), and a DAPT (DAPT) duration of <30 days (OR 28.033, 95% CI 5.302-272.834, P<0.001). The simple EST prediction score provided an area under the curve (AUC) of 0.854 (95% CI 0.777-0.932, P<0.001) with 70.0% sensitivity and 90.0% specificity, and 0.742 (95% CI 0.649-0.835, P<0.001) with 54.5% sensitivity and 81.0% specificity for external validation dataset. CONCLUSIONS: EST may be independently associated with DAPT discontinuation within 30 days, a low hemoglobin concentration, and a high SYNTAX score. The scoring system also has a good ability to predict the risk of EST and may be useful in the clinical setting.

Cilostazol increases adenosine plasma concentration in patients with acute coronary syndrome.

WHAT IS KNOWN AND OBJECTIVE: Cilostazol is a specific and strong inhibitor of phosphodiesterase (PDE) type III which can suppress the platelet aggregation by increasing cyclic adenosine monophosphate (cAMP) levels. The clinical benefit of cilostazol in ACS patients suggested that the drug may have non-platelet-directed properties. Some in vitro and animal studies also indicated that the 'pleiotropic' properties of cilostazol might be related to the interaction with adenosine metabolism. Adenosine is an important regulatory metabolite and an inhibitor of platelet activation. However, no human study has been conducted to determine whether cilostazol could increase the adenosine plasma concentration in vivo. As a result, this study aimed to investigate the impact of cilostazol on adenosine plasma concentration (APC) in acute coronary syndrome (ACS) patients. METHODS: We prospectively analysed 149 ACS patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stents. The included patients were divided into two groups according to the presence (cilostazol group, n = 64) or absence (aspirin group, n = 85) of aspirin intolerance. The inhibition of platelet aggregation (IPA), APC and cAMP concentration was measured. Patient characteristics, medications and 30-day clinical outcomes were examined. RESULTS: Patients receiving cilostazol had a significantly higher adenosine and cAMP plasma concentration than patients receiving aspirin (3.00 ± 0.67 vs 2.56 ± 0.74 mol/L, P < .001; 28.10 ± 14.74 vs 20.48 ± 11.35 pmol/mL, P = .0014). Cilostazol was associated with a higher inhibition rate of ADP induced platelet aggregation than aspirin (63.35 ± 26.71 vs 52.2 ± 28.35, P = .036). The plasma levels of adenosine and cAMP showed a positive correlation with ADP induced platelet aggregation. WHAT IS NEW AND CONCLUSION: Cilostazol increases adenosine concentration compared with aspirin. Its potent antiplatelet effect in ACS patients may be partly mediated by adenosine.

Hepsin Promotes Epithelial-Mesenchymal Transition and Cell Invasion Through the miR-222/PPP2R2A/AKT Axis in Prostate Cancer.

PURPOSE: To determine the role and underlying mechanism of hepsin in epithelial-mesenchymal transition (EMT) and cell invasion in prostate cancer. METHODS: The expression of hepsin in prostate cancer tissue samples and cell lines was measured by immunohistochemical staining and Western blotting. The EMT and cell invasion abilities of prostate cancer cells were detected by Western blot and transwell assays. RNA transfection was used to inhibit or overexpress related genes. The expression of miR-222 was detected by RT-qPCR. A dual­luciferase reporter gene assay was performed to determine the target of miR-222. RESULTS: Hepsin expression was upregulated in prostate cancer tissue samples and cell lines. Inhibition of hepsin attenuated EMT and cell invasion and downregulated the expression of miR-222. Decreased miR-222 expression enhanced the level of PPP2R2A, which in turn attenuated the AKT signaling. Activation of miR-222 or AKT could block the inhibitory effects on EMT and cell invasion induced by hepsin deficiency. CONCLUSION: Hepsin promotes EMT and cell invasion through the miR-222/PPP2R2A/AKT axis in prostate cancer.

Olaparib is effective for recurrent urothelial carcinoma with BRCA2 pathogenic germline mutation: first report on olaparib response in recurrent UC.

Urothelial carcinoma (UC) is a common malignancy of the lower and upper urinary tract. Recurrent UC has poor prognosis due to delayed diagnosis and a lack of clinical management guidance, especially for upper urinary tract UC. Patients with germline or somatic BRCA1/2 mutations are a special population in UC. No evidence is available so far on the effectiveness of poly ADP-ribose polymerase inhibitor (PARPi) in this population. Here, we report a 60-year-old female patient diagnosed with left ureter high-grade UC. Recurrent lesions were found 20 months after radical surgery. Computed tomography (CT) examination showed a slightly high-density soft tissue mass (3.2 × 3.1 cm) on the left posterior wall of the abdomen (waist), soft tissue mass adjacent to the left inner wall of the pelvis (3.2 × 4.2 cm), and multiple enlarged lymph nodes to the left of abdominal aorta. A next-generation sequencing (NGS)-based 605-gene panel detected a novel BRCA2 pathogenic germline mutation c.1670T>A (p.L557*), and a series of somatic insertion and deletion (INDEL) mutations of BRCA1, RB1, and JAK2, and single nucleotide variation (SNV) mutations of TP53, KMT2D, MET, ROS1, and IL7R. The above lesions were reduced significantly or disappeared (partial response, PR) after a 3-month Olaparib treatment, and the patient's general condition remained well. In conclusion, this study proved for the first time that PARPi was effective for UC treatment in patients carrying germline BRCA2 pathogenic mutations, providing new treatment options for such patients. In addition, the circulating tumor DNA (ctDNA) test can be used for drug selection and response monitoring in UC treatment.

Ticagrelor Pharmacokinetics and Pharmacodynamics in Chinese Patients with STEMI and NSTEMI Without Opioid Administration.

INTRODUCTION: The pharmacodynamics (PD) and pharmacokinetics (PK) study of ticagrelor loading dose (LD) in Chinese patients with acute coronary syndrome (ACS) without opioid administration has never been investigated. Therefore, the aim of this study was to evaluate the antiplatelet effects and the PK parameters of ticagrelor in Chinese patients with ACS without opioid administration. METHODS: A sample size of 30 eligible patients with ACS were enrolled in this study. Blood samples were obtained predose and 1, 2, 4, 8, and 12 h after 180 mg LD of ticagrelor. P2Y12 reactivity units (PRU) and plasma concentrations of ticagrelor and its two metabolites were measured. RESULTS: In total, 15 patients were admitted to ST segment elevation myocardial infarction (STEMI) and non-ST segment elevation myocardial infarction (NSTEMI) groups, respectively. For patients with NSTEMI, PRU declined significantly during the first 4 h and maintained a relatively stable antiplatelet effect from 4 to 12 h after LD. A similar trend was found in the STEMI group without significant differences of PRU in each designed time compared with patients with NSTEMI (P > 0.05). Tmax of metabolite AR-C124910XX was 4 h after LD for both groups. There were no significant differences for drug concentration, Cmax, or AUC of ticagrelor and AR-C124910XX between patients with STEMI and NSTEMI (P > 0.05). CONCLUSIONS: For Chinese patients with ACS, at least 4 h was needed to achieve an adequate antiplatelet effect for ticagrelor LD. There were no differences in PK or PD between Chinese patients with STEMI and NSTEMI. CLINICAL TRIAL REGISTRATION: ChiCTR1800014764.

Prognostic value of systemic inflammatory factors NLR, LMR, PLR and LDH in penile cancer.

BACKGROUND: Penile squamous cell carcinoma (PSCC) represents an important public health problem for developing countries. The major prognostic factors in PSCC are pathological subtype, perineural invasion, lymphovascular invasion, depth of invasion and grade, which are hard to obtain precisely before the operation. Besides, micro-metastases will be detected in about 30% of intermediate-risk patients with clinically non-palpable inguinal lymph nodes after inguinal lymph node dissection (ILND). It means approximately 70% of patients are unable to benefit from ILND who might suffered from the complications of surgery. We hope some biomarkers could be found which are able to predict the outcome before surgery and reflect the inguinal lymph nodes metastasis. METHODS: A total of 349 consecutive patients of penile cancer in Yunnan cancer hospital in China between October 2002 and December2017. Two hundred twenty-five was succeed to follow-up. The association between NLR, LMR, PLR, LDH and Overall survival (OS), progression free survival (PFS), inguinal lymph node (N stage) was analyzed with K-M analysis, univariable, multivariable logistic regression and Kendall's tau-b correlation coefficient. RESULTS: Multivariable analysis reveal that only PLR was significant independent factor which is associated with inferior OS and PFS; Age and LDH was associated with inferior OS; Lymph node and metastatic status remained significant for OS and PFS as NCCN and EAU Guidelines indicated; the tumor type, initial treatment and NLR LMR were not significant in predicting both OS and PFS. NLR, LMR and PLR were corresponded to N stage, while LDH was not associated with the N stage based on logistic regression model analysis. NLR, LMR and PLR were found weakly related to N stage through an application of Kendall's tau-b correlation coefficient. CONCLUSIONS: PLR was significant independent factors for OS and PFS, Age and LDH was significant independent factors for OS. NLR, LMR, PLR was corresponded to N stage.

Residual platelet reactivity is preferred over platelet inhibition rate in monitoring antiplatelet efficacy: insights using thrombelastography.

Although thrombelastography (TEG) has been widely implemented in the clinical setting of endovascular intervention, consensus on the optimal parameter for defining high ischemic risk patients is lacking due to the limited data about the relationship between various TEG parameters and clinical outcomes. In this article, we report a post hoc analysis of a prospective, single-center cohort study, including 447 patients with acute coronary syndrome (ACS). Arachidonic acid (AA)- or adenosine diphosphate (ADP)-induced platelet-fibrin clot strength (MAAA or MAADP) was indicative of the net residual platelet reactivity after the treatment with aspirin or clopidogrel, respectively. AA% or ADP% was indices of the relative platelet inhibition rate on AA or ADP pathway. We found that each parameter alone was predictive of the risk of 6-month ischemic event, even after adjusting for confounding factors. However, the association between AA% and clinical outcome disappeared when further adjusted for MAAA. Likewise, inclusion of MAADP changed the significant relation between ADP% and clinical outcome. MAADP > 47.0 mm and MAAA > 15.1 mm were identified as the optimal cutoffs by receiver operating characteristic analysis. High MAAA (HR = 3.963; 95% CI: 1.152-13.632; P = 0.029) and high MAADP (HR = 5.185; 95% CI: 2.228-12.062; P < 0.001) were independent predictors when both were included in multivariable Cox regression hazards model. Interestingly, an even higher risk was found for the coexisting high MAAA and high MAADP (HR = 7.870; 95% CI: 3.462-17.899; P < 0.001). We conclude that when performing TEG to predict clinical efficacy, residual platelet reactivity has superiority over platelet inhibition rate as a measure of thrombotic risk in patients treated with aspirin and clopidogrel after ACS.

Association Between Residual Platelet Reactivity on Clopidogrel Treatment and Severity of Coronary Atherosclerosis: Intrinsic Hypercoagulability as a Mediator.

INTRODUCTION: High on-treatment residual platelet reactivity (HRPR) was associated with greater atherosclerosis burden. We examined whether intrinsic hypercoagulability (IHC) could be attributed to that association in patients treated by drug-eluting stents. METHODS: This retrospective observation enrolled a total of 891 coronary artery disease (CAD) subjects. Platelet and coagulant reactivity was measured by thrombelastography. At least 24 h after a 300-mg dose of clopidogrel, adenosine diphosphate (ADP)-induced maximum amplitude of clot strength (MAadp) > 47 mm represented HRPR. Thrombin-induced platelet-fibrin clot strength (MAthrombin) and blood fibrinogen surrogated intrinsic coagulability. Using mediation analysis to evaluate the effect of IHC on the relationship between the number of narrowed coronaries and HRPR on clopidogrel. RESULTS: More HRPR on clopidogrel and higher intrinsic coagulability were observed in more severe coronary atherosclerosis, especially in the three-vessel disease. After adjustment for confounding factors, the number of narrowed coronaries (ORadj = 1.343, 95% CI 1.063-1.695, p = 0.013), MAthrombin (ORadj = 1.106, 95% CI 1.058-1.157, p < 0.001), and fibrinogen (ORadj = 1.003, 95% CI 1.001-1.005, p = 0.012) were all independent positive predictors for HRPR. MAthrombin and fibrinogen were meaningful mediators for the significant positive association of the number of narrowed vessels and HRPR on clopidogrel, which were enhanced by around 30% and 43%, respectively, for this effect. CONCLUSIONS: This is the first study to demonstrate that the positive correlation between the number of stenotic coronaries and HRPR on clopidogrel may be partly attributed to IHC, which may enhance the risk stratification, guide more precise coagulation in multi-vessel disease after drug-eluting stents, and therefore deserve further study.

A Case of Atrioventricular Block Potentially Associated with Right Coronary Artery Lesion and Ticagrelor Therapy Mediated by the Increasing Adenosine Plasma Concentration.

PURPOSE: To report a case of atrioventricular block (AVB) which might be associated with the right coronary artery lesion and the novel oral antithrombotic drug ticagrelor mediated by the increasing adenosine plasma concentration (APC). CASE REPORT: A 65-year-old man was given loading dose of ticagrelor (180 mg) before coronary angiography with total thrombotic occlusion of right coronary artery and one stent was implanted. On second day after successful percutaneous coronary intervention, ECG monitoring showed second-degree (Mobitz type I) AVB with prolonged PR interval (299 ms). Hypothesis was drawn that elevated APC levels caused by ticagrelor would be the reason for AVB after excluding combination drugs or underlying disease. APC might be an indicator of this side effect caused by the P2Y12 receptor inhibitors. On fourth day after shifting to clopidogrel, the ECG showed normal sinus rhythm and PR interval depressed to 190 ms and APC dropped from 1.62 umol/L to 0.92 umol/L. The bradycardia and AVB did not occur in the three-month follow-up. CONCLUSION: It was important to take the ticagrelor induced bradycardia into account particularly with the myocardial infarction of right coronary artery, treated with atrioventricular block drugs after initiating ticagrelor. Also, we should shift ticagrelor to clopidogrel if AVB occurred.

Tumor angiogenesis targeting and imaging using gold nanoparticle probe with directly conjugated cyclic NGR.

Angiogenesis is a vital process for the growth and metastasis of malignant tumor. Visualization of tumor angiogenesis is thus of great importance in the evaluation of biologic aggressiveness as well as monitoring of the response to anti-angiogenic therapy. Herein, we developed a probe based on gold nanoparticles (GNPs) directly surface-functionalized with a tumor-homing cyclized asparagine-glycine-arginine peptide (SH-cNGR) and carboxylpoly(ethylene glycol)thiol (SH-PEG-COOH) via Au-S bonds. The obtained GNPs-PEG@cNGR probe was used to target the aminopeptidase-N (APN/CD13), which overexpressed in the endothelium of tumor angiogenesis. The CD13 binding affinities of the peptides were assessed by a receptor binding assay based on HUVEC and HepG2 cell (e.g. fluorescence imaging and X-ray computed tomography (CT)). The tumor targeting efficacy and the distribution of the GNPs-PEG@cNGR in vivo were further evaluated in a subcutaneous 4T1 xenograft model by CT imaging and immunohistochemistry study. These results showed that the GNPs-PEG@cNGR rapidly and specifically bound to the tumor vasculature after intravenous injection. Quantitative studies demonstrated that GNPs-PEG@cNGR showed significantly higher and faster tumor uptake after intravenous injection compared to unlabeled GNPs-PEG. Moreover, the distribution of tumor enhancement was consistent with the spatial distribution of angiogenic blood. These results suggest that the designed GNPs-PEG@cNGR probe may serve, in principle, as a promising CT contrast agent for targeted angiogenesis imaging and quantitative analysis.

Harmonic responses and cavitation activity of encapsulated microbubbles coupled with magnetic nanoparticles.

Encapsulated microbubbles coupled with magnetic nanoparticles, one kind of hybrid agents that can integrate both ultrasound and magnetic resonance imaging/therapy functions, have attracted increasing interests in both research and clinic communities. However, there is a lack of comprehensive understanding of their dynamic behaviors generated in diagnostic and therapeutic applications. In the present work, a hybrid agent was synthesized by integrating superparamagnetic iron oxide nanoparticles (SPIOs) into albumin-shelled microbubbles (named as SPIO-albumin microbubbles). Then, both the stable and inertial cavitation thresholds of this hybrid agent were measured at varied SPIO concentrations and ultrasound parameters (e.g., frequency, pressure amplitude, and pulse length). The results show that, at a fixed acoustic driving frequency, both the stable and inertial cavitation thresholds of SPIO-albumin microbubble should decrease with the increasing SPIO concentration and acoustic driving pulse length. The inertial cavitation threshold of SPIO-albumin microbubbles also decreases with the raised driving frequency, while the minimum sub- and ultra-harmonic thresholds appear at twice and two thirds resonance frequency, respectively. It is also noticed that both the stable and inertial cavitation thresholds of SonoVue microbubbles are similar to those measured for hybrid microbubbles with a SPIO concentration of 114.7 µg/ml. The current work could provide better understanding on the impact of the integrated SPIOs on the dynamic responses (especially the cavitation activities) of hybrid microbubbles, and suggest the shell composition of hybrid agents should be appropriately designed to improve their clinical diagnostic and therapeutic performances of hybrid microbubble agents.

Features of S-nitrosylation based on statistical analysis and molecular dynamics simulation: cysteine acidity, surrounding basicity, steric hindrance and local flexibility.

S-Nitrosylation is involved in protein functional regulation and cellular signal transduction. Although intensive efforts have been made, the molecular mechanisms of S-nitrosylation have not yet been fully understood. In this work, we carried out a survey on 213 protein structures with S-nitrosylated cysteine sites and molecular dynamic simulations of hemoglobin as a case study. It was observed that the S-nitrosylated cysteines showed a lower pKa, a higher population of basic residues, a lower population of big-volume residues in the neighborhood, and relatively higher flexibility. The case study of hemoglobin showed that, compared to that in the T-state, Cysß93 in the R-state hemoglobin possessed the above structural features, in agreement with the previous report that the R-state was more reactive in S-nitrosylation. Moreover, basic residues moved closer to the Cysß93 in the dep-R-state hemoglobin, while big-volume residues approached the Cysß93 in the dep-T-state. Using the four characteristics, i.e. cysteine acidity, surrounding basicity, steric hindrance, and local flexibility, a 3-dimensional model of S-nitrosylation was constructed to explain 61.9% of the S-nitrosylated and 58.1% of the non-S-nitrosylated cysteines. Our study suggests that cysteine deprotonation is a prerequisite for protein S-nitrosylation, and these characteristics might be useful in identifying specificity of protein S-nitrosylation.

Fe2O3 nanoparticle mediated molecular growth and soot inception from the oxidative pyrolysis of 1-methylnaphthalene.

While it is well documented iron oxide can reduce soot through burnout in the oxidative regions of flames, it may also impact molecular growth and particle inception. The role of Fe2O3 nanoparticles in mass growth of soot from 1-methylnapthalene (1-MN) was studied in a dual-zone, high-temperature flow reactor. An iron substituted, dendrimer template was oxidized in the first zone to generate ~5 nm Fe2O3 nanoparticles, which were seeded into the second zone of the flow reactor containing 1-MN at 1100°C and ϕ = 1.4-5.0. Enhanced molecular growth in the presence of Fe2O3 nanoparticles resulted in increased yields of polycyclic aromatic hydrocarbons (PAH) and soot compared to purely gas-phase reactions of 1-MN at identical fuel-air equivalence ratios. This also resulted in an increase in soot-number concentration and a slight shift to smaller particles with increasing addition (from no addition to 3 mM) of Fe2O3. Introduction of Fe2O3 nanoparticles resulted in the formation of stabilization of environmentally persistent free radicals (EPFRs), including benzyl, phenoxyl, or semiquinone-type radicals as well as carbon-centered radicals, such as cyclopentadienyl or a delocalized electron in a carbon matrix. At the high concentrations in the flow reactor, these resonance-stabilized free radicals can undergo surface-mediated, radical-radical, molecular growth reactions which may contribute to molecular growth and soot particle inception.