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The effect of enter rolling temperatures on the grain size and toughness was investigated in Q345E H-beam steels. The experimental results shown that the grain size exhibited a complicated phenomenon with rolling temperature instead of refining as the temperature decreased as expected. It would be interpreted by the behaviors of deformation and recrystallization in austenite during rolling. The toughness is not only depended on the average grain size but also on the distribution of grain size as well as morphology of pearlite. The toughness would be decreased by the mixed grain size.

A novel protocol for the aromatic ortho C–H nitration of aryl ureas with Fe(NO3)3·9H2O is developed. The reaction utilizes CuCl2·2H2O as catalyst and p-TSA as additive, showing good functional group tolerance and furnishing the desired products in moderate to excellent yields.

Two clinical ablation protocols, 2C3L and stepwise, have been routinely used in our group to treat atrial fibrillation (AF), but with a less than 60% long-term arrhythmia-free outcome achieved in patients. The goal of this study was to examine the underlying mechanism of low success in clinical outcome. MRI images from one patient were used to reconstruct a human atrial anatomical model, and fibrotic tissue was manually added to represent the arrhythmia substrate. AF was induced with standard protocols used in clinical practice. 2C3L and stepwise were then used to test the efficacy of arrhythmia termination in our model. The results showed that re-entries induced in our model could not be terminated by using either 2C3L or the stepwise protocol. Although some of the induced re-entries were terminated, others emerged in new areas. Ablation using only the 2C3L or stepwise method was not sufficient to terminate all re-entries in our model, which may partially explain the poor long-term arrhythmiafree outcomes in clinical practice. Our findings also suggest that computational heart modelling is an important tool to assist in the establishment of optimal ablation strategies.

An alternative medicinal chemistry approach was conducted on Bruton’s tyrosine kinase (BTK) inhibitor 1 (ibrutinib) by merging the pyrazolo[3,4-d]pyrimidine component into a tricyclic skeleton. Two types of compounds were prepared, and their biochemical activities on BTK as well as stereochemistry effects were determined. Structural optimization focusing on the reactive binding group to BTK Cys481 and on the metabolic site guided by metabolic study were conducted. 7S was identified as the most potent showing an IC50 value of 0.4 nM against BTK and 16 nM against BTK-dependent TMD8 cells. Compared to 1, 7S was slightly more selective with strong inhibition on the B-cell receptor signaling pathway. In a TMD8 cell-derived animal xenograft model, 7S showed a relative tumor volume of 5.3 at 15 mg/kg QD dosage that was more efficacious than 1 (RTV 6.6) at a higher dose of 25 mg/kg QD. All these results suggest 7S as a new BTK inhibitor worthy of further profiling.

Bromodomain-containing Protein 4 (BRD4), an 'epigenetic reader', regulates chromatin structure and gene expression via recognizing and binding acetylated lysine in histones. BRD4 has become a therapeutic target for cancers because it promotes the expression of the tumor genes, such as c-Myc, NF-κB, and Bcl-2. In this study, a new series of 3-methyl-1H-indazole derivatives were designed via virtual screening and structure-based optimization. All compounds were synthesized and evaluated for their inhibitory activities to BRD4-BD1 and their antiproliferative effects in cancer cell lines. Among them, several compounds (such as 9d, 9u and 9w) exhibited strong BRD4-BD1 affinities and inhibition activities, and potently suppressed MV4;11 cancer cell line proliferation. Among them, compound 9d showed excellent selectivity for BRD4 and effectively suppressed c-Myc, the downstream protein of BRD4. This study provided new lead compounds for further biological evaluation on BRD4.

Endo-/lysosome escape is a major challenge in nanoparticle-based protein delivery for cancer therapy. To enhance the endo-/lysosomal escape and increase the efficacy of protein delivery, current strategies mainly focus on destroying endo-/lysosomes by employing modified nanoparticles, such as pH-sensitive polyplexes, cell-penetrating peptides, and photosensitive molecules. Herein, we hypothesize that pretreatment with empty nanocarriers might make endo-/lysosomes occupied and affect the endo/lysosomal escape of protein subsequently delivery by nanocarriers. We first treated breast carcinoma MDA-MB-231 cells with a high concentration of empty nanocarriers, mesoporous silica nanoparticles (MSN), to occupy the endo-/lysosome. After 2 h, we treated the cells with a lower concentration of fluorescein isothiocyanate-labeled MSN (MSN-FITC) and investigated the intracellular spatial and temporal distribution of MSN-FITC and their colocalization with endo-/lysosomes. We discovered the preoccupation of endo-/lysosomes by the empty nanocarriers did exist, mainly through changing the spatial distribution of the subsequently introduced nanocarriers. Furthermore, for the protein delivery, we observed reduced MSN-saporin delivery after endo-/lysosome preoccupation by MSN empty carriers. A similar result is observed for the delivery of cytochrome C by MSN but not for the small-molecule anticancer drug doxorubicin. The results show that the empty nanocarriers inhibit the endo-/lysosome intracellular trafficking process and decrease the endo-/lysosome escape of proteins subsequently delivered by the nanocarriers. This new discovered phenomenon of declined endo-/lysosome escape after endo-/lysosome preoccupation indicates that repeated treatment by nanomaterials with low protein-loading capacity may not yield a good cancer therapeutic effect. Therefore, it provides a new insightful perspective on the role of nanomaterial carriers in intracellular protein delivery.

A convenient and practical method has been developed for the synthesis of substituted oxazolo[5,4-h]pyrrolo[4,3,2-de]quinolones via the intramolecular oxidative cyclization by using PIFA as oxidant and TMSOTf as additive in DCE under an air atmosphere. The reaction proceeds in good yields and has good functional groups tolerance.

We propose the idea of a tunable nearly perfect absorber based on graphene metamaterial consisting of a periodically arranged graphene ribbons (bright mode) and the inverse slots in the thin graphene film (dark mode). The absorption peak has a narrow linewidth of 160 nm and the absorbance approaching to 97.12%. The fascinating absorption feature not merely due to plasmonically induced absorption arising from destructive interference between the bright and dark mode but also the metamaterial absorption. We have testified numerically that the electric fields are highly confined inside the slot. The mid-IR absorption spectrum can be dynamically tuned by a small change in the chemical potential of graphene, in addition to varying geometrical parameters. Our paper considers a situation that represents an intermediate plasmonic coupling regime, between near-field and far-field coupling. Such absorber possesses potential for applications in mid-IR nanophotonic devices.

Mitochondria play a critical role in diverse cellular processes, such as energy production and apoptosis regulation. The mitochondria-targeted drug delivery is becoming a potential novel strategy for overcoming drug resistance in cancer therapy. Herein, we synthesize nature-inspired dopamine-derived polydopamine (PDA) nanoparticles. Using triphenylphosphonium (TPP) as the mitochondrial penetration molecule to improve the target efficiency, we synthesize poly(ethylene glycol) (PEG)-modified PDA (PDA-PEG) and TPP-functionalized PEG-modified PDA (PDA-PEG-TPP) nanoparticles. Then anticancer drug doxorubicin (DOX) was loaded on PDA-PEG and PDA-PEG-TPP (PDA-PEG-DOX and PDA-PEG-TPP-DOX) nanoparticles, which are apt to deliver DOX to cell nuclei and mitochondria, respectively. To mimic the repeated anticancer drug treatment in clinical cases, we repeatedly treated the MDA-MD-231 cancer cells for a long time using DOX-loaded nanoparticles and find that the mitochondria targeting PDA-PEG-TPP-DOX has higher potential to overcome the drug resistance than the regular delivery nanoparticles PDA-PEG-DOX. These results indicate the promising potential of applying PDA-PEG-TPP-DOX nanoparticles in mitochondria-targeted drug delivery to overcome the drug resistance in long-time anticancer chemotherapy.

To compare the sampling efficiency and diagnostic performance of ultrasound (US)-guided fine-needle aspiration cytology (FNAC) and fine-needle non-aspiration cytology (FNNAC) for thyroid nodules.629 thyroid nodules in 629 cases (477 females, 152 males) were randomly subjected to FNAC or FNNAC from Jun 2014 to Feb 2015. Diagnostic performance was calculated in reference to the histological findings or follow-up results.629 patients (152 men, 477 women) with 629 thyroid nodules were enrolled in the study. Pathological results were obtained in 173 nodules and benign nodules at FNA with more than six months' follow-up were found in 65 nodules. Tumor size for FNAC ranges from 3.0 to 51.0 mm (mean±SD; 10.2±6.9 mm); whereas FNNAC (2.0-43.0 mm; 11.9±7.7 mm). Non-diagnostic results were found in 7.59% (24/316) of FNNAC procedures and 7.59% (25/313) of FNAC (P 0.05). Determinate and indeterminate results were found in 50.63% (160/316) and 41.77% (132/316) of FNNAC procedures, whereas 58.15% (182/313) and 33.87% (106/313) of FNAC (P 0.05). In order to obtain determinate cytological results, FNAC might be more suitable than FNNAC for diagnosis of nodules with hypovascularity (51.38% vs. 41.78%, P 0.05) and macrocalcifications (9.72% vs. 6.50%, P 0.05). No US and Color-Doppler US characteristics, such as the presence of hypervascularity (P 0.05), microcalcifications (P 0.05), internal component (P 0.05), or size(P 0.05), were significantly different to obtain determinate cytological results between the FNAC and FNNAC groups. The sensitivity, specificity, positive predictive value, negative predictive value, accuracy of FNAC and FNNAC were as follows: 96.67% vs. 100%, 89.74% vs. 96.5%, 87.88% vs. 96.97%, 97.22% vs. 100%, 92.75% vs.98.36%, respectively (all P 0.05).Both FNAC and FNNAC are effective for diagnosis of thyroid nodules. However, FNAC is more effective than FNNAC to acquire determinate cytological results for nodules which US present hypovascularity and macrocalcifications.

Background VEGFR-2 inhibitors have been widely used in the treatment of cancer. In our continued efforts to search for potent and novel VEGFR-2 inhibitors as antitumor agents, we have identified a series of ureas and amides bearing a oxazolopyrimidine scaffold. Aim of the Study To discover more potent VEGFR-2 inhibitors with stronger binding affinity and better physical and chemical properties. Methods 23 pyrimidinylacetamide-based ureas were designed and synthesized. Replacement of oxazolopyrimidine with a pyrimidinylacetamide generated a series of novel VEGFR-2 inhibitors. Results and Conclusions In HUVEC inhibition assay, the most potent compound (compound 16) possessed an IC 50 value of 0.43 μM. Compound 16 also inhibited the migration and capillary like tube formation of HUVECs with inhibition rate at 22% (1 μM) and 17.5% (0.8 μM) respectively. These results support the further investigation of compound 16 as a potential anti-cancer agent.

To assess the factors associated with initial incomplete ablation (ICA) after radiofrequency ablation for benign thyroid nodules (BTNs).69 BTNs (mean volume 6.35±5.66 ml, range 1.00-25.04 ml) confirmed by fine-needle aspiration cytology (FNAC) in fifty-four patients were treated with ultrasound-guided percutaneous radiofrequency ablation (RFA) and the local treatment efficacy was immediately assessed by intra-procedural contrast-enhanced ultrasound (CEUS). The RFA was performed with a bipolar electrode (CelonProSurge 150-T20, output power: 20 W). CEUS was performed with a second generation contrast agent under low acoustic power (i.e. coded phase inversion, CPI). Characteristics of clinical factors, findings on conventional gray-scale ultrasound, color-Doppler ultrasound, and CEUS were evaluated preoperatively. Factors associated with initial ICA and initial ICA patterns on CEUS were assessed. Volume reduction ratios (VRRs) of ICA nodules were compared with those with complete ablation (CA).The RFA procedures were accomplished with a mean ablation time and mean total energy deposition of 11.13±3.39 min (range, 5.38-22.13 min) and 12612±4466 J (range, 6310-26130 J) respectively. CEUS detected initial ICA in 21 of 69 (30.8%) BTNs and 16 (76.2%) of the 21 BTNs with initial ICA achieved CA after additional RFA, leading to a final CA rate of 92.8% (64/69). The factors associated with initial ICA were predominantly solid nodule, nodule close to danger triangle area, nodule close to carotid artery, and peripheral blood flow on color-Doppler ultrasound (all P 0.05). The mean VRRs of all BTNs were 23.4%, 54.4% and 81.9% at the 1-, 3- and 6-month follow-up, respectively. All BTNs achieved therapeutic success in this series in that all had VRRs of50% at the 6-month follow-up, among which 7 nodules (10.1%) had VRRs of90%. There were significant differences in VRRs between ICA nodules and CA nodules at the 3- and 6-month follow-up (all P 0.05).The factors associated with initial ICA after RFA for BTNs were predominantly solid nodules, nodule close to danger triangle area, nodule close to carotid artery, and peripheral blood flow on color-Doppler ultrasound. CEUS assists quick treatment response evaluation and facilitates subsequent additional RFA and final CA of the nodules. Nodules with CA achieve a better outcome in terms of VRR in comparison with those with ICA.

Object To study the expression of miRNA-146a in sepsis-induced acute lung injury (ALI) patients and its effect on the inflammation in mouse models. Methods miRNA-146a expression in peripheral blood was determined in sepsis-induced ALI patients and healthy volunteers by qRT-PCR. Sepsis-induced ALI mouse model were reproduced by LPS treatment and miRNA-146a mimic, miRNA-146a NC and miRNA-146a inhibitors were injected through trachea. The expressions of miRNA-146a, TNF-α, IL-1βand COX-2 mRNA were determined by qRT-PCR 24h after the intervention. Results The miRNA-146a expression in peripheral blood significantly increased in severe sepsis with ALI patients, compared with the control subjects. For mouse model, the expressions of TNF-α, IL -1βand COX-2 mRNA significantly decreased in miRNA-146a group, while increased in miRNA146a inhibitor group compared with miRNA-146a NC group (P

This paper presents an optimization model for water quantity and quality integrated management of an urban lake in a water deficient city. A representative water quantity and quality safeguard system served urban lake, including multi-source water supply facilities, recirculating water purification facilities and surplus water discharge facilities, is widely used in Chinese water deficient cities. Because it is complicated, any mismanagement will result in water quality deterioration, water waste and high operation cost. The presented model attempts to achieve the objectives of controlling water pollution, reducing economic cost and improving water utilization efficiency through an optimized operating water safeguard system. The model is applied to Qingjing Lake in Tianjin, China. Results show that the model plays a more positive role for water quantity and quality integrated management.

Objectives: The aim of this study was to develop an ultrasound consolidated score (UCS) in determining the activity of Crohn’s disease (CD) and evaluate it with reference to simple endoscopic score (SES). Methods: From June 2014 to June 2017, 66 patients with CD were retrospectively enrolled in this study. Each patient underwent endoscopy and transabdominal ultrasound (US) examination. The morphological symmetry, echogenicity of bowel wall, bowel wall layer structure, echogenicity of peri-bowel fat, bowel wall thickness (BWT), and Limberg type on power Doppler US were assessed with transabdominal US, and an UCS scoring system was developed based on these characteristics. Endoscopic results were used as the reference standard and SES was calculated to determine the CD activity. Receiver operating characteristic curve analysis was performed to assess the diagnostic performance for determining CD activity and the correlation between UCS and SES was assessed using Spearman correlation analysis. Results: 330 intestinal segments in 66 patients were included. The UCS of the segments in the remission phase ranged from 3.0 to 9.0 (mean, 3.6 ± 0.9) whereas in the active phase from 3.0 to 20.0 (mean, 10.6 ± 4.0) (p < 0.001). The cut-off value of UCS was 6. The associated area under ROC curve, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 0.980, 88.3%, 95.5%, 93.8%, 91.3%, and 92.3%, respectively. The correlation coefficient between UCS and SES was 0.90, which was higher than the correlation coefficient of 0.83 between BWT and SES. Conclusions: The newly developed UCS with transabdominal US has a good performance and potentially provides an effective alternative for evaluating the activity of CD. Advances in knowledge: UCS is an effective method to evaluate the activity of CD because it provides comprehensive information of the disease. Therefore, it could be employed as an alternative for diagnosis of CD.

Objectives The purpose of this study was to establish a scoring system for predicting axillary lymph node metastasis (ALNM) in patients with breast invasive ductal carcinoma with negative axillary ultrasound (US) results. Methods In this retrospective study, 156 breast invasive ductal carcinoma lesions from 156 women were retrospectively enrolled. The features of conventional US and contrast-enhanced ultrasound (CEUS) qualitative enhancement patterns and quantitative enhancement parameters were analyzed. Subsequently, a scoring system was created by a multivariate logistic regression analysis. Results The results found that 60 patients (38%) showed ALNM. A scoring system was defined as risk score = 1.75 × (if lesion size ≥20 mm) + 1.93 × (if uncircumscribed margin shown on conventional US) + 1.77 × (if coarse or twisting penetrating vessels shown on CEUS). When the risk scores were less than 1.75, 1.75 to 1.93, 1.94 to 3.70, and 3.70 or higher, the risk rates of ALNM were 0% (0 of 9), 10.7% (5 of 46), 29.2% (14 of 48) and 77.4% (41 of 53), respectively. In comparison with conventional US alone, the scoring system using the combination of conventional US and CEUS showed better discrimination ability in terms of the area under the curve (0.830 versus 0.777; P = .037). Conclusions A scoring system based on conventional US and CEUS may improve the prediction of ALNM.

Proteolysis-targeting chimeric molecules (PROTACs), which attract much more attention today, may be a potential way to treat cancer. PROTACs are made up of ligands of target proteins, E3 ligase recruiting elements and linkers. PROTACs can hijack the intracellular inherent ubiquitin proteasome system in cells to degrade different target proteins. PROTACs targeting different cancer-related proteins have been successfully developed and outperform small inhibitors, the traditional way of treating cancer. In this review, we focus on PROTACs targeting cancer-related proteins and their superiority over inhibitors.

Anaerobic activated sludge was got from Hybrid Loop Anaerobic Baffled Reactor (HLABR), and then pH, alkaline, concentration of pyrimidine, several ions such as Ca2+, Cu2+, Fe2+ were studied as influence factors in static experiment within 24 days. The results were shown as follows: the removal rate of pyrimidine could reach 60% during the range of pH 5.5–9.0 and the pyrimidine concentration of 200–2000 mg/L; pyrimidine couldn’t be degraded when alkaline over 2000 mg/L; Ca2+ had no obvious effect on sludge activation, Cu2+ leaded to low sludge activation at the concentration of 10 mmol/L; Fe2+ coexisted facilitated the removal rate by microbe degradation and the removal rate reached 97.2% at the concentration of 10 mmol/L.

Background Malignant endometriosis in an episiotomy scar is rare; only seven cases have been reported previously. Here, we compare two cases of benign endometriosis and clear cell carcinoma. Case presentation The first case was a 54-year-old woman who presented with a large perineal lesion in her episiotomy scar with high 18F-fluorodeoxyglucose uptake. This location had a history of endometriosis many years ago. She underwent radical excision of the mass and bilateral inguinal lymph node dissection. Histological and immunohistochemical analysis confirmed the presence of clear cell carcinoma arising from endometriosis. Assisted radiotherapy was performed after surgery due to a positive lymph node. No recurrence was detected over a 1-year follow-up period. The second case deals with a 3 × 2 cm mass in the episiotomy scar of a 33-year-old woman. Part of the anal sphincter was resected because of the close proximity of the lesion. Because the disease lay very close to the anus, she received anal sphincter reconstruction combined with mass excision. Pathology result showed typical endometrial glands and interstitial tissues. Conclusions Deleterious change only happens in patients experiencing perineal endometriosis. Complete excision is crucial for this form of disease; sometimes impairment of the anal sphincter is also necessary. Patients with malignancy required a combination of treatments in order to improve their prognosis.

The study aimed to illuminate the role of G protein coupled estrogen receptor( GPER) and its mediated PI3 K/AKT signaling pathway in cryptotanshinone( CPT) induced apoptosis of breast cancer SKBR-3 cells,which is GPER positive and ER negative.The apoptosis rate of SKBR-3 cells was tested by Annexin V-FITC/PI staining and apoptosis effector caspase-3 was determined by Western blot. The key proteins in PI3 K/AKT signaling pathway mediated by GPER were detected by Western blot and immunofluorescence technique. Meanwhile,the agonist G1 and antagonist G15 of GPER and antagonist LY294002 of PI3 K were employed in the test to further clarify the effect of GPER and PI3 K/AKT pathway. The results indicated that the apoptosis rate was increased from 4. 7% to46. 1% and 69. 0% after treatment with 0,5,10 μmol·L~(-1) CPT for 48 h( P0. 01). The expression of PI3 K,AKT and p-AKT were inhibited( P0. 05 or P0. 01),while caspase-3 level increased obviously after treatment with CPT( P0. 01). Importantly,inhibitory effect of PI3 K/AKT signaling pathway by CPT was further enhanced by G1 and attenuated by G15. LY294002 also induced a further inhibition of expression of AKT and p-AKT. The mean fluorescence intensity of AKT and p-AKT could be decreased by CPT. Furthermore,CPT could downregulate GPER expression in SKBR-3 cells( P0. 01),which could be inhibited by G1 and enhanced by G15.In conclusion,CPT could induce the apoptosis of ER negative and GPER positive breast cancer SKBR-3 cells and the molecular mechanism is related to its regulatory effect of GPER and its mediated PI3 K/AKT signaling pathway.

Both salicylic acid (SA) and ethylene induce stomatal closure and positively regulate stomatal immunity, but their interactions in guard cell signaling are unclear. Here, we observed that SA induced the expression of ethylene biosynthetic genes; the production of ethylene, reactive oxygen species (ROS) and nitric oxide (NO); and stomatal closure in Arabidopsis thaliana. However, SA-induced stomatal closure was inhibited by an ethylene biosynthetic inhibitor and mutations in ethylene biosynthetic genes, ethylene-signaling genes [RESPONSE TO ANTAGONIST 1 (RAN1), ETHYLENE RESPONSE 1 (ETR1), ETHYLENE INSENSITIVE 2 (EIN2), EIN3 and ARABIDOPSIS RESPONSE REGULATOR 2 (ARR2)], NADPH oxidase genes [ATRBOHD and ATRBOHF], and nitrate reductase genes (NIA1 and NIA2). Furthermore, SA-triggered ROS production in guard cells was impaired in ran1, etr1, AtrbohD and AtrbohF, but not in ein2, ein3 or arr2. SA-triggered NO production was impaired in all ethylene-signaling mutants tested and in nia1 and nia2. The stomata of mutants for CONSTITUTIVE TRIPLE RESPONSE1 (CTR1) showed constitutive ROS and NO production and closure. These results indicate that ethylene mediates SA-induced stomatal closure by activating ATRBOHD/F-mediated ROS synthesis in an RAN1-, ETR1- and CTR1-dependent manner. This in turn induces NIA1/2-mediated NO production and subsequent stomatal closure via the ETR1, EIN2, EIN3 and ARR2-dependent pathway(s).

Purpose Ethics review processes have become increasingly complex. The objective of this study was to explore the challenges currently faced in ethics reviews of clinical scientific research projects in China, with the goal of standardizing the structure of medical ethics committees and better protecting the rights and interests of research participants. Methods We reviewed and comprehensively analyzed the available literature discussing standardized ethics reviews of clinical scientific research projects. Results We identified the following problems: incomplete legislation, absence of supervision, vague review criteria, limitations of ethics committee competence, inadequate ethics consciousness, and poor tracking of reviews. In this paper, we suggest strategies for the development of future ethical reviews of clinical scientific research projects. Conclusion To standardize the ethics review process of clinical scientific research projects in China, it is necessary to establish relevant laws and regulations and implement supervisory responsibilities. Professional training of medical ethics committees is suggested as an effective way to improve the quality of ethics reviews.

Objective: Increased proliferation and migration of airway smooth muscle cells (ASMCs) are key events in the development of asthma. YiQi GuBen is a traditional Chinese medicinal formula shown to effectively reduce the recurrence rate of asthma and induce anti-asthma effects through multiple pathways; however, its potential role in regulating ASMC proliferation and preventing bronchial asthma remains unexplored. Methods: This study investigated the effects of YiQi GuBen formula on platelet-derived growth factor (PDGF)-BB-induced ASMC proliferation and migration by methylthiazolyldiphenyl-tetrazolium bromide, wound healing, transwell, and cell cycle assays. The influence of YiQi GuBen formula on nuclear factor-κB (NF-κB) signaling-relevant proteins was measured by Western blotting, real-time quantitative PCR (RT-qPCR) assay, and ELISA. Results: We found that pretreatment with YiQi GuBen formula had a dose-dependent inhibitory effect on PDGF-BB-stimulated ASMC proliferation. It also suppressed PDGF-BB-induced ASMC migration and arrested PDGF-BB-induced cell cycle progression. Furthermore, YiQi GuBen formula suppressed PDGF-BB-induced expression of phosphorylated p65 and the release of inflammatory factors TNF-α, IL-1β, IL-6, and IL-8 in ASMCs. Conclusions: In summary, our study shows that YiQi GuBen formula is able to significantly inhibit PDGF-BB-induced ASMC proliferation and migration by suppressing the NF-κB signaling pathway.

To investigate the changes in microbial community structure and metabolic properties of

The growth and astaxanthin production of Chlorella zofingiensis were examined under both heterotrophic and photoautotrophic conditions, and it was found that, in comparison to the photoautotrophic mode, the heterotrophic mode led to high algal densities but attenuated intracellular astaxanthin accumulation. Following the heterotrophy-photoautotrophy transition, a considerable increase in the astaxanthin content was observed, accompanied by the upregulation of key carotenogenic genes, including phytoene synthase (PSY), β-carotenoid hydroxylase (CHYb), β-carotenoid ketolase 1 (BKT1), and β-carotenoid ketolase 2 (BKT2). In contrast, the astaxanthin content and carotenogenic genes underwent an opposite change following the photoautotrophy-heterotrophy transition, suggesting the key role of light in stimulating astaxanthin biosynthesis. To improve the astaxanthin production by C. zofingiensis, a novel heterotrophy-photoinduction culture strategy without dilution was developed and evaluated. The astaxanthin content and productivity reached 2.7 mg g-1 of dry weight and 9.9 mg L-1 day-1, respectively, which were 4.0- and 2.5-fold higher than that obtained under the heterotrophic condition.

Angiogenesis is crucial for tumor growth and inhibition of angiogenesis has been regarded as a promising approach for cancer therapy. Vascular endothelial growth factor receptor-2 (VEGFR-2) is an important factor in angiogenesis. In this work, a novel series of thiazolo[5,4-d]pyrimidine derivatives inhibiting angiogenesis were rationally designed and synthesized. Their inhibitory activities against human umbilical vein endothelial cells (HUVEC) were investigated in vitro. 1-(4-Fluorophenyl)-3-{4-[(5-methyl-2-phenyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl)amino]phenyl}urea (19b) and 1-(3-Fluorophenyl)-3-{4-[(5-methyl-2-phenyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl)amino]phenyl}urea (19g) exhibited the most potent inhibitory effect on HUVEC proliferation (IC50 =12.8 and 5.3 μm, respectively). Compound 19g could inhibit the migration of human umbilical vein endothelial cells. These results support the further investigation of these compounds as potent anticancer agents.

The fast development of nanomedicine and nanobiotechnology has enabled the emerging of versatile therapeutic modalities with high therapeutic efficiency and biosafety, among which nanosonosensitizer-involved sonodynamic therapy (SDT) employs ultrasound (US) as the exogenous activation source for inducing the production of reactive oxygen species (ROS) and disease therapy. The chemoreactive nanosonosensitizers are the critical components participating in the SDT process, which generally determine the SDT efficiency and therapeutic outcome. Compared to the traditional and mostly explored organic sonosensitizers, the recently developed inorganic chemoreactive nanosonosensitizers feature the distinct high stability, multifunctionality and significantly different SDT mechanism. This review dominantly discusses and highlights two types of inorganic nanosensitizers in sonodynamic treatments of various diseases and their underlying therapeutic mechanism, including US-activated generation of electrons (e−) and holes (h+) for facilitating the following ROS production and delivery of organic molecular sonosensitizers. Especially, this review proposes four strategies aiming for augmenting the SDT efficiency on antitumor and antibacterial applications based on inorganic sonosensitizers, including defect engineering, novel metal coupling, increasing electric conductivity and alleviating tumor hypoxia. The encountered challenges and critical issues facing these inorganic nanosonosensitzers are also highlighted and discussed for advancing their clinical translations.

Microalgae represent a rich and naturally occurring source of triacylglycerol (TAG), and the microalgae-derived TAG has enormous potential in bioenergy, bio-based materials and other agricultural innovations. Glycerol-3-phosphate acyltransferase (GPAT) is a key enzyme that catalyzes the biosynthesis of TAG. Previously our lab has reported the first GPAT in the oleaginous alga Myrmecia incisa, and in the present study, a new GPAT was further identified from the same alga, which was designated as MiGPAT2. A full-length cDNA of MiGPAT2 consisting of a 1374-bp ORF, a 153-bp 5′-UTR and a 271-bp 3′-UTR was cloned. The putative protein composed of 457 amino acids, possessing the HX4D motif that acts as the activity center of GPAT catalysis. Emphasis was put on the comparison between two MiGPATs regarding subcellular localization and TAG synthesis function. A polyclonal and monoclonal antibody were separately prepared for MiGPAT1 and MiGPAT2, and the following immunogold labeling showed they were localized on chloroplast and endoplasmic reticulum (ER), respectively. This was further confirmed by the GFP fusion studies. Both MiGPATs were expressed heterologously in a GPAT-deficient yeast mutant, and it was found that MiGPAT2 played key roles in the de novo TAG biosynthesis, whereas MiGPAT1 was more involved in the phospholipid formation, contributing to TAG production via an indirect way. Findings of the present study expanded our knowledge on functional and evolutionary relationships of GPAT members in M. incisa, suggesting the possibility of genetic manipulation of GPAT in this alga for enhanced TAG production.

EGFR and VEGFR-2 are involved in pathological disorders and the progression of different kinds of tumors, the combined blockade of EGFR and VEGFR signaling pathways appears to be an attractive approach to cancer therapy. In this work, a series of 4-anilinoquinazoline derivatives containing substituted diaryl urea or glycine methyl ester moiety were designed and identified as EGFR and VEGFR-2 dual inhibitors. Compounds 19i, 19j and 19l exhibited the most potent inhibitory activities against EGFR (IC50 = 1 nM, 78 nM and 51 nM, respectively) and VEGFR-2 (IC50 = 79 nM, 14 nM and 14 nM, respectively), they showed good antiproliferative activities as well. Molecular docking established the interaction of 19i with the DFG-out conformation of VEGFR-2, suggesting that they might be type II kinase inhibitors.

Aim To evaluate the diagnostic performance of parametric imaging with contrast-enhanced ultrasound(CEUS) for differentiating hepatocellular carcinoma(HCC) from metastatic liver cancer(MLC). Methods 30 HCCs (mean diameter, 3.6±1.3 cm; range, 2.1-5.0 cm) and 30 MLCs (mean diameter, 2.8±1.5 cm; range, 1.2-5.0 cm) pathologically diagnosed or confirmed by clinical criteria that underwent CEUS were randomly included. CEUS was carried out using a multifrequency transducer (2-4 MHz) and a bolus injection of 2.4 mL SonoVue. The CEUS clips of the targeted lesion were recorded continuously for 6 minutes. By analyzing CEUS clips, parametric image could be obtained using the SonoLiver® software automatically. Quantitative parameters were compared between HCC and MLC groups. Receiver operating characteristic (ROC) curve analysis was further performed on parameters with significant difference between two groups. Results On parametric imaging, the maximum intensity, rise time, time to peak, mean transit time and washout time for HCC and MLC were 185.6±148.0 vs. 95.2±58.6 (P = 0.003), 25.7±6.3 s vs. 23.8±8.8 s (P = 0.341), 30.7±7.9 s vs. 27.8±10.5 s (P = 0.246), 90.2±45.7 s vs. 89.3±40.3 s (P = 0.805), 63.4±29.5 s vs. 37.2±33.8 s (P = 0.005), respectively. ROC analysis was further performed for washout time and it showed a cut-off point of 43.765 s for the differentiation between HCC and MLC, with the AUC value of 0.780 (95% CI: 0.646-0.914). The corresponding diagnostic specificity, sensitivity and accuracy were 72.0%, 84.6% and 78.4% respectively. Conclusions Parametric imaging of CEUS can display perfusion effects of HCC and MLC objectively and visually and washout time may serve as a useful parameter on the differential diagnosis between HCC and MLC.

The synthesis of nebularine and its analogs has been achieved via oxidative desulfuration in H2O for the first time. With 50% HNO3 as an oxidant and solvent, 18 products were obtained in good yields (70%–94%). The oxidative desulfuration system could tolerate different functional groups including fluoro, chloro, amino, alkyl, allyl, ribosyl, deoxyribosyl, and arabinofuranosyl groups. More importantly, the drug nebularine could be obtained successfully on a 20 g scale, which made this route more attractive for industrial applications.

To investigate the effect of ginsenosides from stems and leaves of ginseng on ethanol-induced lipid deposition in human L02 hepatocytes. L02 cells were exposed to ethanol for 36 h and treated with or without ginsenosides. The viability of L02 cells was evaluated by methylthiazolyldiphenyl-tetrazolium bromide assay and the triglyceride (TG) content was detected. Lipid droplets were determined by oil red O staining. Intracellular reactive oxygen species (ROS) production and the mitochondrial membrane potential were tested by flow cytometry. The ATP level was measured by reverse phase high performance liquid chromatography. The expression of cytochrome p450 2E1 (CYP2E1) and peroxisome proliferator-activated receptor α (PPARα) was detected by reverse transcriptase-polymerase chain reaction and Western blotting, respectively. Ethanol exposure resulted in the increase of TG level, lipid accumulation and ROS generation, and the decrease of mitochondrial membrane potential and ATP production in the cells. However, ginsenosides significantly reduced TG content (9.69±0.22 μg/mg protein vs. 4.93±0.49 μg/mg protein, P

The purpose of the study was to evaluate the value of 2-D shear wave elastography (SWE) of virtual touch tissue imaging quantification (VTIQ) for ultrasound (US) Breast Imaging-Reporting and Data System (BI-RADS) category 4 lesions. One hundred sixteen lesions were subject to conventional US, conventional strain elastography (SE) of elasticity imaging (EI), acoustic radiation force impulse (ARFI)-induced SE of virtual touch tissue imaging (VTI) and VTIQ before biopsies. Of the 116 lesions, 69 (59.5%) were benign and 47 (40.5%) were malignant. Significant differences were found between benign and malignant lesions in EI score, VTI score and shear wave speed (SWS) on VTIQ (both p

A series of oxazolopyrimidine-based ureas and amides were designed, synthesized, and biologically evaluated for their antiproliferative and antiangiogenic activities. These compounds were identified to exhibit inhibitory activities against human umbilical vein endothelial cells (HUVEC) in vitro. Among these compounds, compound 22 effectively inhibited the migration and capillary-like tube formation of human umbilical vein endothelial cells. It also exhibited a concentration-dependent inhibition on capillary sprouting from the rat aorta rings. Preliminary mechanistic studies revealed that compound 22 suppressed protein kinases activation, by decreasing PI3K and ERK 1/2 phosphorylation. These results support the further investigation of this class of compounds as potential anticancer agents.

Intratumoral immunosuppressive microenvironment (ISM) remains the dominant limitation to disable oncological immunotherapy such as immunogenic cell death (ICD). To resolve the immune escape, a sonodynamic therapy (SDT)-based nanoplatform featuring continuous CO2 bubbling has been engineered to enforce continuous ultrasound-triggered inertial cavitation (UIC) for augmenting ROS production. Systematic in vitro and in vivo results demonstrate that the continuous UIC expedites massive production of reactive oxygen species (ROS), consequently enabling multiple enhancements of SDT under only one administration. More significantly, the highly-accumulative ROS arising from continuous UIC have been demonstrated to induce robust ICD that is typically represented by more antigen exposure and presentation, augmented DCs maturation and more activated effector CD8+ T cells infiltration in vitro & in vivo. Concurrently, the most ISM alleviation via releasing more pro-inflammatory cytokines and facilitating pro-tumorigenic M2-like macrophage polarization into anti-tumorigenic M1-like counterparts is accompanied, enabling immune escape blockade. Contributed by the significant ISM alleviation and massive ROS production for enhancing SDT and ICD, such SDT-based composite nanoplatforms harvest the most substantially enhanced inhibitory consequences against primary and metastatic tumors, which, thus, provide a profound attribute for T cell-based immunotherapy against tumor.

EVA1A (also known as transmembrane protein 166) is a transmembrane protein involved in the regulation of autophagy that acts as an adaptor protein to recruit or bind proteins in the lysosome or endoplasmic reticulum. In the present study, we identified EVA1A as a target of microRNA-125b (miR-125b), a member of a highly conserved family of miRNAs that has been proposed as a biomarker for hepatocellular carcinoma (HCC). Analysis of oxaliplatin-sensitive and oxaliplatin-resistant HCC cell lines showed that miR-125b is downregulated in resistant cells and its overexpression in sensitive cells decreased resistance to oxaliplatin by inhibiting cell proliferation, migration and epithelial-mesenchymal transition (EMT). EVA1A expression was shown to be upregulated in tissue samples from oxaliplatin-resistant HCC patients, and its ectopic expression partially induced autophagy and reversed the effect of miR-125b on inhibiting the growth of oxaliplatin-resistant cell lines and xenograft tumors. Taken together, our results suggest that miR-125b plays a role in the resistance of HCC cells to chemotherapy via a mechanism involving the downregulation of EVA1A-mediated autophagy.

An efficient method for the construction of sulfonylmethyl 1 H-indenes via Cu(I)-mediated sulfonyl radical-enabled 5- exo-trig cyclization of alkenyl aldehydes has been developed for the first time. Mechanistic studies indicated that a radical addition-cyclization-elimination (RACE) process might be involved. The reaction features a relatively broad substrate scope, good annulation efficiency, and varying functional group tolerance.

Both EGFR and VEGFR-2 are important targets for cancer therapy, the combined inhibition of both EGFR and VEGFR-2 signaling pathway represents a promising approach to the treatment of cancers with a synergistic effect. In this study, a series of novel 4-anilinoquinazoline-acylamino derivatives designed as EGFR and VEGFR-2 dual inhibitors were synthesized and evaluated for biological activities. Most of them exhibited interesting inhibitory potencies against EGFR and VEGFR-2 as well as good antiproliferative activities. Compounds 15a, 15b and 15e exhibited the most potent inhibitory activity against EGFR (IC50 = 0.13 μM, 0.15 μM and 0.69 μM, respectively) and VEGFR-2 (IC50 = 0.56 μM, 1.81 μM and 0.87 μM, respectively), among them, compound 15b showed the highest antiproliferative activities against three cancer cell lines (HT-29, MCF-7 and H460) with IC50 of 5.27 μM, 4.41 μM and 11.95 μM, respectively. Molecular docking established the interaction of 15a with the DFG-out conformation of VEGFR-2, suggesting that they might be type II kinase inhibitors.

A convenient method for the regioselective synthesis of unsaturated nucleoside analogs in water under microwave irradiation was developed. All pyrimidine and purine nucleoside derivatives were exclusively alkylated at N1 and N9 respectively in good to excellent yields. In addition, this system could tolerate a broad range of functional groups, such as chloro, bromo, iodo, alkyl, amino, and hydroxyl groups. More importantly, the reaction scale could be enlarged to 50 mmol which made this route attractive for industrial application.

A new approach for the total synthesis of ammosamide B was realized. The strategy is based on an intermolecular Pd-catalyzed N-arylation of 4-chloro-1-methylindoline-2,3-dione (2), which enables construction of the key pyrroloquinoline skeleton precursor 6 within three steps in an overall yield of 80 %. The ammosamide B total synthesis is achieved in 12 simple transformations by starting from a commercially available starting material and proceeds with an overall yield of 23 %. Additionally, key precursor 6 represents an important intermediate in the synthesis of other pyrroloquinoline-containing natural products.

To investigate “particle effect” promoting gas-liquid mass transfer for a better process control, nine species of fine particle ( d 32 = 1-–15 μm), divided into Group 1 (SSA > 65.4 m 2 /g, termed PAC, SiO 2 , Al 2 O 3 and MnO 2 ) and Group 2 (SSA 2 /g, termed Biochar, Graphite, Mg(OH) 2 , CaCO 3 and BaSO 4 ), were comparatively introduced for oxygenation tests in an air-exposed stirred system. Group 1 particles with interfacial-cleaning effect facilitated oxygen transfer better than their counterparts of Group 2. For all the particles employed, however, the “particle effect” interestingly presented under control of solid specific gravity, since enhancement factor ( E f ) globally performed to grew up either when particulate density decreased or liquid density increased (Pb(NO 3 ) 2 as solute). Moreover, the strength of “particle effect” depends largely on interfacial turbulence, because proper agitation allowed optimal acceleration of oxygen transfer (700 rpm for this work), while either more sluggish or turbulent flow regime would hinder or even eliminate “particle effect”. Consequently, interfacial liquid-entrainment of particle entities was assumed to have played an initiative role for induction of “particle effect”, and this hydrodynamic process was elucidated to be subject to particulate specific gravity as well as interfacial turbulence.

Prostate sarcoma is a rare malignancy with an extremely poor prognosis. The extremely low morbidity and atypical clinical symptoms contribute to a missed diagnosis. The typical features of prostate sarcoma in transrectal ultrasound (US) and magnetic resonance imaging, such as a markedly enlarged volume and irregular prostatic contours, cannot usually be found until dysuria or even uroschesis occurs, and may then be too late to treat. However, there appears to no specific tumor marker for the disease in the serum. The present study reports a case of a young male patient who was diagnosed with prostate rhabdomyosarcoma. This was, to the best of our knowledge, the first case of this diagnosis using contrast-enhanced US (CEUS) when the symptoms were not severe. In this case, the intralesional non-enhancement areas and rim-like hyper-enhancement around the lesion were considered to be the main CEUS features of prostate rhabdomyosarcoma. The present study also reviews the associated literature.

For over last couple of decades, there has been a robust activity aimed towards the discovery of novel anti-cancer therapeutics. An approach to identify starting points for new drug candidates is high throughput screening of compound library collection. In this work, we describe the application of a Tetrazolium-based, 96-well small scale screening assay to screen a mini library of 19 compounds bearing Oxazolo[5,4-d]pyrimidine structures against human umbilical vein endothelial cells. Primary actives identified against HUVEC were retested and the IC50 value compounds were estimated for HUVEC. The screening program (Primary screening) identified 4 compounds with inhibition rate percentage ≥ 70% each. Retest screening of these compounds, taking into account criteria required for high cytotoxic compounds, afforded a panel of 1 compound for further biological analysis. This compound had IC50 value of 12.19µM, 12.16µM, 10.24µM, 20.43µM for HUVECs, SGC7901, MCF7, and HeLa respectively. Furthermore, a clonogenic assay was performed in order to confirm the cytotoxic activity of the selected compound on the survival and proliferation of MCF7. This compound was found to significantly effect the survival and proliferation of MCF7. Taken together, the selected compound, namely SCYJ32, was found to be highly cytotoxic against the numerous cell lines. Further studies are ongoing in order to unravel various mechanisms of action of this novel small compound.

The Pd(II)-catalyzed C–H arylation of benzothioamides with boronic acids using thioamides as directing groups, prevalent organic motifs found in vital biological and pharmaceutical molecules, has been achieved for the first time. The reactions proceed with high functional group tolerance in yields of 21–84%.

The application of engineered bacteria-based drug delivery vehicles to treat cancer has been practiced for more than a century. Mitochondria, evolutionarily originated from bacteria, are ubiquitous, semi-autonomous cellular organelles. In this study, we present the first exploration of using mitochondria as a delivery system of carbon quantum dots (CQDs) for in vivo imaging and administration of the anticancer drug doxorubicin (DOX). The results show that mitochondria as carriers are compatible with CQD loading and preserve the optical properties of CQDs. Moreover, the mitochondria delivery system can improve the CQD bio-distribution in organs and prolong the retention time of CQDs after intravenous injection. Furthermore, mitochondria loaded with doxorubicin hydrochloride (Mito-DOX) show an enhanced therapeutic effect compared to free DOX. The mitochondria-based "aircraft" system may be a promising novel therapeutic platform with high potential for biological imaging and drug delivery to fight cancer and other diseases.