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Epidermal growth factor receptor (EGFR), a member of the HER family, is closely related to the development of multiple cancers. Herein, we report the discovery of small molecule EGFR degraders based on the proteolysis targeting chimera (PROTAC) strategy. In the present study, 13 EGFR degraders containing pyrido[3,4-d] pyrimidine moiety were designed and synthesized. Promising PROTACs 2 and 10 induced degradation of EGFR in HCC827 cells with the DC50 values of 45.2 and 34.8 nM, respectively. Cellular protein-controlling machinery ubiquitin proteasome system (UPS) was involved in the degradation process. Furthermore, the degraders 2 and 10 could significantly induce the apoptosis of HCC827 cells and arrest the cells in G1 phase. These findings demonstrated that compounds 2 and 10 could serve as effective EGFRdel19-targeting degraders in HCC827 cells. v.

RB-2 and RB-4 are two structural analogs of polyacetylene from Radix Bupleuri that show antidepressant effects. However, no metabolic data are available to elucidate their systemic homeostasis. Mass spectrometry combined with liver microsomes and recombinant drug-metabolizing enzymes were performed to profile the biotransformations of RB-2/RB-4

Achieving multiferroic two-dimensional (2D) materials should enable numerous functionalities in nanoscale devices. Until now, however, predicted 2D multiferroics are very few and with coexisting yet only loosely coupled (type-I) ferroelectricity and magnetism. Here, a type-II multiferroic MXene Hf$_{2}$VC$_{2}$F$_{2}$ monolayer is identified, where ferroelectricity originates directly from its magnetism. The noncollinear Y-type spin order generates a polarization perpendicular to the spin helical plane. Remarkably, the multiferroic transition is estimated to occur above room temperature. Our investigation should open the door to a new branch of 2D materials for pursuit of intrinsically strong magnetoelectricity., 4 figures

Leptospira spp. comprise both pathogenic and free-living saprophytic species. Little is known about the environmental adaptation and survival mechanisms of Leptospira. Alternative sigma factor, σ54 (RpoN) is known to play an important role in environmental and host adaptation in many bacteria. In this study, we constructed an rpoN mutant by allele exchange, and the complemented strain in saprophytic L. biflexa. Transcriptome analysis revealed that expression of several genes involved in nitrogen uptake and metabolism, including amtB1, glnB-amtB2, ntrX and narK, were controlled by σ54 . While wild-type L. biflexa could not grow under nitrogen-limiting conditions but was able to survive under such conditions and recover rapidly, the rpoN mutant was not. The rpoN mutant also had dramatically reduced ability to survive long-term in water. σ54 appears to regulate expression of amtB1, glnK-amtB2, ntrX and narK in an indirect manner. However, we identified a novel nitrogen-related gene, LEPBI_I1011, whose expression was directly under the control of σ54 (herein renamed as rcfA for RpoN-controlled factor A). Taken together, our data reveal that the σ54 regulatory network plays an important role in the long-term environmental survival of Leptospira spp.

Background The relationship between platelet reactivity and long-term clinical outcomes remains controversial. The present prospective study was designed to explore the association between high platelet reactivity (HPR) on clopidogrel and long-term clinical outcomes following implantation of drug eluting stents (DES). Methods A total of 1769 consecutive patients assessed by Aggrestar (PL-11) were enrolled at our center from February 2011 to December 2017. The primary end point was major adverse cardiovascular and cerebrovascular events (MACCE), defined as definite or probable stent thrombosis, spontaneous myocardial infarction, all cause death, clinically driven target vessel revascularization (TVR), or ischemic stroke. Bleeding served as the safety endpoint. Propensity score matching (PSM) analysis was performed to adjust for baseline differences in the overall cohort. Results Finally, 409 patients (23.1%) were identified with HPR on clopidogrel. At a median follow-up of 4.1 years (interquartile range, 1.8 years), the occurrence of MACCE was significantly higher in HPR on clopidogrel group than normal platelet reactivity (NPR) on clopidogrel group (15.6% vs. 5.4%, p

Background Trichogramma dendrolimi Matsumura is widely used as a biological control agent for control of lepidopteran agricultural pests in China and can be successfully reared using the large eggs of the Chinese silkworm, Antheraea pernyi. In this study, biological parameters of diapaused, non-diapaused, and cold-stored T. dendrolimi were investigated for two generations on host eggs of A. pernyi under laboratory conditions. Results The cold-stored T. dendrolimi performed more poorly than diapaused and non-diapaused T. dendrolimi based on biological parameters. In the F1 generation, the non-diapaused T. dendrolimi had a higher emergence rate, longer longevity, and a lower proportion of deformed individuals than diapaused T. dendrolimi. In the F2 generation, the diapaused T. dendrolimi had a lower proportion of unemerged parasitoids than non-diapaused T. dendrolimi. However, the diapaused T. dendrolimi had a higher number of parasitized hosts than non-diapaused T. dendrolimi in both generations. In the F1 generation, the index of population trend (I) was found to be similar for diapaused (140.792) and non-diapaused (141.542) T. dendrolimi and was approximately 3.4 times that of cold-stored T. dendrolimi (41.698). In the F2 generation, the diapaused T. dendrolimi showed the largest I (146.791), followed by non-diapaused (136.859) and cold-stored T. dendrolimi (59.607). Conclusion In a 3-year augmentative field release from 2014 to 2016, diapaused T. dendrolimi showed effective parasitism on eggs of the Asian corn borer, Ostrinia furnacalis. These results indicated that diapaused T. dendrolimi can be an efficient alternative method for mass rearing of T. dendrolimi for long-term cold storage. © 2017 Society of Chemical Industry.

Background: The relationship between obstructive sleep apnea (OSA) and platelet reactivity in patients undergoing percutaneous coronary intervention (PCI) has not been defined. The present prospective, single-center study explored the relationship between platelet reactivity and OSA in patients with PCI. Methods: A total of 242 patients were finally included in the study. OSA was screened overnight by polysomnography. Platelet reactivity was assessed with a sequential platelet counting method, and the platelet maximum aggregation ratio (MAR) and average aggregation ratio were calculated. All patients were assigned per apnea-hypopnea index (AHI) to non-OSA (n = 128) and OSA (n = 114) groups. The receiver operating characteristic curve analysis was used to evaluate the accuracy of AHI for high platelet reactivity (HPR) on aspirin and clopidogrel, and multivariable logistic regression was used to determine the independent predictors of HPR on aspirin and clopidogrel. Results: Median AHI was significantly higher in the OSA group than in the non-OSA group (34.5 events/h vs. 8.1 events/h, Z= −13.422, P < 0.001). Likewise, median arachidonic acid- and adenosine diphosphate-induced maximum aggregation rate (MAR) in the OSA group was significantly higher than those in the non-OSA group (21.1% vs. 17.7%, Z= −3.525, P < 0.001 and 45.8% vs. 32.2%, Z= −5.708, P < 0.001, respectively). Multivariable logistic regression showed that OSA was the only independent predictor for HPR on aspirin (odds ratio [OR]: 1.055, 95% confidence interval [CI]: 1.033–1.077, P < 0.001) and clopidogrel (OR: 1.036, 95% CI: 1.017–1.056, P < 0.001). The cutoff value of AHI for HPR on aspirin was 45.2 events/h (sensitivity 47.1% and specificity 91.3%), whereas cutoff value of AHI for HPR on clopidogrel was 21.3 events/h (sensitivity 68.3% and specificity 67.7%). Conclusion: Platelet reactivity appeared to be higher in OSA patients with PCI despite having received a loading dose of aspirin and clopidogrel, and OSA might be an independent predictor of HPR on aspirin and clopidogrel. Key words: Antiplatelet Drugs; Maximum Aggregation Rate; Obstructive Sleep Apnea; Percutaneous Coronary Intervention; Platelet Reactivity

Low shear stress (LSS)-induced endothelial inflammation is the basis for the development of atherosclerosis. However, the mechanism underlying LSS-induced inflammation is not well understood. The angiotensin II type 1 receptor (AT1R), a component of the renin-angiotensin system, participates in atherosclerotic plaque progression. The aim of this study was to investigate the role of AT1R in LSS-induced endothelial activation. Using immunohistochemistry, we noted significant increases in AT1R, vascular endothelial adhesion cell-1 (VCAM1), and intercellular adhesion molecule-1 (ICAM1) expression in the inner curvature of the aortic arch in C57BL/6 mice compared to the descending aorta in these mice. Moreover, western blotting revealed that these LSS-induced increases in AT1R, ICAM1 and VCAM1 expression were time dependent. However, the expression of these proteins was significantly abolished by treatment with the AT1R antagonist Losartan (1μM) or AT1R small interfering RNA (siRNA). AT1R inhibition significantly suppressed extracellular signal-regulated kinase 1/2 (ERK) upregulation, which also resulted in decreases in ICAM1 and VCAM1 protein expression. These findings demonstrate that LSS induces endothelial inflammation via AT1R/ERK signaling and that Losartan has beneficial effects on endothelial inflammation.

Covalent organic polymers (COPs) or covalent organic frameworks (COFs) are emerging types of electrode materials for electrochemical CO2 reduction reaction (CO2RR) owing to their controllable structures at the molecular level. However, their activities are often limited by stacking structures and low conductivities. Here we report an ultrathin cobalt tetraamino phthalocyanine-squaraine based COPs (COP-SA) for high-performance CO2RR towards CO. The extended π-conjugated skeleton constitutes the layer, and the zwitterionic structure from the squaraine unit helps the dispersion of layers, leading to an ultrathin thickness of ∼1.7 nm. The ultrathin nanostructure avoids the common agglomeration issues for molecular catalysts and thick nanomaterials, which is beneficial to afford highly exposed active sites and efficient electron transfer for electrochemical reactions. Theoretical calculation suggests that the squaraine unit will enhance the COOH adsorption and favor the CO desorption. These collectively conduce to a high current density of 9.74 mA cm−2 with 96.5 % CO faradaic efficiency, a large turnover frequency of 46 s-1 (by total cobalt site) at -0.65 V vs RHE and excellent cycling stability. This work underscores the structural and electronic effects for the rational design of ultrathin COPs materials for electrochemical CO2RR.

Contemporary clinical trials, registries, and meta-analyses, supported by recent results from the EXCEL (Everolimus-Eluting Stents or Bypass Surgery for Left Main Coronary Artery Disease) and NOBLE (Percutaneous Coronary Angioplasty Versus Coronary Artery Bypass Grafting in Treatment of Unprotected Left Main Stenosis) trials, have established percutaneous coronary intervention of left main coronary stenosis as a safe alternative to coronary artery bypass grafting in patients with low and intermediate SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) scores. As left main percutaneous coronary intervention gains acceptance, it is imperative to increase awareness for patient selection, risk scoring, intracoronary imaging, vessel preparation, and choice of stenting techniques that will optimize procedural and patient outcomes.

Objectives This study aimed to investigate the cutoff of post–drug-eluting stent (DES) fractional flow reserve (FFR) for prediction of 1- to 3-year target vessel failure (TVF). Background FFR immediately after a DES implantation correlates with clinical events. However, the cutoff of post-DES FFR for predicting long-term clinical events remains understudied. Methods Between May 2012 and September 2013, a total of 1,476 patients who had FFR Results By the end of the first year, 88 (6.0%) TVFs were recorded. A post-DES FFR ≤0.88 strongly correlated with TVF. Disease in the left anterior descending coronary artery (LAD), stent length, and stent diameter were independent factors of impaired post-DES FFR, whereas post-procedure FFR ≤0.88 was the only predictor of TVF, with 40 (4.0%) TVFs in the FFR >0.88 and 48 (8.0%) in the FFR ≤0.88 group (p = 0.001), mainly driven by target vessel revascularization (3.8% vs. 8.8%; p = 0.005) and cardiac death (0.2% vs. 1.3%; p = 0.017). The difference in TVF between 2 groups was maintained through 3-year follow-up (p = 0.002). For patients with LAD lesions, a post-DES FFR ≤0.905 predicted 1-year TVF. Conclusions Post-DES FFR strongly correlated with TVF rate. Mechanisms attributed to and treatments for impaired FFR after stenting should be studied in future studies. (Post-DES FFR Predicts the Clinical Outcomes: DK CRUSH-VII, A Prospective, Multicenter, Registry Study [DK CRUSH-VII]; ChiCTR-PRCH-12001976)

The ortho-nitrophenol (ONP) utilizer Alcaligenes sp. strain NyZ215, meta-nitrophenol (MNP) utilizer Cupriavidus necator JMP134 and para-nitrophenol (PNP) utilizer Pseudomonas sp. strain WBC-3 were assembled as a consortium to degrade three nitrophenol isomers in sequential batch reactors. Pilot test were conducted in flasks to demonstrate that a mixture of three mononitrophenols at 0.5 mM each could be mineralized by this microbial consortium within 84 hours. Interestingly, neither ONP nor MNP was degraded until PNP was almost consumed by strain WBC-3. By immobilizing this consortium into polyurethane cubes, all three mononitrophenols were continuously degraded in lab-scale sequential reactors for 6 batch cycles over 18 days. Total concentrations of ONP, MMP and PNP being degraded were 2.8 mM, 1.5 mM and 2.3 mM during this time course, respectively. Quantitative real-time polymerase chain reaction analysis showed that each member in the microbial consortium was relatively stable during the entire degradation process. This study provides a novel approach to treat polluted water, particularly with a mixture of co-existed isomers. This article is protected by copyright. All rights reserved.

Lactide (LA) and PEG as raw materials, 2,2-Dimethylol Propionic Acid (DMPA) as initiator, hexamethylene diisocyanate (HDI) as coupling agent, amphiphilic block copolymer PLA-PEG with side carboxyl group was synthesized. A novel PLA-PEG-PTX pro-drug was prepared through the esterification reaction between the side carboxyl group on copolymer and hydroxyl group on paclitaxel. Its structure was characterized with 1H-NMR and FT-IR. The pro-drug micelles were prepared by solvent evaporation method. The particle size of the micelles was determined by nanoparticle tracking analyzer, the micro structure of the micelles was determined by TEM, and the drug release properties were investigated by dialysis experiments. Results showed that the pro-drug micelles are spherical with core-corona structure and major particles size in 55-85nm. The PLA-PEG750-PTX (molar ratio of LA to DMPA as 40 to 1) pro-drug micelles released paclitaxel slowly and steadily without obvious burst release in buffer solution with pH=7.0, and its cumulative release rate reached to 36% in 10 hours. PLA-PEG750-PTX pro-drug micelles have a certain sustained-release effect, which is beneficial to improve the anti-tumor effect of paclitaxel.

Hepatocellular carcinoma (HCC) is a highly aggressive solid malignancy in the word. Aberrant microRNA (miRNA) expression is involved in human diseases including cancer. In the current study, we explore the function of miR-98 in HCC cell proliferation. We found that expression level of miR-98 was significantly decreased in HCC tissues and cells lines compared with adjacent non-tumor issues and human hepatic cell line LO2. Increased expression of miR-98 suppressed HCC cell proliferation and arrested HCC cell cycle in G0/G1 phase. While, suppressed expression of miR-98 showed the opposite effect. Bioinformatics analysis revealed EZH2, a putative tumor promoter as a potential target of miR-98. Additionally, luciferase reporter assay revealed that miR-98 directly binds to the 3'-untranslated region (3'-UTR) of EZH2 mRNA. Furthermore, we demonstrated that miR-98 could reduce the Wnt/β-catenin signal pathway by suppressing EZH2 directly. Moreover, inhibition of EZH2 abrogated the effect of miR-98 inhibitor on HCC cell proliferation. Taken together, these results suggested that miR-98 functioned as a potential tumor suppressor by regulating Wnt/β-catenin signal pathway through direct suppression of EZH2 expression and might sever as a potential therapeutic target for HCC patients.

This study examines the mechanism of glycocalyx injury under low shear stress (LSS). LSS-induced changes of eNOS phosphorylation and NO production are based on the deficiency of the glycocalyx barrier., Hyaluronan (HA) in the endothelial glycocalyx serves as a mechanotransducer for high-shear-stress–stimulated endothelial nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) production. Low shear stress (LSS) has been shown to contribute to endothelial inflammation and atherosclerosis by impairing the barrier and mechanotransduction properties of the glycocalyx. Here we focus on the possible role of hyaluronidase 2 (HYAL2) in LSS-induced glycocalyx impairment and the resulting alterations in eNOS phosphorylation and NO production in human umbilical vein endothelial cells (HUVECs). We show that LSS strongly activates HYAL2 to degrade HA in the glycocalyx. The dephosphorylation of eNOS–Ser-633 under LSS was triggered after HA degradation by hyaluronidase and prevented by repairing the glycocalyx with high–molecular weight hyaluronan. Knocking down HYAL2 in HUVECs protected against HA degradation in the glycocalyx by inhibiting the expression and activity of HYAL2 and further blocked the dephosphorylation of eNOS–Ser-633 and the decrease in NO production in response to LSS. The LSS-induced dephosphorylation of PKA was completely abrogated in HYAL2 siRNA–transfected HUVECs. The LSS-induced dephosphorylation of eNOS–Ser-633 was also reversed by the PKA activator 8-Br-cAMP. We thus suggest that LSS inhibits eNOS–Ser-633 phosphorylation and, at least partially, NO production by activating HYAL2 to degrade HA in the glycocalyx.

Inhibition of the protein C system (PCS) might be one of the mechanisms of ulcerative colitis (UC).The aim of the study was to explore the role of IgG plasma cells in changes in the PCS in UC.Dextran sulfate sodium (DSS) was chosen to induce mouse UC. Inflammation was assessed using hematoxylineosin (HE) staining and immunofluorescence. The profiling of colonic plasma cells and macrophages from colitis mice was analyzed with flow cytometry. After stimulation of macrophages with IgG type immune complex (IgG-IC), western blot was used to determine tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) protein levels. After co-incubation of colonic mucosa microvascular endothelial cells (MVECs) with TNF-α or IL-6, mitogen-activated protein kinase (MAPK) expression was detected.The DSS-colitis mice showed higher inflammatory indexes (p0.05 or p0.01), accompanied by greater infiltration of CD38+IgG+ plasma cells (p0.01), CD14+CD64+ macrophages (p0.01) and IgG-IC than healthy mice. Enhancement of TNF-α and IL-6 protein expression was demonstrated in this subset of macrophages when stimulated by IgG-IC (p0.01). After MVECs were incubated with TNF-α or IL-6, the expression of β-arrestin1, pP38 MAPK and pJNK MAPK exhibited an increase (p0.05 or p0.01), but downregulation of endothelial protein C receptor (EPCR) expression was observed (p0.05 or p0.01); this inhibition of EPCR expression was reversed by SB203580, SP600125 or U0126 (p0.05 or p0.01). In addition, changes in activated protein C (APC) presented results similar to those for EPCR expression (p0.05 or p0.01).These results reveal that the PCS is inhibited during UC processing. There is a possibility that the interaction between IgG plasma cells and CD14+CD64+ macrophages, as well as further secretion of cytokines from CD14+CD64+ macrophages by the formation and stimulation of IgG-IC, subsequently influence MVECs through the β-arrestin-MAPK pathway. Enhancement of PCS activity may represent a novel approach for treating UC.

Targeting L858R/T790M/C797S mutant EGFR is a major challenge in the new-generation EGFR tyrosine kinase inhibitors development for conquering drug resistant NSCLC. In this study, a series of novel 9-heterocyclyl substituted 9H-purine derivatives were designed as EGFRL858 R/T790 M/C797S tyrosine kinase inhibitors. Among these compounds, D4, D9, D11 and D12 showed significantly potent anti-proliferation and EGFRL858 R/T790 M/C797S inhibition activity. In particular, the most potent compound D9 showed anti-proliferation against HCC827 and H1975 cell lines with the IC50 values of 0.00088 and 0.20 μM, respectively. And D9 inhibited the EGFRL858R/T790M/C797S with an IC50 value of 18 nM. Furtherly, D9 could significantly suppress the EGFR phosphorylation, induce the apoptosis, arrest cell cycle at G0/G1, and inhibit colony formation in HCC827 cell line by a concentration-dependent manner. Molecular docking indicated that the introduction of a cyclopropylsulfonamide group in D9 led to the formation of additional two hydrogen bonds with mutant Ser797 which played key roles in generating efficient EGFRL858 R/T790 M/C797S inhibitory activity. These findings strongly indicated that 9-heterocyclyl substituted 9H-purine derivatives were promising L858R/T790M/C797S mutant EGFR-TKIs. The introduction of extra hydrogen bond interaction with mutant Ser797 is efficient method for the design of the fourth-generation EGFR-TKIs.

Programmed cell death ligand 1 (PD-L1) is a key suppressor of the cytotoxic immune response. In colorectal carcinoma (CRC), PD-L1 expression results in immune escape and poor prognosis. Extensive researches suggested that metformin had a potential efficacy of enhancing anti-tumor immune response in different types of cancer. However, the detail mechanisms underlying the efficacy in CRC are unclear. Here, we showed that metformin decreases PD-L1 and YAP1 expression in vitro and in vivo. After silencing or inhibiting YAP1 expression by Verteporfin (VP), the inhibitor of YAP1, the expression of PD-L1 were decreased in protein level in CRC cells. Furthermore, metformin directly phosphorylated YAP1 and restricted YAP1 to entry in the nucleus, so that PD-L1 was reduced via western blot and immunofluorescence assays in SW480 and HCT116 cells. Finally, subcutaneous xenotransplanted tumor models of HCT116 cells were established in BALB/c nude mice. Compared with the control group, PD-L1 and YAP1 expressions in tumor tissues, detected by immunohistochemistry, were reduced in the group of metformin treatment. These findings illuminate a new regulatory mechanism, metformin activates Hippo signaling pathway to regulate PD-L1 expression and suggests that metformin has the possibility to increase the efficacy of immunotherapy in human CRC.

Acetaminophen (APAP)-induced acute hepatotoxicity is the leading cause of drug-induced acute liver failure. The aim of this study was to evaluate the effects of 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (tempol) on the protection of APAP-induced hepatotoxicity in mice. Mice were pretreated with a single dose of tempol (20 mg/kg per day) orally for 7 days. On the seventh day, mice were injected with a single dose of APAP (300 mg/kg) to induce acute hepatotoxicity. Our results showed that tempol treatment markedly improved liver functions with alleviations of histopathological damage induced by APAP. Tempol treatment upregulated levels of antioxidant proteins, including superoxide dismutase, catalase, and glutathione. Also, phosphorylation of phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt) and protein expression of nuclear factor erythroid 2-related factor (Nrf 2) and heme oxygense-1 (HO-1) were all increased by tempol, which indicated tempol protected against APAP-induced hepatotoxicity via the PI3K/Akt/Nrf2 pathway. Moreover, tempol treatment decreased pro-apoptotic protein expressions (cleaved caspase-3 and Bax) and increased anti-apoptotic Bcl-2 in liver, as well as reducing apoptotic cells of TUNEL staining, which suggested apoptotic effects of tempol treatment. Overall, we found that tempol normalizes liver function in APAP-induced acute hepatotoxicity mice via activating PI3K/Akt/Nrf2 pathway, thus enhancing antioxidant response and inhibiting hepatic apoptosis.

OBJECTIVES This study aimed to investigate the impacts of intravascular ultrasound (IVUS)-guided drug-eluting stent (DES) implantation on patients with chronic kidney disease (CKD) based on the ULTIMATE trial. BACKGROUND IVUS-guided DES implantation improves clinical outcomes in complex lesions. However, routine IVUS guidance in patients with CKD remains controversial. METHODS CKD was defined as an estimated glomerular filtration rate (eGFR)

Recently, the incidence of colorectal cancer has increased each year. Natural orifice specimen extraction surgery (NOSES) removes the specimen from a natural cavity of the human body (anal or vaginal) and completes reconstruction of the digestive tract. There are only a few trocar scars in the abdomen after surgery. Transvaginal specimen extraction for right-sided colon cancer is one of the classic NOSES surgeries. As NOSES is accepted by increasing numbers of colorectal surgeons, NOSES technology is becoming increasingly widely used in China and abroad. Studies have confirmed the feasibility and safety of NOSES. Therefore, it is necessary to conduct further clinical studies to evaluate the short-term efficacy of the NOSES procedure.To investigate the short-term efficacy of transvaginal specimens for laparoscopic right colon cancer (NOSES).We conducted a retrospective analysis of 90 cases of laparoscopic right colon cancer radical surgery performed continuously in the anorectal surgery of our Hospital from June 2015 to December 2018. Thirty-two patients underwent complete laparoscopic anastomosis and transvaginal specimen removal (NOSES group), and 58 patients underwent conventional abdominal wall removal specimen surgery (LAP group). The general data of the patients were matched by the propensity score matching (PSM) method 1:1. Thirty-one pairs of cases were successfully matched, and the intraoperative and postoperative data were analysed.After PSM, the baseline data were balanced between the two groups. A total of 62 patients in the two groups were successfully operated without conversion. There were no significant differences in intraoperative blood loss, lymph node dissection, sputum tumour cell positive rate, bacterial culture positive rate, postoperative follow-up and postoperative pelvic floor function evaluation (P 0.05). Neither tumour cells nor bacteria were detected in the rinse solution at the start of the operation. Compared with the LAP group, the incidence of postoperative complications was lower in the NOSES group (6.4% vs. 29.0%, P = 0.006), and the gastrointestinal function recovery time was shorter (2.58 ± 0.92 vs. 3.42 ± 0.92, P = 0.001), postoperative hospital stay was shorter (6.68 ± 1.47 vs. 9.58 ± 2.22, P 0.001), postoperative pain score was lower (postoperative day 1: 2.35 ± 1.52 vs. 4.87 ± 1.50; postoperative day 3: 1.81 ± 1.11 vs. 4.00 ± 1.18; postoperative day 5: 1.45 ± 1.00 vs. 2.97 ± 1.17; P 0.001), additional analgesic drug use rate was lower (12.9% vs. 61.3%, P 0.001), and patients were more satisfied with the appearance of the abdominal wall after surgery (100% vs. 23.6%, P 0.001).This study used PSM to remove confounding factors and retrospectively analysed the short-term efficacy of transvaginal specimens for laparoscopic right colon cancer radical resection. The results showed that the laparoscopic right colon cancer radical resection was satisfactory, ensuring sterility. At the same time, there is a clear advantage in reducing postoperative pain, shortening postoperative hospital stays, reducing the incidence of postoperative complications, and improving the appearance of the abdominal wall.

We propose a microscopic description for the polarization from the first principle through the spin-orbit coupling in particle collisions. The model is different from previous ones based on local equilibrium assumptions for the spin degree of freedom. It is based on scatterings of particles as wave packets, an effective method to deal with particle scatterings at specified impact parameters. The polarization is then the consequence of particle collisions in a non-equilibrium state of spins. The spin-vorticity coupling naturally emerges from the spin-orbit one encoded in polarized scattering amplitudes of collisional integrals when one assumes local equilibrium in momentum but not in spin., RevTex 4, 54 pages, 4 figures

Background. Oscillatory shear stress (OSS) disrupts endothelial homeostasis and promotes oxidative stress, which can lead to atherosclerosis. In atherosclerotic lesions, Toll-like receptor 4 (TLR4) is highly expressed. However, the molecular mechanism by which TLR4 modulates oxidative changes and the cell signaling transudation upon OSS is yet to be determined. Methods and Results. Carotid artery constriction (CAC) surgery and a parallel-plate flow chamber were used to modulate shear stress. The results showed that OSS significantly increased the oxidative burden, and this was partly due to TLR4 activation. OSS activated NOX2 and had no significant influence to NOX1 or NOX4 in endothelial cells (ECs). OSS phosphorylated caveolin-1, promoted its binding with endothelial nitric oxide synthase (eNOS), and resulted in deactivation of eNOS. TLR4 inhibition restored levels of nitric oxide (NO) and superoxide dismutase (SOD) in OSS-exposed cells. Conclusion. TLR4 modulates OSS-induced oxidative stress by activating NOX2 and suppressing eNOS.

Hyperglycemia-induced apoptosis plays a critical role in the pathogenesis of diabetic cardiomyopathy (DCM). Our previous study demonstrated that ivabradine, a selective If current antagonist, significantly attenuated myocardial apoptosis in diabetic mice, but the underlying mechanisms remained unknown. This study investigated the underlying mechanisms by which ivabradine exerts anti-apoptotic effects in experimental DCM. Pretreatment with ivabradine, but not ZD7288 (an established If current blocker), profoundly inhibited high glucose-induced apoptosis via inactivation of nuclear factor (NF)-κB signaling in neonatal rat cardiomyocytes. The effect was abolished by transfection of an siRNA targeting protein phosphatase 2A catalytic subunit (PP2Ac). In streptozotocin-induced diabetic mice, ivabradine treatment significantly inhibited left ventricular hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) and HCN4 (major components of the If current), activated PP2Ac, and attenuated NF-κB signaling activation and apoptosis, in line with improved histological abnormalities, fibrosis, and cardiac dysfunction without affecting hyperglycemia. These effects were not observed in diabetic mice with virus-mediated knockdown of HCN2 or HCN4 after myocardial injection, but were alleviated by knockdown of PP2Acα. Molecular docking and phosphatase activity assay confirmed direct binding of ivabradine to, and activation of, PP2Ac. In conclusion, ivabradine may directly activate PP2Ac, leading to inhibition of NF-κB signaling activation, myocardial apoptosis, and fibrosis, and eventually improving cardiac function in experimental DCM. Taken together, the present findings suggest that ivabradine may be a promising drug for treatment of DCM.

We have developed a Python package ZMCintegral for multi-dimensional Monte Carlo integration on multiple Graphics Processing Units(GPUs). The package employs a stratified sampling and heuristic tree search algorithm. We have built three versions of this package: one with Tensorflow and other two with Numba, and both support general user defined functions with a user-friendly interface. We have demonstrated that Tensorflow and Numba help inexperienced scientific researchers to parallelize their programs on multiple GPUs with little work. The precision and speed of our package is compared with that of VEGAS for two typical integrands, a 6-dimensional oscillating function and a 9-dimensional Gaussian function. The results show that the speed of ZMCintegral is comparable to that of the VEGAS with a given precision. For heavy calculations, the algorithm can be scaled on distributed clusters of GPUs., Comment: 18 pages, 9 figures

Intravascular ultrasound (IVUS) guidance is not routinely performed in real-word clinical practice partly because the benefit of IVUS guidance is not well established. This updated meta-analysis aims to compare IVUS-guided and angiography-guided drug-eluting stent (DES) implantation, simultaneously stressing the value of an optimal IVUS-defined procedure. Medline, Scopus, Google Scholar, and Cochrane Controlled Trials Registry were searched for the randomized trials comparing IVUS-guided and angiography-guided DES implantation. Nine eligible randomized trials including 4,724 patients were identified. At a mean follow-up of 16.7 months, IVUS guidance was associated with a significant lower risk of major adverse cardiovascular events (MACE) [5.4% vs. 9.0%; relative risks (RR): 0.61, 95% confident interval (CI) 0.49–0.74, p

Purpose To explore whether CT texture analysis can identify thin-cap fibroatheroma (TCFA) determined by optical coherence tomography (OCT). Methods Thirty-three patients with 43 lesions who underwent both CCTA and OCT within 3 months were retrospectively included. 12 conventional CT-derived plaque features, fat attenuation index (FAI) and 1691 plaque radiomics features were extracted to discriminate TCFA lesions and non-TCFA lesions determined by OCT. Minimum redundancy and maximum relevance (mRMR) method was employed to select radiomics features. The top ranked features were used to construct a forward stepwise logistic radiomics model. The performance of radiomics model was compared with the conventional high-risk plaque (HRP) features model and FAI model for the detection of TCFA. Results Out of 1691 features, 35 features were significantly different between TCFA and non-TCFA lesions (all p＜0.05) while only low attenuation plaque (LAP) was more frequent in TCFA group (p = 0.004). There was no significant difference in FAI between TCFA and non-TCFA lesions. Five features were ultimately integrated into the radiomics model after mRMR analysis, which demonstrated significantly higher AUC for the detection of TCFA (0.952; 95 % CI: 0.897–1.000) compared with the conventional HRP features model (0.621; 95 % CI: 0.469−0.773, p Conclusion CT texture analysis performs better at identifying TCFA determined by OCT compared with conventional CT-derived plaque parameters and FAI. Texture analysis may serve as a potential non-invasive method of evaluating vulnerable plaque.

Based on the result in our previous work, we calculate the polarization of quarks from parton scatterings in high energy heavy ion collisions. The result is compared with the STAR data at $\sqrt{s_{NN}}=200$ GeV., Comment: Contribution to the Proceedings of the 28th international conference on ultrarelativistic nucleus-nucleus collisions, Quark Matter 2019

Epidermal growth factor receptor (EGFR) is an important therapeutic target for the treatment of non-small cell lung cancer. A number of efficacious EGFR tyrosine kinase inhibitors have been developed. However, acquired drug resistance largely encumbered their clinical practicability. Therefore, there is an urgent need to develop new therapeutic regime. Herein, we designed and synthesized a set of EGFR-targeting small molecule PROTACs which showed promising efficacy. In particular, VHL-recruiting compound P3 showed potent anti-proliferative activity against HCC827 and H1975 cell lines with IC50 values of 0.83 and 203.01 nM, respectively. Furthermore, both EGFRdel19 and EGFRL858R/T790M could be significantly induced to be degraded under treatment of P3 with DC50 values of 0.51 and 126.2 nM, respectively. Compound P3 was able to dramatically suppress EGFR pathway signal transduction. Moreover, compound P3 could significantly induce cell apoptosis, arrest cell cycle and suppress cell colony formation. In addition, we identified that ubiquitination was indispensable in the degradation process, and found that the degradation was related to autophagy. Our work would provide an alternative approach for development of potentially effective EGFR degraders and give a new clue for investigation of PROTAC-induced protein degradation.

Aims: The study aimed to examine five-year clinical outcomes of complete (CR), partially complete (PCR), and incomplete revascularisation (ICR) in patients with unprotected left main coronary artery (ULMCA) disease treated with drug-eluting stents (DES). Completeness of revascularisation, defined as revascularisation of all vessels ≥1.5 or 2.5 mm in diameter, has been shown to correlate with outcomes after percutaneous coronary intervention (PCI). There are no data to compare revascularisation strategies on long-term clinical outcomes in patients undergoing PCI of ULMCA disease. Methods and results: This prospective registry enrolled 910 consecutive patients with ULMCA disease undergoing PCI with DES implantation. CR included patients who had a successful revascularisation of all diseased segments with diameter ≥1.5 mm. PCR included patients who had successful revascularisation of all diseased segments with diameter ≥2.5 mm. ICR included patients who did not achieve revascularisation for all diseased segments of diameter ≥2.5 mm. The primary endpoint was the incidence of major adverse cardiac events (MACE: a composite of cardiac death, myocardial infarction and repeat revascularisation) at five-year follow-up. CR was achieved in 386 (42.4%), PCR in 227 (25.0%), and ICR in 297 (32.6%) patients. Patients with ICR had a significantly higher rate of MACE (29.6% vs. 22.5% and 15.5%, p

Sphingomonas sp. strain Ndbn-20 degrades and utilizes the herbicide dicamba as its sole carbon and energy source. In the present study, a tetrahydrofolate (THF)-dependent dicamba methyltransferase gene, dmt , was cloned from the strain, and three other genes, metF , dhc , and purU , which are involved in THF metabolism, were found to be located downstream of dmt . A transcriptional study revealed that the four genes constituted one transcriptional unit that was constitutively transcribed. Lysates of cells grown with glucose or dicamba exhibited almost the same activities, which further suggested that the dmt gene is constitutively expressed in the strain. Dmt shared 46% and 45% identities with the methyltransferases DesA and LigM from Sphingomonas paucimobilis SYK-6, respectively. The purified Dmt catalyzed the transfer of methyl from dicamba to THF to form the herbicidally inactive metabolite 3,6-dichlorosalicylic acid (DCSA) and 5-methyl-THF. The activity of Dmt was inhibited by 5-methyl-THF but not by DCSA. The introduction of a codon-optimized dmt gene into Arabidopsis thaliana enhanced resistance against dicamba. In conclusion, this study identified a THF-dependent dicamba methyltransferase, Dmt, with potential applications for the genetic engineering of dicamba-resistant crops. IMPORTANCE Dicamba is a very important herbicide that is widely used to control more than 200 types of broadleaf weeds and is a suitable target herbicide for the engineering of herbicide-resistant transgenic crops. A study of the mechanism of dicamba metabolism by soil microorganisms will benefit studies of its dissipation, transformation, and migration in the environment. This study identified a THF-dependent methyltransferase, Dmt, capable of catalyzing dicamba demethylation in Sphingomonas sp. Ndbn-20, and a preliminary study of its enzymatic characteristics was performed. Introduction of a codon-optimized dmt gene into Arabidopsis thaliana enhanced resistance against dicamba, suggesting that the dmt gene has potential applications for the genetic engineering of herbicide-resistant crops.

Strain Ndbn-20T, a Gram-staining-negative, non-spore-forming bacterium, was isolated from compost of plant litter. The strain was able to degrade dicamba. Phylogenetic analysis based on 16S rRNA gene sequences indicated that Ndbn-20Trepresented a member of the family Sphingomonadaceae of the Alphaproteobacteria and showed high sequence similarities to Rhizorhabdusargentea SP1T (98.8 %), Sphingomonaswittichii RW1T (97.9 %), Sphingomonasstarnbergensis 382T (97.7 %) and Sphingomonashistidinilytica UM2T (97.7 %). However, the strain showed low DNA sequence relatedness with R. argentea SP1T (45.6±1.9 %), S. wittichii RW1T (33.5±2.3 %), S. histidinilytica UM2T (39.4±3.6 %) and S. starnbergensis 382T (42.1±4.1 %). Ndbn-20T possessed Q-10 as the predominant ubiquinone, spermidine as the major polyamine, and summed feature 8 (comprising C18 : 1ω7c/C18 : 1ω6c), summed feature 3 (comprising C16 : 1ω7c/C16 : 1ω6c), C17 : 1ω6c, C16 : 0 and C14 : 02-OH as the major fatty acids (>5 % of the total). The profile of polar lipids consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, glycolipid, sphingoglycolipid, phosphatidyldimethylethanolamine and phosphatidylglycerol. The DNA G+C content was 65.4 mol%. Based on a polyphasic taxonomic analysis, strain Ndbn-20T is proposed to represent a novel species of the genus Rhizorhabdus , with the proposed name of Rhizorhabdus dicambivorans sp. nov. The type strain is Ndbn-20T (=CCTCC AB 2016143=KACC 18661).

The present study aimed to analyze the incidence of SF and its correlation with clinical events after DES implantation and the outcome of re-intervention for symptomatic in-stent restenosis (ISR) induced by stent fracture (SF).SF is associated with a high rate of clinical events after the implantation of drug-eluting stents (DES). However, the chronological rate of SF and the effect of SF on clinical outcomes from a large patient population remain underreported.A total of 6,555 patients with 16482 DES in 10751 diseased vessels and surveillance angiography between November 2003 and January 2014 were prospectively studied. The primary endpoints included the incidence of SF, in-stent restenosis (ISR), target lesion revascularization (TLR), and definite stent thrombosis (ST) at the end of follow-up before and after propensity score matching. Clinical outcomes after TLR were also followed up.The SF rate was detected in 803 (12.3%) patients, 3,630 (22.0%) stents, and 1,852 (17.2%) diseased vessels. SF increased over time. SF was associated with higher unadjusted rates of ISR (42.1%), TLR (24.8%, n = 379), and definite ST (4.6%) compared with stents without fracture (10.7%, 6.6%, and 1.03%, all p 0.001), and the differences remained significant after propensity score matching (all p 0.05). There was no significant difference in any-cause or cardiac mortality between patients with and without SF. After 1,523 days of follow-up since the first surveillance angiography, repeat ISR was detected in 90 of 379 (23.8%) stents after reintervention, and 6 (7.5%) stents required repeat TLR.SF is more frequently observed after DES implantation. TLR was required in almost one-fourth of fractured stents. Increased events in the SF group did not translate into a difference in mortality compared with the non-SF group. Reintervention was associated with acceptable clinical results.

Background— There is a paucity of data from large cohort studies examining the prognostic significance of obstructive sleep apnea (OSA) in patients with coronary artery disease. We hypothesized that OSA predicts subsequent major adverse cardiac and cerebrovascular events (MACCEs) in patients undergoing percutaneous coronary intervention. Methods and Results— The Sleep and Stent Study was a prospective, multicenter registry of patients successfully treated with percutaneous coronary intervention in 5 countries. Between December 2011 and April 2014, 1748 eligible patients were prospectively enrolled. The 1311 patients who completed a sleep study within 7 days of percutaneous coronary intervention formed the cohort for this analysis. Drug-eluting stents were used in 80.1% and bioresorbable vascular scaffolds in 6.3% of the patients, and OSA, defined as an apnea-hypopnea index of ≥15 events per hour, was found in 45.3%. MACCEs, a composite of cardiovascular mortality, nonfatal myocardial infarction, nonfatal stroke, and unplanned revascularization, occurred in 141 patients during the median follow-up of 1.9 years (interquartile range, 0.8 years). The crude incidence of an MACCEs was higher in the OSA than the non-OSA group (3-year estimate, 18.9% versus 14.0%; p =0.001). Multivariate Cox regression analysis indicated that OSA was a predictor of MACCEs, with an adjusted hazard ratio of 1.57 (95% confidence interval, 1.10–2.24; P =0.013), independently of age, sex, ethnicity, body mass index, diabetes mellitus, and hypertension. Conclusions— OSA is independently associated with subsequent MACCEs in patients undergoing percutaneous coronary intervention. Evaluation of therapeutic approaches to mitigate OSA-associated risk is warranted. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01306526.

Objective This study investigated the diagnostic accuracy of three-dimensional quantitative coronary angiography (3D-QCA) compared with conventional 2D-QCA for predicting functional severity assessed by fractional flow reserve (FFR) for true bifurcation lesions. Methods Based on pooled data from the randomized DK-CRUSH II, III, and IV trials, we evaluated the patients with true bifurcation lesions who underwent coronary angiography together with functional evaluations using FFR in both the main vessel and the side branch. Off-line 2D- and 3D-QCA analyses were conducted using dedicated bifurcation QCA analysis software. Measurements of minimum lumen diameter (MLD), percentage diameter stenosis (% DS), and minimum lumen area (MLA) were compared between 2D- and 3D-QCA, and we evaluated their predictive values of functionally significant FFR. Results Ninety patients were eligible for enrollment in the present study. In the main vessel, MLA measured by 3D-QCA was the most accurate predictor of FFR

MicroRNAs (miRNAs) are emerging as critical regulators in carcinogenesis and tumor progression. miR-98 has previously been verified to be important in tumor progression, however, its function in hepatocellular carcinoma (HCC) remains to be elucidated. The expression levels of miR-98 in HCC tissues and cell lines were determined by reverse transcription quantitative polymerase chain reaction. Subsequently, the effect of miR‑98 on cell proliferation, migration and invasion was evaluated by MTT assay, transwell migration assay and transwell invasion assay. Furthermore, a luciferase reporter assay was conducted to confirm the action of miR‑98 on downstream target genes, including collagen triple helix repeat containing 1 (CTHRC1). In the present study, it was confirmed that miR‑98 was significantly downregulated in HCC tissues and cell lines. Overexpression of miR‑98 inhibited HCC cell proliferation, migration and invasion in vitro. In addition, at the molecular level, the tumor oncogene CTHRC1 was identified to be the direct target of miR-98. Our findings suggested that miR‑98 was significantly downregulated in HCC and suppressed HCC cell proliferation, migration and invasion partially via the downregulation of CTHRC1. Thus, these data demonstrated that miR-98 could be a potential therapeutic target in HCC.

The plant growth regulator diethyl aminoethyl hexanoate (DA-6) has proved highly effective on micropropagation of the medicinal plant purple coneflower (Echinacea purpurea (L.) Moench), however, sharp variation of the effects existed among explants in the same treatment, making the application of DA-6 in micropropagation difficult. In order to clarify factors that influencing the treating results of DA-6, explants with different biomass dosage were prepared and inoculated onto medium supplemented with different concentrations of DA-6. It was found that among the three kinds of biomass dosage explants, the lowest biomass explants required the lowest concentration of DA-6, and the highest biomass explants required the highest concentration of DA-6 for the best results on adventitious buds regeneration. Similar results were obtained when regenerated buds of three different biomass dosages were cultured. It could be concluded from the above experimental results that for achieving better DA-6 application results, the concentration of DA-6 should be determined not only by the types but also by the biomass dosage of the explants. The present finding might help to improve the micropropagation efficiency in E. purpurea, and might be applicable for other species

In this updated vesion of ZMCintegral, we have added the functionality of integrations with parameter scan on distributed Graphics Processing Units(GPUs). Given a large parameter grid (up to 10^{10} parameter points to be scanned), the code will evaluate integrations for each parameter grid value. To ensure the evaluation speed, this new functionality employs a direct Monte Carlo method for the integraion. The Python API is kept the same as the previous ones and users have a full flexibility to define their own integrands. The performance of this new functionality is tested for both one node and multi-nodes conditions., 14 pages, 7 figures(including sub-figures)

Cisplatin is one of the most widely used platinum-based anticancer chemotherapeutic drugs. However, its low solubility, serious side effects and the development of cisplatin resistance limit its further use in the clinic. Controlling the delivery and release of cisplatin at the targeted site efficiently is a meaningful way to overcome these undesirable side effects of cisplatin. Herein, a tumor targeted and stimuli responsive nano-delivery system for cisplatin was constructed using branched polyethyleneimine (BPEI) as the backbone, disulfide bond as the redox-responsive covalent linker and hyaluronic acid (HA) as targeting recognition unit which can bind selectively to the receptor of CD44, which is highly expressed on the A549 tumor cells. The cisplatin-polyethyleneimine conjugate BPEI-SS-Pt was prepared and the drug loading of cisplatin was up to 32.66 ± 0.06%. After optimized the coating weight ratio of HA and BPEI-SS-Pt, the nanoparticle delivery system HA-(BPEI-SS-Pt)-1/4 outperformed with smaller particle size of 159.0 ± 21.0 nm, narrow polydispersity index (PDI) of 0.069 ± 0.022 and higher cisplatin loading of 29.23 ± 0.18%, showing specific tumor-targeting ability and redox-responsive drug release manner. Moreover, for the treatment of cancer in vivo, it achieved more effective antitumor performance along with minor side effects and systemic toxicity compared with cisplatin which is of great significance for the chemotherapeutic drug in the clinic.