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As part of our efforts to develop new classes of tubulin inhibitor payloads for antibody-drug conjugate (ADC) programs, we developed a tubulysin ADC that demonstrated excellent in vitro activity but suffered from rapid metabolism of a critical acetate ester. A two-pronged strategy was employed to address this metabolism. First, the hydrolytically labile ester was replaced by a carbamate functional group resulting in a more stable ADC that retained potency in cellular assays. Second, site-specific conjugation was employed in order to design ADCs with reduced metabolic liabilities. Using the later approach, we were able to identify a conjugate at the 334C position of the heavy chain that resulted in an ADC with considerably reduced metabolism and improved efficacy. The examples discussed herein provide one of the clearest demonstrations to-date that site of conjugation can play a critical role in addressing metabolic and PK liabilities of an ADC. Moreover, a clear correlation was identified between the hydrophobicity of an ADC and its susceptibility to metabolic enzymes. Importantly, this study demonstrates that traditional medicinal chemistry strategies can be effectively applied to ADC programs.

Lasers are frequently used to locally open dielectric layers for contacting the front or rear side of advanced silicon wafer solar cell architectures. For reasons of cost, laser processes are usually carried out in ambient environment, which inevitably leads to the oxidation of silicon. In order to achieve maximum solar cell efficiency, the laser processing has to be optimized thoroughly. The current research only focuses on minimizing laser-induced defects in silicon. However, our investigation shows another side effect of laser ablation, i.e., laser-induced oxidation, which is often neglected and undesirable for the subsequent metallization process. In this paper, we investigated the impact of laser-induced oxidation, which is caused by laser ablation in air, on the performance of silicon wafer solar cells. We show that by applying a postlaser etching step, laser-induced defects and oxide film can be removed effectively, providing improved conditions for the subsequent metallization process.

Surface roughness and the material removal rate (MRR) are two important indicators during the grinding process. The former determines the surface quality while the latter reflects the grinding efficiency directly. In this paper, the two indicators are taken into consideration simultaneously and differently by converting them into a comprehensive goal with using weighting objective method. A prediction model was established for each comprehensive goal with each different combination of surface roughness and MRR weighting coefficient. The optimal value of abrasive size, contact force, belt linear speed, and feed speed were obtained under different grinding situations by using a central composite design (CCD) combined with response surface analysis. The experimental results showed that the comprehensive goal can be used effectively as an indicator to control the grinding performance and improve the optimization process.

Low Impact Development (LID) is one of the sustainable approaches to urban stormwater management in areas with rapid urbanization. Although LID has been shown to have a positive effect in flood reduction, the hydrological balance regulation effect of LID under a variety of rainfall events is not fully understood. In this study, we assessed the hydrological efficiency of LID at two residential&ndash, commercial mixed sites in Korea to investigate the main function of LID in terms of diverse rainfall characteristics. Storm Water Management Model (SWMM) was constructed to simulate the hydrological process numerical simulations in the pre-development, post-development and LID design scenarios, respectively. The model was calibrated and validated by using five observed rainfall&ndash, runoff events. Then, four single and four multiple LID practices (LIDs) were used to estimate their effectiveness under seven different designed rainfall events. The results indicate that LIDs substantially influence the hydrology cycle system, while the regulating effect varies with rainfall amounts. The efficiency of LIDs in flood reduction is proved to be more effective during lower storm events. However, LIDs should be designed to primarily prioritize the restoration of hydrological balance when the rainfall return period is longer.

A cycloidal ball planetary transmission (CBPT) is a new type of transmission system with a large transmission ratio and a phenomenon of tooth undercutting. Nonlinear dynamic differential equations of the CBPT in the undercutting state are constructed. Firstly, the complete tooth profile equations of cycloidal grooves are established. With the increase of the radius of the deceleration balls, the tooth undercutting is firstly occurred in the inner part, and then in the outer part of the epicycloid grooves. Secondly, considering time-varying meshing stiffness, damping, meshing state, pre-tightening and external excitation, a strong nonlinear coupling dynamic model (70-DOF) of translation-torsion is established to further construct the nonlinear differential equations of the CBPT according to Lagrange equation. Thirdly, the response signal of the system is decomposed into low frequency and high frequency response signals. Fourthly, the nonlinear dynamic characteristics with three parameters (the damping, radius of rolling circle, short amplitude coefficient) are investigated. Finally, the effectiveness of the proposed model has been validated in part by testing vibration signals of CBPT. The stability of the system is affected by the damping, radius of rolling circle and short amplitude coefficient, which will provide useful support for the design of CBPT.

In this work, two-dimensional (2D) Janus Bi2XYZ (X≠Y≠Z, X/Y/Z = S, Se, Te) are predicted to be stable by means of the first-principles calculations. It is of interest that inversion asymmetry induced out-of-plane electric field causes the indirect–direct band gap crossover, band gaps for Bi2SeSTe, Bi2SSeTe and Bi2STeSe are approximately 0.7 eV (at HSE + SOC level of theory). For these Janus structures, carrier mobility reaches up to 3282.05 cm2 V−1 s−1, highly desirable for electronics, light harvesting and energy conversion. Janus Bi2XYZ show strong light–matter interactions, with the optical absorption covering almost the entire incident solar spectrum, thus ensuring efficient utilization of solar energy. For Janus Bi2XYZ, the piezoelectric coefficient d 11 can be as high as 15.01 pm/V due to the inversion symmetry breaking, higher than most of the reported Janus structures. And there is a linear relationship between the piezoelectric coefficient d 11 and the potential energy difference Δ φ between two outmost atomic layers. Our work thus demonstrates that 2D Janus Bi2XYZ hold great promise in applications in such as electronics, light harvesting and energy conversion.

A potent class of DNA-damaging agents, natural product bis-intercalator depsipeptides (NPBIDs), was evaluated as ultrapotent payloads for use in antibody-drug conjugates (ADCs). Detailed investigation of potency (both in cells and via biophysical characterization of DNA binding), chemical tractability, and in vitro and in vivo stability of the compounds in this class eliminated a number of potential candidates, greatly reducing the complexity and resources required for conjugate preparation and evaluation. This effort yielded a potent, stable, and efficacious ADC, PF-06888667, consisting of the bis-intercalator, SW-163D, conjugated via an N-acetyl-lysine-valine-citrulline- p-aminobenzyl alcohol- N, N-dimethylethylenediamine (AcLysValCit-PABC-DMAE) linker to an engineered variant of the anti-Her2 mAb, trastuzumab, catalyzed by transglutaminase.

We propose for the first time a kind of van der Waals (vdW) heterostructure composed of three distinct transition-metal dichalcogenide (TMD) monolayers, where step-like band alignment could be realized. In this case, excitons can be spatially separated into constituent top and bottom layers segregated by the middle layer. In light of the reduced binding energy and long lifetime of the interlayer excitons, trilayer TMD heterostructures hold great promise in applications such as solar cells and light-harvesting. In addition, heterostructures with different constituents and stacking orders give rise to distinct band offsets between neighboring layers. Other factors, like strain and SOC, also have apparent effects on the band offset. Our results reveal that 2H stacking can enhance valence band splitting, while 3R stacking has a significant influence on conduction band splitting. On account of the proper step-like band alignment and stacking-dependent band splitting, these trilayer TMD heterostructures also have great potential for applications in spintronics.

Because of the unique climate characteristics, the runoff law in mid-temperate zone is very different from other regions in spring. Accurate runoff simulation and forecasting is of great importance to spring flood control and efficient use of water resources. Baishan reservoir is located in the upper Second Songhua River Basin in Northeast China, where snowmelt is an important source of runoff that contributes to the water supply. This study utilized long-term hydrometeorological data, in the contributing area of Bashan reservoir, to investigate factors and time-lag effects on spring snowmelt and to establish a snowmelt-runoff model. Daily precipitation, temperature, and wind data were collected from three meteorological stations in this region from 1987–2016. Daily runoff into the Baishan reservoir was selected for the same period. The snowmelt period was identified from March 23 to May 4 through baseflow segmentation with the Eckhardt recursive digital filtering method combined with statistical analyses. A global sensitivity analysis, based on the back propagation neural network method, was used to identify daily radiation, wind speed, mean temperature, and precipitation as the main factors affecting snowmelt runoff. Daily radiation, precipitation, and mean temperature factors had a two-day lag effect. Based on these factors, an empirical snowmelt runoff model was established by genetic algorithm (GAS) to estimate the snowmelt runoff in this area. The model showed an acceptable performance with coefficient of determination (R2) of 73.6%, relative error (Re) of 25.10%, and Nash-Sutcliffe efficiency coefficient (NSE) of 66.2% in the calibration period of 1987–2010, while reasonable performance with R2 of 62.3%, Re of 27.2%, and NSE of 46.0% was also achieved during the 2011–2016 validation period.

The calculation of hydrologic frequency is an important basic step in the planning and design stage of any water conservancy project. The purpose of the frequency analysis is to deduce the hydrologic variables under different guarantee rates, and to provide hydrologic information for water conservancy project planning and design. The calculation of hydrologic frequency requires that the sample size is large enough, as only then can the statistical characteristics of samples take the place of the total statistical eigenvalues. This means that the samples can reveal the statistical characteristics of hydrologic variables and identify the randomness rule of hydrologic phenomena. Many countries in the East Asian monsoon climate zone (China, Japan and South Korea) have stipulated a sample size of 30 years for hydrologic frequency analysis. In this paper the rationality of the 30-year sample size is proved by analyzing the periodic and random rules of hydrologic phenomenon and the influencing mechanism of solar activity, and by adopting the general conclusion of the sampling theorem. Then, using the wavelet analysis method to examine annual precipitation data in a long series generated from representative precipitation observation stations in China, the strong-weak cycle of solar activity is proved to be 10 years, which is consistent with the wet-dry cycle of the representative precipitation stations (10–12 years). Finally, adopting numerical modeling to analyze the normal distribution of randomly generated samples and long-range annual precipitation data collected from representative stations, hypothesis testing (u, F and t) is used to prove that a 30-year sample size is reasonable. This research provides a reference as to how to prove the necessary sample size for relevant statistical analyses (for example, how large the sample should be for analyzing hydrologic factors trend evolution, hydrologic data consistency and ergodicity of statistical samples), thus ensuring the reliability of the analytical results.

1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3) has an anti-inflammatory effect on human monocytes incubated with sera from patients with type 2 diabetes/diabetic nephropathy; however, the detailed mechanism behind the effect remains to be explored. The current study further validated the effects of 1,25-(OH)2D3 and lipopolysaccharide (LPS) + human recombinant interleukin (IL)-15 on the expression of the vitamin D receptor (VDR) and phosphorylated signal transducer and activator of transcription 5 (p-STAT5) in human monocytes and explored the possible interaction between VDR and p-STAT5. Synchronized THP-1 cells were divided into pre-intervened groups, namely the control, LPS + IL-15 and 1,25-(OH)2D3, groups, according to their differing treatments. The expression of STAT5 and p-STAT5 was evaluated by western blot analysis; the concentration of IL-6 in the supernatant was determined using an enzyme-linked immunosorbent assay; the expression of cytoskeletal proteins was observed using immunofluorescence and laser confocal microscopy; and the possible intranuclear interaction between VDR and p-STAT5 was investigated using immunofluorescence, immuno-coprecipitation and western blot analysis. LPS + IL-15 upregulated p-STAT5 expression and the IL-6 level (P

Micro/nanostructures are fabricated on the stainless steel surfaces by a nanosecond laser in different gaseous environments, including air, O2, N2 and Ar. Our results indicate that the dimensional feature of the micro/nanostructures is greatly affected by laser scanning speed as well as gaseous environment. The chemical composition of the structures can be flexibly adjusted by laser processing parameters. Oxygen-rich environment is found to boost the growth of the nanostructures. The coloring by the laser processing can be achieved on the laser treated stainless steel surfaces. The multicolor effect on the surfaces is found to be attributed to both feature dimension and chemical composition of the structures. The coloring of the metal surfaces has promising applications in surface marking and code identifying.

As the antibody drug conjugate (ADC) community continues to shift towards site-specific conjugation technology, there is a growing need to understand how the site of conjugation impacts the biophysical and biological properties of an ADC. In order to address this need, we prepared a carefully selected series of engineered cysteine ADCs and proceeded to systematically evaluate their potency, stability, and PK exposure. The site of conjugation did not have a significant influence on the thermal stability and in vitro cytotoxicity of the ADCs. However, we demonstrate that the rate of cathepsin-mediated linker cleavage is heavily dependent upon site and is closely correlated with ADC hydrophobicity, thus confirming other recent reports of this phenomenon. Interestingly, conjugates with high rates of cathepsin-mediated linker cleavage did not exhibit decreased plasma stability. In fact, the major source of plasma instability was shown to be retro-Michael mediated deconjugation. This process is known to be impeded by succinimide hydrolysis, and thus, we undertook a series of mutational experiments demonstrating that basic residues located nearby the site of conjugation can be a significant driver of succinimide ring opening. Finally, we show that total antibody PK exposure in rat was loosely correlated with ADC hydrophobicity. It is our hope that these observations will help the ADC community to build “design rules” that will enable more efficient prosecution of next-generation ADC discovery programs.

This study investigated the role of the JAK2/STAT3/SOCS pathway in type 2 diabetes mellitus (T2DM) and macrovascular complications (DV) (T2DM+DV) conditions. Human umbilical vein endothelial cells (HUVECs) were co-cultured with human monocytes (THP-1) and exposed to peripheral blood sera from 30 T2DM patients, 30 patients with T2DM+DV and 30 healthy controls; the groups were divided into the control, T2DM, DV, T2DM+AG490 and DV+AG490 groups. Chemotaxis of treated HUVECs toward THP-1 cells was assessed using Transwell migration. The mRNA expression of JAK2, STAT3, VEGF and FLT1 was evaluated using RT-PCR, whereas the protein levels of ICAM-1, p-JAK2, JAK2, STAT3, p-STAT3, SOCS1 and SOCS3 were determined using western blotting. p-STAT3 was observed using immunofluorescence. The IL-1β concentrations were assessed by ELISA. AG90 was used as a specific inhibitor of JAK2/STAT3 signaling. The chemotaxis assays revealed a migratory order of DV>DM>control, and AG490 treatment decreased chemotaxis. Additionally, p-STAT3 fluorescence was noticeably increased in the DM group and more so in the DV group. The mRNA expression of JAK2, STAT3, VEGF and FLT1 and the protein levels of ICAM-1, p-JAK2, p-STAT3, SOCS1 and SOCS3 were significantly higher in the T2DM and DV groups than in the control group and in the AG490-treated groups than in the untreated groups. The supernatant concentrations of IL-1β in the DV and T2DM groups were higher than those in the control group, and treatment with AG490 decreased the IL-1β concentration. The JAK2/STAT3/SOCS axis contributes to the development of DV by mediating inflammation associated with vascular endothelial cells and/or monocytes.

Additional file 4: Table S4. Clinical and pathological characteristics of CRC patients.

A facile and environmental friendly synthesis strategy based on pulsed laser ablation has been developed for potential mass production of Ag-loaded TiO2 (Ag/TiO2) nanoparticles. By sequentially irradiating titanium and silver target substrates, respectively, with the same 1064 nm 100 ns fiber laser, Ag/TiO2 particles can be fabricated. A postannealing process leads to the crystallization of TiO2 to anatase phase with high photocatalytic activity. The phase composition, microstructure, and surface state of the elaborated Ag/TiO2 are characterized by X-ray diffraction (XRD), energy dispersive X-ray (EDX), field emission scanning electron microscope (FESEM), transmission electron microscope (TEM), and X-ray photoelectron spectroscopy (XPS) techniques. The results suggest that the presence of silver clusters deposited on the surface of TiO2 nanoparticles. The nanostructure is formed through laser interaction with materials. Photocatalytic activity evaluation shows that silver clusters could significantly enhance the photocatalytic activity of TiO2 in degradation of methylene blue (MB) under UV light irradiation, which is attributed to the efficient electron traps by Ag clusters. Our developed Ag/TiO2 nanoparticles synthesized via a straightforward, continuous, and green pathway could have great potential applications in photocatalysis.

Summary The Songhua River Basin (SRB) is located in the high latitude region of China’s far northeast and is sensitive to global warming. This study utilized long-term meteorological and river discharge records in the SRB to assess spatiotemporal variability and trends in temperature, precipitation, and discharge. Daily precipitation and temperature data were collected from 37 meteorological stations across the SRB for the period from January 1960 to December 2009. Monthly discharges from 33 major river gauge stations in three sub-basins of the SRB were gathered for the same period. The modified Mann–Kendall tests, flow duration curves and correlation statistics were performed to identify the long-term trend and interrelation of the hydrometeorological variables. The results showed that temperature in the SRB has steadily increased in the past five decades, while precipitation fluctuated greatly among the years and the decades with a declining trend since 1980s. The largest change in temperature was found in the last two decades, with a decadal increase of about 1 °C. Concurrently, a declining trend in annual discharge from the SRB was found after 1990, while intra-annual variation of discharge increased. Overall, annual discharge at most gauge stations across the SRB showed a downward trend in the past five decades, with a significantly decreasing trend in the Lower Songhua River. Seasonally, the declining trend in discharge was prevalent in spring and discharge mainly declined in the lower Nenjiang River and the Lower Songhua River throughout most of a year. The flow duration analysis showed a decrease in high flow (Q5), but an increase in low flow (Q95) after 1990 at most mainstream stations of the SRB. However, both the lowest and highest monthly discharge displayed a declining trend during 1960–2009. Because precipitation in this river basin is concentrated during the summer and fall months, annual discharge was closely and positively correlated with precipitation amount occurred during these two seasons.

The objectives of this study were to assess land use changes and their hydrological impacts in the Nenjiang River Basin (NRB). The Soil and Water Assessment Tool (SWAT) model was employed to evaluate the impacts of land use changes. The Cellular Automata-Markov model was used to predict a land use map in 2038. Streamflow under each land use state was simulated by the SWAT model. The results showed that there was a significant expansion of agriculture area at the expense of large areas of grassland, wetland, and forest during 1975&ndash, 2000. The land use changes during the period of 1975 to 2000 had decreased the water yield (3.5%), surface runoff (1.7%), and baseflow (19%) while they increased the annual evapotranspiration (2.1%). For impacts of individual land use type, the forest proved to have reduced streamflow in the flood season (10&ndash, 28%) and increased surface runoff in the drought season (20&ndash, 38%). Conversely, grassland, dry land, and paddy land scenarios resulted in increase of streamflow during summer months by 7&ndash, 37% and a decrease of streamflow in the cold seasons by 11.7&ndash, 59.7%. When the entire basin was changed to wetland, streamflow reduced over the whole year, with the largest reduction during January to March. The 2038 land use condition is expected to increase the annual water yield, surface runoff and wet season flow, and reduce evapotranspiration and baseflow. These results could help to improve sustainable land use management and water utilization in the NRB.

Aim: Complex nature of bioconjugates require multiple bioanalytical approaches to support PK and absorption, distribution, metabolism and excretion characterization. For antibody-drug conjugate (ADC) bioanalysis both LC–MS and ligand-binding assays (LBAs) are employed. Results: A method consisting of immunocapture extraction of ADC from biomatrices followed by LC–MS analysis of light and heavy chain is described. Drug antibody ratio (DAR) profiles of ADC Tras-mcVC-PF06380101 dosed at 0.3, 1 and 3 mg/kg in Sprague Dawley rats were obtained. Combined with total antibody (monoclonal antibody) measurement by LBA, conjugated payload concentration was calculated. Conclusion: PK profiles from LBA, ADC and calculated conjugated payload (DAR × monoclonal antibody) were in good agreement. We present a new tool for PK assessment of ADCs while also exploring ADC metabolism and DAR sensitivity of LBA ADC assay.

The Songhua River Basin (SRB) in Northeast China is one of the areas most sensitive to global climate change because of its high-latitude location. In this study, we conducted a modeling assessment on the potential change of water resources in this region for the coming three decades using the Soil and Water Assessment Tool (SWAT). First, we calibrated and validated the model with historical streamflow records in this basin. Then, we applied the calibrated model for the period from 2020 to 2049 with the projected and downscaled climatic data under two emission scenarios (RCP 4.5 and RCP 8.5). The study results show: (1) The SWAT model performed very well for both the calibration and validation periods in the SRB; (2) The projected temperatures showed a steady, significant increase across the SRB under both scenarios, especially in two sub-basins, the Nenjiang River Basin (NRB) and the Lower SRB (LSRB). With regard to precipitation, both scenarios showed a decreasing trend in the NRB and LSRB but an increasing trend in the Upper Songhua River Basin (USRB); and (3), generally, the hydrologic modeling suggested a decreasing trend of streamflow for 2020–2049. Compared to baseline conditions (1980–2009), the streamflow in the NRB and LSRB would decrease by 20.3%–37.8%, while streamflow in the USRB would experience an increase of 9.68%–17.7%. These findings provide relevant insights into future surface water resources, and such information can be helpful for resource managers and policymakers to develop effective eco-environment management plans and strategies in the face of climate change.

Aim. To explore nurses’ views and experiences regarding job satisfaction and their intention to leave in Shanghai. Background. The widespread nursing shortage and nurses’ high turnover rate has become a global issue. Job satisfaction is the most consistent predictor of nurses’ intention to leave and has been reported as explaining most of the variance on their intention to leave. Design. A cross-sectional survey. Methods. A convenience sample of nurses was recruited from 19 large general hospitals in Shanghai and the research assistants distributed 2850 questionnaires to nurses. The response rate of this study was 78·95%, and 2250 nurses completed the questionnaire. Results. Regarding the overall job satisfaction, 50·2% nurses were dissatisfied and 40·4% nurses reported that they had intention to leave the current employment. Respondents’ characteristics had an impact on job satisfaction and their intention to leave. The results showed that age, marital status, work experience, overall job satisfaction, job satisfaction: extrinsic rewards, interaction, praise/recognition and control/responsibility were significant factors contributing to nurses’ intention to leave. Conclusions. The finding may be a cause of concern for hospital management and highlights the importance of the two concepts (job satisfaction and intention to leave) in Shanghai. Innovative and adaptable managerial interventions need to be taken to improve nurses’ job satisfaction and to strengthen their intention to stay. Relevance to clinical practice. Our findings outline some issues contributing to these problems and provide nurse administrators with information regarding specific influences on nurses’ job satisfaction and intention to leave in Shanghai and innovative and adaptable managerial interventions that are needed. Our findings may also provide direction for nurse managers and healthcare management to implement strategies to improve nurses’ job satisfaction and their intention to stay.

A highly sensitive gas sensor based on thermal desorption coupled with cataluminescence (TD/CTL) using TiO 2 -Y 2 O 3 (mass ratio 1:3) as a probe was firstly proposed for the determination of formaldehyde in air. Quantitative analysis was performed at an optimal adsorbent of active carbon, thermal desorption temperature of 140 °C, catalytic temperature of 195 °C, a wavelength of 490 nm and a flow rate of 280 mL/min. The linear range of CTL intensity versus concentration of formaldehyde was 0.026–1.30 mg/m 3 ( r = 0.9990, n = 7), and the detection limit (3 σ ) was 0.01 mg/m 3 . There was no or weak response to foreign substances, such as benzene, ethanol, chloroform, carbon tetrachloride, toluene, dimethylbenzene and n -hexane. This proposed formaldehyde gas sensor showed the high sensitivity, rapid response, good stability, and allowed on-line monitoring of formaldehyde in air.

A novel thermionic cusp electron gun operating in the temperature-limited regime that produces a large-orbit electron beam through a nonadiabatic magnetic-field reversal was designed, analyzed, and optimized to give an electron-beam ideal for driving gyro-devices, particularly in the millimeter-to-submillimeter-wavelength range due to its small cross-sectional size. The annular-shaped axis-encircling electron beam had a beam current of 1.5 A at an acceleration potential of 40 kV, a tunable velocity ratio alpha (= vperp/vz) between one and three, an optimized axial velocity spread A.vx/vz of ~8%, and a relative alpha spread Deltakappa/alpha of ~10% at an alpha value of 1.65.

Aim Previous randomized controlled trials and meta-analyses have demonstrated the ineffectiveness of fluorouracil-based adjuvant chemotherapy for patients with rectal cancer who have undergone neoadjuvant chemoradiotherapy and subsequent surgery. The role of oxaliplatin/fluorouracil-based adjuvant chemotherapy in such patients is unknown. We performed a meta-analysis to evaluate the efficacy of oxaliplatin/fluorouracil-based adjuvant chemotherapy based on a comparison with fluorouracil-based adjuvant chemotherapy for patients with rectal cancer. Method A literature search of MEDLINE, Embase, Web of Science, Cochrane Library and ClinicalTrials.gov was performed to identify eligible studies. The primary end-point of interest was disease-free survival (DFS). The secondary end-points were overall survival, compliance and the incidence of Grade 3 or 4 toxicity. Results The literature search identified four randomized controlled trials that met the inclusion criteria for the meta-analysis, and 2793 patients with pathological TNM or clinical TNM Stage II or III disease were included. The meta-analysis showed that oxaliplatin/fluorouracil-based adjuvant chemotherapy was associated with a significantly improved DFS (hazard ratio 0.85; 95% CI 0.73−0.98; P = 0.03), comparable compliance (OR 1.18; 95% CI 0.95−1.46; P = 0.13) and a higher incidence of vomiting or nausea (OR 2.47; 95% CI 1.21−5.05; P = 0.01). No significant differences were observed between the groups with respect to overall survival and the incidence of leucopaenia, anaemia, thrombocytopaenia and diarrhoea. Conclusion Adjuvant oxaliplatin/fluorouracil-based chemotherapy can improve the DFS of patients after neoadjuvant chemoradiotherapy and radical surgery, compared with adjuvant fluorouracil-based chemotherapy. Data of the longer-term survival outcome are needed.

To evaluate the epithelial-to-mesenchymal transition (EMT) of circulating tumor cells (CTCs) in gastric cancer patients.We detected tumor cells for expression of four epithelial (E(+)) transcripts (keratins 8, 18, and 19 and epithelial cell adhesion molecule) and two mesenchymal (M(+)) transcripts (Vimentin and Twist) by a quantifiable, dual-colorimetric RNA-in situ hybridization assay. Between July 2014 and October 2014, 44 patients with gastric cancer were recruited for CTC evaluation. Blood samples were obtained from selected patients during the treatment course [before surgery, after surgery and at the 6(th) cycle of XELOX based chemotherapy (about 6 mo postoperatively)].We found the EMT phenomenon in which there were a few biphenotypic E(+)/M(+) cells in primary human gastric cancer specimens. Of the 44 patients, the presence of CTCs was reported in 35 (79.5%) patients at baseline. Five types of cells including from exclusively E(+) CTCs to intermediate CTCs and exclusively M(+) CTCs were identified (4 patients with M(+) CTCs and 10 patients with M(+) or M(+)E(+) CTCs). Further, a chemotherapy patient having progressive disease showed a proportional increase of mesenchymal CTCs in the post-treatment blood specimens. We used NCI-N87 cells to analyze the linearity and sensitivity of CanPatrol(TM) system and the correlation coefficient (R(2)) was 0.999.The findings suggest that the EMT phenomenon was both in a few cells of primary tumors and abundantly in CTCs from the blood of gastric cancer patients, which might be used to monitor therapy response.

Background: NOTCH3, a cell surface receptor involved in cell-cell communications, is over-expressed or amplified in certain human tumors. NOTCH3 is known to regulate proliferation, differentiation and survival of cancer cells or cancer stem cells and thus an important therapeutic target. NOTCH3 antibody drug conjugate (ADC) is comprised of humanized anti-NOTCH3 antibody conjugated to an auristatin based cytotoxic payload. NOTCH3-ADC has shown promising results in pre-clinical tumor models. In this study we evaluated the kinetics, dose-dependent tissue distribution, tumor accumulation and targeting specificity of the NOTCH3-ADC in OVCAR3 xenograft model using fluorescence molecular tomography (FMT) imaging. The NOTCH3-ADC is mouse cross-reactive thus providing an accurate assessment of biodistribution. Methods: NOTCH3-ADC was conjugated to the near-infrared dye, AlexaFluor680 (AF680). The in vitro cellular binding was evaluated by cell-based ELISA. In vivo biodistribution was evaluated using OVCAR3 subcutaneous xenograft model. NOTCH3-ADC-AF680 (1mg/kg; 3mg/kg and 10mg/kg) was injected when the tumors were ~300mm3 and imaged 5 min, 24, 48, 96, 168 and 240 h post-injection. Ex vivo FMT imaging, pharmacokinetic analysis and immunohistochemistry (IHC) was performed at 48 and 240 h after whole-body perfusion. An in vivo receptor competition FMT study was performed by injecting excess of unconjugated anti-NOTCH3 antibody (Ab) or a non-targeted control Ab. Results: In vitro cell binding studies showed that conjugation of AF680 to NOTCH3-ADC did not change its binding ability. A dose-dependent tumor regression was also observed after a single injection of NOTCH3-ADC-AF680. In vivo FMT imaging showed dose-dependent whole-body clearance kinetics of NOTCH3-ADC. Dose-dependent accumulation in the tumors was observed with peak accumulation at 24-48 h post-injection and a slow decline at later time-points. A maximum accumulation of ~10 %ID/g was observed which was independent of the dose of NOTCH3-ADC-AF680. Ex vivo FMT quantitation of tumor was consistent with the IHC for antibody and LC/MS analysis of released payload. Pharmacological competition with excess unlabeled control Ab did not block tumor accumulation of NOTCH3-ADC-AF680, whereas excess unlabeled NOTCH3-Ab blocked ~47% of NOTCH3-ADC-AF680 accumulation. There was no significant specific accumulation of NOTCH3-ADC in other organs as observed by FMT imaging or IHC. Conclusions: These imaging studies provided understanding of the kinetics, tumor accumulation and biodistribution of NOTCH3-ADC. Further this work showcase the utility of non-invasive FMT imaging in better understanding of pharmacology and behavior of biologic drugs. Citation Format: Anand Giddabasappa, Parul Gupta, Mauricio Leal, Jonathan Golas, Fengping Li, Bing Yang, Antonio Esparza, Christopher Winkelmann, Kenneth Geles. Dose-dependent tissue distribution and tumor targeting of Notch3-ADC using fluorescence molecular tomography imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2861. doi:10.1158/1538-7445.AM2017-2861

We study two-dimensional (2D) germanene supported on Au(1 1 1) to determine the structural, electronic and interface interaction properties on the basis of first-principles electronic calculations. In light of the lattice commensurability, (2 × 2)/(√7 × √7) and (√3 × √3)/(√7 × √7) germanene/Au(1 1 1) superstructures are obtained with low-binding energy. We find that the interface effects between germanene and Au(1 1 1) break the inversion symmetry of germanene to a significant extent. The electron accumulation layer between germanene and Au(1 1 1) bonds the adlayer and substrate together, indicating strong adsorption behavior. Charge transfer occurs from Au(1 1 1) to germanene with the formation of a dipole layer. In addition, the intense electronic orbital hybridization effects between germanene and Au(1 1 1) are revealed through the atomic projected band structures. Clearly, resonant behavior occurs between germanene p orbitals and Au(1 1 1) s orbitals. As germanene is peeled off from Au(1 1 1), the band structures are characterized as metallic, and in the absence of the Au(1 1 1) substrate the band structure of (√3 × √3) single layer germanene demonstrates a lower effective mass due to its higher geometrical symmetry, which is similar to that of planar graphene. This paper shows that Au(1 1 1) is a suitable candidate for the growth of germanene, and our results offer useful information for the application of germanene in electronic devices.

Climate variation and human activities are commonly recognized as two major factors affecting basin hydrology. However, quantifying their individual effect on runoff is challenging. In this study, long-term (1960–2009) river discharge and weather data in the Songhua River Basin (SRB, 556,800 km2), Northeast China, were gathered to separate the impacts of climate variation and human activities on runoff in five sub basins of the SRB. Mann-Kendall test, moving t-test and precipitation-runoff double cumulative curve were utilized to identify trends and change points of the hydrometeorlogical variables. Based on the change point, the 50-year study period was divided into two time series: 1960–1974 where minimal human activities took place and 1975–2009 where extensive land use change occurred and river engineering projects were undertaken. Subsequently, individual contributions of climate and human factors were assessed through a hydrologic sensitivity analysis. Our study found a significant decline in runoff of the SRB over the past 50 years. Contribution of climate variation and human activities to the change varied temporally and spatially. For the 1975–2009 period, human activities made a greater contribution (62%–82%) to the total runoff decline of the SRB. However, climate variation played a bigger role in runoff reduction in two sub river basins (63%–65%) between 1975 and 1989, as well as in runoff increase in other two sub river basins (85%–86%) between 1990 and 1999. Spatially, the effect of human activities on runoff decline was relatively stronger in the lower basin areas in the 1960s and 1970s while showing an increasing role in the upper basin areas in the past two decades.

1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3) has an anti-inflammatory effect on human monocytes incubated with sera from patients with type 2 diabetes/diabetic nephropathy; however, the detailed mechanism behind the effect remains to be explored. The current study further validated the effects of 1,25-(OH)2D3 and lipopolysaccharide (LPS) + human recombinant interleukin (IL)-15 on the expression of the vitamin D receptor (VDR) and phosphorylated signal transducer and activator of transcription 5 (p-STAT5) in human monocytes and explored the possible interaction between VDR and p-STAT5. Synchronized THP-1 cells were divided into pre-intervened groups, namely the control, LPS + IL-15 and 1,25-(OH)2D3, groups, according to their differing treatments. The expression of STAT5 and p-STAT5 was evaluated by western blot analysis; the concentration of IL-6 in the supernatant was determined using an enzyme-linked immunosorbent assay; the expression of cytoskeletal proteins was observed using immunofluorescence and laser confocal microscopy; and the possible intranuclear interaction between VDR and p-STAT5 was investigated using immunofluorescence, immuno-coprecipitation and western blot analysis. LPS + IL-15 upregulated p-STAT5 expression and the IL-6 level (P

In this paper, laser interaction with materials and its applications in precision engineering are mainly introduced. To further explore the physics behind laser interaction with materials, it is of much significance to investigate the mechanisms in the process. First of all, it is desired to understand the characteristics and principle of laser. Laser is generated by stimulated radiation, and has excellent physical properties, such as high monochromaticity, high brightness, high directivity and high coherence. Meanwhile, it benefits much to study the dynamic process of interactions and its mechanisms. There exist both photo-chemical and photo-thermal processes when laser and materials interact. Furthermore, developing laser application in nanomaterial synthesis is also an unique area. It is worth further studying the design and fabrication of nanostructured materials. Last but not least, it is interesting to explore the specific process and characteristics of laser processing, which play an important role in advanced manufacturing. In precision engineering, the tool of laser has also been more applicable considering its great advantages in microprocessing and nanofabrication. Several case studies are introduced, which have great potential and high impact applications, such as ultrafast laser direct writing, laser micro-lens lithography, laser nanofabrication to break through optical diffraction limit and hybrid micro/nanostructures with unique functions fabricated by laser. These studies have triggered intensive research interests due to their great application prospect.

The typical rise time of PTS machine is ∼110 ns with about 10 MA peak current under short pulse mode when all 24 modules discharge simultaneously. By distributing the trigger times of 12 laser beams logically and adjusting the statues of the pulse output switches, longer rise-time pulse can be obtained on the PTS facility. Based on the required pulse shape, whole circuit simulations will be used to calculate the trigger times of each laser triggering gas switch and the status of the pulse output switches. The rise time of the current is determined by the time difference between the first and last trigged laser triggering gas switches. In order to trigger the laser triggering gas switch, sufficient laser power is needed to be sent into the gap of the gas switches. The gas pressure and voltage difference on the two electrodes of the gas switches also affect the triggering of the gas switches, and the voltage added on the gas switch is determined by its transition time. Traditionally the trigger time difference should be less than the transition time of the two neighboring modules. A new simulation model of PTS shows one can break this transition time limits. Series of current pulse shaping experiments have been investigated on the PTS (Primary Test Stand). As results, more than 5 MA peak current were successfully achieved on the load with a rise time of 600 ns. This study and experiments of the pulse shaping on PTS demonstrate the adaptable ability of the PTS for offering different waveform of mega ampere current pulse for different research purpose.

A thermionic cusp electron gun has been designed, numerically optimized and experimentally measured and is presented. A 40 kV, 1.5 A annular axis-encircling electron beam has been simulated to generate a beam with low velocity and alpha spreads. The electron gun performance has been verified through experiments and the results are given.

Summary form only given. The European Gyrotron Consortium (EGYC) is responsible for developing one set of 170 GHz mm-wave sources, in support of Europe's contribution to ITER1. The original plan of targeting a 2 MW coaxial gyrotron is currently under discussion, in view of essential delays and damages. This paper reports on the latest results and plans with regard to the 2 MW gyrotron prototypes.

The experimental demonstration of a W-band gyrotron backward-wave oscillator (gyro-BWO) using both thermionic cusp electron gun and helically corrugated waveguide will be presented. The cusp gun is designed to generate an axis-encircling electron beam of 1.5 A at 40 kV with an adjustable velocity ratio of up to 3.0. The beam had a simulated axial velocity spread (Δv z /v z ) of ∼8% and alpha spread (Δ α /α) of ∼10%. The beam had an averaged radius of 0.35 mm and beam thickness of 0.05 mm which is ideal to drive sub-mm wave gyro-devices under investigation. The gyro-BWO has been experimentally measured and the latest results will be presented.