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Duocarmycins are a class of DNA minor-groove-binding alkylating molecules. For the past decade, various duocarmycin analogues have been used as payloads in the development of antibody-drug conjugates (ADCs). Currently, more than 15 duocarmycin-based ADCs have been studied preclinically, and some of them such as SYD985 have been granted Fast-Track Designation status. Nevertheless, progress in duocarmycin-based ADCs also faces challenges, with setbacks including the termination of BMS-936561/MDX-1203. In this review, we discuss issues associated with the efficacy, pharmacokinetic profile, and toxicological activity of these biotherapeutics. Furthermore, we summarize the latest advances in duocarmycin-based ADCs that have different target specificities and linker chemistries. Evidence from preclinical and clinical studies has indicated that duocarmycin-based ADCs are promising biotherapeutics for oncological application in the future.

BACKGROUND Sulongga-4 (SL-4) is a herbal formula used in traditional Mongolian medical clinics for the treatment of peptic ulcers and gastroenteritis, even though its pharmacological mechanism has not been well characterized. AIM To evaluate the protective effect and identify the mechanisms of action of SL-4 on gastroduodenal ulcer induced by pyloric ligation (PL) in rats. METHODS PL was performed to induce gastric and duodenal ulcers in rats, which were then treated with oral SL-4 (1.3, 2.6, or 3.9 g/kg per day) for 15 d. PL-induced gastroduodenal ulceration. Therapeutic effects were characterized by pathological and histological evaluations and inflammatory indicators were analyzed by enzyme-linked immunosorbent assay. Microarray analyses were conducted to identify gene expression profiles of gastroduodenal tissue in PL rats with or without SL-4 treatment. The candidate target genes were selected and verified by quantitative reverse transcription polymerase chain reaction (qRT-PCR). RESULTS SL-4 decreased histopathological features in the PL-induced ulcerated rats. SL-4 significantly (P < 0.05) decreased expression of tumor necrosis factor-α, interleukin (IL)-1β, IL-6, endotoxin, platelet-activating factor, and increased prostaglandin E2 and epidermal growth factor in ulcer tissue. Microarray analysis was used to identify a panel of candidate target genes for SL-4 acting on PL-induced ulceration. Genes included some complement and coagulation cascade and retinol metabolism pathways that are closely associated with inflammatory responses and gastric mucosal protective mechanisms. qRT-PCR showed that altered expression of the selected genes, such as CYP2b2, UGT2b1, A2m, and MASP1 was consistent with the microarray results. CONCLUSION SL-4 exerts protective effects against PL-induced gastroduodenal ulcers via reducing inflammatory cytokines and elevating expression of gastric acid inhibitory factors. Downregulation of CYP2b2 and UGT2b1 genes in retinol metabolism and upregulation of A2m and MASP1 genes in the complement and coagulation cascades pathways are possibly involved in SL-4-mediated protection against gastroduodenal ulcer.

Pharmaceutical innovation in the development of novel antibody-based biotherapeutics with increased therapeutic indexes makes MET-targeted cancer therapy a clinical reality.

In this paper, the generation of relativistic electron mirrors (REMs) and the reflection of an ultra-short laser off this mirrors are discussed, applying two-dimensional particle-in-cell (2D-PIC) simulations. REMs with ultra-high acceleration and expanding velocity can be produced from a solid nanofoil illuminated normally by an ultra-intense femtosecond laser pulse with a sharp rising edge. Chirped attosecond pulse can be produced through the reflection of a counter-propagating probe laser off the accelerating REM. In the electron moving frame, the plasma frequency of the REM keeps decreasing due to its rapidly expanding. The laser frequency, on the contrary, keeps increasing due to the acceleration of REM and the relativistic Doppler shift from the lab frame to the electron moving frame. Within an ultra-short time interval, the two frequencies will be equal in the electron moving frame, which leads the resonance between laser and REM. The reflected radiation near this interval and the corresponding spectra will be amplified due to the resonance. Through adjusting the arriving time of the probe laser, certain part of the reflected field could be selectively amplified or depressed, leading to the selectively adjusting of the corresponding spectra.

Advanced colorectal adenocarcinoma (CRAC), featured by distinctive histopathological appearance, distant organ metastasis, acquired chemoresistance, and tumorigenic stemness is a group of heterogeneous cancers with unique genetic signatures and malignant phenotypes. Treatment of CRAC is a daunting task for oncologists. Currently, various strategies including molecular targeting using therapeutic monoclonal antibodies, small molecule kinase inhibitors and immunoregulatory checkpoint therapy have been applied to combat this deadly disease. However, these therapeutic modalities and approaches achieve only limited success. Thus, there is a pharmaceutical need to discover new targets and develop novel therapeutics for CRAC therapy. MET and RON receptor tyrosine kinases have been implicated in CRAC pathogenesis. Clinical studies have revealed that aberrant MET and/or RON expression and signaling are critical in regulating CRAC progression and malignant phenotypes. Increased MET and/or RON expression also has prognostic value for CRAC progression and patient survival. These features provide the rationale to target MET and RON for clinical CRAC intervention. At present, the use of small molecule kinase inhibitors targeting MET for CRAC treatment has achieved significant progress with several approvals for clinical application. Nevertheless, antibody-based biotherapeutics, although under clinical trials for more than 8 years, have made very little progress. In this review, we discuss the importance of MET and/or RON in CRAC tumorigenesis and development of anti-MET, anti-RON, and MET and RON-dual targeting antibody-drug conjugates for clinical application. The findings from both preclinical studies and clinical trials highlight the potential of this novel type of biotherapeutics for CRAC therapy in the future.

The optimization of the turbocharger structure can significantly improve its properties. In order to establish the dynamic coupling formula, the blade was simplified as a thin flexible rectangular plate moving in space, and the Lagrange dynamic equation was used to solve the problem. At the same time, the ANSYS analysis shows that the mode conversion and frequency conversion are ubiquitous and have certain influence on the life of compressor impeller. A new kind of curved leading edge with wide chord sweepback blade is presented, and proves that compared with the old blade, the stress and fatigue fracture are relived.

Triple-negative breast cancer (TNBC) is a highly diverse group of malignant neoplasia with poor outcome. Currently, the lack of effective therapy has fostered a major effort to discover new targets to treat this malignant cancer. Here we identified the RON receptor tyrosine kinase as a therapeutic target for potential TNBC treatment. We analyzed RON expression in 168 primary TNBC samples via tissue microarray using anti-RON IHC staining and demonstrated that RON was widely expressed in 76.8% TNBC samples with overexpression in 76 cases (45.2%). These results provide the molecular basis to target RON for TNBC therapy. To this end, anti-RON monoclonal antibody Zt/g4-drug monomethyl auristatin E conjugate (Zt/g4-MMAE) was developed with a drug to antibody ratio of 3.29 and tested in a panel of TNBC cell lines with different phenotypes. In vitro, Zt/g4-MMAE rapidly induced RON internalization, resulted in cell-cycle arrest followed by massive cell death. The calculated IC50 values ranged from 0.06 to 3.46 μg/mL dependent on individual TNBC cell lines tested. Zt/g4-MMAE also effectively killed TNBC stem-like cells with RON+/CD44+/CD24− phenotypes and RON-negative TNBC cells through the bystander effect. In vivo, Zt/g4-MMAE at 10 mg/kg in a Q12 × 2 regimen completely eradicated TNBC xenografts without the regrowth of xenograft tumors. In conclusion, increased RON expression is a pathogenic feature in primary TNBC samples. Zt/g4-MMAE is highly effective in eradicating TNBC xenografts in preclinical models. These findings lay the foundation for using anti-RON Zt/g4-MMAE in clinical trials as a novel strategy for TNBC treatment.

In this paper, an efficient sparse representation-based method is presented for detecting surface defects. The proposed method uses the sparse degree of coefficient in the redundant dictionary for checking whether the test image is defective or not, and the binary representation of the defective images is obtained, according to the global coefficient feature. Owing to the requirements for the efficiency and detecting quality, the block proximal gradient operator is introduced to speed up the online dictionary learning. Considering the correlation among the testing samples, prior knowledge is applied in the orthogonal-matching-pursuit sparse representation algorithm to improve the speed of sparse coding. Experimental results demonstrate that the proposed detection method can effectively detect and extract the defects of the surface images, and has broad applicability.

OBJECTIVE: This study aimed to compare the clinical and radiological results of percutaneous mesh-container-plasty (PMCP) versus percutaneous kyphoplasty (PKP) in the treatment of osteoporotic thoracolumbar burst fractures. METHODS: A prospective study of 122 patients with osteoporotic thoracolumbar burst fractures was conducted. The patients were nonrandomly assigned to receive PKP (62; 16 men, 46 women) and PMCP (60; 14 men, 46 women). The epidemiological data, surgical outcomes, and clinical and radiological features were compared between the 2 groups. Cement leakage, height restoration, deformity correction, canal compromise, and cement distribution were calculated from the radiographs. Visual pain analog scale (VAS), the Oswestry disability index (ODI), and short-form 36 health survey domains role physical (SF-36 rp) and bodily pain (SF-36 bp) were calculated before surgery and immediately and 2 years after surgery. RESULTS: Although VAS, ODI, SF-36 bp, and SF-36 rp scores improved from 7 (6–9), 71.28±16.38, 22 (0–32), and 25 (0–50) preoperatively to 2 (1–3), 20.02±8.97, 84 (84–84), and 75 (75–100) immediately postoperatively in the PMCP group (p

Background: PD-L1 immunotherapy remains poorly efficacious in colorectal cancer. The RON receptor tyrosine kinase plays an important role in regulating tumor immunity. Here, we identify patterns of RON and PD-L1 expression and explore the clinical significance of these patterns in colorectal cancer. Methods: Gene expression data were obtained from the Gene Expression Omnibus database (GEO; n = 290) and patients at the First Affiliated Hospital, Zhejiang University School of Medicine (FAHZUSM; n = 381) and were analyzed to determine the prognostic value of RON and PD-L1 expression within the tumor cells and the tumor microenvironment of colorectal cancer. Human colorectal cancer cell lines were treated with BMS-777607 to explore the relationship between RON activity and PD-L1 protein expression. Signaling pathways and protein expression perturbed by RON inhibition were evaluated by cellular immunofluorescence and western blot. Results: In the GEO cohort, cut-off values for RON and PD-L1 expression of 7.70 and 4.30, respectively, were determined. Stratification of patients based on these cutoffs demonstrated that high expression of RON and PD-L1 associated with poor prognosis. In the FAHZUSM cohort, rates of high expression of RON in tumor cells, high PD-L1 expression in tumor cells and in tumor infiltrating monocytes, and both high RON and high PD-L1 expression in the tumor microenvironment were 121 (32%), 43 (11%), 91 (24%), and 51 (13.4%), respectively. High expression of RON and high expression of PD-L1 in the tumor cell compartment was significantly correlated (p < 0.001). High expression of RON and PD-L1 were independent prognostic factors for poorer overall survival. Concurrent high expression of both RON and PD-L1 in the tumor microenvironment was significantly associated with poor prognosis. In vitro , BMS-777607 inhibited the phosphorylation of RON, inhibited PD-L1 expression, and attenuated activation of the ERK1/2 and AKT signaling pathways in colorectal cancer cells. Conclusions: RON, PD-L1 and the crosstalk between these proteins plays an important role in predicting the prognostic value of colorectal cancer. Moreover, phosphorylation of RON upregulates the expression of PD-L1, which provides a novel approach to immunotherapy in colorectal cancer.

Advanced epithelial cancers such as gastric, lung, and pancreatic tumors are featured by invasive proliferation, distant metastasis, acquired chemoresistance, and tumorigenic stemness. For the last decade, molecular-targeted therapies using therapeutic antibodies, small molecule kinase inhibitors and immune-checkpoint blockades have been applied for these diseases with significant clinical benefits. Nevertheless, there is still a large gap to achieve curative outcomes. MET (mesenchymal-epithelial transition protein), a receptor tyrosine kinase, is a tumorigenic determinant that regulates epithelial cancer initiation, progression, and malignancy. Increased MET expression also has prognostic value for cancer progression and patient survival. These features provide the rationale to target MET for cancer treatment. In this review, we discuss the importance of MET in epithelial tumorigenesis and the development of antibody-based biotherapeutics, including bispecific antibodies and antibody-drug conjugates, for clinical application. The findings from both preclinical and clinical studies highlight the potential of MET-targeted biotherapeutics for cancer therapy in the future.

The recepteur d’origine nantais (RON) receptor tyrosine kinase, belonging to the mesenchymal-to-epithelial transition proto-oncogene family, has been implicated in the pathogenesis of cancers derived from the colon, lung, breast, and pancreas. These findings lay the foundation for targeting RON for cancer treatment. However, development of RON-targeted therapeutics has not gained sufficient attention for the last decade. Although therapeutic monoclonal antibodies (TMABs) targeting RON have been validated in preclinical studies, results from clinical trials have met with limited success. This outcome diminishes pharmaceutical enthusiasm for further development of RON-targeted therapeutics. Recently, antibody–drug conjugates (ADCs) targeting RON have drawn special attention owing to their increased therapeutic activity. The rationale for developing anti-RON ADCs is based on the observation that cancer cells are not sufficiently addicted to RON signaling for survival. Thus, TMAB-mediated inhibition of RON signaling is ineffective for clinical application. In contrast, anti-RON ADCs combine a target-specific antibody with potent cytotoxins for cancer cell killing. This approach not only overcomes the shortcomings in TMAB-targeted therapies but also holds the promise for advancing anti-RON ADCs into clinical trials. In this review, we discuss the latest advancements in the development of anti-RON ADCs for targeted cancer therapy including drug conjugation profile, pharmacokinetic properties, cytotoxic effect in vitro, efficacy in tumor models, and toxicological activities in primates.

BACKGROUND Both pulsed electromagnetic field (PEMF) stimulation and sclerostin monoclonal antibody are useful for treating osteoporosis, but whether the two therapies have synergistic effects on both screw fixation quality and bone metabolism of ovariectomy-induced osteoporosis has not been reported. METHODS We used ovariectomy to create a rabbit model of postmenopausal osteoporosis. Then, specimens were fixed with pedicle screws in the L4 vertebral body. Rabbits were randomly divided into an OVX control group, PEMF group, Scl-Ab group, and PEMF+Scl-Ab group. The PEMF group was given PEMF magnetic therapy, the Scl-Ab group was administered a subcutaneous Scl-Ab injection, and the PEMF+SclAb group received both therapies. The OVX group was injected subcutaneously with the same dose of saline instead. After eight weeks of treatment, the bone metabolism index, bone mineral density (BMD), and bone microstructural, biological, and biomechanical parameters were evaluated. RESULTS BMD significantly decreased six months post-ovariectomy. Compared with that of the OVX group, the BMD of the PEMF, Scl-Ab, and PEMF+Scl-Ab groups increased by 20.3%, 19.9%, and 35.0%, respectively. The maximum pulling force of pedicle screws increased by 14.0%,15.0% and 19.1%, and the maximum failure power consumption of pedicle screws increased by 27.9%, 27.2% and 33.6%, respectively; these differences were statistically significant (P

Treatment of triple-negative breast cancer (TNBC) is a challenge to oncologists. Currently, the lack of effective therapy has fostered a major effort to discover new targets and therapeutics to combat this disease. The recepteur d’origine nantais (RON) receptor has been implicated in the pathogenesis of TNBC. Clinical studies have revealed that aberrant RON expression is crucial in regulating TNBC malignant phenotypes. Increased RON expression also has prognostic value for breast cancer progress. These features provide the rationale to target RON for TNBC treatment. In this review, we discuss the importance of RON in TNBC tumorigenesis and the development of anti-RON antibody–drug conjugates (ADCs) for clinical application. The findings from preclinical studies lay the foundation for clinical trials of this novel biotherapeutic for TNBC therapy.

RON (recepteur d'origine nantais) and MET (hepatocyte growth factor receptor) are tyrosine kinase receptors. Various cancers have aberrant RON and MET expression and activation, which contribute to cancer cell proliferation, invasiveness, and metastasis. Here, we explored RON and MET expression in pancreatic cancer and their relationship with overall survival (OS) time, and evaluated their significance as therapeutic targets of tyrosine kinase inhibitors in pancreatic cancer. We enrolled 227 patients with pancreatic cancer in the study. RON and MET expression was analyzed by immunohistochemical staining. Four human pancreatic cancer cell lines expressing variable levels of RON or MET and four MET superfamily inhibitors (BMS777607, PHA665752, INCB28060, Tivantinib) were used. The effect of the four tyrosine kinase inhibitors on cell viability, migration, and apoptosis were determined using cell viability, scratch wound healing, and Caspase-Glo 3/7 assays. Cellular signaling was analyzed by immunoprecipitation and western blotting. The therapeutic efficacy of the tyrosine kinase inhibitors was determined with mouse xenograft pancreatic cancer models in vivo. There was wide aberrant RON and MET expression in the cancer tissues. In 227 pancreatic cancer samples, 33% had RON overexpression, 41% had MET overexpression, and 15.4% had RON and MET co-overexpression. RON and MET expression were highly correlated. RON and MET expression levels were significantly related to OS. Patients with RON and MET co-overexpression had poorer OS. BMS777607 and PHA665752 inhibited pancreatic cancer cell viability and migration, and promoted apoptosis by inhibiting RON and MET phosphorylation and further inhibiting the downstream signaling pathways in vitro. They also inhibited tumor growth and further inhibited phosphorylated (phosphor)-RON and phospho-MET expression in the mouse xenograft models in vivo effectively. INCB28060, which inhibits the MET signaling pathway alone, was not effective. RON and MET can be important indicators of prognosis in pancreatic cancer. Tyrosine kinase inhibitors targeting RON and MET in pancreatic cancer are a novel and potential approach for pancreatic cancer therapy.

Purpose Triple-negative breast cancer (TNBC) is highly malignant and has poor prognosis and a high mortality rate. The lack of effective therapy has spurred our investigation of new targets for treating this malignant cancer. Here, we identified RON (macrophage-stimulating 1 receptor) and MET (MET proto-oncogene, receptor tyrosine kinase) as a prognostic biomarker and therapeutic targets for potential TNBC treatment.Materials and MethodsWe analyzed RON and MET expression in 187 primary TNBC clinical samples with immunohistochemistry. We validated the targeted therapeutic effects of RON and MET in TNBC using three tyrosine kinase inhibitors (TKIs): BMS-777607, INCB28060, and tivantinib. The preclinical therapeutic efficacy of the TKIs was mainly estimated using a TNBC xenograft model.ResultsPatients with TNBC had widespread, abnormal expression of RON and MET. There was RON overexpression, MET overexpression, and RON and MET co-overexpression in 63 (33.7%), 63 (33.7%), and 43 cases (23.0%), respectively, which had poor prognosis and short survival. In vivo, the TKI targeting RON ant MET inhibited the activation of the downstream signaling molecules, inhibited TNBC cell migration and proliferation, and increased TNBC cell apoptosis; in the xenograft model, they significantly inhibited tumor growth and shrank tumor volumes. The TKI targeting RON and Met, such as BMS-777607 and tivantinib, yielded stronger anti-tumor effects than INCB28060.ConclusionRON and MET co-overexpression can be significant pathological characteristics in TNBC for poor prognosis. TKIs targeting RON and MET have stronger drug development potential for treating TNBC.

Aberrant expression of the RON receptor tyrosine kinase, a cell surface protein, is a pathogenic feature in pancreatic cancer, which renders it a drug target for targeted therapy. Nevertheless, development of therapeutics targeting RON for pancreatic cancer therapy is hampered due to the lack of full addiction by pancreatic cancer cells to RON signaling for growth and survival. Here we describe a novel strategy using anti-RON antibody-directed drug delivery in the form of an antibody-drug conjugate for inhibition and/or eradication of pancreatic cancers. Monoclonal antibody Zt/g4 specific to the RON Sema domain was selected as the drug carrier based on its ability to induce robust RON internalization. Conjugation of Zt/g4 with monomethyl auristatin E, designated as Zt/g4-MMAE, was achieved through a protease-sensitive dipeptide linker to reach a drug to antibody ratio of 3.29:1. Zt/g4-MMAE was stable in human plasma with a dissociation rate less than 4% within a 10 day period. In vitro, Zt/g4-MMAE rapidly induced RON internalization, resulting in cell cycle arrest followed by massive cell death. The maximal effect was seen in pancreatic cancer cells with more than 10 000 receptor molecules per cell. Zt/g4-MMAE also synergized in vitro with chemotherapeutics including gemcitabine, 5-fluorouracil, and oxaliplatin to further reduce PDAC cell viability. In vivo, Zt/g4-MMAE exerts a long-lasting activity, which not only inhibited but also eradicated pancreatic xenograft tumors. These finding indicate that Zt/g4-directed drug delivery is highly effective for eradicating pancreatic tumors. Thus, Zt/g4-MMAE is a novel biotherapeutic with potential for therapy of RON-expressing pancreatic malignancies.

The development of optical fiber sensors has led to the possibility of accumulating vast, real-time databases of acoustic and other measurements throughout fiber networks, which brings even more widespread concern on improving the sampling effectiveness. In this paper, we present two kinds of sweep frequency methods based on using a neural network to extract temperature from the Brillouin gain spectrum (BGS). Gauss centralization and variance weight probability methods are proposed to compare with the uniform sweep frequency method. By analyzing formulas of the ideal BGS model, we find the gain near the peak of Brillouin gain spectrum has greater correlation with temperature extraction than other positions. Therefore, the Gaussian centralized sweep method is proposed. We further investigate the variation of the weights in the neural network and Brillouin data distribution in different positions and find that the variance is positively correlated with the weights in hidden layers. So, we propose the sweep frequency method based on variance weight probability and make a complement to interpret the rationality of this method in neural network. In all the aforementioned approaches, 281 points are obtained between the 9.07 GHz to 9.35 GHz range under the same condition. The data of each method is trained ten times and tested through the same neural network structure. All the RMSE of each test stage covers all data collecting the passage. The result shows that the RMSE of variance weight probability sweep frequency method is 0.5277, which is superior to the Gauss centralization sweep frequency method that was 0.6864 and the uniform sweep frequency method that was 0.9140.

Utilizing silicon nanoporous pillar array (Si-NPA) as substrate, a kind of CdS/ZnO sesame-seed-candy structure was prepared by successively growing ZnO nanorods and CdS nanograins via chemical vapor deposition and successive ion layer adsorption reaction method, respectively. The capacitive humidity sensing properties of CdS/ZnO/Si-NPA were studied by constructing coplanar interdigital electrodes. With the relative humidity (RH) increasing from 11% to 95%, a capacitance response over 201,530% was achieved, which indicates that CdS/ZnO/Si-NPA is highly sensitive to humidity. The response and the recovery times were determined to be ∼110 s and 32 s, respectively, with a maximum hysteresis being ∼2.67% at 75% RH. The high humidity sensitivity of CdS/ZnO/Si-NPA is attributed to the enlarged specific surface area induced by its unique nanostructure, while the short response/recovery times and the small hysteresis were due to the channel network brought by Si-NPA. These results indicate that CdS/ZnO/Si-NPA might be an ideal material system for fabricating high-performance humidity sensors.

Weather-strip seals in automotive door systems play a major role in determining the door closing effort, isolating the passenger compartment from water and reducing the wind noise inside the vehicle. The phenomenon of a wrinkle often occurs in weather-strips when they are assembled on the door surfaces which have bent or twisted profiles. Wrinkles in automobile weather-strip seals will affect the closing effort and noise isolation characteristics of the automotive door system. The wrinkle of anethylene-propylene-diene (EPDM) automobile weather-strip seals when bent and the critical conditions for a wrinkle to develop were characterized in this study. The hyperelastic material behavior of the EPDM sponge and EPDM dense rubber in the seal were modeled using the Foam model and Mooney–Rivlin model, respectively. Then a finite element analysis (FEA) model of the automobile weather-strip seal in assembly was developed and analyzed using then on linear FEA software Marc. The deformation of the seal and t...

This paper studied a flight gate assignment problem where both the passenger service quality and the flight taxiing distance are considered in the objective function. A more efficient flight gate assignment model is built. Based on this model, we further propose an improved particle swarm optimization algorithm to solve it. A novel "flight-to-gate" coding scheme is designed to convert a particle position vector into the priority sequence of gates for each flight. Some tournament selection comparison rules are employed to update the position vectors of particles where a small part of infeasible individuals are kept in the iterative process of PSO. In order to improve the performance of PSO algorithm, a local search strategy based on swap operation is introduced to exploit more latitude of search space to anchor the global optimum. The algorithm is tested based on the simulated operational data from the actual airport. Experimental results reveal that our algorithm can achieve a good performance.

Aberrant expression of the RON receptor tyrosine kinase is a pathogenic feature and a validated drug target in various types of cancers. Currently, therapeutic antibodies targeting RON for cancer therapy are under intensive evaluation. Here we report the development and validation of a novel humanized anti-RON antibody-drug conjugate for cancer therapy.Antibody humanization was achieved by grafting sequences of complementarity-determining regions from mouse monoclonal antibody Zt/g4 into human IgG1/κ acceptor frameworks. The selected humanized Zt/g4 subclone H1L3 was conjugated with monomethyl auristatin E using a dipeptide linker to form H-Zt/g4-MMAE. Pharmacokinetic analysis of H-Zt/g4-MMAE was determined using hydrophobic interaction chromatography and a MMAE ADC ELISA kit. Biochemical and biological assays were used for measuring RON expression, internalization, cell viability and death. Therapeutic efficacies of H-Zt/g4-MMAE were validated in vivo using three pancreatic cancer xenograft models. Toxicological activities of H-Zt/g4-MMAE were determined in mouse and cynomolgus monkey.H-Zt/g4-MMAE had a drug to antibody ratio of 3.77:1 and was highly stable in human plasma with a dissociation rate less than 5% within a 20 day period. H-Zt/g4-MMAE displayed a favorable pharmacokinetic profile in both mouse and cynomolgus monkey. In vitro, H-Zt/g4-MMAE induced RON internalization, which results in killing of pancreatic cancer cells with ICH-Zt/g4-MMAE is superior in eradication of pancreatic cancer xenografts with favorable pharmacokinetic profiles and manageable toxicological activities. These findings warrant the transition of H-Zt/g4-MMAE into clinical trials in the future.

Aberrant expression and/or activation of the MET receptor tyrosine kinase is characterized by genomic recombination, gene amplification, activating mutation, alternative exon-splicing, increased transcription, and their different combinations. These dysregulations serve as oncogenic determinants contributing to cancerous initiation, progression, malignancy, and stemness. Moreover, integration of the MET pathway into the cellular signaling network as an addiction mechanism for survival has made this receptor an attractive pharmaceutical target for oncological intervention. For the last 20 years, MET-targeting small-molecule kinase inhibitors (SMKIs), conventional therapeutic monoclonal antibodies (TMABs), and antibody-based biotherapeutics such as bispecific antibodies, antibody–drug conjugates (ADC), and dual-targeting ADCs have been under intensive investigation. Outcomes from preclinical studies and clinical trials are mixed with certain successes but also various setbacks. Due to the complex nature of MET dysregulation with multiple facets and underlying mechanisms, mechanism-based validation of MET-targeting therapeutics is crucial for the selection and validation of lead candidates for clinical trials. In this review, we discuss the importance of various types of mechanism-based pharmaceutical models in evaluation of different types of MET-targeting therapeutics. The advantages and disadvantages of these mechanism-based strategies for SMKIs, conventional TMABs, and antibody-based biotherapeutics are analyzed. The demand for establishing new strategies suitable for validating novel biotherapeutics is also discussed. The information summarized should provide a pharmaceutical guideline for selection and validation of MET-targeting therapeutics for clinical application in the future.

Deep learning is an important research topic in the field of educational technology, the Horizon Report released by the New Media Alliance in 2017 points out that deep learning is a key direction in promoting educational development and reform. This research is based on the CRS review discussion teaching mode, applying classroom response system in interactive teaching environment, in order to promot students' deep learning. Aiming at the problems of single teaching method, simple classroom communication, fuzzy monitoring of learning situation and low efficiency of teaching goal in junior high school physics review course, this paper takes junior high school physics review course as an example, discusses the teaching efficiency of CRS-based review course qualitatively, and uses comparative experiment to analyze the difference between teaching effect, students' deep learning achievement degree and learning type. The results show that, Based on the CRS junior high school physics review class in-depth learning model can improve students' academic performance, enhance the degree of achievement of students' deep learning. Therefore, we should actively explore the deep integration path of CRS and physics teaching, give full play to the advantages of CRS in focusing on the core issues in the classroom, evaluation of innovative learning process to improve the effectiveness of physics teaching.

Supplemental Digital Content is available in the text, Background: Magnesium sulfate (MgSO4) is widely used in analgesia for different conditions. Recent randomized controlled trials (RCTs) have evaluated the effects of MgSO4 on renal colic; however, this new evidence has not been synthesized. Thus, we conducted a systematic review and meta-analysis to assess the efficacy and safety of MgSO4 in comparison with control for renal colic. Methods: PubMed, EMBASE, and Scopus databases were searched from inception to February 2020. We included RCTs that evaluated MgSO4 vs control for patients with renal colic. Data were independently extracted by 2 reviewers and synthesized using a random-effects model. Results: Four studies with a total of 373 patients were analyzed. Intravenous MgSO4 15 to 50 mg/kg did not significantly reduce renal colic pain severity at 15 minutes (mean difference [MD] = 0.35, 95% confidence interval [CI] −0.51 to 1.21; 2 RCTs), 30 minutes (MD = 0.19, 95% CI −0.74 to 1.13; 4 RCTs), and 60 minutes (MD = −0.28, 95% CI −0.72 to 0.16; 3 RCTs) in comparison with controls. In patients who failed to respond to initial analgesics, intravenous MgSO4 15 mg/kg or 2 ml of 50% solution provided similar pain relief to ketorolac or morphine at 30 minutes (P = .90) and 60 minutes (P = .57). No significant hemodynamic changes were observed with short-term use of MgSO4 in these studies. Conclusion: MgSO4 provides no superior therapeutic benefits in comparison with control treatments. MgSO4 may be used as a rescue medication in patients not responding to initial analgesics. The short-term use of MgSO4 did not affect hemodynamic values.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with poor prognosis and high mortality. Molecular aberrations associated with PDAC pathogenesis and progression have been extensively investigated. Nevertheless, these findings have not been translated into clinical practice. Lack of therapeutics for PDAC treatment is another challenge. Recent application of molecularly targeted and immunoregulatory therapies appears to be disappointing. Thus, discovery of new targets and therapeutics is urgently needed to combat this malignant disease. The RON receptor tyrosine kinase is a tumorigenic determinant in PDAC malignancy, which provides the rationale to target RON for PDAC treatment. In this review, we summarize the latest evidence of RON in PDAC pathogenesis and the development of anti-RON antibody-drug conjugates for potential PDAC therapy. The finding that anti-RON antibody-drug conjugates show efficacy in preclinical animal models highlights the potential of this novel class of anti-cancer biotherapeutics in future clinical trials.

Ethnopharmacological relevance “Shanghuo”, a concept based on Traditional Chinese Medicine (TCM) theory, describes a status of Yin-Yang imbalance when Yang overwhelms Yin. The imbalance of Yin-Yang resembles the breaking of homeostasis and manifests by the impaired physiological functions, which leads to the onset, recurrence, and progression of diseases. Since ancient times, Chinese Materia Medica (CMM), such as herbal tea, has been applied as a treatment for “Shanghuo”. Aim of the study This review is aimed to describe the origin of “Shanghuo” from the Yin-Yang theory in TCM, as well as explore the relevance and correlations between “Shanghuo” and diseases susceptibility from the perspective of modern medicine. We also propose several strategies from CMM to improve the status of “Shanghuo” for the purpose of treating diseases. Methods Systematic research of articles with keywords including Shanghuo, Yin-Yang, emotional stress and disease susceptibility was done by using the literature databases (Web of Science, Google Scholar, PubMed, CNKI). Related books, PhD and master's dissertations were also researched. Full scientific plant names were validated by “The Plant List” ( www.theplantlist.org ). Results To date, a large number of publications have reported research on sub-health status, but studies about the theory or intervention of “Shanghuo” are rarely found. The articles we reviewed indicate that accumulated emotional stress is critical for the cause of “Shanghuo”. As a status similar to sub-health, “Shanghuo” is also manifested by impaired physiological functions and decreased nonspecific resistance, which increase susceptibility to various diseases. What's more, some studies highlight the importance of TCM treatment towards “Shanghuo” in maintaining normal physiological functions, such as immunity, lipid metabolism and ROS clearance. Conclusions Researches on “Shanghuo” and its mechanism are every rare currently and are in need of investigation in the future. Studies on disease susceptibility recently are mostly about susceptible genes that relate to a few parts of people, however, for most of the people, accumulated emotional stress or other stressors is accountable for the susceptibility of diseases. Given that emotional stress plays an important factor in the causation of “Shanghuo”, we reviewed the articles about this relevance and discussed the connection of “Shanghuo” with disease susceptibility in a novel perspective. In addition, we have reviewed the disease susceptibility model of restraint stress from its biochemical manifestation to application in CMM assessment. Although it would be a breakthrough in evaluating CMM efficacy of attenuating disease-susceptibility, understanding the comprehensive theory and establishing more models of “Shanghuo” would be required in further investigation.

A 74-year-old man presented with recurrent right lower quadrant abdominal pain and diarrhoea for many years. He had no systemic disease. However, he had taken Chinese herbs for more than 50 years. Physical examination revealed right-sided abdomen tenderness. Laboratory examination showed his white

In recent years, the number of imported Chinese pressure pipeline valves has been increasing, and the Administration of Quality Supervision Inspection and Quarantine (AQSIQ) issued Circular No. 151 in 2012 to clarify that the imported pressure piping valves need to have type test by the bodies approved by the type testing administration verified by AQSIQ. This paper makes a comparative study on the differences of the valve test and the test standard commonly used in China and in the foreign countries, as well as on the relevant requirements of the valve manufacturing standards involved in the imported valve type test. Through the comparison on above test standards and type test requirements, the foreign manufacturers will understand the standard differences, inspection requirements and precautions when importing China’s pressure pipeline valve. Combined with imported valve inspection and type test case analysis to help foreign enterprises fully understand our laws and regulations to ensure that when they import Chinese valve, they can meet our requirements to ensure the use security.

The pension robot can guide the elderly in community. The path planning environment of community for pension robot is so complicated that it is a NP-Hard problem in the optimization research. The local optimization solution is solved by the traditional swarm intelligent algorithm in path optimization problem. The novel model of path planning with community pension robot is presented, and the Quantum Particle Swarm Optimization algorithm is proposed for path planning. The robot can walk with global path in community, so as to avoid obstacle collision. The simulation results are implemented for verifying effective and robust algorithm, as well as the algorithm can overcome the shortcoming by traditional swarm intelligent algorithm. The performance is obviously improved for robot path planning.

This paper studied a flowshop scheduling problem with fuzzy due dates where the objective of maximizing the sum of customer satisfaction for the completion times of jobs is concerned. A self-adaptive differential evolution (SDE) algorithm has been employed to solve the fuzzy flowshop problem (FFP). The mutation scaling factor F and crossover probability CR are self-adaptive during the evolutionary process which can balance the exploration and the exploitation effectively. In order to make the SDE algorithm more effective and efficient, a local search strategy based on insert operation is introduced to exploit more latitude of search space to anchor the global optimum. The experimental results on the problem instance from literature demonstrate the good performance of the proposed SDE, thereby proving its worth as an attractive alternative for flowshop problems in uncertain environments.

An ultra-wide-angle THz metamaterial absorber (MA) utilizing sixteen-circular-sector (SCR) resonator for both transverse electric (TE) and transverse magnetic (TM) mode is designed and investigated numerically. At normal incidence, the absorptivity of the proposed MA is higher than 93.7% at 9.05 THz for different polarization angles, due to the rotational symmetry structure of the unit cell. Under oblique incidence, the absorptivity can still exceed 90%, even when the incident angle is up to 70° for both TE and TM mode. Especially, the frequency variation in TE mode is less than 0.25% for different incident angles from 0° to 70°. The electric field (Ez) distributions are used to explain the absorption mechanism. Numerical simulation results show that the high absorption with wide-angle independence stems from fundamental dipole resonance and gap surface plasmons. The broadband deep-infrared MA is also obtained by stacking three metal-dielectric layers. The designed MA has great potential in bolometric pixel elements, biomedical sensors, THz imaging, and solar cells.

The surface defects is an important factor affecting the quality of hot-rolled round steel, so the recognition of surface defects plays a very important role in the daily usage of the hot-rolled round steel. This paper aims to bring forward an appropriate method to find out the surface defects of the hot-rolled round steel under the help of Matlab software. First of all, the image edge of the round steel was detected, and the image was segmented. Secondly, the segmented image may appear bended, so it would be straightened to make the surface defects recognition easy. The third step is to eliminate image noise. Finally the processed image was analyzed and the appropriate recognition method was figured out. The results show that the method proposed in this paper is effective and accurate.

Mycotic or infected aneurysms are focal vascular dilatations from inflammation or infection that results in weakening of the blood vessel wall. It poses a high risk of complications such as aneurysm rupture, uncontrolled sepsis and extensive periaortic infection. Symptoms are frequently minimal during the early stages and a high index of suspicion is essential to make the diagnosis. They are more likely to expand rapidly and rupture without surgical intervention. We report a case of a middle-aged man presented with 3-week history of fever, abdominal pain and low back pain. Initially presented as acute pyelonephritis with subsequent findings of liver abscess, right epididymoorchitis and left infrarenal mycotic aneurysm, which rapidly increased in size and underwent successful endovascular surgery.

Dueto the shortage of domestic and foreign books sorting machine, the innovativedesign for the book sorting device is carried out with a small volume, lowcost, high efficiency characteristics by using TRIZ theory. The sorting deviceconsists of lifting platform device and trolley rail unit, and it greatlyreduces the size and cost of production and sorts books into 22x9 categories, soit has larger applications prospect in college library. Research andapplication of TRIZ theory in mechanical product innovation design has a veryimportant theoretical and realistic significance.

Purpose: The receptor tyrosine kinase RON is critical in epithelial tumorigenesis and a drug target for cancer therapy. Here, we report the development and therapeutic efficacy of a novel anti-RON antibody Zt/g4–maytansinoid (DM1) conjugates for targeted colorectal cancer (CRC) therapy. Experimental Design: Zt/g4 (IgG1a/κ) was conjugated to DM1 via thioether linkage to form Zt/g4–DM1 with a drug-antibody ratio of 4:1. CRC cell lines expressing different levels of RON were tested in vitro to determine Zt/g4–DM1-induced RON endocytosis, cell-cycle arrest, and cytotoxicity. Efficacy of Zt/g4–DM1 in vivo was evaluated in mouse xenograft CRC tumor model. Results: Zt/g4–DM1 rapidly induced RON endocytosis, arrested cell cycle at G2–M phase, reduced cell viability, and caused massive cell death within 72 hours. In mouse xenograft CRC models, Zt/g4–DM1 at a single dose of 20 mg/kg body weight effectively delayed CRC cell-mediated tumor growth up to 20 days. In a multiple dose-ranging study with a five injection regimen, Zt/g4–DM1 inhibited more than 90% tumor growth at doses of 7, 10, and 15 mg/kg body weight. The minimal dose achieving 50% of tumor inhibition was approximately 5.0 mg/kg. The prepared Zt/g4–DM1 is stable at 37°C for up to 30 days. At 60 mg/kg, Zt/g4–DM1 had a moderate toxicity in vivo with an average of 12% reduction in mouse body weight. Conclusion: Zt/g4–DM1 is highly effective in targeted inhibition of CRC cell-derived tumor growth in mouse xenograft models. This work provides the basis for development of humanized Zt/g4–DM1 for RON-targeted CRC therapy in the future. Clin Cancer Res; 20(23); 6045–58. ©2014 AACR.

This paper introduces an improved differential evolution algorithm for solving short-term multipurpose multistage batch scheduling problems (MMBSP) with the objective of minimizing the maximum completion time of all batches. A novel individual encoding and decoding scheme is designed for representing a scheduling solution for MMBSP. To improve the performance of DE further, a local search mechanism is introduced to exploit more latitude of search space to anchor the global optimum. In addition, the proposed DE is combined with a position bound disturbance strategy to add population diversity. Using those strategies, the proposed DE algorithm can get good balance between exploitation and exploration. The experimental results on some random generated problem instances demonstrate the good performance of the proposed DE.

Solenoid valve is the key component to determine the performance of electronic fuel injection system for the diesel engine. By theoretically analyzing the characteristics of solenoid valve driver, we found out that one of the factors that affect the closing & opening speed of solenoid valve is drive current. In this paper, GT-Flow software is used to simulate and analyze the drive current, and come to the optimal combination of current. The selected drive current is used to analyze the emission performance of 16V265H diesel engine, to determine the best advance angle for fuel supply, and to compare the simulation results with the experimental values.

This paper estimates the static strength of a certain type of cooling fan designed by a company in the rotating speed of 1260 rpm and 1380 rpm, evaluates static strength according to the cooling fan’s permissible stress in F state and T1 state, estimates the fatigue strength according to the operation load of cooling fan suffering from different direction when locomotive running and evaluates the cooling fan fatigue life according to the IIW standard. Static strength and fatigue strength calculation using ANSYS companies in the United States commercial version of the ANSYS software to complete.

With the increasing number of internet user, the authentication technology is more and more important. Iris recognition as an important method for identification, which has been attention by researchers. In order to improve the predictive accuracy of iris recognition algorithm, the iris recognition method is proposed based feature discrimination and category correlation. The feature discrimination and category correlation are calculated by laplacian score and mutual information. The formula about feature discrimination and category correlation are built. Aiming at texture characteristic of iris image, the multi-scale circular Gabor filter is used to feature extraction. The computational efficiency of algorithm is improved. In order to verify the validity of the algorithm, the CASIA iris database of Chinese Academy of Sciences is used to do the experiment. The experimental results show that our method has high predictive accuracy.

The investigation of the flow characteristics inside the nozzle becomes more and more important because the flow status in the nozzle and fuel injection significantly influence the emission and economy of diesel engines. Due to limited experimental conditions, we can make use of computer simulation, UG models can be used to predict the flow pattern inside the injectors and promote the level of selection and design of injectors. In this investigation, the UG model is calculated by FLUENT software after considering the compressibility and the viscosity of the fuel. By studying, we can predict the distribution of flow field inside the nozzle, analysis the rationality of the design of nozzle, determine the appropriate boundary conditions, mainly includes the nozzle pressure chamber and the needle tip structure, points out that the improvement direction.