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Delta-like ligand 4 (Dll4), one of the Notch ligands, is overexpressed in ovarian cancer, especially in tumors resistant to anti-VEGF therapy. Here, we examined the biologic effects of dual anti-Dll4 and anti-VEGF therapy in ovarian cancer models. Using Dll4-Fc blockade and anti-Dll4 antibodies (murine REGN1035 and human REGN421), we evaluated the biologic effects of Dll4 inhibition combined with aflibercept or chemotherapy in orthotopic mouse models of ovarian cancer. We also examined potential mechanisms by which dual Dll4 and VEGF targeting inhibit tumor growth using immunohistochemical staining for apoptosis and proliferation markers. Reverse-phase protein arrays were used to identify potential downstream targets of Dll4 blockade. Dual targeting of VEGF and Dll4 with murine REGN1035 showed superior antitumor effects in ovarian cancer models compared with either monotherapy. In the A2780 model, REGN1035 (targets murine Dll4) or REGN421 (targets human Dll4) reduced tumor weights by 62% and 82%, respectively; aflibercept alone reduced tumor weights by 90%. Greater therapeutic effects were observed for Dll4 blockade (REGN1035) combined with either aflibercept or docetaxel (P < 0.05 for the combination vs. aflibercept). The superior antitumor effects of REGN1035 and aflibercept were related to increased apoptosis in tumor cells compared with the monotherapy. We also found that GATA3 expression was significantly increased in tumor stroma from the mice treated with REGN1035 combined with docetaxel or aflibercept, suggesting an indirect effect of these combination treatments on the tumor stroma. These findings identify that dual targeting of Dll4 and VEGF is an attractive therapeutic approach. Mol Cancer Ther; 15(6); 1344–52. ©2016 AACR.

Although progesterone receptor (PR)–targeted therapies are modestly active in patients with uterine cancer, their underlying molecular mechanisms are not well understood. The clinical use of such therapies is limited because of the lack of biomarkers that predict response to PR agonists (progestins) or PR antagonists (onapristone). Thus, understanding the underlying molecular mechanisms of action will provide an advance in developing novel combination therapies for cancer patients. Nuclear translocation of PR has been reported to be ligand-dependent or -independent. Here, we identified that onapristone, a PR antagonist, inhibited nuclear translocation of ligand-dependent or -independent (EGF) phospho-PR (S294), whereas trametinib inhibited nuclear translocation of EGF-induced phospho-PR (S294). Using orthotopic mouse models of uterine cancer, we demonstrated that the combination of onapristone and trametinib results in superior antitumor effects in uterine cancer models compared with either monotherapy. These synergistic effects are, in part, mediated through inhibiting the nuclear translocation of EGF-induced PR phosphorylation in uterine cancer cells. Targeting MAPK-dependent PR activation with onapristone and trametinib significantly inhibited tumor growth in preclinical uterine cancer models and is worthy of further clinical investigation. Mol Cancer Ther; 17(2); 464–73. ©2017 AACR.

Supplementary Figure 1. Representative OVCAR3-inoculated mice after aflibercept, Dll4-Fc, and the combination. Supplementary Figure 2. In vivo study of Dll4 blockade, aflibercept, and docetaxel, alone and in combinations, in A2780 and HeyA8 models. Supplementary Figure 3. Immunohistochemical staining of CX3CL1 in the tumor stroma of mice inoculated with A2780 ovarian cancer cells. Supplementary Figure 4. Quantitative real-time PCR of CX3CL1 expression in A2780 cells cultured with primary dendritic cells isolated from C57/BL6 mice. Supplementary Figure 5. ELISA analysis of plasma IFN-gamma in the mice inoculated with A2780 ovarian cancer cells. Supplementary Figure 6. RT-PCR analysis of E-cadherin expression in tumors (tumor cells and stroma) obtained from A2780 mice treated with a single agent or a combination.

Supplementary Figure 1. In vitro effects of PR silencing on onapristone sensitivity in PR-high-expressing uterine cancer cell line (Ishikawa). Supplementary Figure 2. In vitro effects of onapristone and trametinib in PR-weak-expressing uterine cancer cell line (SKUT2). Supplementary Figure 3. In vivo effects of therapy with onapristone in uterine cancer model. Supplementary Figure 4. In vivo effect of onapristone, trametinib, and the combination of both drugs on total PR expression in the ISHIKAWA model.

PDF file - 55K, Correlation between key transcription factors and Notch3 overexpression.

PDF file - 765K, Overall Survival (OS) Analysis in Patients With High-Grade Serous Ovarian Cancer HGS-OvCa (S1); In Vitro Functional Studies of Notch3 siRNA or GSI and combined with Paclitaxel in OvCa Cells (S2); qRT-PCR Analysis of Expression of Gamma-Secretase Complex in Ovarian Cancer Cells (S3); In vitro effects of blocking endocytosis on Jagged-1/Notch3 pathway in cancer cells (S4); In vivo study of Notch3 siRNA in orthotopic mouse models of ovarian cancer (S5).

PDF file - 65K, Microarray Analysis of Significantly Down- regulated Genes in OVCAR3 cells With or Without Notch3 Silencing.

PDF file - 183K, The siRNA and Primer Sequences.

PDF file - 96K, Notch Pathway Alterations in Patients with HGS-OvCa.

We consider a fundamental pricing model in which a fixed number of units of a reusable resource are used to serve customers. Customers arrive to the system according to a stochastic process and upon arrival decide whether or not to purchase the service, depending on their willingness-to-pay and the current price. The service time during which the resource is used by the customer is stochastic and the firm may incur a service cost. This model represents various markets for reusable resources such as cloud computing, shared vehicles, rotable parts, and hotel rooms. In the present paper, we analyze this pricing problem when the firm attempts to maximize a weighted combination of three central metrics: profit, market share, and service level. Under Poisson arrivals, exponential service times, and standard assumptions on the willingness-to-pay distribution, we establish a series of results that characterize the performance of static pricing in such environments. In particular, while an optimal policy is fully dynamic in such a context, we prove that a static pricing policy simultaneously guarantees 78.9% of the profit, market share, and service level from the optimal policy. Notably, this result holds for any service rate and number of units the firm operates. Our proof technique relies on a judicious construction of a static price that is derived directly from the optimal dynamic pricing policy. In the special case where there are two units and the induced demand is linear, we also prove that the static policy guarantees 95.5% of the profit from the optimal policy. Our numerical findings on a large testbed of instances suggest that the latter result is quite indicative of the profit obtained by the static pricing policy across all parameters.

Red phosphorus (RP) has a suitable energy band structure and excellent photocatalytic properties. However, there are some problems, such as low quantum efficiency and serious photogenerated electron-hole recombination. The S-scheme heterostructure shows great potential in facilitating the separation and transfer of photogenerated carriers and obtaining strong photo-redox ability. Herein, hydrothermally treated red phosphorus (HRP) was combined with Bi2O2CO3 to construct Bi2O2CO3/HRP S-scheme heterojunction composite. The Bi2O2CO3 content was optimized, and the 5%Bi2O2CO3/HRP composite obtained at 5%Bi2O2CO3 mass fraction exhibited the strongest photoreduction ability. The Cr(VI) photoreduction and photolytic hydrogen production rates were as high as 0.22 min-1 and 157.2 μmol•g-1 •h-1, which were 7.3 and 3.0 times higher than those of HRP, respectively. The promoted photocatalytic activity could be attributed to the formation of S-scheme heterojunctions, which accelerated the separation and transfer of useful photogenerated electron-hole pairs, while enhancing the recombination of relatively useless photogenerated electron-hole pairs, thereby resulting in the highest photocurrent density (17.3 μA/cm2) of the 5%Bi2O2CO3/HRP composite, which was 1.6 and 4.3 times higher than pure Bi2O2CO3 (10.5 μA/cm2) and pure HRP (4.0 μA/cm2), respectively. This work would provide an advanced approach to enhance the photocatalytic activity of RP.

Purpose Tumor-associated macrophages (TAMs) are known to contribute to adaptive resistance to anti-vascular endothelial growth factor (VEGF) antibody (AVA) therapy in ovarian cancer. BET (bromodomain and extra-terminal domain) inhibitors (BETi) may have unique roles in targeting TAMs. Our objective was to examine the effects of BETi on TAMs, especially in the context of enhancing the efficacy of AVA therapy. Methods We conducted a series of in vitro (MTT assay, apoptosis, flow cytometry, and RNA sequencing) and in vivo (xenograft ovarian cancer model) experiments to determine the biological effects of BETi combined with AVA in ovarian cancer. For statistical analysis, a two-tailed Student’s t test (equal variance) or ANOVA was used for multiple groups’ comparison, and p Results BETi resulted in a dose-dependent decrease in cell viability and induced apoptosis (p p p +/CD80+) was significantly increased after treatment with low-dose BETi (ABBV-075 0.1 µM; p +/CCR2+ macrophages was significantly decreased (p + macrophages and re-polarize the macrophages into an M1-like phenotype. RNA-seq analysis revealed that BETi selectively targeted macrophage infiltration-related cytokines/chemokines in ovarian cancer (adjusted p p p Conclusions Our findings indicate a previously unrecognized role for BETi in selectively targeting CCR2+ TAMs and enhancing the efficacy of AVA therapy in ovarian cancer.

In order to investigate the explosion mechanism of sucrose in the air atmosphere, the explosion intensity under different ignition delay times (IDT), powder input pressures (PIP), and concentrations were studied using a 20L-sphere. The sucrose particles were analyzed in a synchronized thermal analyzer (STA) and scanning electron microscope (SEM). The results are as follows: 1. The DSC curve has two endothermic peaks and one exothermic peak, respectively at T = 180.5 ℃, 510.2 ℃ and 582.6 ℃. 2. The explosion intensity varies with the experiment conditions. The maximum explosion pressure (Pmax) appears when IDT = 90 ms, PIP = 1.5 MPa and concentration = 625 g/m3. 3. The explosive mechanism is a homogeneous combustion mechanism based on particle surface pyrolysis and volatilization. Because of the decomposition, H2, CO, furfural, and other flammable gas-phase products are released, then surface burn appears, which leads to the crystal rupture on account of thermal imbalance, resulting in multiple flame points and a chain explosion. As the temperature of the 20L-sphere rises, more explosive products are released, which causes a rapidly expanding explosion and eventually forms the explosion. This paper can be used as a reference for the prevention of explosion accidents in sucrose production processing.

In order to mitigate the potential issue of abrupt water inrush in coal mining operations, the elastic-plastic mechanics theory was employed to simplify the water barrier of the floor strata into a thin rectangular plate. Subsequently, a fluid-solid coupling damage model was designed through the utilization of COMSOL Multiphysics software to investigate the coupled seepage and damage effects of the rock mass in an equivalent continuous medium. The results indicate that (1) the analysis of the theoretical equation of elastic mechanics shows that the fracture position of the four-sided clamped thin plate is in the center of the four sides, and the theoretical limit span and the theoretical limit water pressure formula are derived. (2) The damage factor is used to characterize the damaging effect of different mining distances and different pore water pressures on the rock mass of the floor aquiclude in the numerical simulation. It is found that the damage tends to the open-off cut and stop-mining line of the floor waterproof layer and the center position on both sides of the coal wall, and the stress is the most concentrated. (3) The results obtained by the two research methods are highly consistent, which provides a theoretical basis for the prevention and control of water in ground mining mines, so as to realize safe mining above the confined aquifer.

Tumor-associated macrophages (TAMs) are known to contribute to adaptive resistance to anti-vascular endothelial growth factor (VEGF) antibody (AVA) therapy in ovarian cancer. BET (bromodomain and extra-terminal domain) inhibitors (BETi) may have unique roles in targeting TAMs. Our objective was to examine the effects of BETi on TAMs, especially in the context of enhancing the efficacy of AVA therapy.We conducted a series of in vitro (MTT assay, apoptosis, flow cytometry, and RNA sequencing) and in vivo (xenograft ovarian cancer model) experiments to determine the biological effects of BETi combined with AVA in ovarian cancer. For statistical analysis, a two-tailed Student's t test (equal variance) or ANOVA was used for multiple groups' comparison, and p 0.05 was considered significant.BETi resulted in a dose-dependent decrease in cell viability and induced apoptosis (p 0.01) in ovarian cancer cells (SKOV3ip1, OVCAR5, and OVCAR8). Treatment with BETi significantly increased apoptosis in THP-1 monocytes and macrophages (PMA-differentiated THP-1; p 0.01). Furthermore, BETi selectively induced greater apoptosis in M2-like macrophages (PMA and IL-4, IL-13-differentiated THP-1) (31.3%-36.1%) than in M1-like macrophages (PMA and LPS-differentiated THP-1) (12.4%-18.5%) (p 0.01). Flow cytometry revealed that the percentage of M1-like macrophages (CD68Our findings indicate a previously unrecognized role for BETi in selectively targeting CCR2

Red phosphorus (RP) has a suitable energy band structure and excellent photocatalytic properties. However, there are some problems, such as low quantum efficiency and serious photogenerated electron-hole recombination. The S-scheme heterostructure shows great potential in facilitating the separation and transfer of photogenerated carriers and obtaining strong photo-redox ability. Herein, hydrothermally treated red phosphorus (HRP) was combined with Bi

Zearalenone (ZEN) is a kind of estrogen-like mycotoxin which contaminates primary crops and their products under natural conditions and becomes a serious hazard to human health. In this study, we prepared a sensitive and specific anti-ZEN monoclonal antibody (mAb) belonging to the IgG2b subclass, with a 50%-inhibitory concentration of 0.034 ng mL−1. A lateral flow fluorescence microsphere immunochromatographic test strip (FM-ICTS) for the rapid and ultrasensitive detection of zearalenone in corn and wheat samples was developed based on this mAb. After optimizing experimental parameters, the visual limit of detection (LOD) of the strip assay in both corn and wheat samples was 2.5 ng mL−1, and the cut-off value was 25 ng mL−1. The LOD was calculated to be 0.68 ng mL−1 in corn samples and 0.48 ng mL−1 in wheat samples. Recovery experiments showed that the test results of the strip were consistent with those of ic-ELISA. As a result, this FM-ICTS assay is reliable, simple and sensitive, and can be used for rapid detection of ZEN in corn and wheat.

BACKGROUND: Our pilot clinical study of EphA2 inhibitor (dasatinib) plus paclitaxel and carboplatin showed interesting clinical activity in endometrial cancer with manageable toxicity. However, the underlying mechanisms of dasatinib resistance in uterine cancer are unknown. Here, we investigated potential mechanisms underlying resistance to EphA2 inhibitors in uterine cancer and examined the anti-tumor activity of EphA2 inhibitors alone and in combination with a MEK inhibitor. METHODS: We evaluated the antitumor activity of EphA2 inhibitors plus a MEK inhibitor using in vitro and in vivo orthotopic models of uterine cancer. RESULTS: EphA2 inhibitor induced MAPK in dasatinib-resistant uterine cancer cells (HEC-1A and Ishikawa) and BRAF/CRAF heterodimerization in HEC-1A cells. EphA2 inhibitor and trametinib significantly increased apoptosis in cancer cells resistant to EphA2 inhibitors compared with controls (p

In this study, typical TC6 titanium alloy was taken to investigate the effects of multiple laser peening (LP) on the vibration fatigue properties and microstructural evolution. The vibration fatigue experiments were conducted, while the vibration fatigue life of the specimens before and after LP was compared and the fracture morphologies were observed by scanning electron microscopy (SEM). In addition, the measurements of residual stress and microhardness were carried out. The microstructures produced by different treatments were also characterized by transmission electron microscopy (TEM) and electron backscattered diffraction (EBSD). The experimental results indicated that multiple LP could indeed enhance the vibration fatigue properties of TC6 titanium alloy. Comparing with the investigated specimen without LP, the vibration fatigue life of the specimen subjected to 5 times LP increased by 105.2%. Meanwhile, after 5 times LP, the surface residual stress transformed from tensile stress (+26 MPa) to compressive stress (−485 MPa), and the surface microhardness was 428 HV, which increased by 32.9% compared with the untreated sample. Additionally, high-density of dislocation and deformation twin were also generated after multiple LP. The improvement of vibration fatigue properties was attributed to the rewarding compressive residual stress and the beneficial microstructural evolution induced by multiple LP.

OBJECTIVE: To determine the feasibility of pharmacologic beta-adrenergic blockade in women with newly diagnosed stage II-IV epithelial ovarian cancer (EOC) throughout primary treatment. METHODS: Patients initiated propranolol prior to beginning chemotherapy or surgery. Feasibility was assessed as proportion able to complete 6 chemotherapy cycles while on adrenergic suppression. Descriptive statistics summarized surveys, and paired changes were analyzed using signed rank tests. Random-intercept Tobit models examined immune response. RESULTS: Median age was 59.9; 88.5% were stage IIIC/IV; and 38.5% underwent primary debulking. Thirty-two patients were enrolled; 3 excluded because they never took propranolol; an additional 3 didn’t meet inclusion criteria, leaving 26 evaluable. Eighteen of 26 (69%), 90% credible interval (CI) of 53–81%, completed 6 chemotherapy cycles plus propranolol (an 82% posterior probability that the true proportion of success is ≥60%). Among the 23 patients with baseline and six month follow up data, overall QOL, anxiety, and depression improved (P

The tensile fatigue performance of 2024-T351 aluminum alloy processed by room temperature laser peening (RT-LP) and cryogenic laser peening (CLP) were explored. The nanoindentation measurement was performed. Scanning electron microscopic and transmission electron microscopic were used to inspect the microstructure evolution. Experimental results indicated that tensile fatigue life of the specimen subjected to CLP increased by 6.8% when compared with the RT-LP specimen. Additionally, CLP could induce finer grain and higher-density of dislocation structure, which have an important contribution to improving the nano-hardness and tensile fatigue properties of 2024-T351 aluminum alloy.

Objective To use gene chip technology to study the effects of evodiamine (EVO) on the gene expression profile of tongue squamous cell carcinoma (TSCC) CAL‐27 cell line, for the purpose of analyzing the mechanisms underlying the effects of EVO on gene expression and functional regulation of TSCC cells at the gene level. Method Differentially expressed genes in CAL‐27 cells treated with EVO were detected using gene chip technology and analyzed using ingenuity pathway analysis. Results Microarray results showed that there were 1243 differentially expressed genes following treatment with CAL‐27 cells; 684 genes were upregulated and 559 were downregulated. Classical pathway analysis revealed a total of 89 signal transduction pathways with upregulated gene set enrichment, including lipopolysaccharide/interleukin (IL)‐1‐mediated inhibition of retinoid X receptor (RXR) function, agrin interactions at neuromuscular junctions, cholecystokinin/gastrin‐mediated signaling, toll‐like receptor signaling, and IL‐6 signaling. A total of 39 signal transduction pathways were enriched for the downregulated genes, including interferon signals, liver X receptor/RXR activation signals, and RhoGDI signals. In the disease and function analysis, the upregulated genes were enriched in viral infection, RNA virus replication, viral replication, cancer cell invasion, cell invasion, and other related functions, while downregulated genes were enriched in neuromuscular diseases, and leukocyte differentiation, antiviral response, connective tissue cell death and other functions. Conclusions Gene chip analysis offers an effective means of screening differential gene expression between EVO‐treated TSCCs and controls, thus providing a sound basis for further research.

The aim of this study was to investigate the effects of laser peening (LP) on the friction and wear properties of medical Ti6Al4V alloy. Wear tests were conducted on the samples before and after LP with a ball-on-disk wear tester in Hank's solution. The surface roughness and micro-hardness of the differently treated samples were measured. The friction and wear properties of the samples were evaluated by comparing their coefficient of friction (COF) and wear mass loss. The morphologies of wear scar and the wear mechanism were characterized by optical microscope (OM), scanning electron microscope (SEM) and energy dispersive spectrometer (EDS). The results showed that the surface micro-hardness of the specimen subjected to LP was significantly increased by 25.7% and the corresponding depth of the hardened layer was more than 0.3 mm. The average COF and wear mass loss were significantly reduced to 50% and 29.2%, respectively, as a result of the increasing laser energy and impact times. After LP, the wear mechanism turned from the severe oxidative wear to a slight adhesive wear and abrasive wear. Experimental results proved that LP treatment could effectively improve the friction and wear properties of the medical Ti6Al4V alloy.

The microstructural response and tensile properties on 2024-T351 aluminum alloy specimens induced by cryogenic laser peening were investigated. The microstructure behaviors were characterized by transmission electron microscopic examination and electron backscattered diffraction analysis. Tensile properties tests at room temperature were also performed. The experimental results cleared that compared with room temperature laser peening, cryogenic laser peening can induce higher-density of dislocation and smaller-size grain, while the strength and plasticity of the processed 2024-T351 aluminum alloy were simultaneously increased. The analysis results suggested that the more excellent tensile properties were attributed to the more beneficial microstructural evolution induced by cryogenic laser peening.

The purpose of this study was to explore the effects of Cryogenic Laser Peening (CLP) on the high-temperature wear properties and microstructural response of 40CrNiMo structural steel. The high-temperature wear characteristics and the microhardness in depth direction were measured, as well as the worn surface morphologies were observed by Scanning Electron Microscopy (SEM), while the microstructure was also characterized by Transmission Electron Microscopy (TEM) observation. The experimental results cleared that CLP could effectively increase the microhardness, as well as a large number of twins, higher-density of dislocation structures and ultra-fine grains were produced by CLP, leading to a remarkable decrease of wear mass loss and thus an improved high-temperature wear resistance. Moreover, the microscopic strengthening mechanism of CLP was also analyzed in detail.

The aim of this study was to investigate the influence of the synergistic function of cryogenic temperature and ultrahigh strain rate deformation during the process of Cryogenic Laser Peening (CLP) on the mechanical properties and microstructural evolution of TC6 titanium alloy. The measurements of tensile properties at room and elevated temperatures, as well as micro-hardness on the cross-sectional direction were carried out. Meanwhile, the microstructural evolution was characterizated by Electron Backscattered Diffraction (EBSD) analysis and Transmission Electron Microscopy (TEM) observation. The experimental results demonstrated that cryogenic laser peening could significantly improve the strength and ductility, as well as the stability at elevated temperature condition of TC6 titanium alloy. At the same time, cryogenic laser peening could provide higher surface micro-hardness than room temperature laser peening (RT-LP), the surface micro-hardness of the specimen subjected to cryogenic laser peening increased by 4.86% than that of the specimen treated by room temperature laser peening. Additionally, cryogenic laser peening could generate finer grains and higher-density of dislocation structures, while large numbers of sub-grains and mechanical twins were also observed in the surface layer. Finally, the microscopic strengthening mechanism of cryogenic laser peening for better mechanical properties on TC6 titanium alloy was also analyzed in detail.

In this study, the mechanical properties and microstructural characteristics of TC6 titanium alloy subjected to Cryogenic Treatment (CT) prior to Laser Peening (LP) were experimentally investigated by means of x-ray diffraction (XRD) technology, Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM) observations. Surface micro-hardness and tensile tests were also carried out. Experimental results showed that in comparison to single CT or LP process, CT prior to LP can induce finer grain size and higher dislocation density. Meanwhile, CT prior to LP can provide better mechanical properties. The surface micro-hardness and tensile strength of the specimen subjected to LP after CT with 18 h achieved an increase with 28.11% and 28.71%, respectively, while its elongation only reduced by the extent of 4.19% compared with untreated sample. Meanwhile, in comparison to the process of single CT or LP, LP after CT with 18 h provided the maximum amplitude compressive residual stress and Full Width at Half Maximum (FWHM) values, the values reached to −633 MPa and 2.47°, respectively. Additionally, based on the experimental results, the microscopic strengthening mechanism of CT prior to LP on the mechanical properties of TC6 titanium alloy was analyzed in detail.

In this paper, we describe a comprehensive approach to pricing analytics for reusable resources in the context of rotable spare parts, which are parts that can be repeatedly repaired and resold. Working in collaboration with a major aircraft manufacturer, we aim to instill a new pricing culture and develop a scalable new pricing methodology. Pricing rotable spare parts presents unique challenges ranging from complex inventory dynamics and minimal demand information to limited data availability. We develop a novel pricing analytics approach that tackles all of these challenges and that can be applied across all rotable spare parts. We then describe a large-scale implementation of our approach with our industrial partner, which led to an improvement in profits of over 3.9% over a 10-month period.

Summary Chronic stress-related hormones modulate tumor pathogenesis at multiple levels; however, the molecular pathways involved in stress and cervical cancer progression are not well understood. We established a preclinical orthotopic mouse model of cervical cancer and used the model to show that daily restraint stress increased tumor growth and metastatic tumor burden. Exposure to norepinephrine significantly protected cervical cancer cells from anoikis. We demonstrated that YAP1 was dephosphorylated and translocated from the cytoplasm to the nucleus by norepinephrine, a process initiated by ADRB2/cAMP/protein kinase A activation. Furthermore, anoikis resistance and YAP1 activation induced by norepinephrine could be rescued by a broad β-adrenergic receptor antagonist, propranolol. Collectively, our results provide a pivotal molecular pathway for disrupting pro-tumor neuroendocrine signaling in cervical cancer., Highlights • Daily restraint stress increases tumor growth and metastatic tumor burden • Norepinephrine protects cervical cancer cells from anoikis • Norepinephrine induces YAP1 dephosphorylation and nuclear translocation • Norepinephrine - induced anoikis resistance can be reversed by propranolol, Biological Sciences; Cancer

The influence of cryogenic laser peening (CLP) on mechanical performance and microstructure of 2024-T351 aluminum alloy was explored. The microhardness, residual stress and tensile properties of the specimens processed by different treatments were tested, while the microstructural evolution was also characterized with electron backscattered diffraction (EBSD) analysis and transmission electron microscopy (TEM) observation. Experimental results revealed that cryogenic temperature could further improve the strengthening effect of laser peening (LP). Cryogenic treatment (CT) for 4 hrs followed by CLP could provide higher surface microhardness, compressive residual stress and tensile strength for the 2024-T351 aluminum alloy. Moreover, CLP induced higher dislocation density and smaller grain size for the 2024-T351 aluminum alloy. The strengthening mechanism was mainly due to the suppression of dynamic recovery and annihilation of dislocation structure caused by cryogenic temperature being conducive to promoting grain refinement.

Objectives To assess the tolerability and efficacy of bevacizumab with carboplatin and weekly paclitaxel as first-line adjuvant therapy for advanced stage ovarian cancer. Methods After IRB approval, this single-institution, phase II study enrolled patients with stage III or IV epithelial ovarian cancer after primary cytoreductive surgery to treatment with carboplatin (AUC 5), weekly paclitaxel (80mg/m2), and bevacizumab (15mg/kg) every 3weeks for at least 6cycles. The primary endpoint was tolerability of at least 4cycles of therapy, with a target treatment success rate of >60%. Secondary endpoints included progression-free survival (PFS) and response rate. Plasma biomarkers were analyzed by the multiplex ELISA assays. Results Thirty-three patients were enrolled with 30 evaluable patients receiving at least one cycle of combination treatment. Twenty-three patients (77%) were able to complete at least 4cycles of therapy per protocol, and the posterior probability that the treatment success rate is >60% is 0.77. Twenty-one patients (70%) were able to complete ≥6cycles of therapy. Median PFS was 22.4months for patients with optimal (R0) compared to 16.9months for optimal≤1cm (HR 1.71, 95% CI 0.58–4.98, p=0.33), and 16.9months for suboptimal>1cm (HR 3.75, 95% CI 1.05–13.34, p=0.04) disease. Increases in mean Flt-3L was significantly higher in responders versus non-responders (83.4 vs. 28pg/mL, p=0.05). Conclusions Adjuvant bevacizumab with dose-dense chemotherapy is associated with acceptable toxicity and a high likelihood of completing 4cycles of therapy. Dynamic changes in Flt-3L may represent a predictive marker to treatment response.

Although progesterone receptor (PR)–targeted therapies are modestly active in patients with uterine cancer, their underlying molecular mechanisms are not well understood. The clinical use of such therapies is limited because of the lack of biomarkers that predict response to PR agonists (progestins) or PR antagonists (onapristone). Thus, understanding the underlying molecular mechanisms of action will provide an advance in developing novel combination therapies for cancer patients. Nuclear translocation of PR has been reported to be ligand-dependent or -independent. Here, we identified that onapristone, a PR antagonist, inhibited nuclear translocation of ligand-dependent or -independent (EGF) phospho-PR (S294), whereas trametinib inhibited nuclear translocation of EGF-induced phospho-PR (S294). Using orthotopic mouse models of uterine cancer, we demonstrated that the combination of onapristone and trametinib results in superior antitumor effects in uterine cancer models compared with either monotherapy. These synergistic effects are, in part, mediated through inhibiting the nuclear translocation of EGF-induced PR phosphorylation in uterine cancer cells. Targeting MAPK-dependent PR activation with onapristone and trametinib significantly inhibited tumor growth in preclinical uterine cancer models and is worthy of further clinical investigation. Mol Cancer Ther; 17(2); 464–73. ©2017 AACR.

When designing a higher order output power filter for a transformerless grid-tied converter using pulsewidth modulation (PWM), the requirements on the leakage current, the electromagnetic interference (EMI) noise, and the harmonics of the grid-injected current should be addressed. For an LCL-filter-based single-phase grid-tied full-bridge inverter system, it is possible to decrease the total inductance as well as the size and the cost, if the harmonic currents around the switching frequency can be fully suppressed. In this paper, the grid-injected current harmonics and the conducted EMI noise are investigated for the conventional LCL-filter-based system. Based on this, a modified LCL-filter topology using an extra parallel LrCr resonant circuit is proposed to reduce the total inductance value, without increasing the capacitive reactive power. The validity is verified through the experiments on a 500-W 110-V/50-Hz prototype.

For a transformerless grid-tied converter using pulse width modulation, the harmonics of grid-injected current, the leakage current, and the electromagnetic interference (EMI) noise are three important issues during designing of the output filter. In this paper, the common mode and the differential mode EMI noises are investigated for the LCL- and LLCL-filter-based single-phase full-bridge grid-tied inverters. Based on this, a modified LLCL-filter topology is proposed to provide enough attenuation on the conducted EMI noise as well as to reduce the dc-side leakage current. The parameter design method of the filter is also developed. The comparative analysis and discussion on four filter cases (the conventional LCL filter, the conventional LLCL filter, the modified LCL filter, and the modified LLCL filter) are carried out and verified through simulations and experiments on a 0.5-kW, 110 V/50 Hz single-phase full-bridge grid-tied inverter prototype.

The Notch pathway plays an important role in the growth of high-grade serous ovarian (HGS-OvCa) and other cancers, but its clinical and biologic mechanisms are not well understood. Here, we found that the Notch pathway alterations are prevalent and significantly related to poor clinical outcome in patients with ovarian cancer. Particularly, Notch3 alterations, including amplification and upregulation, were highly associated with poor patient survival. Targeting Notch3 inhibited ovarian cancer growth and induced apoptosis. Importantly, we found that dynamin-mediated endocytosis was required for selectively activating Jagged-1–mediated Notch3 signaling. Cleaved Notch3 expression was the critical determinant of response to Notch-targeted therapy. Collectively, these data identify previously unknown mechanisms underlying Notch3 signaling and identify new, biomarker-driven approaches for therapy. Cancer Res; 74(12); 3282–93. ©2014 AACR.

Wnt/β-catenin signaling plays an essential role in colon carcinogenesis. Galectin-3, a β-galactoside–binding protein, has been implicated in Wnt signaling, but the precise mechanisms by which galectin-3 modulates the Wnt pathway are unknown. In the present study, we determined the effects of galectin-3 on the Wnt/β-catenin pathway in colon cancer cells, as well as the mechanisms involved. Galectin-3 levels were manipulated in human colon cancer cells by stable transfection of galectin-3 antisense, short hairpin RNA, or full-length galectin-3 cDNA, and effects on β-catenin levels, subcellular distribution, and Wnt signaling were determined. Galectin-3 levels correlated with β-catenin levels in a variety of colon cancer cell lines. Down-regulation of galectin-3 resulted in decreased β-catenin protein levels but no change in β-catenin mRNA levels, suggesting that galectin-3 modulates β-catenin by another mechanism. Reduction of galectin-3 led to reduced nuclear β-catenin with a concomitant decrease in TCF4 transcriptional activity and expression of its target genes. Conversely, transfection of galectin-3 cDNA into colon cancer cells increased β-catenin expression and TCF4 transcriptional activity. Down-regulation of galectin-3 resulted in AKT and glycogen synthase kinase-3β (GSK-3β) dephosphorylation and increased GSK activity, increasing β-catenin phosphorylation and degradation. Ly294002, an inhibitor of phosphatidylinositol 3-kinase, and dominant-negative AKT, suppressed TCF4 transcriptional activity induced by galectin-3 whereas LiCl, a GSK-3β inhibitor, increased TCF4 activity, mimicking the effects of galectin-3. These results suggest that galectin-3 mediates Wnt signaling, at least in part, by regulating GSK-3β phosphorylation and activity via the phosphatidylinositol 3-kinase/AKT pathway, and, thus, the degradation of β-catenin in colon cancer cells. [Cancer Res 2009;69(4):1343–9]

Cyclooxygenase-2 (COX-2) is a transcriptional target and downstream effector of the ErbB-1 (EGFR) and ErbB-2 signaling pathways. We found that anti-EGFR and anti-ErbB-2 antibodies inhibited ERK phosphorylation and downregulated COX-2 protein expression in HCA-7 human colon carcinoma cells. Both antibodies also augmented the cytotoxic effects of the selective COX-2 inhibitor, NS-398. Inhibition of EGFR and ErbB-2 attenuated cell growth by increasing cell death, and the antibody combination suppressed cell growth to a greater extent than did either antibody alone. In conclusion, EGFR and ErbB-2 regulate ERK-mediated COX-2 expression and their selective inhibition enhanced NS-398-induced cell death. Cooperative inhibition of cell growth by EGFR and ErbB-2 blockade suggests the therapeutic potential of targeting multiple ErbB receptors.