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Overlapped genes between Genes upregulated in Ptenpc-/-Smad4pc-/- tumors as compared to Ptenpc-/- tumors ({greater than or equal to}2 fold) and genes upregulated in GFP+ tumors cells from Ptenpc-/-Smad4pc-/- mice as compared to Tomato+ cells ({greater than or equal to}4 fold).

Oncogenic KRAS (KRAS*) is a key tumor maintenance gene in pancreatic ductal adenocarcinoma (PDAC), motivating pharmacologic targeting of KRAS* and its effectors. Here, we explored mechanisms involving the tumor microenvironment (TME) as a potential basis for resistance to targeting KRAS*. Using the inducible KrasG12D;Trp53−/− PDAC mouse model, gain-of-function screens of epigenetic regulators identified HDAC5 as the top hit enabling KRAS* independent tumor growth. HDAC5-driven escaper tumors showed a prominent neutrophil-to-macrophage switch relative to KRAS*-driven tumors. Mechanistically, HDAC5 represses Socs3, a negative regulator of chemokine CCL2, resulting in increased CCL2, which recruits CCR2+ macrophages. Correspondingly, enforced Ccl2 promotes macrophage recruitment into the TME and enables tumor recurrence following KRAS* extinction. These tumor-associated macrophages in turn provide cancer cells with trophic support including TGFβ to enable KRAS* bypass in a SMAD4-dependent manner. Our work uncovers a KRAS* resistance mechanism involving immune cell remodeling of the PDAC TME.Significance:Although KRAS* is required for PDAC tumor maintenance, tumors can recur following KRAS* extinction. The capacity of PDAC cancer cells to alter the TME myeloid cell composition to support KRAS*-independent tumor growth illuminates novel therapeutic targets that may enhance the effectiveness of therapies targeting KRAS* and its pathway components.See related commentary by Carr and Fernandez-Zapico, p. 910.This article is highlighted in the In This Issue feature, p. 890

shRNA and sgRNA information

Supplementary Figure S1. CyTOF analysis of biological samples from Ptenpc-/-Smad4pc-/- mice (Related to Figure 2). Supplementary Figure S2. Strategy used for MDSCs Isolation (Related to Figure 3). Supplementary Figure S3. Treatment scheme for Gr-1 antibody, peptibody, and Cxcr2 inhibitor SB225002. Supplementary Figure S4. IHC staining of Ki67, CD45, Vimentin, Smooth muscle actin (SMA) and Trichrome staining of mouse prostate tissues treated with IgG control or Gr1 antibody. Supplementary Figure S5. The top 10 differentially expressed genes in Ptenpc-/-Smad4pc-/- tumors as compared to Ptenpc-/- tumors, identified by microarray analysis (n=5). Figure S6. Top 10 activated oncogenic signatures identified by GSEA analysis in Ptenpc-/- Smad4pc-/- tumors as compared to Ptenpc-/- tumors (n=5). Figure S7. Clustering of primary prostate tumors from Wallace et al into MDSC-high and MDSC-low subtypes.

Purpose The purpose of this study is to prepare a robust superhydrophobic coating on concrete substrate with remarkable chemical and mechanical durability through “all-covalent” strategy. Design/methodology/approach Amino-modified silica nano/micro-particles were prepared through two synthetic steps. “All-covalent” strategy was introduced to prepare a robust superhydrophobic coating on concrete surface via a “all-in-one” dispersion and a simple spraying method. The successful construction of the products was confirmed by Fourier transform infrared spectroscopy, water contact angles (WCA), X-ray photoelectron spectroscopy (XPS) and scanning electron microscope (SEM). The concrete protective properties were verified by solution immersion test, pull-off test and rapid chloride migration coefficient test. The mechanical durability was tested by falling sand impact. Findings Hierarchical structures combined with the low-surface-energy segments lead to typically superhydrophobic coating with a WCA of 156° and a sliding angle of 1.3°. The superhydrophobic coating prepared through “all-covalent” strategy not only improves chemical and mechanical durability but also achieves higher corrosion and wear resistance than the comparison sample prepared by physically blending strategy. More importantly, the robust superhydrophobic coating showed excellent adhesion and protective performance of concrete engineerings. Practical implications This new “all-covalent” superhydrophobic coating could be applied as a concrete protective layer with properties of self-cleaning, anti-graffiti, etc. Originality/value Introduction of both silica nanoparticles and silica microparticles to prepare a robust superhydrophobic coating on concrete surface through “all-covalent” strategy has not been systematically studied previously.

Aberrant activation of KRAS signaling is common in cancer, which has catalyzed heroic drug development efforts to target KRAS directly or its downstream signaling effectors. Recent works have yielded novel small molecule drugs with promising preclinical and clinical activities. Yet, no matter how a cancer is addicted to a specific target - cancer's genetic and biological plasticity fashions a variety of resistance mechanisms as a fait accompli, limiting clinical benefit of targeted interventions. Knowledge of these mechanisms may inform combination strategies to attack both oncogenic KRAS and subsequent bypass mechanisms.

Pancreatic ductal adenocarcinoma (PDAC) is considered ‘non-immunogenic’ with trials demonstrating its recalcitrance to PD1 and CTLA4 immune checkpoint therapies (ICTs). Here, we sought to systematically characterize the mechanisms underlying de novo ICT resistance and identify effective therapeutic options for PDAC. We report that agonist 41BB and antagonist LAG3 ICT alone and in combination, increased survival and anti-tumor immunity, characterized by modulating T cell subsets with anti-tumor activity, increased T cell clonality and diversification, decreased immunosuppressive myeloid cells and increased antigen presentation/decreased immunosuppressive capability of myeloid cells. Translational analyses confirmed the presence of 41BB and LAG3 in human PDAC. Since single and dual ICTs were not curative, T cell-activating ICTs were combined with a CXCR1/2 inhibitor, targeting immunosuppressive myeloid cells. Triple therapy resulted in durable complete responses. Given similar profiles in human PDAC and availability of these agents for clinical testing, our findings provide a testable hypothesis for this lethal disease.

Activating mutations in KRAS (KRAS*) are present in nearly all pancreatic ductal adenocarcinoma (PDAC) cases and critical for tumor maintenance. By using an inducible KRAS* PDAC mouse model, we identified a deubiquitinase USP21-driven resistance mechanism to anti-KRAS* therapy. USP21 promotes KRAS*-independent tumor growth via its regulation of MARK3-induced macropinocytosis, which serves to maintain intracellular amino acid levels for anabolic growth. The USP21-mediated KRAS* bypass, coupled with the frequent amplification of USP21 in human PDAC tumors, encourages the assessment of USP21 as a novel drug target as well as a potential parameter that may affect responsiveness to emergent anti-KRAS* therapy.

Yes-associated protein 1 (YAP1), a key player in the Hippo pathway, has been shown to play a critical role in tumor progression. However, the role of YAP1 in prostate cancer cell invasion, migration, and metastasis is not well defined. Through functional, transcriptomic, epigenomic, and proteomic analyses, we showed that prolyl hydroxylation of YAP1 plays a critical role in the suppression of cell migration, invasion, and metastasis in prostate cancer. Knockdown (KD) or knockout (KO) of YAP1 led to an increase in cell migration, invasion, and metastasis in prostate cancer cells. Microarray analysis showed that the EMT pathway was activated in Yap1-KD cells. ChIP-seq analysis showed that YAP1 target genes are enriched in pathways regulating cell migration. Mass spectrometry analysis identified P4H prolyl hydroxylase in the YAP1 complex and YAP1 was hydroxylated at multiple proline residues. Proline-to-alanine mutations of YAP1 isoform 3 identified proline 174 as a critical residue, and its hydroxylation suppressed cell migration, invasion, and metastasis. KO of P4ha2 led to an increase in cell migration and invasion, which was reversed upon Yap1 KD. Our study identified a novel regulatory mechanism of YAP1 by which P4HA2-dependent prolyl hydroxylation of YAP1 determines its transcriptional activities and its function in prostate cancer metastasis.

Purpose The purpose of this study is to prepare a chemically stable superhydrophobic coating with remarkable mechanical properties and concrete protective properties. Design/methodology/approach One synthetic step was adopted to prepare superhydrophobic coating. The process and product were analyzed and confirmed by fourier transform-infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA), water contact angle (WCA), transmission electron microscopy (TEM), scanning electron microscope (SEM), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS). The mechanical properties were confirmed by tensile test. The concrete protective properties were confirmed by solution immersion test and rapid chloride migration coefficient test. Findings MSiO2 nanoparticles (NPs) were chosen to enhance the hydrophobicity of fluorosilicone coatings. With a 4:1 mass ratio of fluorosilicone resin and MSiO2 NPs, the coatings show superhydrophobicity with a WCA of 156° and a SA of 3.1°. In addition, the tensile mechanical property was improved, and the chloride ion diffusion coefficient was decreased significantly after the addition of MSiO2 NPs. Practical implications This new fluorosilicone coating hybrid by MSiO2 NPs could be applied as a concrete protective layer with properties of self-cleaning, antifouling, etc. Originality/value Introduction of MSiO2 NPs hybrid to prepare fluorosilicone coating with superhydrophobicity on concrete surface has not been systematically studied previously.

A series of catechol-modified epoxy resin biomimetic coatings (CE-X, X represents the weight fraction of catechol-modified epoxy resin, X = 0, 5%, 10%, 15%, 20%, 25%) with high adhesive strength on saturated concrete substrate were designed and synthesized. The chemical structures of the CE-X were confirmed by proton nuclear magnetic resonance (1H NMR), carbon-13 nuclear magnetic resonance spectroscopy (13C NMR), and Fourier transform infrared spectroscopy (FTIR). The thermal property of CE-X was characterized by thermogravimetric analysis (TGA). The adhesive properties were characterized by pull-off tests. Results showed that when the content of catechol–epoxy resin was under 20% by weight, the adhesive strength could be further increased by forming hydrogen bonds and coordination complexes in the interface of coating and saturated concrete of the substrate. When the content of catechol–epoxy resin was above 20% by weight, the pull-off tests showed cohesive failure, and the adhesive strength on saturated concrete substrate reached the maximum value of 4.61 ± 0.8 MPa, which was improved by ~ 3 MPa compared to that of the control sample. The adhesive properties of epoxy coatings on saturated concrete substrate could be improved by adding a proper amount of catechol groups. In addition, when it was immersed in water for 30 and 120 days, its adhesive strength was reduced by about 7.8% and 22%, respectively. This work provides a new method for designing and synthesizing protective coatings with high adhesive strength on the saturated concrete substrate.

Purpose The purpose of this study is to prepare a polydopamine (PDA)–palygorskite (Pal) hybrid-reinforced epoxy coating with high adhesion strength on wet concrete surface. Design/methodology/approach One synthetic step was adopted to prepare novel PDA–Pal hybrid epoxy coating. The process and product were analyzed and confirmed by FIRT, thermogravimetric analysis and scanning electron microscopy. The mass fraction of PDA–Pal hybrid affecting the adhesion strength of epoxy coating was analyzed and confirmed by pull-off test. Findings PDA–Pal hybrid mass fractions of 0, 1, 3 and 5 were added to the coatings. For a 5 Wt.% PDA–Pal hybrid content, the adhesive strengths on the saturated or underwater concrete surfaces increased to 4.0 and 2.5 MPa, respectively. In addition, the tensile mechanical property of the epoxy coating improved significantly after PDA–Pal addition. Practical implications This new epoxy coating hybrid by PDA–Pal could be applied as a concrete protective layer near water or in wet or damp environments. Originality/value Introduction of PDA–Pal hybrid to prepare epoxy coating with high adhesion strength on wet concrete surface has not been systematically studied previously.

Oncogenic KRAS (KRAS*) is a key tumor maintenance gene in pancreatic ductal adenocarcinoma (PDAC), motivating pharmacologic targeting of KRAS* and its effectors. Here, we explored mechanisms involving the tumor microenvironment (TME) as a potential basis for resistance to targeting KRAS*. Using the inducible KrasG12D;Trp53−/− PDAC mouse model, gain-of-function screens of epigenetic regulators identified HDAC5 as the top hit enabling KRAS* independent tumor growth. HDAC5-driven escaper tumors showed a prominent neutrophil-to-macrophage switch relative to KRAS*-driven tumors. Mechanistically, HDAC5 represses Socs3, a negative regulator of chemokine CCL2, resulting in increased CCL2, which recruits CCR2+ macrophages. Correspondingly, enforced Ccl2 promotes macrophage recruitment into the TME and enables tumor recurrence following KRAS* extinction. These tumor-associated macrophages in turn provide cancer cells with trophic support including TGFβ to enable KRAS* bypass in a SMAD4-dependent manner. Our work uncovers a KRAS* resistance mechanism involving immune cell remodeling of the PDAC TME. Significance: Although KRAS* is required for PDAC tumor maintenance, tumors can recur following KRAS* extinction. The capacity of PDAC cancer cells to alter the TME myeloid cell composition to support KRAS*-independent tumor growth illuminates novel therapeutic targets that may enhance the effectiveness of therapies targeting KRAS* and its pathway components. See related commentary by Carr and Fernandez-Zapico, p. 910. This article is highlighted in the In This Issue feature, p. 890

The rotational speed is a crucial parameter for bearing condition monitor. The present study shows the influence of the rotational speed on the impact characteristics caused by a localized defect of the outer raceway. A 2 Nb + 5-degrees-of-freedom nonlinear dynamic model for a ball bearing is developed. The waviness of bearing components, a localized defect of the outer raceway, and the centrifugal forces of balls caused by rotational speed are involved in the ball bearing model. Spectral kurtosis (SK) analysis and envelope spectrum analysis are used to extract the impact signal and confirm the position of the optimal frequency band affected by the impact signal. The peak of the impact signal rises with the increase in rotational speed. The position of the optimal frequency band affected by the impact signal is a linear piecewise function of the rotational speed. These simulated results are verified through vibration experiments of a ball bearing with a localized defect of the outer raceway under an axial load. In addition, considering both a localized defect on the outer raceway and the waviness of bearing components, only when the size of the localized defect is large enough, can the impact signal overcome the influence of the structural vibration of the system to extract impact characteristics. The case studies of high-speed spindle bearing state diagnosis show that high speed is not conducive to the extraction of the impact characteristics.

The ubiquitin-specific protease (USP) family is the largest group of cysteine proteases. Cancer genomic analysis identified frequent amplification of USP21 (22%) in human pancreatic ductal adenocarcinoma (PDAC). USP21 overexpression correlates with human PDAC progression, and enforced expression of USP21 accelerates murine PDAC tumor growth and drives PanIN to PDAC progression in immortalized human pancreatic ductal cells. Conversely, depletion of USP21 impairs PDAC tumor growth. Mechanistically, USP21 deubiquitinates and stabilizes the TCF/LEF transcription factor TCF7, which promotes cancer cell stemness. Our work identifies and validates USP21 as a PDAC oncogene, providing a potential druggable target for this intractable disease.

This study examined the effects of emotional intelligence and emotional labor on job satisfaction in a moderated mediation model, which posits surface and deep acting strategies as mediators between emotional intelligence and job satisfaction and perceived organizational support as a moderator to the mediation effects. Based on a sample of 279 Chinese hotel employees, results showed that: 1) while deep acting partially mediated the effect of emotional intelligence on job satisfaction, surface acting did not mediate; 2) Perceived organizational support effectively moderated the mediation of deep acting between emotional intelligence and job satisfaction; but the moderated mediation was not found with surface acting as a mediator. This study contributes to a better understanding of the roles of emotional intelligence and emotional labor strategies in affecting hotel employees’ job satisfaction and how organizational support can function as an organization resource in changing the psychological mechanisms underlying emotional labor and job satisfaction.

Pancreatic ductal adenocarcinoma (PDAC) remains recalcitrant to all forms of cancer treatment and carries a five-year survival rate of only 8%1. Inhibition of oncogenic KRAS (hereafter KRAS*), the earliest lesion in disease development that is present in more than 90% of PDACs, and its signalling surrogates has yielded encouraging preclinical results with experimental agents2–4. However, KRAS*-independent disease recurrence following genetic extinction of Kras* in mouse models anticipates the need for co-extinction strategies5,6. Multiple oncogenic processes are initiated at the cell surface, where KRAS* physically and functionally interacts to direct signalling that is essential for malignant transformation and tumour maintenance. Insights into the complexity of the functional cell-surface-protein repertoire (surfaceome) have been technologically limited until recently and—in the case of PDAC—the genetic control of the function and composition of the PDAC surfaceome in the context of KRAS* signalling remains largely unknown. Here we develop an unbiased, functional target-discovery platform to query KRAS*-dependent changes of the PDAC surfaceome, which reveals syndecan 1 (SDC1, also known as CD138) as a protein that is upregulated at the cell surface by KRAS*. Localization of SDC1 at the cell surface—where it regulates macropinocytosis, an essential metabolic pathway that fuels PDAC cell growth—is essential for disease maintenance and progression. Thus, our study forges a mechanistic link between KRAS* signalling and a targetable molecule driving nutrient salvage pathways in PDAC and validates oncogene-driven surfaceome annotation as a strategy to identify cancer-specific vulnerabilities. In an inducible mouse model of pancreatic ductal adenocarcinoma, the signalling defect that underlies 90% of these tumours causes increased cell-surface expression of syndecan 1, leading to misregulation of macropinocytosis, and linking the defective signalling with nutrient-salvage pathways.

With the advent of China’s aging society, the elderly have become an important force in tourism activities and tourism consumption. Senior tourism has gradually become the focus of social attention...

Germline telomere maintenance defects are associated with an increased incidence of inflammatory diseases in humans, yet whether and how telomere dysfunction causes inflammation are not known. Here, we show that telomere dysfunction drives pATM/c-ABL-mediated activation of the YAP1 transcription factor, up-regulating the major pro-inflammatory factor, pro-IL-18. The colonic microbiome stimulates cytosolic receptors activating caspase-1 which cleaves pro-IL-18 into mature IL-18, leading to recruitment of interferon (IFN)-γ-secreting T cells and intestinal inflammation. Correspondingly, patients with germline telomere maintenance defects exhibit DNA damage (γH2AX) signaling together with elevated YAP1 and IL-18 expression. In mice with telomere dysfunction, telomerase reactivation in the intestinal epithelium or pharmacological inhibition of ATM, YAP1, or caspase-1 as well as antibiotic treatment, dramatically reduces IL-18 and intestinal inflammation. Thus, telomere dysfunction-induced activation of the ATM-YAP1-pro-IL-18 pathway in epithelium is a key instigator of tissue inflammation., How telomere dysfunction is directly linked to inflammation in humans is currently unclear. Here the authors reveal that telomere dysfunction drives activation of the YAP1 transcription factor, up-regulating the pro inflammatory factor, pro-IL-18 thus revealing a link between telomere dysfunction and initiation of intestinal inflammation.

A kind of SiO2/Diatomite/PDMS/KH-570/Me-MQ composite superhydrophobic self-cleaning building coating material was successfully synthesised at room temperature. Without any subsequent heat treatment process, the coating can be prepared by spraying or brushing on smooth internal wall and rough external wall of building with a water contact angle (WCA) larger than 160o and a sliding angle (SA) less than 1.5o. The coating can maintain excellent superhydrophobic and self-cleaning properties after various tests including sand impact, sandpaper abrasion, acid/alkali solution immersion, water impact and outdoor weatherability test. Moreover, after 0.5 h impact by pH 4 methyl blue solution, the superhydrophobic performance of the coating still keep excellent and indicates that the coating can withstand a certain degree of acid rain impact. Futhermore, the coating also can be brushed or sprayed on various smooth, rough, hard or soft substrates, and they all can exhibit excellent superhydrophobic performance. It is reasonable to believe that such superhydrophobic coating material has a good practical application potential in building self-cleaning and antifouling.

In this work, N-doped TiO2 hierarchical microspheres were prepared by a hydrothermal process for high performance supercapacitor. This structured microsphere can provide a large specific surface area and a suitable pore size, which is conducive to electrolyte infiltration, and the nitrogen doping can improve the electrical properties of intrinsic TiO2. Combining these two strategies, the specific capacitance of N-doped TiO2 microspheres increases from 2.26 to 11.89 mF/cm2 at current density of 1 mA/cm2 and the capacitance remains 90.5% of the original capacity after 10,000 cycles.

Purpose This study mainly aims to examine the mediating effect of perceived organizational support (POS) and the moderating effect of locus of control and job autonomy on the relationship between customer mistreatment behavior and organizational citizenship behavior. Design/methodology/approach Through a questionnaire survey of 231 employees and their direct supervisors of five hotels in Guangzhou. This paper analyzed five variables (customer mistreatment, POS, locus of control, job autonomy and organizational citizenship behavior) relationships through a variety of data analysis. Findings Results indicate that customer mistreatment behavior has a negative effect on employees’ organizational citizenship behavior. The relationship between customer mistreatment behavior and employees’ organizational citizenship behavior is partially mediated by employees’ POS. Staffs’ locus of control and job autonomy can modulate the relationship between customers’ mistreatment behavior and POS. Furthermore, the indirect mediating effect of POS on customer mistreatment behavior is revealed. The organizational citizenship behavior linkage is significant only to staff who perceived they have a high level of job autonomy and a high locus of control. Practical implications Hotels are advised to provide organizational support and the management of customer mistreatment behavior so as to reflect their employees’ value, seek service innovation and promote production efficiency in practice. Furthermore, it maintains and promotes operational efficiency for service organizations and means the organization pays more attention to meet the social, emotional and psychological needs of its employees. Originality/value This article reveals the mechanism relationship between customer mistreatment behavior and employee organizational citizenship behavior. First, it defines the concept of customer mistreatment in the hotel industry and enriches the related research. Second, the study, from the perspective of customer mistreatment, has opened up a new view of organizational citizenship behavior research. Third, we built a research model and it is helpful to grasp the inner mechanism between customer mistreatment and employees’ organizational citizenship behavior. Fourth, this research benefits service organizations so as to maintain and improve their operation efficiency. Furthermore, it can have theoretical guidance for service-oriented organizations to develop a harmonious consumption culture and organizational culture.

The signaling mechanisms between prostate cancer cells and infiltrating immune cells may illuminate novel therapeutic approaches. Here, utilizing a prostate adenocarcinoma model driven by loss of Pten and Smad4, we identify polymorphonuclear myeloid-derived suppressor cells (MDSC) as the major infiltrating immune cell type, and depletion of MDSCs blocks progression. Employing a novel dual reporter prostate cancer model, epithelial and stromal transcriptomic profiling identified CXCL5 as a cancer-secreted chemokine to attract CXCR2-expressing MDSCs, and, correspondingly, pharmacologic inhibition of CXCR2 impeded tumor progression. Integrated analyses identified hyperactivated Hippo–YAP signaling in driving CXCL5 upregulation in cancer cells through the YAP–TEAD complex and promoting MDSC recruitment. Clinicopathologic studies reveal upregulation and activation of YAP1 in a subset of human prostate tumors, and the YAP1 signature is enriched in primary prostate tumor samples with stronger expression of MDSC-relevant genes. Together, YAP-driven MDSC recruitment via heterotypic CXCL5–CXCR2 signaling reveals an effective therapeutic strategy for advanced prostate cancer. Significance: We demonstrate a critical role of MDSCs in prostate tumor progression and discover a cancer cell nonautonomous function of the Hippo–YAP pathway in regulation of CXCL5, a ligand for CXCR2-expressing MDSCs. Pharmacologic elimination of MDSCs or blocking the heterotypic CXCL5–CXCR2 signaling circuit elicits robust antitumor responses and prolongs survival. Cancer Discov; 6(1); 80–95. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 1

Cracking of thin hard films on ductile substrates under indentation was investigated considering the effects of interfacial delamination. The fracture behavior of the film was analyzed using the extended finite element method (XFEM), and the evolution of the interfacial delamination was simulated using a cohesive zone model (CZM). Results showed that at the location within the contact area, interfacial delamination hastened the cracking at the bottom surface of the film because of the enhancement of the film stretching. However, at the location outside the contact area, the cracking on the top surface of the film was postponed by the interfacial delamination due to the reduction in the film bending. The interfacial strength and toughness had significant effects on the delamination evolution at film/substrate interfaces, and therefore strongly affected the cracking behavior of thin hard films.

The surface damage of M50 steel at impact-sliding contacts was investigated considering thermal effects of materials. The mechanical response and thermal response of materials were analyzed using the thermo-elasto-plastic finite element method. The heat dissipation resulting from the frictional work and plastic deformation work were determined and the effects of impact and sliding velocities were discussed. The results indicated that at low impact and sliding velocities, the temperature rise resulted primarily from the frictional work, leading to thermal softening of the near-surface material. At high impact and sliding velocities, the material underwent high-strain-rate plastic deformation. Consequently, the temperature increased further due to the heat of strain energy dissipation, which promoted thermal softening and led to surface damage of M50 steel.

Many common instigators drive the processes of inflammation and carcinogenesis. We have found such a common node in Yap1. In the context of cancer, YAP-TEAD complex is important in modulating the immune microenvironment, such that Yap 1-mediated transcriptional upregulation of CXCL5 by the prostate cancer cells in a PTEN/SMAD4 deficient mouse model leads to the recruitment of MDSCs through the interaction with CXCR2 on them. Depletion of MDSCs or pharmacologic inhibition of CXCR2 leads to impediment of cancer progression. In another well-established pancreatic cancer model (PDAC), Yap1/Tead2 governs escape from mutant Kras (G12D) inhibition through cooperative upregulation of E2F transcription factors to activate a cell cycle and DNA replication program. In the context of inflammation, specifically inflammatory bowel disease, telomere dysfunction is shown to activate pAtm/c-Abl-mediated phosphorylation and stabilization of Yap1 upregulating pro-IL-18, a major proinflammatory factor in IBD. This signaling axis cooperates with the gut microbiome stimulating cytosolic receptors causing activation of caspase-1 cleaving pro-IL-18 into mature IL-18. Epithelial IL-18 leads to recruitment of IFNγ-secreting T cells and other immunocytes provoking classical IBD pathology. Consistent with a role for DNA damage signaling driving IBD, newly diagnosed IBD patient samples exhibited elevated expression of pγH2AX, YAP1, Caspase-1, and IL-18 and significantly reduced telomere lengths. Telomerase reactivation in intestinal epithelium or pharmacologic inhibition of Atm, Yap1, or caspase-1 as well as antibiotic treatment of mice dramatically reduced IL-18 and inflammation. Thus, telomere dysfunction-induced activation of the Atm-Yap1-pro-IL-18 pathway identifies DNA damage signaling as a key instigator and promoter of IBD, illuminating novel therapeutic strategies. Citation Format: Guocan Wang, Xin Lu, Deepavali Chakravarti, Avnish Kapoor, Wantong Yao, Haoqiang Ying, Prasenjit Dey, Chiachin Wu, Denise Spring, Pingping Hou, Pingna Deng, Di Zhao, Baoli Hu, Mao Xizeng, Christopher Logothesis, Michael McArthur, Lynda Chin, Alan Wang, Sujun Hua, Hongai Xia, Gerald C Chu, Carol Lim, Eduardo Vilar, Sarah Blutt, Ronald A. DePinho. YAP in cancer and inflammation [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr IA24.

Fracture behaviors of thin hard diamond-like carbon (DLC) films were investigated considering the effects of plastic deformation of steel substrates. Nano-indentation tests for DLC films on SUS304 and M50 steels were conducted. The nucleation and propagation of film cracks were analyzed using the extended finite element method (XFEM). The ultimate tensile strength, fracture energy release rate and toughness of the films were evaluated. Results showed that cracks in DLC films on M50 steel substrates nucleated on the top surface of the films during nano-indentation; however, the first crack initiated at the bottom surface of DLC films on SUS304 steel because of its low yield strength. Large plastic deformation of the steel substrate was generated under nano-indentation, leading to consequent high tensile stress that concentrated first at the bottom surface of the films due to the film bending effect.

This presentation will highlight our use of mouse models to dissect molecular and cellular interactions in the tumor microenvironment, including (i) the illumination of the role of myeloid cells in driving immune suppression in prostate cancer, and the impact of combined MDSC-targeted and immune checkpoint blockade therapies in the treatment of metastatic castration-resistant prostate cancer; (ii) the generation and analysis of oncogenic Kras in an inducible colorectal cancer mouse model, revealing the role of IRF2 in the recruitment of myeloid cells into the tumor microenvironment and informing patient selection for more effective ICB therapy in CRC; (iii) the concept of “synthetic essentiality” (a means by which to target specific tumor-suppressor gene deficiencies in cancer), exemplified by the identification of the role of CHD1 in modulation of the tumor microenvironment in Pten-deficient prostate cancer; (iv) the discovery of a symbiotic interaction between glioma cell (LOX) and macrophage (SPP1) in PTEN-null glioma, as well as macrophage reprogramming in immune suppression in glioblastoma; and (v) the role of KRAS in cancer metabolism, in particular how the tumor microenvironment may support KRAS-directed cancer cell metabolism and provide a nonautonomous mechanism enabling escape from Kras-dependent tumor growth. These illustrative examples provide translational opportunities to improve cancer patient treatment and survival. Citation Format: Adam Boutin, Peiwen Chen, Prasenjit Dey, Pingping Hou, Wen-Ting Liao, Xin Lu, Haoqiang Ying, Di Zhao, Ronald A. DePinho. Modeling and understanding tumor biologic mechanisms [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA01.

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer deaths, with an estimated 44,330 deaths per year in the United States alone. Deubiquitinases play fundamental roles in maintenance of cellular homeostasis, and deregulation of ubiquitin-specific proteases (USPs), the largest group of deubiquitinases, has been reported in multiple cancer types. In particular, we found that USP21 is amplified in 22% of PDAC cases in the patient dataset from the University of Texas Southwestern Medical Center, and it is the most frequently deregulated USP. However, little is known about the role of USP21 in PDAC. To examine biologic function of USP21 amplification in PDAC, we employed a novel “iKPC” mouse model, harboring tetO-LSL-KrasG12D (a transgenic allele with doxycycline-controlled tet-ON system regulating transcriptionally activated KRASG12D), ROSA26-LSL-rtTA, p53L/+ and p48Cre. We induced overexpression of USP21 in PDAC cells isolated from iKPC mice and found that USP21 promotes iKPC pancreatic tumor growth in vivo and drives KRAS-independent pancreatic tumor growth after blockage of KRAS expression. USP21 has a nuclear export signal and shuttles between the nucleus and cytoplasm. By modulating its subcellular localization, we discovered different functions of USP21 in supporting pancreatic cancer growth. Specifically, the nuclear function of USP21 supports pancreatic tumor growth by increasing tumor cell stemness via enhanced activation of the Wnt/beta-catenin signaling pathway. We showed that USP21 directly regulates proteasome pathway-dependent degradation of TCF7 protein. The cytoplasmic function of USP21 stimulates tumor cells to bypass KRAS extinction via MARK3, which phosphorylated its substrates and blocked their function by generating 14-3-3 binding sites. We found that MARK3 interacts with and is deubiquitinated by USP21. Knockdown of Ptpn3, a reported substrate of MARK3, increased protein level of PDGFRA, overexpression of which bypassed KRAS extinction. Moreover, we showed that inhibition of PDGF receptor pathway impairs KRAS-independent PDAC tumor growth driven by USP21 in vivo. Thus, our work demonstrated distinct oncogenic functions of USP21 in the presence and absence of KRAS signaling in PDAC, suggesting that KRAS-mutant PDAC patients with USP21 amplification may become resistant to KRAS inhibition. Citation Format: Pingping Hou, Xingdi Ma, Jeffery Ackroyd, Jianhua Zhang, Shan Jiang, Alan Y. Wang, Ronald A. DePinho. USP21 promotes stemness of pancreatic cancer cells and bypass of KRAS extinction [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr A28.

Hydrogenated amorphous silicon carbon nitride (a-Si-C-N:H) films embedded with carbon nanoclusters were deposited by plasma enhanced chemical vapour deposition (PECVD) method. The microstructure and oxidation properties of the films were mainly analysed by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), X-ray photoelectroscopy (XPS), Raman and high-resolution transmission electron microscopy (HRTEM). The influence of the NH3 flow rate on the film oxidation properties in air at room temperature has been investigated. The results showed that the carbon atoms tend to bond with each other during the film deposition and then form carbon nanoclusters. In addition, with increasing NH3 flow rate, the results also indicated that more N and C atoms bonded with Si atoms would be replaced by O atoms, and the N atoms mainly bonded with C atoms and the O atoms mainly bonded with Si atoms. Furthermore, the films became more and more dense, but the film oxidation was more and more serious. The oxidation of the film was mainly attributed to the production of the related silicon dangling bonds and the formation of the smaller carbon nanoclusters.

Tourism Industry Cluster can adjust the structure of the tourism industry to achieve coordinated development of tourism in the development of the tourism industry. The cultivation of tourism industrial cluster is an effective regional tourism development strategy and effective way to improve the competitiveness of the regional tourism economy. The literature of governance and upgrading of tourism industry cluster is less. This study based on the value chain theory to explore the governance mechanism and countermeasures of local tourism industry cluster. This research used value chain management analysis framework of Kolinsky and Morris (2000) and put forward the supervision system of government legislation, internal governance and industry association in the value chain. This paper researches the local tourism industry cluster from three aspects of business, government and industry associations.

Tourism is one of the pillar industries in Hong Kong and Taiwan; they have accumulated a set of more perfect and mature management system in travel agency and operation mechanism. The current development of China’s travel industry still has a lot of room for improvement. Referencing and learning travel agency industry management experience of Hong Kong and Taiwan will promote our tourism industry management process. The study focuses on the difference of the mainland, Hong Kong, Taiwan’s tourism management system and their respective advantages of management. Then it puts forward corresponding suggestions according to the present situation of the development of travel industry of the mainland, and provides reference for the travel industry management and the organization system innovation.

The molecular instigators and therapeutic strategies for inflammatory bowel disease (IBD) are limited. Here, telomere dysfunction is shown to activate pAtm/c-Abl-mediated phosphorylation and stabilization of Yap1 up-regulates pro-IL-18 expression, a major pro-inflammatory factor in IBD. This signaling axis cooperates with gut microbiome which stimulates cytosolic receptors causing activation of caspase-1, which in turn cleaves pro-IL-18 into its mature IL-18 form. Epithelial-derived IL-18 leads to recruitment of IFNγ-secreting T cells and other immunocytes to provoke classical IBD pathology. Consistent with a role for DNA damage signaling as a driver of IBD, newly diagnosed IBD patient samples exhibited elevated expression of pγH2AX, YAP1, Caspase-1 and IL-18 along with significantly reduced telomere lengths compared to healthy tissue controls. Alleviation of IBD pathology can be achieved in mice via telomerase reactivation in intestinal epithelium or pharmacological inhibition of Atm, Yap1, or caspase-1 as well as antibiotic treatment - each intervention dramatically reducing pro-IL-18 cleavage and inflammation. Thus, telomere dysfunction-induced activation of the Atm-Yap1-pro-IL-18 pathway identifies DNA damage signaling as a key instigator and promoter of IBD, illuminating several novel therapeutic strategies for disease interception and management. Note: This abstract was not presented at the meeting. Citation Format: Deepavali Chakravarti, Asha Multani, Prasenjit Dey, Baoli Hu, Di Zhao, Kyle Chang, Mao Xizeng, Guocan Wang, Christoper Terranova, Wen-ting Liao, Denise Spring, Pingping Hou, Jianhua Zhang, Pablo Okhuysen, Eduardo Vilar, Mary K. Estes, Sarah blutt, Alan Wang, Ronald DePinho. Telomere dysfunction is a driver of inflammatory bowel disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-290.

A simple preparation process for the monodispersed pH-sensitive core-shell magnetic microspheres was carried out consisting of chitosan self-assembled on magnetic iron oxide nanoparticles. Meanwhile, glucoamylase was immobilized as a model enzyme on this carrier of Fe(3)O(4)/CS microspheres by ionic adsorption. The morphology, inner structure, and high magnetic sensitivity of the resulting magnetic chitosan microspheres were studied, respectively, with a field emission scanning electron microscope (SEM), transmission electron microscope (TEM), FT-IR spectroscopy, thermogravimetric analysis (TGA), and a vibrating sample magnetometer (VSM). Subsequently, the properties of glucoamylase immobilized on the regenerated supports were also investigated by determining storage stability, pH stability, reusability, magnetic response, and regeneration of supports. The results from characterization and determination remarkably indicated that the immobilized glucoamylase obtained presents excellent storage stability, pH stability, reusability, magnetic response, and regeneration of supports. Therefore, this kind of magnetic Fe(3)O(4)/CS microspheres with perfect monodispersity should be an ideal support for enzyme immobilization.

SummaryInduced pluripotent stem (iPS) cells can be generated from somatic cells by transduction with several transcription factors in mouse and human. However, direct reprogramming in other species has not been reported. Here, we generated monkey iPS cells by retrovirus-mediated introduction of monkey transcription factors OCT4, SOX2, KLF4, and c-MYC.

Meeting abstracts Myeloid-derived suppressor cells (MDSCs) represent a phenotypically heterogeneous population of immature myeloid cells that play a tumor-promoting role by maintaining a state of immunological anergy and tolerance. Similar to other solid tumor types, Prostate cancer (PCa) is

The introduction of four transcription factors Oct4, Klf4, Sox2 and c-Myc by viral transduction can induce reprogramming of somatic cells into induced pluripotent stem cells (iPSCs), but the use of iPSCs is hindered by the use of viral delivery systems. Chemical-induced reprogramming offers a novel approach to generating iPSCs without any viral vector-based genetic modification. Previous reports showed that several small molecules could replace some of the reprogramming factors although at least two transcription factors, Oct4 and Klf4, are still required to generate iPSCs from mouse embryonic fibroblasts. Here, we identify a specific chemical combination, which is sufficient to permit reprogramming from mouse embryonic and adult fibroblasts in the presence of a single transcription factor, Oct4, within 20 days, replacing Sox2, Klf4 and c-Myc. The iPSCs generated using this treatment resembled mouse embryonic stem cells in terms of global gene expression profile, epigenetic status and pluripotency both in vitro and in vivo. We also found that 8 days of Oct4 induction was sufficient to enable Oct4-induced reprogramming in the presence of the small molecules, which suggests that reprogramming was initiated within the first 8 days and was independent of continuous exogenous Oct4 expression. These discoveries will aid in the future generation of iPSCs without genetic modification, as well as elucidating the molecular mechanisms that underlie the reprogramming process.