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Alzheimer's disease (AD) is a progressive neurodegenerative disease with insidious onset, and the deposition of amyloid-β (Aβ) is believed to be one of the main cause. Fluorescence imaging is a promising technique for this task, but the Aβ gold standard probe ThT developed based on this still has shortcomings. The development of a new fluorescent probe to detect Aβ plaques is thought to be essential. Herein, a series of red to near-infrared emitting fluorescent probes

Supplementary Figure from The COX-2–PGE2 Pathway Promotes Tumor Evasion in Colorectal Adenomas

The mechanisms underlying the regulation of a checkpoint receptor, PD-1, in tumor-infiltrating immune cells during the development of colorectal cancer are not fully understood. Here we demonstrate that COX-2–derived PGE2, an inflammatory mediator and tumor promoter, induces PD-1 expression by enhancing NFκB's binding to the PD-1 promoter via an EP4–PI3K–Akt signaling pathway in both CD8+ T cells and macrophages. Moreover, PGE2 suppresses CD8+ T-cell proliferation and cytotoxicity against tumor cells and impairs macrophage phagocytosis of cancer cells via an EP4–PI3K–Akt–NFκB–PD-1 signaling pathway. In contrast, inhibiting the COX-2–PGE2–EP4 pathway increases intestinal CD8+ T-cell activation and proliferation and enhances intestinal macrophage phagocytosis of carcinoma cells accompanied by reduction of PD-1 expression in intestinal CD8+ T cells and macrophages in ApcMin/+ mice. PD-1 expression correlates well with COX-2 levels in human colorectal cancer specimens. Both elevated PD-1 and COX-2 are associated with poorer overall survival in patients with colorectal cancer. Our results uncover a novel role of PGE2 in tumor immune evasion. They may provide the rationale for developing new therapeutic approaches to subvert this process by targeting immune checkpoint pathways using EP4 antagonists. In addition, our findings reveal a novel mechanism explaining how NSAIDs reduce colorectal cancer risk by suppressing tumor immune evasion.Prevention Relevance:These findings provide a potential explanation underlying the chemopreventive effect of NSAIDs on reducing colorectal cancer incidence during premalignancy and provide a rationale for developing EP4 antagonists for colorectal cancer prevention and treatment. Simply targeting PGE2 signaling alone may be efficacious in colorectal cancer prevention and treatment, avoiding side effects associated with NSAIDs.

BACKGROUND Primary intracranial alveolar soft-part sarcoma (PIASPS) is a rare malignancy. We aimed to investigate the clinical profiles and outcomes for PIASPS. CASE SUMMARY We firstly reported five consecutive cases from our institute. Then, the cases from previous studies were pooled and analyzed to delineate the characteristics of this disease. Our cohort included two males and three females. The median age was 21-years-old (range: 8-54-years-old). All the patients received surgical treatment. Gross total resection (GTR), radiotherapy, and chemotherapy were administered in 3 patients, 4 patients, and 1 patient, respectively. After a median follow-up of 36 mo, tumor progression was noticed in 4 patients; and 3 patients died of the disease. Pooled data (n = 14) contained 5 males and 9 females with a median age of 19 years. The log-rank tests showed that GTR (P = 0.011) could prolong progression-free survival, and radiotherapy (P < 0.001) resulted in longer overall survival. CONCLUSION Patients with PIASPS suffer from poor outcomes. Surgical treatment is the first choice, and GTR should be achieved when the tumor is feasible. Patients with PIASPS benefit from radiotherapy, which should be considered as a part of treatment therapies.

Supplementary methods, figures, and figure legends Supplemental Figure S1. gMDSCs in pre-metastatic livers Supplemental Figure S2. The CXCL1-CXCR2 axis is required for formation of pre-metastatic niches and liver metastasis Supplemental Figure S3. The effect of VEGF knockdown on cecal tumor growth and the VEGFR levels on macrophages

Emerging evidence suggests that the primary tumor influences the development of supportive metastatic microenvironments, referred to as premetastatic niches, in certain distant organs before arrival of metastatic cells. However, the mechanisms underlying the contributions of the primary tumor to premetastatic niche formation are not fully understood. Here, we demonstrate that colorectal carcinoma cells secrete VEGFA, which stimulates tumor-associated macrophages to produce CXCL1 in the primary tumor. Elevation of CXCL1 in premetastatic liver tissue recruited CXCR2-positive myeloid-derived suppressor cells (MDSC) to form a premetastatic niche that ultimately promoted liver metastases. Importantly, premetastatic liver-infiltrating MDSCs induced tumor cell survival without involvement of innate or adaptive immune responses. Our study provides the first evidence that primary malignant cell-secreted VEGFA stimulates tumor-associated macrophages to produce CXCL1, which recruits CXCR2-positive MDSCs to form a premetastatic niche to promote liver metastases. Our findings not only shed light on how the tumor microenvironment contributes to premetastatic niche formation at distant sites, but they also provide comprehensive insights into how MDSCs are recruited to other organs where they contribute to metastatic spread of disease. Moreover, our work also provides a rationale for development of CXCR2 antagonists to inhibit or prevent metastatic spread of disease. Cancer Res; 77(13); 3655–65. ©2017 AACR.

Overexpression of Pim-1 and Pim-3 is associated with acquired resistance to MET inhibitors in MKN45 cells.

PDF file - 1094K, Supplementary Methods including antibodies, PCR primers, constructs, 7-Methyl-GTP cap binding assay, Phospho-RTK arrays, and Methionine incorporation assay. Supplementary Figure 1. AKT inhibition induces expression of Pim-1 and RTKs. Supplementary Figure 2. GSK690693 induced RTK upregulation is blocked by a Pim kinase inhibitor in prostate cancer cells. Supplementary Figure 3. Phospho-RTK array analysis of cells treated with AKT and Pim inhibitors. Supplementary Figure 4. Pim kinase inhibitors reduce the expression of RTKs. Supplementary Figure 5. RTK levels are insensitive to mTOR inhibitors. Supplementary Figure 6. Pim-1 does not control RTK mRNA expression or protein half-life. Supplementary Figure 7. Knockdown of Pim-1 suppresses GSK690693-induced MET and IGF1R IRES activities. Supplementary Figure 8. GSK690693 and SMI-4a synergistically blocks the proliferation of DU145 cells. Supplementary Figure 9. Inhibition of protein translation by GSK690693 and PP242.

The PI3K/AKT pathway is hyperactivated in prostate cancer but its effective therapeutic targeting has proven difficult. In particular, the antitumor activity of AKT inhibitors is attenuated by upregulation of receptor tyrosine kinases (RTK) through an uncharacterized feedback mechanism. In this report, we show that RNA interference-mediated silencing or pharmacologic inhibition of Pim-1 activity curtails AKT inhibitor-induced upregulation of RTKs in prostate cancer cells. Although Pim kinases have been implicated in cap-dependent translational control, we find that in the context of AKT inhibition, the expression of RTKs is controlled by Pim-1 in a cap-independent manner by controlling internal ribosome entry. Combination of Pim and AKT inhibitors resulted in synergistic inhibition of prostate tumor growth in vitro and in vivo. Together, our results show that Pim-1 mediates resistance to AKT inhibition and suggest its targeting to improve the efficacy of AKT inhibitors in anticancer therapy. Cancer Res; 73(11); 3402–11. ©2013 AACR.

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Mesenchymal-epithelial transition (MET) blockade offers a new targeted therapy particularly in those cancers with MET amplification. However, the efficacy and the duration of the response to MET inhibitors are limited by the emergence of drug resistance. Here, we report that resistance to small-molecule inhibitors of MET can arise from increased expression of the prosurvival Pim protein kinases. This resistance mechanism was documented in non–small cell lung cancer and gastric cancer cells with MET amplification. Inhibition of Pim kinases enhanced cell death triggered by short-term treatment with MET inhibitors. Pim kinases control the translation of antiapoptotic protein Bcl-2 at an internal ribosome entry site and this mechanism was identified as the basis for Pim-mediated resistance to MET inhibitors. Protein synthesis was increased in drug-resistant cells, secondary to a Pim-mediated increase in cap-independent translation. In cells rendered drug resistant by chronic treatment with MET inhibitors, genetic or pharmacologic inhibition of Pim kinases was sufficient to restore sensitivity in vitro and in vivo. Taken together, our results rationalize Pim inhibition as a strategy to augment responses and blunt acquired resistance to MET inhibitors in cancer. Cancer Res; 75(24); 5318–28. ©2015 AACR.

For exploring novel natural product-derived herbicides, 16 novel

Background: Rheumatoid arthritis (RA) is a common autoimmune disease. Paederia scandens (Lour.) Merr is a common folk remedy used in Hainan, China, to dispel the wind and dampness associated with RA. Methods: The active components of Paederia scandens were extracted using network pharmacology. The potential targets of active components were used to determine activated pathways, and the in vitro effects of Paederia scandens extracts were verified in RA fibroblast-like synoviocytes (HFLS-RA). Results: We identified 27 active components using ultra-high-performance liquid chromatography (UHPLC)-quadrupole time-of-flight (QTOF)-mass spectrometry (MS). Among the major target genes with high connectivity, IL-1β, PI3K, TNF, and JAK2 are known to play key roles in RA development. High-affinity interactions were identified between active compounds in Paederia scandens extract and Janus kinase JAK 2, which are key components of the JAK-signal transducer and activator of transcription (STAT) signaling pathway. In HFLS-RA cells, Paederia scandens extract treatment reduced the mRNA levels of IL-6, IL-1β, and IL-17. Paederia scandens extract treatment also significantly inhibited the phosphorylation of JAK 2 and STAT3, regulating cell proliferation. Conclusions: Based on these results, we confirmed that Paederia scandens has potential for application as a therapeutic and preventive food and acts through the modulation and suppression of JAK-STAT pathway activation to control the inflammatory response in RA.

The mechanisms underlying the regulation of a checkpoint receptor, PD-1, in tumor-infiltrating immune cells during the development of colorectal cancer are not fully understood. Here we demonstrate that COX-2–derived PGE2, an inflammatory mediator and tumor promoter, induces PD-1 expression by enhancing NFκB's binding to the PD-1 promoter via an EP4–PI3K–Akt signaling pathway in both CD8+ T cells and macrophages. Moreover, PGE2 suppresses CD8+ T-cell proliferation and cytotoxicity against tumor cells and impairs macrophage phagocytosis of cancer cells via an EP4–PI3K–Akt–NFκB–PD-1 signaling pathway. In contrast, inhibiting the COX-2–PGE2–EP4 pathway increases intestinal CD8+ T-cell activation and proliferation and enhances intestinal macrophage phagocytosis of carcinoma cells accompanied by reduction of PD-1 expression in intestinal CD8+ T cells and macrophages in ApcMin/+ mice. PD-1 expression correlates well with COX-2 levels in human colorectal cancer specimens. Both elevated PD-1 and COX-2 are associated with poorer overall survival in patients with colorectal cancer. Our results uncover a novel role of PGE2 in tumor immune evasion. They may provide the rationale for developing new therapeutic approaches to subvert this process by targeting immune checkpoint pathways using EP4 antagonists. In addition, our findings reveal a novel mechanism explaining how NSAIDs reduce colorectal cancer risk by suppressing tumor immune evasion. Prevention Relevance: These findings provide a potential explanation underlying the chemopreventive effect of NSAIDs on reducing colorectal cancer incidence during premalignancy and provide a rationale for developing EP4 antagonists for colorectal cancer prevention and treatment. Simply targeting PGE2 signaling alone may be efficacious in colorectal cancer prevention and treatment, avoiding side effects associated with NSAIDs.

Succinate dehydrogenase (SDH) is an important target enzyme for designing agricultural chemical fungicides. In order to explore novel natural product-based antifungal agents, twenty-one unreported anisaldehyde-derived amide-thiourea compounds were designed and synthesized using the principle of active splicing, and structurally confirmed by

BackgroundPrimary brainstem lymphoma (PBSL) is rare and malignant. An understanding of this disease is lacking. We aimed to characterize clinical features, estimate survival, and explore survival-related factors of PBSL.MethodsPatients with a histological diagnosis of primary lymphoma in the brainstem (C71.7) from 1975 to 2016 were retrieved from the Surveillance, Epidemiology, and End Results (SEER) program. Log-rank tests and univariate and multivariate Cox proportional hazard analyses were used to identify survival-related factors.ResultsPBSL constituted 2.7% of brainstem malignancies. The median age of the PBSL patients was 59.5 years. Diffuse large B cell lymphoma (n = 49, 84.5%) was the most prevalent histology among the 58 cases with reported specific lymphoma subtype. The majority of PBSLs were localized (n = 46, 52.3%), at low Ann Arbor Stage (I/II, n = 63, 70.5%), and presented as a single primary (n = 71, 80.7%). Chemotherapy was applied in 50 (56.8%) cases. Three-year overall survival (OS) and disease-specific survival (DSS) rates were 42.7% and 53.5%, respectively. Multivariate analyses showed that independent predictive/prognostic factors for OS were age (P = 0.004), tumor number (P = 0.029), and chemotherapy (P = 0.001); DSS-related factors only included age (P = 0.014) and chemotherapy (P = 0.008).ConclusionsWe estimated survival rates for PBSL patients. Factors associated with OS and DSS were also identified. Our findings addressed the importance of chemotherapy in treating PBSL patients.

In search of novel bioactive compounds with excellent and broad-spectrum antifungal activity and nanopesticides with sustained releasing property, a series of novel myrtenal-based diacylhydrazines were designed, synthesized, and characterized. The preliminary bioassay showed that myrtenal-based 2-picolinyl hydrazide exhibited better or comparable antifungal activity than that of the commercial fungicides boscalid and chlorothalonil against the tested fungi. Furthermore, myrtenal-based nanocellulose was designed as a nanopesticide carrier and prepared from two biomass materials, bleached bagasse pulp and turpentine oil. Drug-loading capacities (LCs) of these carriers and sustained releasing properties of corresponding complexes were also evaluated, and the results indicated that the esterification reaction in the different solvents would affect the micromorphology of carriers, which was the important influential factor for loading or releasing drugs. To our delight, complex VIII-3 (LC = 0.32, total releasing amount/time = 99.8%/168 h) showed a macroporous framework with the drug evenly distributed across the opening network and staged drug-releasing performance that deserved further study as a nanopesticide.

Purpose. Primary brainstem lymphoma (PBSL) is rare and malignant. Understanding of this disease is lacking. We aimed to characterize clinical features, estimate survival and explore survival-related factors of PBSL.Methods. Patients with a histological diagnosis of primary lymphoma in the brainstem (C71.7) from 1975 to 2016 were retrieved from Surveillance, Epidemiology, and End Results (SEER) program. Log-rank tests, univariate and multivariate Cox proportional hazard analyses were used to identify survival-related factors. Results. PBSL constituted 2.7% of brainstem malignancies. The median age of the PBSL patients were 59.5 years. Diffuse large B cell lymphoma (n = 49, 84.5%) was the most prevalent histology among the 58 cases with reported specific lymphoma subtype. The majority of PBSLs were localized (n = 46, 52.3%), at low Ann Arbor Stage (I/II, n = 63, 70.5%), and presented as a single primary (n = 71, 80.7%). Chemotherapy was applied in 50 (56.8%) cases. Three-year overall survival (OS) and disease-specific survival (DSS) rates were 42.7% and 53.5%, respectively. Multivariate analyses showed that independent predictive/prognostic factors for OS were age (P = 0.004), tumor number (P = 0.029), and chemotherapy (P = 0.001); DSS-related factors only included age (P = 0.014) and chemotherapy (P = 0.008). Conclusions. We estimated survival rates for PBSL patients. Factors associated with OS and DSS were also identified. Our findings addressed the importance of chemotherapy in treating PBSL patients.

PD-L1 expression is elevated in various human cancers, including colorectal cancer. High levels of PD-L1 expressed on tumor epithelial cells are one of the potential mechanisms by which tumor cells become resistant to immune attack. However, PD-L1 regulation in tumor cells is not fully understood. Here we demonstrate that mutations in the adenomatous polyposis coli (APC) gene lead to colonic epithelial cell resistance to CD8+ T cell cytotoxicity by induction of PD-L1 expression. Mechanistically, this occurs as a result of the β-catenin/TCF4 complex binding to the PD-L1 promoter, leading to increased transcription. Our findings not only reveal a novel mechanism by which APC mutations induce tumor immune evasion via an immune checkpoint pathway but also pave the way for developing β-catenin or TCF4 inhibitors as possible new options for immune checkpoint inhibition.

Background: Central neurocytoma is a rare intracranial tumor. Due to the limited number of reported cases, the treatment strategy for central neurocytomas, especially large central neurocytomas, remains controversial. This paper discusses our clinical experience in the treatment of large central neurocytomas.Methods: A retrospective analysis of 29 patients with intraventricular central neurocytomas diagnosed and treated by the same surgeon between April 2012 and September 2019 at the Neurosurgery Departments of Beijing Tiantan Hospital and Hainan General Hospital was performed. The clinical characteristics, treatment plans and prognoses of these patients were reviewed.Results: Among the 29 patients, the average age of onset was 31.93 (17-61) years, and the average maximum tumor diameter was 54.17 ± 15.62 mm. Twenty-three patients (79.3%) had an average maximum diameter greater than 50 mm. Twenty-seven patients (93.1%) underwent transcortical tumor resection. Twenty-seven patients (93.1%) underwent gross total tumor resection. Five patients (17.2%) received radiotherapy after the first operation, and 3 patients (10.3%) had tumor recurrence. None of the patients died.Conclusions: Surgical resection via transcortical fistulotomy is a reliable approach for removal of large central neurocytomas in the ventricle. Patients should be closely observed postoperatively, and MRI of the head should be performed regularly. If a tumor shows progression, then radiotherapy should be considered.

Ketol–acid reductoisomerase catalyzes the second step reaction in the biosynthesis of essential branched-chain amino acid, and is an important target enzyme to design the safe herbicides and fungic...

Background Central neurocytoma is a rare intracranial tumor. Due to the limited number of reported cases in the past, there is still controversy about the treatment strategy for central neurocytoma, especially large central neurocytomas occupying bilateral ventricles. This paper will discuss our clinical experience in the treatment of large central neurocytoma. Methods A retrospective analysis of 29 patients with intraventricular central neurocytoma diagnosed and treated by the same surgeon between April 2012 and September 2019 at the Neurosurgery Departments of Beijing Tiantan Hospital and Hainan General Hospital was performed. The clinical characteristics, treatment plan and prognosis of these patients were discussed. Results Among the 29 patients, the average age of onset was 31.93 (17-61) years, and the average maximum tumor diameter was 54.17 ± 15.62 mm. Among them, 23 patients (79.3%) had an average maximum diameter greater than 5 cm. Twenty-seven patients (93.1%) underwent transcortical tumor resection. Twenty-seven patients (93.1%) achieved gross total tumor resection. Five patients (17.2%) received radiotherapy after the first operation, and 3 patients (10.3%) had tumor recurrence. None of the patients died. Conclusion Operation is the basis of the treatment of central neurocytoma. It is possible for patients to be cured by total resection of the tumor and protection of normal ventricular structure. Transcortical fistulotomy is a reliable approach for the removal of large central neurocytomas in the ventricle. Patients should be closely observed post-operation, and MRI of the head should be rechecked regularly. If tumor progression occurs, then radiotherapy should be considered.

Four novel host materials C1–C4 based on carbazole derivatives have been designed, synthesized, characterized, and applied as organic light-emitting devices. This report presents a novel approach, which combines carbazole and aromatic hydrocarbons through methylene. The formed molecules exhibited twisted structures, which resulted in high glass transition temperatures (Tg), ranged from 90.4 to 148.0 °C. They also had high optical bandgaps (Eg), their optical energy bandgaps are determined by absorption edge technique as 3.22 to 3.50 eV, evaluated photo-physical properties of these synthesized novel chromophores, the optical properties such as maximum absorption and emission wavelengths (λ, nm), molar extinction coefficients (e, cm− 1 M− 1), Stoke’s shifts (ΔλST, nm), and quantum yields (φF) also studied the effect of solvent polarity on absorption and emission of these carbazole derivatives, and these compounds exhibited intense absorption bonds between 250 and 325 nm, which are attributed to the π–π* transition of the carbazole-centered units. In addition, they showed blue fluorescence in different solvents. These compounds showed bathochromic shift with the increase in the solvent polarity.

Wire rope isolator (WRI) is widely used in the power machinery and chemical equipment, and has a better dry friction damping and stiffness softening characteristics compared with other vibration isolators. The aim of this article is to create a simplified finite element model of polycal WRI and to avoid the use of overall model on the stiffness characteristic caused by the waste of time. The numerical simulation method used in this paper is to simplify the 1 + 6 +12 single strand into a single wire. The simplified WRI model subjects to the compression load by finite element analysis and obtained the vertical static stiffness characteristics which are consistent with the experimental results.

A series of homoleptic lanthanide complexes [(L1–6)3Ln] (Ln = La, L1 1, L2 3, L3 5, L4 7, L5 9, L6 11; Ln = Gd, L1 2, L2 4, L3 6, L4 8, L5 10, L6 12) supported by Schiff-base ligands were synthesized by the amine elimination reactions of monophenol ligands [2,4-tBu2-6-CH=N-C6H4-p-CH3-PhOH (HL1), 2,4-tBu2-6-CH=N-C6H4-o-CH3-PhOH (HL2), 2,4-tBu2-6-CH=N-C6H4-o-C2H5-PhOH (HL3), 2,4-tBu2-6-CH=N-C6H4-p-OCH3-PhOH (HL4), 2,4-tBu2-6-CH=N-C6H4-p-Br-PhOH (HL5), 2,4-tBu2-6-CH=N-Cy-PhOH (HL6)] with Ln[N(SiMe3)2]3 (Ln = La, Gd) in 3: 1 M ration in THF. Complexes 1, 3, 5, 7, 9 and 11 were characterized by NMR spectra and all twelve complexes were characterized using elemental analysis and infrared spectra. Complexes 4, 5 and 6 have been determined by single-crystal X-ray diffraction, which reveals that they have possessed isostructural unsolvated mononuclear structures and the metal center has exhibited a distorted octahedral geometry, in which the O(1), O(2), O(3) atoms have occupied three positions and N(1), N(2), N(3) atoms have occupied the other three positions. The catalytic properties of complexes 1–12 for the ring-opening polymerization of e-caprolactone were studied and found that all complexes were efficient initiators for this ring-opening polymerization reaction that afforded polycaprolactone with high molecular weights and moderate molecular-weight distributions (1.23–2.46).

Composite foam sandwich is a new, energy-absorbing and load-bearing type of structure, which is widely used in engineering. Furthermore, utilization of connection between composite foam sandwich panels is essential. In this paper, an adhesive joint between two GFRP foam sandwich panels is proposed (model A) and several main failure modes of the novel adhesive joint structure are investigated through four-point bending test. Based on 3D-Hashin failure criterion, cohesive behavior failure criterion and brittle cracking failure criterion of novel GFRP foam sandwich adhesive joints, a progressive damaged model is established to simulate the strength and the results of FEM model and experiments are in good agreements. In order to analyze the effects of stiffness and strength on the structure's mechanical properties, three more connection were proposed to compare the simulation results, which established a simple engineering design for joint structure.

The objective of this study was to investigate the effect of preserving an infiltrated pituitary stalk during the resection of craniopharyngioma of pituitary stalk origin on postoperative outcomes and thus provide a theoretical basis for microsurgical treatment and prognosis.We screened the clinical data of all 103 pediatric patients with craniopharyngioma undergoing surgical treatment at our department between January 2006 and January 2013 and conducted a retrospective analysis of 82 patients with craniopharyngioma originating in the pituitary stalk. The patients were followed up from 12 months to 8 years. We analyzed the effect of preserving the pituitary stalk on the early and persistent diabetes insipidus rates, postoperative relapse rate, and mortality.In the total resection group (n = 67), the early and persistent diabetes insipidus rates were significantly lower in the 46 patients (68.7%) with a pituitary stalk than in those whose pituitary stalk was removed (P 0.05); no significant difference was observed in the relapse rate between the 2 subgroups (P 0.05). In the subtotal resection group (n = 15), a significant difference was observed in the early and persistent diabetes insipidus rates (P 0.05), but no significant difference was observed in the relapse rate between the patients with a pituitary stalk and those whose pituitary stalk was removed (P 0.05).For children with craniopharyngioma of pituitary stalk origin, preserving the pituitary stalk has a significant effect on the early and persistent diabetes insipidus rates. When intraoperative exploration showed excessive adhesion between the tumor and pituitary stalk, we opted to preserve the pituitary stalk, which significantly reduced the early and persistent postoperative diabetes insipidus rates, without significantly increasing the relapse or mortality rate.

Emerging evidence suggests that the primary tumor influences the development of supportive metastatic microenvironments, referred to as premetastatic niches, in certain distant organs before arrival of metastatic cells. However, the mechanisms underlying the contributions of the primary tumor to premetastatic niche formation are not fully understood. Here, we demonstrate that colorectal carcinoma cells secrete VEGFA, which stimulates tumor-associated macrophages to produce CXCL1 in the primary tumor. Elevation of CXCL1 in premetastatic liver tissue recruited CXCR2-positive myeloid-derived suppressor cells (MDSC) to form a premetastatic niche that ultimately promoted liver metastases. Importantly, premetastatic liver-infiltrating MDSCs induced tumor cell survival without involvement of innate or adaptive immune responses. Our study provides the first evidence that primary malignant cell-secreted VEGFA stimulates tumor-associated macrophages to produce CXCL1, which recruits CXCR2-positive MDSCs to form a premetastatic niche to promote liver metastases. Our findings not only shed light on how the tumor microenvironment contributes to premetastatic niche formation at distant sites, but they also provide comprehensive insights into how MDSCs are recruited to other organs where they contribute to metastatic spread of disease. Moreover, our work also provides a rationale for development of CXCR2 antagonists to inhibit or prevent metastatic spread of disease. Cancer Res; 77(13); 3655–65. ©2017 AACR.

In order to get a strong, stiff and lightweight structure, a novel glass fiber reinforced composite (GFRC) lattice sandwich panel (LSP) was designed and manufactured. The lattice core consists of orthogonal corrugated GFRC truss and foam cubes. A modified vacuum assisted resin infusion (VARI) method was used to manufacture the LSP. Flatwise compression test, theoretical analysis and finite element analysis were carried out to reveal the modulus and failure modes of the structure. A local buckling failure and delamination at the corner of strut were observed in compression. Experimental, theoretical and simulation result show great agreement with each other on the modulus of the structure. The experimental modulus and ultimate failure strength are about 1.798 GPa and 5.59 MPa, respectively.

Connecting rod cap and connecting bolts of a reciprocating compressor are subjected to complex dynamic loads therefore they are of critical machine elements. The causes for the failure of connecting rod cap and connecting bolts after approximately 175,200 h in service have been investigated. To determine the failure mechanism of the connecting system and to figure out which of the connecting rod cap and connecting bolts was broken first, material characterization and numerical analysis are conducted on the connecting rod and connecting bolts. Scanning electron microscope (SEM) and optical microscope are applied to analysis the macro and microstructures. The chemical composition and metallographic structure investigation are carried out to study characteristics of the materials. Tensile tests, hardness and impact tests are performed to check the mechanical properties of the connecting rod cap and three connecting bolts. A finite element analysis of the connecting system is employed to evaluate the overall stress distribution with maximum stress criterion. Results of this investigation indicate that the reason of failure was high cycle fatigue and the initial crack location was consistent with high stress concentration at the curvature mutation position of connecting rod cap which was broken before the connecting bolts.

The level of microRNA‐9‐5p (miRNA‐9‐5p) in brain tissues is significantly changed after traumatic brain injury (TBI). However, the effect of miRNA‐9‐5p for brain function in TBI has not been elucidated. In this study, a controlled cortical impact model was used to induce TBI in Sprague–Dawley rats, and an oxygen glucose deprivation model was used to mimic the pathological state in vitro. Brain microvascular endothelial cells (BMECs) and astrocytes were extracted from immature Sprague–Dawley rats and cocultured to reconstruct blood–brain barrier (BBB) in vitro. The results show that the level of miRNA‐9‐5p was significantly increased in brain tissues after TBI, and up‐regulation of miRNA9‐5p contributed to the recovery of neurological function. Up‐regulation of miRNA‐9‐5p with miRNA agomir may significantly alleviate apoptosis, neuroinflammation, and BBB damage in rats after TBI. Moreover, a dual luciferase reporter assay confirmed that miRNA‐9‐5p is a post‐transcriptional modulator of Ptch‐1. In in vitro experiments, the results confirmed that up‐regulation of miRNA‐9‐5p with miRNA mimic alleviates cellular apoptosis, inflammatory response, and BBB damage mainly by inhibiting Ptch‐1. In addition, we found that the activation of Hedgehog pathway was accompanied by inhibition of NF‐κB/MMP‐9 pathway in the BMECs treated with miRNA‐9‐5p mimic. Taken together, these results indicate that up‐regulation of miRNA‐9‐5p alleviates BBB damage and neuroinflammatory responses by activating the Hedgehog pathway and inhibiting NF‐κB/MMP‐9 pathway, which promotes the recovery of neurological function after TBI., Hedgehog pathway and NF‐κB proteins play important roles in cellular apoptosis and inflammatory responses. Using bioinformatics techniques, we find that Ptch‐1, which is an inhibitor of Hedgehog pathway, and NF‐κB are potential targets for microRNA‐9‐5p. We propose the following cascade for microRNA‐9‐5p that alleviates the damage of blood–brain barrier and neuroinflammation after traumatic brain injury: over‐expression of microRNA‐9‐5p activates Hedgehog pathway and blocks NF‐κB/MMP‐9 pathway by inhibiting Ptch‐1 and NF‐κB, which inhibit cellular apoptosis and inflammatory responses of brain microvascular endothelial cells. We think these findings may provide a new target for the treatment of traumatic brain injury.

BACKGROUND & AIMS: Prostaglandin E(2) (PGE(2)) promotes colorectal tumor formation and progression by unknown mechanisms. We sought to identify microRNAs (miRNAs) might mediate the effects of PGE(2) on colorectal cancer (CRC) development. METHODS: We incubated LS174T colorectal cancer cells with PGE(2) or without (control) and used miRNA-seq technology to compare expression patterns of miRNAs. We knocked down levels of specific miRNAs or proteins in cells using small interfering RNAs or genome editing. Cells were analyzed by immunoblot, quantitative PCR, chromosome immunoprecipitation, cell invasion, and luciferase reporter assays; we measured gene expression, binding activity, cell migration and invasion, and transcriptional activity of transcription factors. NSG mice were given injections of LS174T cells and growth of primary tumors and numbers of liver and lung metastases were quantified and analyzed by histology. We used public databases to identify correlations in gene expression pattern with patient outcomes. RESULTS: We identified miRNA 675-5p (MIR675-5p) as the miRNA most highly upregulated by incubation of colorectal cancer cells with PGE(2). PGE(2) increased expression of MIR675-5p by activating expression of Myc, via activation of AKT, NF-κB, and β-catenin. β-catenin PGE(2) increased the invasive activities of cultured CRC cells. LS174T cells incubated with PGE2 formed more liver and lung metastases in mice than control LS174T cells. We identified a 3’UTR in the TP53 mRNA that bound MIR675-5p; binding resulted in loss of the p53 protein. Expression of MIR675-5p or its precursor RNA, H19, correlated with expression of cyclooxygenase-1 and cyclooxygenase-2 and shorter survival times of patients with CRC. CONCLUSIONS: We found incubation of CRC cells with PGE(2) to increase their invasive activity and ability to form liver and lung metastases in mice. PGE(2) downregulates expression of p53 by increasing expression of MIR675-5p, which binds to and prevents translation of TP53 mRNA. These findings provide insight into the mechanisms by which PGE(2) promotes tumor development and progression. Strategies to target the PGE(2) might be developed for treatment of CRC. BACKGROUND AND CONTEXT: Prostaglandin E(2) (PGE(2)) promotes colorectal tumor formation and progression by unknown mechanisms. NEW FINDINGS: We found incubation of CRC cells with PGE2 to increase their invasive activity and ability to form liver and lung metastases in mice. PGE(2) downregulates expression of p53 by increasing expression of MIR675-5p, which binds to TP53 mRNA and prevents its translation. LIMITATIONS: These studies were performed in cell lines and mice. Studies in humans are needed. IMPACT: These findings provide insight into the mechanisms by which PGE(2) promotes tumor development and progression. Strategies to target the PGE(2) might be developed for treatment of CRC.

Background Intramedullary schwannomas of the spinal cord are extremely rare. Most previous studies are case reports, which have found that intramedullary schwannomas could be homogeneous or asymmetrically enhanced with gadolinium. However, intramedullary schwannomas with minimal enhancement have not been reported. Case Description This article describes a 34-year-old patient who presented with nonradiative neck pain, progressive weakness of the left limbs, and sensory deficit of both lower extremities. Preoperative examinations such as magnetic resonance imaging (MRI) were performed, and the patient underwent surgical treatment. MRI showed that the lesion presented unsharp enhancement with gadolinium on T1-weighted images. Histopathologic findings were consistent with the diagnosis of schwannoma. Conclusions We report a case of intramedullary schwannoma that presented inconspicuous enhancement with gadolinium. MRI is useful but cannot be used to differentiate schwannomas from other intramedullary spinal tumours. Surgical resection is the most vital factor for the treatment of intramedullary schwannoma.

Wind velocity and saltating grain count rate in the natural unsteady aeolian sediment transport are synchronously measured on the gently inclined windward slope of one horn of a large barchan. The obtained time series of these two variables are analyzed, by using the improved complete ensemble empirical mode decomposition and wavelet coherence, to investigate the wind-saltation interactions at different timescales. It is found that the wind-saltation trend relation obeys the traditional low-order polynomial expressions, and saltation mode is roughly proportional to its corresponding wind mode if they are strongly correlated. As a conclusion, it is probable to partly predict instantaneous saltation activities near the surface by the empirical trend and effective modes of wind speed at a given height.

Two types of copillar[5]arenes bearing mono-functionalized bulky substituents such as phenyl and naphthyl groups were synthesized and their conformational characteristics were studied by 1H NMR spectroscopy. Their rotation mode can be induced and controlled by the bulky substituents. The OCH3 groups on phenolic units, the same side as the bulky substituent, were rotating regularly in the mode of OR-opposite-the-annulus rotation while the mode of OR-through-the-annulus was seen for the other OCH3 groups on the other side. Furthermore, their excellent binding properties with 1,4-dibromobutane(DBB) can be maintained as the fully symmetrical pillar[5]arenes.

The PIM1 oncogene is over-expressed in human prostate cancer epithelial cells. Importantly, we observe that in human hyperplastic and cancerous prostate glands PIM1 is also markedly elevated in prostate fibroblasts, suggesting an important role for this kinase in epithelial/stromal crosstalk. The ability of PIM1 to regulate the biologic activity of stromal cells is demonstrated by the observation that expression of PIM1 kinase in human prostate fibroblasts increases the level and secretion of the extracellular matrix molecule, collagen 1A1 (COL1A1), the pro-inflammatory chemokine CCL5, and the platelet-derived growth factor receptors (PDGFR). PIM1 is found to regulate the transcription of CCL5. In co-cultivation assays where PIM1 over-expressing fibroblasts are grown with BPH1 prostate epithelial cells, PIM1 activity markedly enhances the ability of these fibroblasts to differentiate into myofibroblasts and express known markers of cancer-associated fibroblasts (CAFs). This differentiation can be reversed by the addition of small molecule PIM kinase inhibitors. Western blots demonstrate that PIM1 expression in prostate fibroblasts stimulates the phosphorylation of molecules that regulate 5'Cap driven protein translation, including 4EBP1 and eIF4B. Consistent with the hypothesis that the kinase controls translation of specific mRNAs in prostate fibroblasts, we demonstrate that PIM1 expression markedly increases the level of COL1A1 and PDGFRβ mRNA bound to polysomes. Together these results point on PIM1 as a novel factor in regulation of the phenotype and differentiation of fibroblasts in prostate cancer by controlling both the transcription and translation of specific mRNAs.

A series of the electrochemical and long-term corrosion tests was carried out in a 3.5 wt% Na2SO4 solution on thermal-sprayed WC-17Co and WC-10Co-4Cr cermet coatings in order to examine the effect of composition of binder materials on the corrosion behavior. The results reveal that the overall corrosion resistance of the WC-17Co coating is inferior to that of the WC–Co–Cr coatings due to the corrosion of binder materials which induce WC particles to fall off. CoO and WO3 oxide films form on the surface of WC-17Co coating in Na2SO4 solution electrochemical corrosion process, which will protect the coating in the process of corrosion. Cr2O3 oxide film formed on the WC-10Co-4Cr coating surface has a strong hindered role to corrosion. The corrosion mechanism of WC-17Co coating in Na2SO4 solution is entire corrosion of Co matrix, while it is film-hole corrosion mechanism for WC-10Co-4Cr coating.

In an attempt to search for natural product-based insecticidal agents, a series of novel dehydroabietic acid derivatives bearing 1,3,4-thiadiazole moiety were designed and synthesized. Their structures were characterized by IR, MS, 1H-NMR, 13C-NMR, and elemental analysis. The insecticidal activities against cotton bollworm (Helicoverpa armigera), corn borer (Ostrinia nubilalis Hubner), and diamondback moth (Plutella xylostella (L.)) were evaluated. The bioassay test showed that some of the target compounds exhibited excellent insecticidal activities at the concentration of 200 µg/ml; compound 3a had the best mortality rate of 90.0 and 80.0 % against H. armigera and O. nubilalis Hubner, respectively.