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Highway bridges are an important part of the transportation industry and can promote social economic construction and development. In actual operation, highway bridges are often damaged due to overload and natural factors, which tend to affect the safety and shorten the service life of these bridges. Assessing the overall state and performance of highway bridges is therefore a key element. Static load test, which is a type of sustainable detection experiment, has many advantages, including low cost, high efficiency, and high accuracy. In this paper, the bridge structure is analyzed through the application of theoretical calculations and relevant comparisons, so as to judge the operating state of the bridge.

With the continuous development of China, the requirements for road construction are also increasing. Among them, strengthening the performance of roadbed test can effectively improve road construction. Besides, it is also crucial to perform suitable tests in a timely manner. Therefore, highway inspection technology should be improved for the continuous development of highway construction, which will be explained in this paper, in hopes of improving the construction of highway in China.

The acceleration of urbanization has promoted the increase in the number of urban highway projects, resulting in an increase of emphasis on the quality of urban highway projects. The quality and safety of highway construction directly affects the driving comfort, safety, and service life after it is put into operation. Among them, asphalt pavement is an important structure in highway construction, and it is also a key link that directly affects the construction quality. In order to ensure the quality of construction, it is necessary to strengthen on-site testing during the construction process to discover problems in time, and to ensure that the construction is up to standard. This paper mainly presents an analysis on the necessity and application of on-site quality inspection technology for asphalt pavement construction of highway engineering, and outlines measures to improve highway engineering construction testing technology.

With the development of sharing economy, more and more enterprises choose crowd logistics for distribution. Because the crowd logistics platform uses social freelancers, the service quality is difficult to guarantee. Considering the reward-penalty mechanism, dynamic differential game models are constructed to study the optimal pricing and quality of crowd logistics services under stochastic demand based on the optimal control theory and Pontryagin maximum principle. The numerical simulation results show that the optimal dynamic decisions change with the fluctuation of demand dynamically. Furthermore, the platform needs to adjust the value of the reward-penalty factor to ensure the level of service quality and revenue in different situations.

Supplementary Materials and Methods; Supplementary Tables (Table S1. Antibodies used in Western blotting, immunoprecipitation and IHC studies. Table S2. Sequences of primers used for real-time PCR analysis. Table S3. Combination index (CI) of bromocriptine and docetaxel treatment in C4-2 cells); Supplementary Figures ( Figure S1. Quantitative PCR analysis of mRNA expression of AR and survivin in C4-2 cells treated with varying concentrations of bromocriptine (24 h). Figure S2. Body weights of athymic nude mice bearing C4-2-Luc tumors and treated with the vehicle control, docetaxel, bromocriptine and the combination. *: p < 0.05. Figure S3. Western blot analysis of p-AR (Ser650) expression in C4-2 cells treated with bromocriptine for varying times)

Docetaxel resistance remains a major obstacle in the treatment of prostate cancer bone metastasis. In this study, we demonstrate that the dopamine D2 receptor (DRD2) agonist bromocriptine effectively enhances docetaxel efficacy and suppresses skeletal growth of prostate cancer in preclinical models. DRD2 is ubiquitously expressed in prostate cancer cell lines and significantly reduced in prostate cancer tissues with high Gleason score. Bromocriptine has weak to moderate cytotoxicity in prostate cancer cells, but effectively induces cell-cycle arrest. At the molecular level, bromocriptine inhibits the expression of c-Myc, E2F-1, and survivin and increases the expression of p53, p21, and p27. Intriguingly, bromocriptine markedly reduces androgen receptor levels, partially through Hsp90-mediated protein degradation. The combination of bromocriptine and docetaxel demonstrates enhanced in vitro cytotoxicity in prostate cancer cells and significantly retards the skeletal growth of C4-2-Luc tumors in mice. Collectively, these results provide the first experimental evidence for repurposing bromocriptine as an effective adjunct therapy to enhance docetaxel efficacy in prostate cancer. Mol Cancer Ther; 17(9); 1859–70. ©2018 AACR.

Supplementary Figure 2 from β2-Microglobulin Induces Epithelial to Mesenchymal Transition and Confers Cancer Lethality and Bone Metastasis in Human Cancer Cells

Supplementary Figure 3 from β2-Microglobulin Induces Epithelial to Mesenchymal Transition and Confers Cancer Lethality and Bone Metastasis in Human Cancer Cells

Supplementary Figure 1 from β2-Microglobulin Induces Epithelial to Mesenchymal Transition and Confers Cancer Lethality and Bone Metastasis in Human Cancer Cells

Supplementary Figure 4 from β2-Microglobulin Induces Epithelial to Mesenchymal Transition and Confers Cancer Lethality and Bone Metastasis in Human Cancer Cells

Bone metastasis is one of the predominant causes of cancer lethality. This study demonstrates for the first time how β2-microglobulin (β2-M) supports lethal metastasis in vivo in human prostate, breast, lung, and renal cancer cells. β2-M mediates this process by activating epithelial to mesenchymal transition (EMT) to promote lethal bone and soft tissue metastases in host mice. β2-M interacts with its receptor, hemochromatosis (HFE) protein, to modulate iron responsive pathways in cancer cells. Inhibition of either β2-M or HFE results in reversion of EMT. These results demonstrate the role of β2-M in cancer metastasis and lethality. Thus, β2-M and its downstream signaling pathways are promising prognostic markers of cancer metastases and novel therapeutic targets for cancer therapy. Cancer Res; 71(7); 2600–10. ©2011 AACR.

Graph clustering has been a hot research topic and is widely used in many fields, such as community detection in social networks. Lots of works combining auto-encoder and graph neural networks have been applied to clustering tasks by utilizing node attributes and graph structure. These works usually assumed the inherent parameters (i.e. size and variance) of different clusters in the latent embedding space are homogeneous, and hence the assigned probability is monotonous over the Euclidean distance between node embeddings and centroids. Unfortunately, this assumption usually does not hold since the size and concentration of different clusters can be quite different, which limits the clustering accuracy. In addition, the node embeddings in deep graph clustering methods are usually L2 normalized so that it lies on the surface of a unit hyper-sphere. To solve this problem, we proposed D eep A daptive G raph C lustering via von Mises-Fisher distributions, namely DAGC. DAGC assumes the node embeddings H can be drawn from a von Mises-Fisher distribution and each cluster k is associated with cluster inherent parameters ρ k which includes cluster center μ and cluster cohesion degree κ . Then we adopt an EM-like approach (i.e. \(\mathcal {P}(\mathbf {H}|\mathbf {\rho }) \) and \(\mathcal {P}(\mathbf {\rho }|\mathbf {H}) \) respectively) to learn the embedding and cluster inherent parameters alternately. Specifically, with the node embeddings, we proposed to update the cluster centers in an attraction-repulsion manner to make the cluster centers more separable. And given the cluster inherent parameters, a likelihood-based loss is proposed to make node embeddings more concentrated around cluster centers. Thus, DAGC can simultaneously improve the intra-cluster compactness and inter-cluster heterogeneity. Finally, extensive experiments conducted on four benchmark datasets have demonstrated that the proposed DAGC consistently outperforms the state-of-the-art methods, especially on imbalanced datasets.

The polycomb repressive complex 2 (PRC2) can methylate at lysine 27 of histone H3 at the trimethylation level (H3K27me3). This leads to gene silencing and is known to be dysregulated in many cancers. PRC2 is made up of three core subunits: EZH2, SUZ12, and EED. EED is essential for the regulation of PRC2 function by binding to H3K27me3. Targeting the allosteric site within EED offers new strategies to disrupt the PRC2 activity. In this minireview, we summarize some of the recent developments in small molecules that target EED and its interaction with other core proteins in the PRC2 complex.

A major challenge to the treatment of advanced prostate cancer (PCa) is the development of resistance to androgen-deprivation therapy (ADT) and chemotherapy. It is imperative to discover effective therapies to overcome drug resistance and improve clinical outcomes. We have developed a novel class of silicon-containing compounds and evaluated the anticancer activities and mechanism of action using cellular and animal models of drug-resistant PCa. Five organosilicon compounds were evaluated for their anticancer activities in the NCI-60 panel and established drug-resistant PCa cell lines. GH1504 exhibited potent in vitro cytotoxicity in a broad spectrum of human cancer cells, including PCa cells refractory to ADT and chemotherapy. Molecular studies identified several potential targets of GH1504, most notably androgen receptor (AR), AR variant 7 (AR-v7) and survivin. Mechanistically, GH1504 may promote the protein turnover of AR, AR-v7 and survivin, thereby inducing apoptosis in ADT-resistant and chemoresistant PCa cells. Animal studies demonstrated that GH1504 effectively inhibited the in vivo growth of ADT-resistant CWR22Rv1 and chemoresistant C4-2B-TaxR xenografts in subcutaneous and intraosseous models. These preclinical results indicated that GH1504 is a promising lead that can be further developed as a novel therapy for drug-resistant PCa.

Neurofilament light chain (NfL) levels have proved to be a good biomarker in cerebrospinal fluid (CSF) correlating with the degree of neuronal injury and neurodegeneration. However, little is known about the value of plasma neurofilament light chain (pNfL) levels in predicting the clinical prognosis of patients with acute cerebral infarction. This study aimed to explore whether pNfL could be used as a biomarker to predict the severity of the outcomes of acute ischemic stroke (AIS). Patients with AIS were included from the Department of Neurology of the First People's Hospital of Bengbu City from January 2018 to May 2019, as well as health control (HC). The plasma levels of NfL in patients with AIS (n = 60) at 2 days, 7 days, and 6 months after stroke, as well as in HCs (n = 60) were measured by electrochemiluminescence immunoassay(ECL) on the Meso Scale Discovery platform. Stroke severity was analyzed at admission using the National Institutes of Health Stroke Scale score. Functional outcomes were assessed at different times using the modified Rankin Scale (mRS) and Barthel Index. The mean level of pNfL in patients with ischemic stroke (IS) at 2 days (225.86 pg/L) after stroke was significantly higher than that in HC (107.02 pg/L) and gradually increased 7 days after stroke (316.23 pg/L) (P.0001). The mean level of pNfL in patients with IS at 6 months after stroke was 173.38 pg/L, which was still significantly higher than that of HC. The levels of pNfL at 7 days after stroke independently predicted modified Rankin Scale scores (mRS) (R = 0.621, P.001), Barthel Index (R = -0.716, P.001), and National Institutes of Health Stroke Scale (R = -0.736, P.001). The diagnostic severity and prognosis were evaluated by ROC curve, an area under the receiver operator curve of 0.812 (P = .001, 95% CI: 0.69-0.93) at 7 days. Plasma NfL levels reflect neuronal injury after AIS. It changes with time and has a certain relationship with prognosis and may be a promising biomarker for predicting the severity of neuroaxonal injury in patients with acute IS.

Purpose: Despite numerous therapeutic modalities, including chemotherapy and next-generation androgen deprivation therapy, metastatic castration-resistant prostate cancer (mCRPC) remains a dreadful evolution and still bears a poor prognosis for most patients who develop metastases to bones and other organs, which have no cure. It is urgent to identify new molecular targets and develop novel therapeutic agents against lethal mCRPC. Methods: We developed a novel small-molecule anticancer compound named GH501 via a “molecular hybridization” approach. The in vitro cytotoxicity of GH501 was evaluated in the NCI-60 human cancer cell panel and human mCRPC cell lines. Molecular targets of GH501 were investigated using in silico docking, biolayer interferometry, cellular thermal shift assay, and other molecular and cellular approaches. The in vivo anticancer efficacy of GH501 against mCRPC was evaluated in clinically-relevant xenograft models. Results: GH501 effectively inhibited the in vitro proliferation of NCI-60 human cancer cell lines and established mCRPC cell lines, including African American prostate cancer (PCa) cells, at nanomolar potency by inducing cell cycle arrest and apoptosis. Mechanistically, GH501 might bind S-phase kinase-associated protein 1 (Skp1) and disrupt the physical interaction between Skp1 and S-phase kinase-associated protein 2 (Skp2), thereby affecting multiple oncogenic signals implicated in mCRPC progression. RNA-Seq analyses indicated that GH501 treatment in C4-2 cells significantly inhibited E2F-, G2/M checkpoint, c-Myc- and β-catenin-regulated genes, androgen receptor (AR) transcription, androgen-responsive genes, and enhancer of zeste homolog 2 (EZH2)-activated genes. Proteomic studies identified 109 proteins upregulated and 154 proteins downregulated significantly by GH501 in CRW22Rv1 cells. The top physiological processes and signaling pathways affected by GH501 included cell cycle, autophagy, steroid biosynthesis, DNA replication, p53, AMP-activated protein kinase (AMPK), and mitogen-activated protein kinase (MAPK). As a lead compound, GH501 had excellent preclinical safety. In animal studies, GH501 monotherapy effectively inhibited the skeletal and subcutaneous growth of four mCRPC xenografts with heterogeneous genetic backgrounds. Conclusion: These results support that pharmacological interruption of Skp1-Skp2 interaction is a promising therapeutic strategy for mCRPC. To our knowledge, GH501 is the first synthetic Skp1 inhibitor with a unique chemical structure that can serve as the basis for lead optimization and development. Citation Format: Xin Li, Kenza Mamouni, Rui Zhao, Yifei Wu, Zhong-Ru Xie, Giuseppe Sautto, Degang Liu, Nathan Bowen, Alira Danaher, Lajos Gera, Daqing Wu. A novel Skp1 inhibitor has potent preclinical efficacy against metastatic castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 519.

The aryl hydrocarbon receptor (AhR) is a nuclear transcription factor and xenobiotic sensor reported to mediate diet-induced obesity and is upregulated in high-grade prostate cancer (PCa). Previously published data from our lab shows AhR protein is overexpressed and constitutively active in castration-resistant PCa cells. AhR signaling is promoted by high fat diet-induced obesity, when circulating leptin levels are also high. Physiologically relevant leptin concentration is proportional to BMI and is secreted by adipose cells to inhibit hunger under normal circumstances. Our preliminary results suggest that both AhR and leptin independently desensitize PCa cells to clinically-relevant chemotherapeutics however, the underlying mechanisms must be elucidated and may require sustained AhR signaling. We also conducted an integrative bioinformatics analysis to explore the role of AHR and LEPR in PCa, which revealed AHR and LEPR mRNA expression positively correlates in prostate cancer (P Citation Format: Kofi K. Khamit-Kush, Joann B. Powell, Jeffrey A. Handy, Nathan J. Bowen, Valerie Odero-Marah, Daqing Wu. Aryl hydrocarbon receptor and leptin promote prostate cancer progression and may be associated with chemoresistance [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C023.

The aryl hydrocarbon receptor (AhR) is a nuclear transcription factor and xenobiotic sensor reported to mediate diet-induced obesity and is upregulated in high-grade prostate cancer (PCa). Previously published data from our lab shows that AhR protein is overexpressed and constitutively active in castration-resistant prostate cancer cells. Physiologically relevant leptin concentration is proportional to BMI and it is secreted by adipose cells to inhibit hunger under normal circumstances. Our preliminary results suggest that obesity-associated leptin concentrations desensitize PCa cells to cancer drugs however, the underlying mechanisms must be elucidated and may require sustained AhR signaling. In this study, we conducted an integrative bioinformatics analysis to explore the role of AHR and LEPR in PCa, which revealed AHR and LEPR mRNA expression positively correlates in prostate cancer (P Citation Format: Kofi Kyenku Khamit-Kush, Joann B. Powell, Jeffrey A. Handy, Nathan Bowen, Daqing Wu, Valerie Odero-Marah. Elevated aryl hydrocarbon receptor and leptin receptor expression correlates with prostate cancer progression and may be associated with obesity-associated leptin-mediated chemoresistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 394.

Background: It is imperative to develop novel therapeutics to overcome chemoresistance, a major obstacle in the clinical management of prostate cancer (PCa) and other cancers. Drug repositioning is being pursued as an attractive approach due to its potentially lower overall development costs and shorter timelines. The purpose of this study is to investigate the preclinical efficacy and mechanism of action of nicardipine, an FDA-approved hypertension drug, as a new treatment against chemoresistant prostate cancer. Methods: A panel of FDA-approved non-oncology drugs was screened for their selectivity and potency to inhibit chemoresistant PCa cells using a two-tier phenotypic screening platform (Theranostics, 2021, 11(14): 6873-6890). The mechanism of action of potential candidate(s) was evaluated using in silico docking, cellular and molecular assays in ARCaPE-shEPLIN and C4-2B-TaxR, two independent chemoresistant PCa cell lines. The in vivo efficacy was evaluated in clinically-relevant xenograft models of PCa. Results: Nicardipine exhibited high selectivity and potency against chemoresistant PCa cells via effectively inducing apoptosis and cell cycle arrest. The IC50 of nicardipine was determined as 0.5 μM and 2.1 μM in ARCaPE-shEPLIN and C4-2B-TaxR cells, respectively. Mechanically, nicardipine targeted a novel non-canonical enhancer of zeste homolog 2 (EZH2) signal pathway in chemoresistant PCa cells. Specifically, nicardipine might bind embryonic ectoderm development (EED), interrupt the integrity and stability of the polycomb repressive complex 2 (PRC2), reduce the phosphorylation and expression of EZH2, and subsequently inhibit downstream effectors including signal transducer and activator of transcription 3 (Stat3), S-phase kinase-associated protein 2 (SKP2), ATP binding cassette B1 (ABCB1) and survivin. In animal models, as a monotherapy, nicardipine significantly suppressed the intratibial growth of chemoresistant C4-2B-TaxR xenografts, with an average PSA level of 43.47 ng/ml, 36.63 ng/ml, and 28.78 ng/ml for the vehicle control, docetaxel, and nicardipine groups at the endpoint, respectively (p < 0.05 between the nicardipine group and the vehicle control or docetaxel groups). As a combination regime, nicardipine synergistically enhanced the efficacy of docetaxel against the intratibial growth of C4-2 xenografts, with an average PSA level of 79.17 ng/ml, 49.04 ng/ml, 42.80 ng/ml, and 23.23 ng/ml for the vehicle control, docetaxel, nicardipine, and combination groups at the endpoint, respectively (p < 0.0001 or 0.01 between the combination group and the vehicle control or docetaxel groups, respectively). Conclusion: These results demonstrated that, for the first time, nicardipine could be a novel EED inhibitor that has the potential to be promptly tested in PCa patients to overcome chemoresistance and improve clinical outcomes. Citation Format: Xin Li, Alira Danaher, Jason M. Wu, Yifei Wu, Zhong-Ru Xie, Nicholas Cook, Nathan Bowen, Daqing Wu. Repositioning nicardipine as a novel targeted therapy for chemoresistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5365.