Background: Melanoma is an aggressive tumor of the skin. Drug resistance is still a major problem in melanoma therapy. Novel targets and effective agents to overcome drug resistant melanoma are urgently needed in clinical therapy.Methods: Gene Expression Omnibus (GEO) database analysis, pathway enrichment analysis, survival rate analysis were utilized to identify the candidate target. Anchorage-independent cell growth assay, flow cytometry, western blot and xenograft mouse model were conducted to study the function of AURKB in melanoma in both drug-sensitive and drug-resistant melanoma. Next, HI-511, a novel dual-target inhibitor of AURKB and BRAF V600E, was designed and confirmed by in vitro kinase assay. Anchorage-independent cell growth assay, flow cytometry. western blot, xenograft and BRAF V600E/PTEN-loss melanoma mouse models were conducted to demonstrate the effect of HI-511 on melanoma development in vitro and in vivo.Findings: AURKB is high expression in melanoma and even higher in vemurafenib-resistant melanoma, which correlated with patient's survival rate. Knocking down AURKB inhibits cells growth and induces apoptosis in melanoma, which is associated with BRAF/MEK/ERKs and PI3K/AKT signaling pathways. Importantly, we find HI-511 suppresses both vemurafenib-sensitive and vemurafenib-resistant melanoma in vitro and in vivo by inducing apoptosis and mediating the activation of BRAF/MEK/ERKs and PI3K/AKT signaling pathways. Interpretation: AURKB could be a potential target for melanoma treatment. HI-511, a novel dual-target inhibitor of both AURKB and BRAF V600E, could achieve durable suppression of melanoma, even drug-resistant melanoma. Funding Statement: This work was supported by the Hormel Foundation.Declaration of Interests: The authors declare no potential conflicts of interest.Ethics Approval Statement: All studies were performed following guidelines approved by the University of Minnesota Institutional Animal Care and Use Committee (Minneapolis, MN).
BackgroundHospitals in China are classified into tiers (1, 2 or 3), with the largest (tier 3) having more equipment and specialist staff. Differential health insurance cost-sharing by hospital tier (lower deductibles and higher reimbursement rates in lower tiers) was introduced to reduce overcrowding in higher tier hospitals, promote use of lower tier hospitals, and limit escalating healthcare costs. However, little is known about the effects of differential cost-sharing in health insurance schemes on choice of hospital tiers.MethodsIn a 9-year follow-up of a prospective study of 0.5 M adults from 10 areas in China, we examined the associations between differential health insurance cost-sharing and choice of hospital tiers for patients with a first hospitalisation for stroke or ischaemic heart disease (IHD) in 2009–2017. Analyses were performed separately in urban areas (stroke: n = 20,302; IHD: n = 19,283) and rural areas (stroke: n = 21,130; IHD: n = 17,890), using conditional logit models and adjusting for individual socioeconomic and health characteristics.FindingsAbout 64–68% of stroke and IHD cases in urban areas and 27–29% in rural areas chose tier 3 hospitals. In urban areas, higher reimbursement rates in each tier and lower tier 3 deductibles were associated with a greater likelihood of choosing their respective hospital tiers. In rural areas, the effects of cost-sharing were modest, suggesting a greater contribution of other factors. Higher socioeconomic status and greater disease severity were associated with a greater likelihood of seeking care in higher tier hospitals in urban and rural areas.InterpretationPatient choice of hospital tiers for treatment of stroke and IHD in China was influenced by differential cost-sharing in urban areas, but not in rural areas. Further strategies are required to incentivise appropriate health seeking behaviour and promote more efficient hospital use.FundingWellcome Trust, Medical Research Council, British Heart Foundation, Cancer Research UK, Kadoorie Charitable Foundation, China Ministry of Science and Technology, and National Natural Science Foundation of China.
Abstract The most active anticancer component in green tea is epigallocatechin-3-gallate (EGCG). Protein interaction with EGCG is a critical step mediating the effects of EGCG on the regulation of various key proteins involved in signal transduction. By using computational docking screening methods for protein identification, we identified a serine/threonine kinase, 90-kDa ribosomal S6 kinase (RSK2), as a novel molecular target of EGCG. RSK2 includes two kinase catalytic domains in the N-terminal (NTD) and the C-terminal (CTD) and its activation requires phosphorylation of both the NTD and CTD. The computer prediction was confirmed by an in vitro kinase assay in which EGCG inhibited RSK2 activity in a dose-dependent manner. Pull-down assay results showed that EGCG could bind with RSK2 at both kinase catalytic domains in vitro and ex vivo. Furthermore, results of an ATP competition assay and a computer-docking model showed that EGCG binds with RSK2 in an ATP-dependent manner. In RSK2+/+ and RSK2-/- murine embryonic fibroblasts, EGCG decreased viability only in the presence of RSK2. EGCG also suppressed epidermal growth factor-induced neoplastic cell transformation by inhibiting histone H3 Ser10 phosphorylation. Overall, these results indicate that EGCG is a novel natural compound for suppressing RSK2 kinase activity. Citation Format: Hanyong Chen, Ke Yao, Xiaoyu Chang, Jung-Hyun Shim, Hong-Gyum Kim, Margarita Malakhova, Dong-Joon Kim, Ann M. Bode, Zigang Dong. Computational and biochemical discovery of RSK2 as a novel target for epigallocatechin gallate (EGCG). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1080. doi:10.1158/1538-7445.AM2015-1080
Melanoma is an aggressive tumor of the skin. Although BRAF V600E inhibitors have been developed to treat melanoma, drug resistance and metastasis are still the major problems in melanoma therapy. Novel targets and effective agents to overcome drug resistant melanoma and reduce metastasis are urgently needed in clinical therapy. In this study, AURKB was defined as the target for melanoma therapy in an effort to overcome drug resistance. Notably, HI-511, a novel dual-target inhibitor for AURKB and BRAF V600E, inhibits development of both drug-sensitive and drug-resistant melanoma. We analyzed the Gene Expression Omnibus (GEO) database, utilized gene editing, and a xenograft mouse model to show AURKB is crucial for development of both drug-sensitive and drug-resistant melanoma. Inhibition of AURKB suppresses the cell growth and the rate of induced apoptosis in melanoma. Knocking down expression of AURKB decreased activation of the BRAF/MEK/ERKs and PI3K/AKT signaling pathways. Notably, a novel AURKB and BRAF V600E dual-target inhibitor HI-511 was developed. HI-511 strongly suppresses development of vemurafenib-sensitive and vemurafenib-resistant melanoma in vitro and in vivo, which is evidenced by in vitro kinase assays, cell base studies, xenograft mouse models and the BRAF V600E/PTEN-loss melanoma mouse model. Moreover, we also analysis the metastatic melanoma database and utilized the wound healing assay and a luciferase-linked xenograft mouse model to demonstrate HI-511 could reduce melanoma metastasis. Overall, AURKB could be a potential target for melanoma treatment and could overcome the resistance to BRAF V600E inhibitor and reduce melanoma metastasis. HI-511 is a novel dual-target inhibitor for both AURKB and BRAF V600E and could achieve durable suppression of melanoma, even drug-resistant melanoma and metastatic melanoma.
To investigate the morbidity of cerebrovascular disease among residents ≥30 years in Pengzhou, Sichuan Province, and analyze the effect of physical activity level on the risk of morbidity of cerebrovascular disease.
Abstract Glioblastoma is one of the most aggressive and treatment‐resistant forms of primary brain cancer, posing significant challenges in effective therapy. This study aimed to enhance the effectiveness of glioblastoma therapy by developing a unique nanomedicine composed of Pluronic F127‐complexed PEGylated poly(glutamic acid)‐cisplatin (PLG‐PEG/PF127‐CDDP). PLG‐PEG/PF127‐CDDP demonstrated an optimal size of 133.97 ± 12.60 nm, facilitating efficient cell uptake by GL261 glioma cells. In vitro studies showed significant cytotoxicity against glioma cells with a half‐maximal (50%) inhibitory concentration (IC50) of 12.61 µg mL −1 at 48 h and a 72.53% ± 1.89% reduction in cell invasion. Furthermore, PLG‐PEG/PF127‐CDDP prolonged the circulation half‐life of cisplatin to 9.75 h in vivo, leading to a more than 50% reduction in tumor size on day 16 post‐treatment initiation in a murine model of glioma. The treatment significantly elevated lactate levels in GL261 cells, indicating enhanced metabolic disruption. Therefore, PLG‐PEG/PF127‐CDDP offers a promising approach for glioblastoma therapy due to its effects on improving drug delivery efficiency, therapeutic outcomes, and safety while minimizing systemic side effects. This work underscores the potential of polymer‐based nanomedicines in overcoming the challenges of treating brain tumors, paving the way for future clinical applications.
MgxZn1–xO thin films were deposited on quartz glass substrate by radio-frequency magnetron sputtering using Mg0.4Zn0.6O as the target.The Mg contents in the thin films prepared at different substrate temperatures were analyzed by energy dispersive X-ray spectroscopy.The phase structures and optical properties of the thin films were investigated via X-ray diffraction and absorption spectra.The results show that the structure of the MgxZn1–xO films prepared at different substrate temperatures is hexagonal ZnO wurtzite with good c-axis orientation.And the(002) diffraction peak of the film with(002) orientation prepared at 200 ℃ is the strongest,which indicates that the film has good crystallinity at this temperature.The film prepared at substrate temperature of 300 ℃ has the highest Mg content of 0.438 mol,and its absorption edge at room temperature locates at 281 nm.
Abstract Barrett's esophagus (BE), a complication of gastroesophageal reflux disease (GERD), predisposes patients to esophageal adenocarcinoma (EAC). Reliable biomarkers for early detection and discovery of potential drug targets are urgently needed for improved BE and EAC patient outcomes. In this study, COX2 and TBXAS are highly expressed in BE and EAC patients accompanied by a pronounced elevation of circulating TXA2 levels in patient biopsy samples. Acetylsalicylic acid (ASA) suppressed BE and EAC growth by targeting the TXA2 pathway in a esophagoduodenostomy mouse model of reflux. Additionally, biopsies from patients showed that ASA substantially decreased serum TXA2 levels, resulting in reduced inflammation in a window opportunity clinical trial. Overall, this study establishes the importance of the COX1/2-driven TXA2 pathway in BE and EAC pathophysiology and lays the groundwork for introducing a TXA2-targeting strategy for EAC prevention and early detection. ASA targets the TXA2 pathway and suppresses BE and EAC. Citation Format: Tianshun Zhang, Qiushi Wang, Wei-Ya Ma, Keke Wang, Xiaoyu Chang, Michele L. Johnson, Ruihua Bai, Ann M. Bode, Nathan R. Foster, Gary W. Falk, Prasad G. Iyer, Zigang Dong. Inhibition of COX1/2-driven thromboxane A2 pathway suppresses Barrett's esophagus and esophageal adenocarcinoma development [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2593.
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