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Combined gemcitabine and CHK1 inhibitor treatment induces apoptosis resistance in cancer stem cell-like

null

《医学前沿（英文）》 2013年第7卷第4期页码 462-476 doi: 10.1007/s11684-013-0270-6

摘要：

Evaluating the effects of novel drugs on appropriate tumor models has become crucial for developing more effective therapies that target highly tumorigenic and drug-resistant cancer stem cell (CSC) populations. In this study, we demonstrate that a subset of cancer cells with CSC properties may be enriched into tumor spheroids under stem cell conditions from a non-small cell lung cancer cell line. Treating these CSC-like cells with gemcitabine alone and a combination of gemcitabine and the novel CHK1 inhibitor PF-00477736 revealed that PF-00477736 enhances the anti-proliferative effect of gemcitabine against both the parental and the CSC-like cell populations. However, the CSC-like cells exhibited resistance to gemcitabine-induced apoptosis. Collectively, the spheroid-forming CSC-like cells may serve as a model system for understanding the mechanism underlying the drug resistance of CSCs and for guiding the development of better therapies that can inhibit tumor growth and eradicate CSCs.

关键词： drug resistance cancer stem cell checkpoint kinase 1 (CHK1) PF-00477736 lung cancer tumorigenicity

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protect breast cancer cells from accumulating replication stress by ensuring productive splicing of checkpointkinase 1

Andrew Best,Katherine James,Gerald Hysenaj,Alison Tyson-Capper,David J. Elliott

《化学科学与工程前沿（英文）》 2016年第10卷第2期页码 186-195 doi: 10.1007/s11705-015-1540-4

摘要： Increased expression levels of the RNA splicing regulator Transformer2 (abbreviated Tra2 ) have been reported in several types of cancer. Recent work has revealed an intimate cross-regulation between Tra2 and the highly similar Tra2 protein in human breast cancer cells, though these two proteins are encoded by separate genes created by a gene duplication that occurred over 500 million years ago. This cross-regulation involves splicing control of a special class of exons, called poison exons. Down-regulation of Tra2 reduces splicing inclusion of a poison exon in the mRNA encoding Tra2 , thereby up-regulating Tra2 protein expression. This buffers any splicing changes that might be caused by individual depletion of Tra2 alone. Discovery of this cross-regulation pathway, and its by-pass by joint depletion of both human Tra2 proteins, revealed Tra2 proteins are essential for breast cancer cell viability, and led to the identification of important targets for splicing control. These exons include a critical exon within the checkpoint kinase 1 (CHK1) gene that plays a crucial function in the protection of cancer cells from replication stress. Breast cancer cells depleted for Tra2 proteins have reduced CHK1 protein levels and accumulate DNA damage. These data suggest Tra2 proteins and/or their splicing targets as possible cancer drug targets.

关键词： RNA splicing gene expression breast cancer DNA damage CHK1

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Molecular classification and precision therapy of cancer: immune checkpoint inhibitors

null

《医学前沿（英文）》 2018年第12卷第2期页码 229-235 doi: 10.1007/s11684-017-0581-0

摘要：

On May 23, 2017, the US Food and Drug Administration (FDA) approved a treatment for cancer patients with positive microsatellite instability-high (MSI-H) markers or mismatch repair deficient (dMMR) markers. This approach is the first approved tumor treatment using a common biomarker rather than specified tumor locations in the body. FDA previously approved Keytruda for treatment of several types of malignancies, such as metastatic melanoma, metastatic non-small-cell lung cancer, recurrent or metastatic head and neck cancer, refractory Hodgkin lymphoma, and urothelial carcinoma, all of which carry positive programmed death-1/programmed death-ligand 1 biomarkers. Therefore, indications of Keytruda significantly expanded. Several types of malignancies are disclosed by MSI-H status due to dMMR and characterized by increased neoantigen load, which elicits intense host immune response in tumor microenvironment, including portions of colorectal and gastric carcinomas. Currently, biomarker-based patient selection remains a challenge. Pathologists play important roles in evaluating histology and biomarker results and establishing detection methods. Taking gastric cancer as an example, its molecular classification is built on genome abnormalities, but it lacks acceptable clinical characteristics. Pathologists are expected to act as “genetic interpreters” or “genetic translators” and build a link between molecular subtypes with tumor histological features. Subsequently, by using their findings, oncologists will carry out targeted therapy based on molecular classification.

关键词： molecular classification precision medicine pembrolizumab PD-1/PD-L1 MSI-H

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Metabolic interventions combined with CTLA-4 and PD-1/PD-L1 blockade for the treatment of tumors: mechanisms

《医学前沿（英文）》页码 805-822 doi: 10.1007/s11684-023-1025-7

摘要： Immunotherapies based on immune checkpoint blockade (ICB) have significantly improved patient outcomes and offered new approaches to cancer therapy over the past decade. To date, immune checkpoint inhibitors (ICIs) of CTLA-4 and PD-1/PD-L1 represent the main class of immunotherapy. Blockade of CTLA-4 and PD-1/PD-L1 has shown remarkable efficacy in several specific types of cancers, however, a large subset of refractory patients presents poor responsiveness to ICB therapy; and the underlying mechanism remains elusive. Recently, numerous studies have revealed that metabolic reprogramming of tumor cells restrains immune responses by remodeling the tumor microenvironment (TME) with various products of metabolism, and combination therapies involving metabolic inhibitors and ICIs provide new approaches to cancer therapy. Nevertheless, a systematic summary is lacking regarding the manner by which different targetable metabolic pathways regulate immune checkpoints to overcome ICI resistance. Here, we demonstrate the generalized mechanism of targeting cancer metabolism at three crucial immune checkpoints (CTLA-4, PD-1, and PD-L1) to influence ICB therapy and propose potential combined immunotherapeutic strategies co-targeting tumor metabolic pathways and immune checkpoints.

关键词： CTLA-4 PD-1 PD-L1 immune checkpoint blockade (ICB) metabolic reprogramming combined tumor therapeutic strategies

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Activation of phagocytosis by immune checkpoint blockade

null

《医学前沿（英文）》 2018年第12卷第4期页码 473-480 doi: 10.1007/s11684-018-0657-5

摘要：

Inhibition of macrophage-mediated phagocytosis has emerged as an essential mechanism for tumor immune evasion. One mechanism inhibiting the innate response is the presence of the macrophage inhibitory molecule, signal regulatory protein-α (SIRPα), on tumor-associated macrophages (TAMs) and its cognate ligand cluster of differentiation 47 (CD47) on tumor cells in the tumor microenvironment. On the basis of a recently discovered programmed death protein 1 (PD-1) in TAMs, we discuss the potential inhibitory receptors that possess new functions beyond T cell exhaustion in this review. As more and more immune receptors are found to be expressed on TAMs, the corresponding therapies may also stimulate macrophages for phagocytosis and thereby provide extra anti-tumor benefits in cancer therapy. Therefore, identification of biomarkers and combinatorial therapeutic strategies, have the potential to improve the efficacy and safety profiles of current immunotherapies.

关键词： CD47 PD-1 PD-L1 immunotherapy TAM phagocytosis macrophage

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PD-1/PD-L1 blockade in cervical cancer: current studies and perspectives

Yumeng Wang, Guiling Li

《医学前沿（英文）》 2019年第13卷第4期页码 438-450 doi: 10.1007/s11684-018-0674-4

摘要： Cervical cancer (CC) is the fourth most commonly diagnosed female malignancy and a leading cause of cancer-related mortality worldwide, especially in developing countries. Despite the use of advanced screening and preventive vaccines, more than half of all CC cases are diagnosed at advanced stages, when therapeutic options are extremely limited and side effects are severe. Given these circumstances, new and effective treatments are needed. In recent years, exciting progress has been made in immunotherapies, including the rapid development of immune checkpoint inhibitors. Checkpoint blockades targeting the PD-1/PD-L1 axis have achieved effective clinical responses with acceptable toxicity by suppressing tumor progression and improving survival in several tumor types. In this review, we summarize recent advances in our understanding of the PD-1/PD-L1 signaling pathway, including the expression patterns of PD-1/PD-L1 and potential PD-1/PD-L1-related therapeutic strategies for CC.

关键词： PD-1 PD-L1 immune checkpoint blockade antibody immunotherapy cervical cancer

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Loss of liver kinase B1 causes planar polarity defects in cochlear hair cells in mice

null

《医学前沿（英文）》 2016年第10卷第4期页码 481-489 doi: 10.1007/s11684-016-0494-3

摘要：

The tumor suppressor gene liver kinase B1 (LKB1), also called STK11, encodes a serine/threonine kinase. LKB1 plays crucial roles in cell differentiation, proliferation, and polarity. In this study, LKB1 conditional knockout mice (LKB1^Pax2 CKO mice) were generated using Pax2-Cre mice to investigate the function of LKB1 in inner ear hair cells during early embryonic period. LKB1^Pax2 CKO mice died perinatally. Immunofluorescence and scanning electron microscopy revealed that stereociliary bundles in LKB1^Pax2 CKO mice were clustered and misoriented, respectively. Moreover, ectopic distribution of kinocilium bundles resulting from abnormal migration of kinocilium was observed in the mutant mice. The orientation of stereociliary bundles and the migration of kinocilia are critical indicators of planar cell polarity (PCP) of hair cells. LKB1 deficiency in LKB1^Pax2 CKO mice thus disrupted hair cell planar polarity during embryonic development. Our results suggest that LKB1 is required in PCP formation in cochlear hair cells in mice.

关键词： LKB1 stereociliary bundles kinocilium planar cell polarity hearing mice

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Monitoring checkpoint inhibitors: predictive biomarkers in immunotherapy

Min Zhang, Jingwen Yang, Wenjing Hua, Zhong Li, Zenghui Xu, Qijun Qian

《医学前沿（英文）》 2019年第13卷第1期页码 32-44 doi: 10.1007/s11684-018-0678-0

摘要：

Immunotherapy has become the fourth cancer therapy after surgery, chemotherapy, and radiotherapy. In particular, immune checkpoint inhibitors are proved to be unprecedentedly in increasing the overall survival rates of patients with refractory cancers, such as advanced melanoma, non-small cell lung cancer, and renal cell carcinoma. However, inhibitor therapies are only effective in a small proportion of patients with problems, such as side effects and high costs. Therefore, doctors urgently need reliable predictive biomarkers for checkpoint inhibitor therapies to choose the optimal therapies. Here, we review the biomarkers that can serve as potential predictors of the outcomes of immune checkpoint inhibitor treatment, including tumor-specific profiles and tumor microenvironment evaluation and other factors.

关键词： immune checkpoint companion diagnosis PD-L1 tumor mutation burden immune score

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PAK1 is a novel cardiac protective signaling molecule

null

《医学前沿（英文）》 2014年第8卷第4期页码 399-403 doi: 10.1007/s11684-014-0380-9

摘要：

We review here the novel cardiac protective effects of the multifunctional enzyme, p21-activated kinase 1 (PAK1), a member of a serine/threonine protein kinase family. Despite the large body of evidence from studies in noncardiac tissue indicating that PAK1 activity is key in the regulation of a number of cellular functions, the role of PAK1 in the heart has only been revealed over the past few years. In this review, we assemble an overview of the recent findings on PAK1 signaling in the heart, particularly its cardiac protective effects. We present a model for PAK1 signaling that provides a mechanism for specifically affecting cardiac cellular processes in which regulation of protein phosphorylation states by protein phosphatase 2A (PP2A) predominates. We discuss the anti-adrenergic and antihypertrophic cardiac protective effects of PAK1, as well as its role in maintaining ventricular Ca²⁺ homeostasis and electrophysiological stability under physiological, β-adrenergic and hypertrophic stress conditions.

关键词： p21-activated kinase 1 (PAK1) heart

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Liver-directed treatment is associated with improved survival and increased response to immune checkpoint

《医学前沿（英文）》页码 878-888 doi: 10.1007/s11684-023-0993-y

摘要： Metastases of uveal melanoma (UM) spread predominantly to the liver. Due to low response rates to systemic therapies, liver-directed therapies (LDT) are commonly used for tumor control. The impact of LDT on the response to systemic treatment is unknown. A total of 182 patients with metastatic UM treated with immune checkpoint blockade (ICB) were included in this analysis. Patients were recruited from prospective skin cancer centers and the German national skin cancer registry (ADOReg) of the German Dermatologic Cooperative Oncology Group (DeCOG). Two cohorts were compared: patients with LDT (cohort A, n = 78) versus those without LDT (cohort B, n = 104). Data were analyzed for response to treatment, progression-free survival (PFS), and overall survival (OS). The median OS was significantly longer in cohort A than in cohort B (20.1 vs. 13.8 months; P = 0.0016) and a trend towards improved PFS was observed for cohort A (3.0 vs. 2.5 months; P = 0.054). The objective response rate to any ICB (16.7% vs. 3.8%, P = 0.0073) and combined ICB (14.1% vs. 4.5%, P = 0.017) was more favorable in cohort A. Our data suggest that the combination of LDT with ICB may be associated with a survival benefit and higher treatment response to ICB in patients with metastatic UM.

关键词： uveal melanoma liver-directed therapy immune checkpoint blockade SIRT anti-PD-1 anti-CTLA-4

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The role of CDK1 siRNA interference in cell cycle and cell apoptosis

Hui XIAO PhD, Ming TIAN MM, Junna GE MM, Xin Wei MD, Zhaoming LI MM, Xiaolan LI MS, Deding TAO PhD, Junbo HU MD, Jianping GONG MD,

《医学前沿（英文）》 2009年第3卷第4期页码 384-389 doi: 10.1007/s11684-009-0070-1

摘要： In the present report, cyclin-dependent kinase1 (CDK1) siRNA was transfected into cells to silence the CDK1 gene expression and study its role in the cell cycle and cell apoptosis. The siRNA targeting CDK1 gene was chemically synthesized and transfected into Hela cells by lipofectamine 2000. The expression levels of CDK1 gene and protein were examined by real-time quantitative polymerase chain reaction (PCR) and Western blot, respectively. The cell cycle was analyzed by using DNA content analysis by flow cytometry. Cell apoptosis was detected by the Annexin V/PI method. The morphological changes of transfected cells were examined under the microscopy by Wright-Giemsa stain. CDK1 gene was successfully silenced by its siRNA, and the CDK1 protein expression level was decreased significantly, especially from 48thh to 60thh after transfection. The DNA content analysis showed that transfection of CDK1 siRNA led to cells accumulating in G/M phase. There was no significant difference in the apoptotic rate between transfected cells and the control cells after transfection of CDK1 siRNA for 48 or 60h. More double nucleus or multinucleus cells could be seen under the microscopy among the transfected cells. The decreased CDK1 expression by siRNA silencing gave rise to cell cycle arrest in G/M phase but did not induce apoptosis.

关键词： cyclin-dependent kinase1 siRNA interference cell cycle apoptosis

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灰色预测模型GM（１，１）的适用性分析及在火灾风险预测中的应用

陈子锦,王福亮,陆守香

《中国工程科学》 2007年第9卷第5期页码 91-94

摘要：

通过对灰色预测模型———GM（１，１）的理论分析，证明了该模型的预测值及其变化趋势均具有单调性，进而提出了GM（１，１）模型的适用性判据，并给出了该判据在火灾风险灰色预测中的应用实例。

关键词：火灾预测 GM(1 1)模型火灾伤人率

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渤海辽东带地质认识的突破与金县1-1大油田的发现

邓运华

《中国工程科学》 2011年第13卷第10期页码 13-18

摘要：在此认识指导下选择研究方向，评价有利目标，经钻探发现了金县1-1大油田，储量达1.5×10⁸ m³，充分显示了科研在油气勘探中的作用。

关键词：渤海辽东带金县1-1 地质认识大油田

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联邦无监督表示学习 Research Article

张凤达1,况琨1,陈隆1,游兆阳1,沈弢1,肖俊1,张寅1,吴超2,吴飞1,庄越挺1,李晓林3,4,5

《信息与电子工程前沿（英文）》 2023年第24卷第8期页码 1181-1193 doi: 10.1631/FITEE.2200268

摘要： FURL提出了两个新挑战：（1）客户端之间的数据分布转移（非独立同分布）会使本地模型专注于不同的类别，从而导致表示空间的不一致；（2）如果FURL中客户端之间没有统一的信息，客户端之间的表示就会错位。

关键词：联邦学习；无监督学习；表示学习；对比学习

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非等间距GM(1,1)幂模型及其工程应用

王正新,党耀国,刘思峰

《中国工程科学》 2012年第14卷第7期页码 98-102

摘要：

针对工程中大量存在的非等间距序列的建模问题，提出了非等间距GM(1, 1)幂模型。以平均相对误差绝对值最小化为目标，以模型参数之间的关系为约束，构建了一个非线性优化模型实现非等间距GM(1, 1)幂模型的参数估计。结果表明，非等间距GM(1, 1)幂模型的形式较为灵活，非等间距GM(1, 1)模型和灰色Verhulst模型均是非等间距GM(1, 1)幂模型的特殊情形，幂指数的优化有利于提高建模精度。最后通过一个工程实例验证了非等间距GM(1, 1)幂模型的有效性与实用性。