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Aldolase B attenuates clear cell renal cell carcinoma progression by inhibiting CtBP2

《医学前沿（英文）》 2023年第17卷第3期页码 503-517 doi: 10.1007/s11684-022-0947-9

摘要： Aldolase B (ALDOB), a glycolytic enzyme, is uniformly depleted in clear cell renal cell carcinoma (ccRCC) tissues. We previously showed that ALDOB inhibited proliferation through a mechanism independent of its enzymatic activity in ccRCC, but the mechanism was not unequivocally identified. We showed that the corepressor C-terminal-binding protein 2 (CtBP2) is a novel ALDOB-interacting protein in ccRCC. The CtBP2-to-ALDOB expression ratio in clinical samples was correlated with the expression of CtBP2 target genes and was associated with shorter survival. ALDOB inhibited CtBP2-mediated repression of multiple cell cycle inhibitor, proapoptotic, and epithelial marker genes. Furthermore, ALDOB overexpression decreased the proliferation and migration of ccRCC cells in an ALDOB-CtBP2 interaction-dependent manner. Mechanistically, our findings showed that ALDOB recruited acireductone dioxygenase 1, which catalyzes the synthesis of an endogenous inhibitor of CtBP2, 4-methylthio 2-oxobutyric acid. ALDOB functions as a scaffold to bring acireductone dioxygenase and CtBP2 in close proximity to potentiate acireductone dioxygenase-mediated inhibition of CtBP2, and this scaffolding effect was independent of ALDOB enzymatic activity. Moreover, increased ALDOB expression inhibited tumor growth in a xenograft model and decreased lung metastasis in vivo. Our findings reveal that ALDOB is a negative regulator of CtBP2 and inhibits tumor growth and metastasis in ccRCC.

关键词： ALDOB kidney cancer cell proliferation

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Normoalbuminuric diabetic kidney disease

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《医学前沿（英文）》 2017年第11卷第3期页码 310-318 doi: 10.1007/s11684-017-0542-7

摘要：

Diabetic kidney disease (DKD) is one of the primary causes of end-stage renal disease (ESRD). Early diagnosis is very important in preventing the development of DKD. Urinary albumin excretion rate (UAER) and glomerular filtration rate (GFR) are widely accepted as criteria for the diagnosis and clinical grading of DKD, and microalbuminuria has been recommended as the first clinical sign of DKD. The natural history of DKD has been divided into three stages: normoalbuminuria, microalbuminuria, and macroalbuminuria. However, this clinical paradigm has been questioned recently, as studies have shown that a portion of diabetes mellitus (DM) patients with normoalbuminuria have progressive renal insufficiency, referred to as normoalbuminuric diabetic kidney disease (NADKD) or nonalbuminuric diabetic nephropathy. Epidemiologic research has demonstrated that normoalbuminuric diabetic kidney disease is common, and the large number of NADKD patients suggests that the traditional paradigm needs to be shifted. Currently, the pathogenesis of NADKD remains unclear, but many clinical studies have identified some clinical and pathological features of NADKD. In addition, the long-term outcomes of NADKD patients remain controversial. In this article, we reviewed the latest studies addressing the pathogenesis, pathology, treatment and prevention of NADKD.

关键词： diabetes diabetic kidney disease normoalbuminuria renal impairment

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Successful kidney transplantation in highly sensitized patients

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《医学前沿（英文）》 2011年第5卷第1期页码 80-85 doi: 10.1007/s11684-011-0115-0

摘要：

Highly sensitized patients experience an increased number of rejection episodes and have poorer graft survival rates; hence, sensitization is a significant barrier to both access to and the success of organ transplantation. This study reports our experience in kidney transplantation in highly sensitized patients. Fourteen patients with sensitization or high levels of panel-reactive antibodies (PRA) were studied. All patients were desensitized with pre-transplant intravenous immunoglobulin (IVIG)/plasmapheresis (PP) with or without rituximab and thymoglobulin induction therapy, combined with a Prograf/MMF/Pred immunosuppressive regimen. Of 14 patients, 10 showed good graft functions without acute rejection (AR) episodes. Acute cellular rejection in two patients was reversed by methylprednisolone. Two patients underwent antibody-mediated rejection; one was treated with PP/IVIG successfully, whereas the other lost graft functions due to the de novoproduction of donor-specific antibodies (DSA). Graft functions were stable, and there were no AR episodes in other patients. Conclusively, desensitization using PP/IVIG with or without rituximab increases the likelihood of successful live-donor kidney transplantation in sensitized recipients.

关键词： Kidney transplantation desensitization

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Mechanisms of “kidney governing bones” theory in traditional Chinese medicine

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《医学前沿（英文）》 2014年第8卷第3期页码 389-393 doi: 10.1007/s11684-014-0362-y

摘要：

Studies conducted by our group on the mechanism of “kidney governing bones” theory in traditional Chinese medicine (TCM) are reviewed in this paper. Conclusions can be summarized as follows. (1) Neuroendocrine-immune network (NIN)-osteoclast regulatory pathway OPG-RANKL-RANK is one of the mechanisms of “kidney governing bones.” Although kidney-reinforcing therapy is regarded as one of the holistic regulatory mechanisms of the body, characteristic holistic regulation in TCM can be reflected through nonselective regulation of the NIN during kidney reinforcement therapy, which can be used to treat osteoporosis through microadjustments in the microenvironment of the bone marrow. (2) Marrow exhaustion in TCM, which is the state wherein lipocytes in the bone marrow increase whereas other cells decrease, serves as the pathogenesis of osteoporosis brought about by failure of the “kidney governing bones.” (3) The kidney in TCM can be regarded as a complex system comprising multiple functional units in the body, including the unit “governing bones.” Kidney deficiency refers to a deficiency in only one or more units of the kidney system and not the whole system itself, which explains the kidney-reinforcing effect of many herbs; some herbs can treat osteoporosis, but some cannot. Although both classified as kidney-reinforcing agents, the former can resolve failure of the “kidney governing bones” unit while the latter regulates the failure of other units in the kidney system. Despite the current understanding on “kidney governing bones” theory, the mechanism of “kidney governing bones” remains complicated and unresolved. Thus, further studies in this area are warranted.

关键词： kidney governing bones kidney deficiency marrow osteoporosis neuroendocrine-immune network osteoclast regulatory pathway

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Risk factors of prognosis after acute kidney injury in hospitalized patients

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《医学前沿（英文）》 2017年第11卷第3期页码 393-402 doi: 10.1007/s11684-017-0532-9

摘要：

The risk factors, especially laboratory indicators, of prognosis after acute kidney injury (AKI) remain unclear. We conducted a retrospective survey of Chinese People’s Liberation Army General Hospital from January 1, 2012 to December 31, 2012 according to the AKI diagnosis standard issued by Kidney Disease Improving Global Outcomes. The epidemiological features and factors influencing hospital mortality and renal function recovery were evaluated through logistic regression analysis. Among 77 662 cases of hospitalized patients, 1387 suffered from AKI. The incidence rate and mortality of AKI were 1.79% and 14.56%, respectively. Multivariate logistic regression analysis revealed that high AKI stage, age greater than 80 years, neoplastic disease, low cardiac output, increased white blood cell count, and decreased platelet count and serum albumin levels were the risk factors affecting the mortality of AKI patients. Conversely, body mass index between 28 and 34.9 was a protective factor. Increased AKI stage, tumor disease, post-cardiopulmonary resuscitation, and RRT were the risk factors of renal function recovery upon discharge. In addition to traditional risk factors, white blood cell count, platelet count, albumin, and BMI were the predictors of the mortality of AKI patients. No laboratory indicators were found to be the risk factors of renal function recovery in AKI patients.

关键词： acute kidney injury risk factors prognosis

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Effect of renal function and hemodialysis on the serum tumor markers in patients with chronic kidney

YU Xiaofang, XU Xialian, YE Zhibin

《医学前沿（英文）》 2007年第1卷第3期页码 308-311 doi: 10.1007/s11684-007-0059-6

摘要： In patients with chronic renal failure, whether they have had hemodialysis or not, the specificity of some of the serum tumor markers for the diagnosis of the corresponding tumors is decreased while others remain as valuable as they are in patients with normal kidney function. The detection of tumor markers is extensively used for the diagnosis of corresponding tumors. It has been recently shown that some tumor markers are higher in patients with chronic kidney disease (CKD) than in the normal population. The effects of renal function and hemodialysis were examined on serum levels of some of the tumor markers including CEA, CA, CA, AFP, CA, CA, CYFRA, NSE, SCC-Ag, PSA, and fPSA. The 232 non-dialysis patients with CKD and 37 chronic uremic patients treated with maintenance hemodialysis were enrolled in this study. The 232 non-dialysis patients were divided into three groups according to their Ccr. In group 1, Ccr was ≤25 mL/min. In group 2, Ccr was between 25 and 50 mL/min. In group 3, Ccr was ≥50 mL/min. The male patients were also divided into three groups to compare the serum levels of PSA and fPSA among the three groups. Nine tumor markers in 37 uremic patients were tested. For comparison, 37 non-dialysis patients with similar Ccr of the same age and gender served as controls. There existed significant differences in serum levels of CEA, CA, CYFRA, NSE, and SCC-Ag among different Ccr groups and the markers bore a negative correlation with Ccr. There were no significant differences among the three groups in the serum concentrations of CA, AFP, CA, CA, PSA and fPSA. The serum levels of CA and NSE were significantly higher (199, CYFRA, NSE, CA and SCC-Ag for the diagnosis of the corresponding tumors was decreased while serum AFP, CA, CA, PSA and fPSA were as valuable as they were in patients with normal kidney function. Hemodialysis further increased the serum level of CA and NSE.

关键词： CKD non-dialysis valuable detection chronic

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Netrin-1 works with UNC5B to regulate angiogenesis in diabetic kidney disease

Xiaojing Jiao, Dong Zhang, Quan Hong, Lei Yan, Qiuxia Han, Fengmin Shao, Guangyan Cai, Xiangmei Chen, Hanyu Zhu

《医学前沿（英文）》 2020年第14卷第3期页码 293-304 doi: 10.1007/s11684-019-0715-7

摘要： Netrin-1, an axon guidance factor, and its receptor UNC5B play important roles in axonal development and angiogenesis. This study examined netrin-1 and UNC5B expression in kidneys with diabetic kidney disease (DKD) and investigated their roles in angiogenesis. Netrin-1 and UNC5B were upregulated in streptozotocin-induced DKD Wistar rats, and their expression was compared with that in healthy controls. However, exogenous netrin-1 in UNC5B-depleted human renal glomerular endothelial cells (HRGECs) inhibited cell migration and tubulogenesis. This effect was likely associated with SRC pathway deactivation. Netrin-1 treatment also eliminated the pro-angiogenic effects of exogenous VEGF-165 on UNC5B-silenced HRGECs. These results indicate that UNC5B antagonizes netrin-1 and that UNC5B upregulation contributes partly to enhancing angiogenesis in DKD. Therefore, introducing exogenous netrin-1 and depleting endogenous UNC5B are potential strategies for reducing the incidence of early angiogenesis and mitigating kidney injury in DKD.

关键词： netrin-1 VEGF-165 UNC5B angiogenesis diabetic kidney disease

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Identification of differentially expressed miRNAs associated with chronic kidney disease–mineral bone

null

《医学前沿（英文）》 2017年第11卷第3期页码 378-385 doi: 10.1007/s11684-017-0541-8

摘要：

The purpose of this study is to characterize a meta-signature of differentially expressed mRNA in chronic kidney disease (CKD) to predict putative microRNA (miRNA) in CKD–mineral bone disorder (CKD–MBD) and confirm the changes in these genes and miRNA expression under uremic conditions by using a cell culture system. PubMed searches using MeSH terms and keywords related to CKD, uremia, and mRNA arrays were conducted. Through a computational analysis, a meta-signature that characterizes the significant intersection of differentially expressed mRNA and expected miRNAs associated with CKD–MBD was determined. Additionally, changes in gene and miRNA expressions under uremic conditions were confirmed with human Saos-2 osteoblast-like cells. A statistically significant mRNA meta-signature of upregulated and downregulated mRNA levels was identified. Furthermore, miRNA expression profiles were inferred, and computational analyses were performed with the imputed microRNA regulation based on weighted ranked expression and putative microRNA targets (IMRE) method to identify miRNAs associated with CKD occurrence. TLR4 and miR-146b levels were significantly associated with CKD–MBD. TLR4 levels were significantly downregulated, whereas pri-miR-146b and miR-146b were upregulated in the presence of uremic toxins in human Saos-2 osteoblast-like cells. Differentially expressed miRNAs associated with CKD-MBD were identified through a computational analysis, and changes in gene and miRNA expressions were confirmed with an in vitro cell culture system.

关键词： chronic kidney disease microRNA mineral bone disorder uremia

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Midline2 is overexpressed and a prognostic indicator in human breast cancer and promotes breast cancer

《医学前沿（英文）》 2021年第15卷第6期页码 942-942 doi: 10.1007/s11684-021-0876-z

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组织工程中肾脏血管化构建的领先方法 Review

Diana S. Lim, John D. Jackson, Anthony Atala, James J. Yoo

《工程（英文）》 2022年第19卷第12期页码 117-127 doi: 10.1016/j.eng.2022.05.004

摘要：

由于肾衰竭发病率升高的速度远超治疗方法进展的速度，因而对这种疾病的新的治疗方法的需求也以前所未有的速度不断增加。目前的治疗受制于可供应的活器官，而世界范围内均缺乏这种器官。这些治疗模式还需要大量的基础结构，这也极大地限制了大多数国家的患者获得医疗服务的机会。通过肾脏组织工程方法有望开发出替代的解决方案，解决目前治疗中仍存在的许多不足之处。尽管在生物制造和全器官组织工程方面已经取得了许多进展——主要是在过去的10 年中取得的，但仍然存在许多挑战。当前组织工程方法进展中的一个主要障碍是如何对已形成的工程化组织构建体实施成功的血管化。本文主要涉及近年来解决血管问题取得的进展，包括脉管系统的生物制造、通过脱细胞和再细胞化方法实施全器官工程、微尺度器官形成，以及在肾脏组织工程背景下使用类器官取得血管化。本文还着重探讨了在制定成功的临床转化策略中仍然存在的具体问题。

关键词：肾脏血管形成组织工程生物制造类器官

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Progress and challenges in RET-targeted cancer therapy

《医学前沿（英文）》 2023年第17卷第2期页码 207-219 doi: 10.1007/s11684-023-0985-y

摘要： The rearranged during transfection (RET) is a receptor protein tyrosine kinase. Oncogenic RET fusions or mutations are found most often in non-small cell lung cancer (NSCLC) and in thyroid cancer, but also increasingly in various types of cancers at low rates. In the last few years, two potent and selective RET protein tyrosine kinase inhibitors (TKIs), pralsetinib (BLU-667) and selpercatinib (LOXO-292, LY3527723) were developed and received regulatory approval. Although pralsetinib and selpercatinib gave high overall response rates (ORRs), < 10% of patients achieved a complete response (CR). The RET TKI-tolerated residual tumors inevitably develop resistance by secondary target mutations, acquired alternative oncogenes, or MET amplification. RET G810 mutations located at the kinase solvent front site were identified as the major on-target mechanism of acquired resistance to both selpercatinib and pralsetinib. Several next-generation of RET TKIs capable of inhibiting the selpercatinib/pralsetinib-resistant RET mutants have progressed to clinical trials. However, it is likely that new TKI-adapted RET mutations will emerge to cause resistance to these next-generation of RET TKIs. Solving the problem requires a better understanding of the multiple mechanisms that support the RET TKI-tolerated persisters to identify a converging point of vulnerability to devise an effective co-treatment to eliminate the residual tumors.

关键词： pralsetinib selpercatinib RET-alteration lung cancer thyroid cancer tumor-agnostic therapy drug resistance

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FANG Baijun, SONG Yongping, LIN Quande, ZHAO Chunhua, SHI Mingxia

《医学前沿（英文）》 2007年第1卷第2期页码 185-191 doi: 10.1007/s11684-007-0035-1

摘要： Previously, we reported that a cell population derived from human fetal bone marrow (BM), termed here Flk1CD34 postembryonic pluripotent stem cells (PPSCs) that have the characteristics of mesenchymal stem cells (MSCs), could differentiate into ectodermal, endodermal and mesodermal cell types at the single cell level , and that these cells could also differentiate into the epithelium of liver, lung, gut, as well as the hematopoietic and endothelial lineages after transplantion into irradiated non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice. In this study, we further isolated pluripotent stem cells from human fetal heart, liver, muscle, lung, derma, kidney, and fat and then analyzed the characteristics and function of these stem cells. It was found that the phenotype of the culture-expanded pluripotent stem cells from different fetal tissues was similar to BM-derived Flk1CD34 PPSCs, i.e. Flk1 and CD44 positive, GlyA, CD34, CD45, class I-HLA and HLA-DR negative. Morphologically, these cells were fibroblast-like and the doubling time was about 30 h. More importantly, culture-expanded pluripotent stem cells from all these fetal tissues were able to differentiate into cells with morphologic and phenotypic characteristics of adipocytes, osteocytes, neurons, glial cells and hepatocytes. These pluripotent stem cells with characteristics similar to fetal BM-derived Flk1CD34 PPSCs can be selected and cultured from tissues other than the BM. This phenomenon may help explain the stem cell plasticity found in multiple human tissues. In addition, as fetal BM-derived Flk1CD34 PPSCs, these pluripotent stem cells from different fetal tissues had the capacity for self-renewal and multi-lineage differentiation even after being expanded for more than 40 population doublings . Thus, they may be an ideal source of stem cells for treatment of inherited or degenerative diseases.

关键词： endothelial phenomenon ectodermal Flk1CD34 postembryonic irradiated non-obese

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Epithelial-to-mesenchymal transition in cancer: complexity and opportunities

Yun Zhang, Robert A. Weinberg

《医学前沿（英文）》 2018年第12卷第4期页码 361-373 doi: 10.1007/s11684-018-0656-6

摘要：

The cell-biological program termed the epithelial-to-mesenchymal transition (EMT) plays an important role in both development and cancer progression. Depending on the contextual signals and intracellular gene circuits of a particular cell, this program can drive fully epithelial cells to enter into a series of phenotypic states arrayed along the epithelial-mesenchymal phenotypic axis. These cell states display distinctive cellular characteristics, including stemness, invasiveness, drug-resistance and the ability to form metastases at distant organs, and thereby contribute to cancer metastasis and relapse. Currently we still lack a coherent overview of the molecular and biochemical mechanisms inducing cells to enter various states along the epithelial-mesenchymal phenotypic spectrum. An improved understanding of the dynamic and plastic nature of the EMT program has the potential to yield novel therapies targeting this cellular program that may aid in the management of high-grade malignancies.

关键词： epithelial-to-mesenchymal transition cancer metastasis cancer stem cell

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Metformin for cancer prevention

Yonghua Yang

《医学前沿（英文）》 2011年第5卷第2期页码 115-117 doi: 10.1007/s11684-011-0112-3

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Orlistat induces ferroptosis-like cell death of lung cancer cells

《医学前沿（英文）》 2021年第15卷第6期页码 922-932 doi: 10.1007/s11684-020-0804-7

摘要： Aberrant de novo lipid synthesis is involved in the progression and treatment resistance of many types of cancers, including lung cancer; however, targeting the lipogenetic pathways for cancer therapy remains an unmet clinical need. In this study, we tested the anticancer activity of orlistat, an FDA-approved anti-obesity drug, in human and mouse cancer cells in vitro and in vivo, and we found that orlistat, as a single agent, inhibited the proliferation and viabilities of lung cancer cells and induced ferroptosis-like cell death in vitro. Mechanistically, we found that orlistat reduced the expression of GPX4, a central ferroptosis regulator, and induced lipid peroxidation. In addition, we systemically analyzed the genome-wide gene expression changes affected by orlistat treatment using RNA-seq and identified FAF2, a molecule regulating the lipid droplet homeostasis, as a novel target of orlistat. Moreover, in a mouse xenograft model, orlistat significantly inhibited tumor growth and reduced the tumor volumes compared with vehicle control (P<0.05). Our study showed a novel mechanism of the anticancer activity of orlistat and provided the rationale for repurposing this drug for the treatment of lung cancer and other types of cancer.

关键词： orlistat ferroptosis FAF2 lung cancer