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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

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    

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    

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    

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

Role of the forkhead transcription factor FOXO-FOXM1 axis in cancer and drug resistance

null

《医学前沿(英文)》 2012年 第6卷 第4期   页码 376-380 doi: 10.1007/s11684-012-0228-0

摘要:

The forkhead transcription factors FOXO and FOXM1 have pivotal roles in tumorigenesis and in mediating chemotherapy sensitivity and resistance. Recent research shows that the forkhead transcription factor FOXM1 is a direct transcriptional target repressed by the forkhead protein FOXO3a, a vital downstream effector of the PI3K-AKT-FOXO signaling pathway. Intriguingly, FOXM1 and FOXO3a also compete for binding to the same gene targets, which have a role in chemotherapeutic drug action and sensitivity. An understanding of the role and regulation of the FOXO-FOXM1 axis will impact directly on our knowledge of chemotherapeutic drug action and resistance in patients, and provide new insights into the design of novel therapeutic strategy and reliable biomarkers for prediction of drug sensitivity.

关键词: FOXO3a     FOXM1     transcription factor     cancer     drug resistance     tumorigenesis    

Low-dose CT for lung cancer screening: opportunities and challenges

null

《医学前沿(英文)》 2018年 第12卷 第1期   页码 116-121 doi: 10.1007/s11684-017-0600-1

摘要:

Lung cancer is among the most frequently diagnosed cancers worldwide and the leading cause of cancer death in both males and females. Screening for lung cancer coupled with earlier intervention has long been studied as an approach to mortality reduction. However, minimal progress was achieved until recently, when low-dose spiral computed tomography (LDCT) screening demonstrated a 20% reduction in mortality from lung cancer in a randomized controlled trial (RCT), the National Lung Screening Trial, from the United States. On the basis of this finding, LDCT has been recommended for lung cancer screening in high-risk populations by several clinical guidelines. However, results from the following independent RCTs in Europe failed to show consistent conclusions. In addition, intractable problems gradually emerged with the progress of LDCT screening. This paper summarizes and discusses the main observations and challenges of LDCT screening for lung cancer. Before spreading implementation of LDCT screening, challenges, including high false-positive rates, overdiagnosis, enormous costs, and radiation risk, must be addressed. Complementary biomarkers and technical improvement are expected in the field of lung cancer screening in the near future.

关键词: lung cancer     low-dose computerized tomography     early detection     opportunities     challenges    

Developments in cancer prevention and treatment using traditional Chinese medicine

Hongsheng Lin, Jie Liu, Ying Zhang

《医学前沿(英文)》 2011年 第5卷 第2期   页码 127-133 doi: 10.1007/s11684-011-0137-7

摘要: Through the joint efforts of several generations of practitioners in traditional Chinese medicine (TCM) and integrated medicine of oncology, we have made some achievements in cancer treatment using TCM in over 50 years, including treatment concepts, methods, and basic and clinical research. Currently, TCM plays an indispensable role in cancer prevention and treatment. However, we also clearly recognize that there are some issues that have yet to be resolved. In the future, cancer treated with TCM will face unprecedented opportunities and challenges. This article reviews the developments of TCM in the treatment of cancer.

关键词: traditional Chinese medicine (TCM)     cancer    

Treatment of advanced non-small cell lung cancer with driver mutations: current applications and future

《医学前沿(英文)》 2023年 第17卷 第1期   页码 18-42 doi: 10.1007/s11684-022-0976-4

摘要: With the improved understanding of driver mutations in non-small cell lung cancer (NSCLC), expanding the targeted therapeutic options improved the survival and safety. However, responses to these agents are commonly temporary and incomplete. Moreover, even patients with the same oncogenic driver gene can respond diversely to the same agent. Furthermore, the therapeutic role of immune-checkpoint inhibitors (ICIs) in oncogene-driven NSCLC remains unclear. Therefore, this review aimed to classify the management of NSCLC with driver mutations based on the gene subtype, concomitant mutation, and dynamic alternation. Then, we provide an overview of the resistant mechanism of target therapy occurring in targeted alternations (“target-dependent resistance”) and in the parallel and downstream pathways (“target-independent resistance”). Thirdly, we discuss the effectiveness of ICIs for NSCLC with driver mutations and the combined therapeutic approaches that might reverse the immunosuppressive tumor immune microenvironment. Finally, we listed the emerging treatment strategies for the new oncogenic alternations, and proposed the perspective of NSCLC with driver mutations. This review will guide clinicians to design tailored treatments for NSCLC with driver mutations.

关键词: non-small cell lung cancer     driver mutations     treatment strategy     resistant mechanism     immune-checkpoint inhibitors    

Intracellular and extracellular TGF-β signaling in cancer: some recent topics

null

《医学前沿(英文)》 2018年 第12卷 第4期   页码 387-411 doi: 10.1007/s11684-018-0646-8

摘要:

Transforming growth factor (TGF)-β regulates a wide variety of cellular responses, including cell growth arrest, apoptosis, cell differentiation, motility, invasion, extracellular matrix production, tissue fibrosis, angiogenesis, and immune function. Although tumor-suppressive roles of TGF-β have been extensively studied and well-characterized in many cancers, especially at early stages, accumulating evidence has revealed the critical roles of TGF-β as a pro-tumorigenic factor in various types of cancer. This review will focus on recent findings regarding epithelial-mesenchymal transition (EMT) induced by TGF-β, in relation to crosstalk with some other signaling pathways, and the roles of TGF-β in lung and pancreatic cancers, in which TGF-β has been shown to be involved in cancer progression. Recent findings also strongly suggested that targeting TGF-β signaling using specific inhibitors may be useful for the treatment of some cancers. TGF-β plays a pivotal role in the differentiation and function of regulatory T cells (Tregs). TGF-β is produced as latent high molecular weight complexes, and the latent TGF-β complex expressed on the surface of Tregs contains glycoprotein A repetitions predominant (GARP, also known as leucine-rich repeat containing 32 or LRRC32). Inhibition of the TGF-β activities through regulation of the latent TGF-β complex activation will be discussed.

关键词: TGF-β     EMT     lung cancer     pancreatic cancer     latent form     immune function     GARP    

Dendritic cell vaccines in cancer immunotherapy: from biology to translational medicine

Hongmei Xu, Xuetao Cao

《医学前沿(英文)》 2011年 第5卷 第4期   页码 323-332 doi: 10.1007/s11684-011-0172-4

摘要:

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

null

《医学前沿(英文)》 2016年 第10卷 第1期   页码 41-51 doi: 10.1007/s11684-016-0429-z

摘要:

Midline2 (MID2) is an ubiquitin-conjugating E2 enzyme linked to tumor progression and a novel interacting partner of breast cancer 1, early-onset (BRCA1). However, the role of MID2 in breast cancer remains unknown. This study investigated the expression, prognostic value, and role of MID2 in breast cancer. The expression of MID2 mRNA and protein was significantly upregulated in breast cancer tissue and established cell lines compared with that in normal breast epithelial cells and paired adjacent non-tumor tissue (P<0.001). Immunohistochemical analysis demonstrated that MID2 was overexpressed in 272 of 284 (95.8%) paraffin-embedded, archived breast cancer tissue. Moreover, MID2 expression increased with advanced clinical stage (P<0.001). High MID2 expression was significantly associated with advanced clinical stages and T, N, and M staging (all P<0.05). Univariate and multivariate analyses indicated that high MID2 expression was an independent prognostic factor for poor overall survival in the entire cohort (93.73 vs. 172.1 months; P<0.001, log-rank test) and in subgroups with stages Tis+ I+ II and III+ IV. Furthermore, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide colony formation, and anchorage-independent growth ability assays were conducted. Results showed that siRNA silencing of MID2 expression significantly reduced MCF-7 and MDA-MB-231 cell proliferation in vitro and blocked the growth of MDA-MB-231 cell xenograft tumors in vivo (P<0.05). This study indicated that MID2 may be a novel prognostic marker and interventional target in breast cancer.

关键词: breast cancer     MID2     proliferation     overall survival     xenograft    

Breast cancer-associated fibroblasts: their roles in tumor initiation, progression and clinical applications

null

《医学前沿(英文)》 2016年 第10卷 第1期   页码 33-40 doi: 10.1007/s11684-016-0431-5

摘要:

Breast cancer is the most common malignant tumor in women, and the incidence of this disease has increased in recent years because of changes in diet, living environment, gestational age, and other unknown factors. Previous studies focused on cancer cells, but an increasing number of recent studies have analyzed the contribution of cancer microenvironment to the initiation and progression of breast cancer. Cancer-associated fibroblasts (CAFs), the most abundant cells in tumor stroma, secrete various active biomolecules, including extracellular matrix components, growth factors, cytokines, proteases, and hormones. CAFs not only facilitate the initiation, growth, angiogenesis, invasion, and metastasis of cancer but also serve as biomarkers in the clinical diagnosis, therapy, and prognosis of breast cancer. In this article, we reviewed the literature and summarized the research findings on CAFs in breast cancer.

关键词: cancer-associated fibroblast     breast cancer     progression     prognosis    

Exploring the cancer genome in the era of next-generation sequencing

null

《医学前沿(英文)》 2012年 第6卷 第1期   页码 48-55 doi: 10.1007/s11684-012-0182-x

摘要:

The emergence of next-generation sequencing technologies has led to dramatic advances in cancer genome studies. The increased efficiency and resolution of next-generation sequencing greatly facilitate the detection of genetic, genomic, and epigenomic alterations, such as single nucleotide mutations, small insertions and deletions, chromosomal rearrangements, copy number variations, and DNA methylation. Comprehensive analysis of cancer genomes through approaches of whole genome, exome, and transcriptome sequencing has significantly improved the understanding of cancer biology, diagnosis, and therapy. The present study briefly reviews the recent pioneering studies on cancer genome sequencing and provides an unprecedented insight into the landscape of genomic alterations in human sporadic cancers.

关键词: next-generation sequencing     cancer genome     whole genome sequencing     exome     transcriptome    

Hydroxyl radical-involved cancer therapy via Fenton reactions

《化学科学与工程前沿(英文)》 2022年 第16卷 第3期   页码 345-363 doi: 10.1007/s11705-021-2077-3

摘要: The tumor microenvironment features over-expressed hydrogen peroxide (H2O2). Thus, versatile therapeutic strategies based on H2O2 as a reaction substrate to generate hydroxyl radical (•OH) have been used as a prospective therapeutic method to boost anticancer efficiency. However, the limited Fenton catalysts and insufficient endogenous H2O2 content in tumor sites greatly hinder •OH production, failing to achieve the desired therapeutic effect. Therefore, supplying Fenton catalysts and elevating H2O2 levels into cancer cells are effective strategies to improve •OH generation. These therapeutic strategies are systematically discussed in this review. Furthermore, the challenges and future developments of hydroxyl radical-involved cancer therapy are discussed to improve therapeutic efficacy.

关键词: hydroxyl radical     Fenton catalyst     hydrogen peroxide     cancer therapy    

标题 作者 时间 类型 操作

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

期刊论文

Progress and challenges in RET-targeted cancer therapy

期刊论文

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

Yun Zhang, Robert A. Weinberg

期刊论文

Orlistat induces ferroptosis-like cell death of lung cancer cells

期刊论文

Metformin for cancer prevention

Yonghua Yang

期刊论文

Role of the forkhead transcription factor FOXO-FOXM1 axis in cancer and drug resistance

null

期刊论文

Low-dose CT for lung cancer screening: opportunities and challenges

null

期刊论文

Developments in cancer prevention and treatment using traditional Chinese medicine

Hongsheng Lin, Jie Liu, Ying Zhang

期刊论文

Treatment of advanced non-small cell lung cancer with driver mutations: current applications and future

期刊论文

Intracellular and extracellular TGF-β signaling in cancer: some recent topics

null

期刊论文

Dendritic cell vaccines in cancer immunotherapy: from biology to translational medicine

Hongmei Xu, Xuetao Cao

期刊论文

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

null

期刊论文

Breast cancer-associated fibroblasts: their roles in tumor initiation, progression and clinical applications

null

期刊论文

Exploring the cancer genome in the era of next-generation sequencing

null

期刊论文

Hydroxyl radical-involved cancer therapy via Fenton reactions

期刊论文