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Functional role of ATM in the cellular response to DNA damage

Ming LIU, Wenxiang HU

《化学科学与工程前沿（英文）》 2011年 第5卷 第2期   页码 179-187 doi: 10.1007/s11705-009-0268-4

摘要： Ataxia-telangiectasia mutated (ATM) plays a key role in regulating the cellular response to ionizing radiation. The tumor-suppressor gene ATM, mutations in which cause the human genetic disease ataxia telangiectasia, encodes a key protein kinase that controls the cellular response to double-stranded breaks. Activation of ATM results in phosphorylation of many downstream targets that modulate numerous damage response pathways, most notably cell cycle checkpoints. Here, we highlight some of the new developments in the field in our understanding of the mechanism of activation of ATM and its signaling pathways, explore whether DNA double-strand breaks are the sole activators of ATM and ATM-dependent signaling pathways, and address some of the prominent, unanswered questions related to ATM and its function. The scope of this article is to provide a brief overview of the recent literature on this subject and to raise questions that could be addressed in future studies.

关键词： ataxia-telangiectasia mutated (ATM)     cell cycle checkpoint     DNA damage     signalling transduction    

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Analysis on carbon emission reduction intensity of fuel cell vehicles from a life-cycle perspective

《能源前沿（英文）》 doi: 10.1007/s11708-023-0909-1

摘要： The hydrogen fuel cell vehicle is rapidly developing in China for carbon reduction and neutrality. This paper evaluated the life-cycle cost and carbon emission of hydrogen energy via lots of field surveys, including hydrogen production and packing in chlor-alkali plants, transport by tube trailers, storage and refueling in hydrogen refueling stations (HRSs), and application for use in two different cities. It also conducted a comparative study for battery electric vehicles (BEVs) and internal combustion engine vehicles (ICEVs). The result indicates that hydrogen fuel cell vehicle (FCV) has the best environmental performance but the highest energy cost. However, a sufficient hydrogen supply can significantly reduce the carbon intensity and FCV energy cost of the current system. The carbon emission for FCV application has the potential to decrease by 73.1% in City A and 43.8% in City B. It only takes 11.0%–20.1% of the BEV emission and 8.2%–9.8% of the ICEV emission. The cost of FCV driving can be reduced by 39.1% in City A. Further improvement can be obtained with an economical and “greener” hydrogen production pathway.

关键词： hydrogen energy     life-cycle assessment (LCA)     fuel cell vehicle     carbon emission     energy cost    

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Innate immune checkpoint Siglec10 in cancers: mining of comprehensive omics data and validation in patient

《医学前沿（英文）》 2022年 第16卷 第4期   页码 596-609 doi: 10.1007/s11684-021-0868-z

摘要： Sialic acid binding Ig-like lectin 10 (Siglec10) is a member of innate immune checkpoints that inhibits the activation of immune cells through the interaction with its ligand CD24 on tumor cells. Here, by analyzing public databases containing 64 517 patients of 33 cancer types, we found that the expression of Siglec10 was altered in 18 types of cancers and was associated with the clinical outcomes of 11 cancer types. In particular, Siglec10 was upregulated in patients with kidney renal clear cell carcinoma (KIRC) and was inversely associated with the prognosis of the patients. In 131 KIRC patients of our settings, Siglec10 was elevated in the tumor tissues of 83 (63.4%) patients compared with that in their counterpart normal kidney tissues. Moreover, higher level of Siglec10 was associated with advanced disease (stages III and IV) and worse prognosis. Silencing of CD24 in KIRC cells significantly increased the number of Siglec10-expressing macrophages phagocytosing KIRC cells. In addition, luciferase activity assays suggested that Siglec10 was a potential target of the transcription factors c-FOS and GATA1, which were identified by data mining. These results demonstrate that Siglec10 may have important oncogenic functions in KIRC, and represents a novel target for the development of immunotherapies.

关键词： innate immune checkpoint     Siglec10     kidney renal clear cell carcinoma    

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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    

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Immunometabolism: a new dimension in immunotherapy resistance

《医学前沿（英文）》 2023年 第17卷 第4期   页码 585-616 doi: 10.1007/s11684-023-1012-z

摘要： Immune checkpoint inhibitors (ICIs) have demonstrated unparalleled clinical responses and revolutionized the paradigm of tumor treatment, while substantial patients remain unresponsive or develop resistance to ICIs as a single agent, which is traceable to cellular metabolic dysfunction. Although dysregulated metabolism has long been adjudged as a hallmark of tumor, it is now increasingly accepted that metabolic reprogramming is not exclusive to tumor cells but is also characteristic of immunocytes. Correspondingly, people used to pay more attention to the effect of tumor cell metabolism on immunocytes, but in practice immunocytes interact intimately with their own metabolic function in a way that has never been realized before during their activation and differentiation, which opens up a whole new frontier called immunometabolism. The metabolic intervention for tumor-infiltrating immunocytes could offer fresh opportunities to break the resistance and ameliorate existing ICI immunotherapy, whose crux might be to ascertain synergistic combinations of metabolic intervention with ICIs to reap synergic benefits and facilitate an adjusted anti-tumor immune response. Herein, we elaborate potential mechanisms underlying immunotherapy resistance from a novel dimension of metabolic reprogramming in diverse tumor-infiltrating immunocytes, and related metabolic intervention in the hope of offering a reference for targeting metabolic vulnerabilities to circumvent immunotherapeutic resistance.

关键词： immune cell     immunometabolism     metabolic reprogramming     immunotherapy     resistance     tumor microenvironment     immune checkpoint inhibitor    

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Challenges of NK cell-based immunotherapy in the new era

null

《医学前沿（英文）》 2018年 第12卷 第4期   页码 440-450 doi: tzg@ustc.edu.cn

摘要：

Natural killer cells (NKs) have a great potential for cancer immunotherapy because they can rapidly and directly kill transformed cells in the absence of antigen presensitization. Various cellular sources, including peripheral blood mononuclear cells (PBMCs), stem cells, and NK cell lines, have been used for producing NK cells. In particular, NK cells that expanded from allogeneic PBMCs exhibit better efficacy than those that did not. However, considering the safety, activities, and reliability of the cell products, researchers must develop an optimal protocol for producing NK cells from PBMCs in the manufacture setting and clinical therapeutic regimen. In this review, the challenges on NK cell-based therapeutic approaches and clinical outcomes are discussed.

关键词： natural killer cells     immunotherapy     adoptive transfer     genetic modification     immune checkpoint inhibitor    

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Discovery of small molecule degraders for modulating cell cycle

《医学前沿（英文）》   页码 823-854 doi: 10.1007/s11684-023-1027-5

摘要： The cell cycle is a complex process that involves DNA replication, protein expression, and cell division. Dysregulation of the cell cycle is associated with various diseases. Cyclin-dependent kinases (CDKs) and their corresponding cyclins are major proteins that regulate the cell cycle. In contrast to inhibition, a new approach called proteolysis-targeting chimeras (PROTACs) and molecular glues can eliminate both enzymatic and scaffold functions of CDKs and cyclins, achieving targeted degradation. The field of PROTACs and molecular glues has developed rapidly in recent years. In this article, we aim to summarize the latest developments of CDKs and cyclin protein degraders. The selectivity, application, validation and the current state of each CDK degrader will be overviewed. Additionally, possible methods are discussed for the development of degraders for CDK members that still lack them. Overall, this article provides a comprehensive summary of the latest advancements in CDK and cyclin protein degraders, which will be helpful for researchers working on this topic.

关键词： PROTAC     molecular glue     degrader     cell cycle     CDK     cyclin    

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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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Impact of siRNA targeting pirh2 on proliferation and cell cycle control of the lung adenocarcinoma cell

SU Yuan, JIN Yang, ZHANG Xiaoju, ZHOU Qiong, BAI Ming, ZHU Liping

《医学前沿（英文）》 2007年 第1卷 第4期   页码 359-363 doi: 10.1007/s11684-007-0069-4

摘要： The aim of this study was to investigate the role of pirh2 (p53-induced RING-H2) protein in the proliferation, apoptosis and cell cycle control of the lung cancer cell line A549. Pirh2 expression was detected by immunofluorescence, Western blot analysis and real-time polymerase chain reaction (PCR). Cell proliferation was assessed by cell counting kit-8 (CCK-8). Cell cycle control and apoptosis were analyzed by flow cytometry. The results showed that pirh2 was expressed in the cytoplasm of A549 cells. The inhibition of pirh2 expression by siRNA (psiRNA-pirh2) resulted in reduced cell proliferation and increased apoptosis. In addition, the number of G/G phase cells was increased but G/M cells were not affected significantly. Taken together, the inhibition of pirh2 expression in the lung adenocarcinoma cell line A549 resulted in reduced tumor cell growth via the inhibition of cell proliferation, the activation of apoptosis and the interruption of cell cycle transition.

关键词： control     interruption     cytoplasm     number     growth    

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Effects of galectin-3 inhibition on endometrial cell cycle and adhesion

LEI Caixia, ZHANG Wei, SUN Xiaowei, DU Guoping, WANG Li, LIU Yinkun

《医学前沿（英文）》 2007年 第1卷 第4期   页码 390-397 doi: 10.1007/s11684-007-0076-5

摘要： Galectin-3 (gal-3) and its ligands have been implicated in cell transformation and cancer metastasis. Gal-3 protein has been found in uterine epithelial cells adjacent to implanting blastocysts in different cell types. In order to investigate the role of gal-3 in the establishment of human endometrial receptivity, the expression of gal-3 in human endometrial cell line RL95-2 was silenced by RNA interference technology using gal-3 specific small RNA. The expression of gal-3 was detected by the reverse transcriptase-polymerase chain reaction and Western blot analysis. After the suppression of gal-3, cell cycle changes and the expression of integrin 1 were detected by flow cytometry. The adhesive ability of RL95-2 cells was analyzed by the adhesion test. Gal-3 siRNA transfection efficiency reached 70%–90%. The expression of gal-3 mRNA and protein in RL95-2 cells was strongly inhibited by 70%–90% after RNA interference. Inhibition of gal-3 expression decreased S-phase but increased G1 phase cells. Integrin 1 expression was down-regulated, and the adhesive ability of RL95-2 cells to fibronectin (FN) was significantly reduced. Gal-3 may be involved in the establishment of endometrial receptivity by regulating the proliferation and adhesion of endometrial cells. The influence on adhesion may be related with the integrin modulation.
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Screening responsive or resistant biomarkers of immune checkpoint inhibitors based on online databases

Zhen Xiang, Yingyan Yu

《医学前沿（英文）》 2019年 第13卷 第1期   页码 24-31 doi: 10.1007/s11684-019-0679-7

摘要： Immune checkpoint inhibitors are a promising strategy in the treatment of cancer, especially advanced types. However, not all patients are responsive to immune checkpoint inhibitors. The response rate depends on the immune microenvironment, tumor mutational burden (TMB), expression level of immune checkpoint proteins, and molecular subtypes of cancers. Along with the Cancer Genome Project, various open access databases, including The Cancer Genome Atlas and Gene Expression Omnibus, provide large volumes of data, which allow researchers to explore responsive or resistant biomarkers of immune checkpoint inhibitors. In this review, we introduced some methodologies on database selection, biomarker screening, current progress of immune checkpoint blockade in solid tumor treatment, possible mechanisms of drug resistance, strategies of overcoming resistance, and indications for immune checkpoint inhibitor therapy.

关键词： immune checkpoint blockade     sensitivity     resistance     data mining    

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Analysis of interactions of immune checkpoint inhibitors with antibiotics in cancer therapy

《医学前沿（英文）》 2022年 第16卷 第3期   页码 307-321 doi: 10.1007/s11684-022-0927-0

摘要： The discovery of immune checkpoint inhibitors, such as PD-1/PD-L1 and CTLA-4, has played an important role in the development of cancer immunotherapy. However, immune-related adverse events often occur because of the enhanced immune response enabled by these agents. Antibiotics are widely applied in clinical treatment, and they are inevitably used in combination with immune checkpoint inhibitors. Clinical practice has revealed that antibiotics can weaken the therapeutic response to immune checkpoint inhibitors. Studies have shown that the gut microbiota is essential for the interaction between immune checkpoint inhibitors and antibiotics, although the exact mechanisms remain unclear. This review focuses on the interactions between immune checkpoint inhibitors and antibiotics, with an in-depth discussion about the mechanisms and therapeutic potential of modulating gut microbiota, as well as other new combination strategies.

关键词： tumor immunotherapy     immune checkpoint inhibitor     antibiotics     gut microbiota     drug–drug interaction    

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Effects of 3-aminobenzamide on poly (ADP-ribose) polymerase expression, apoptosis and cell cycle progression

DU Xiang, ZHAO Hongguang, GUO Wei, GONG Shouliang, WANG Wen

《医学前沿（英文）》 2008年 第2卷 第2期   页码 204-206 doi: 10.1007/s11684-008-0039-5

摘要： The aim of this paper is to study the changes of apoptosis and cell cycle progression in HeLa cells after the poly (ADP-ribose) polymerase (PARP) was inhibited by its inhibitor 3-aminobenzamide (3-AB) and the mechanisms of PARP action on HeLa cells damaged by irradiation. Flow cytometry (FCM) was used to examine the PARP expression and the percentage of apoptotic cells and cell cycle progression. The percentage of HeLa cells with positive expression of PARP protein 2, 4, 8 and 12 h after administrated with 3-AB was significantly lower than that of the control ( < 0.01). The percentages of apoptotic cells in the 3-AB plus irradiation group at the time points of 2, 8, 12 and 24 h after 2 Gy irradiation were higher than that in the irradiation group ( < 0.01 or < 0.05) and the percentage of G cells decreased significantly ( < 0.01 or < 0.05). It indicates that 3-AB can rapidly inhibit PARP expression of HeLa cells, promote cell apoptosis and block G arrest induced by irradiation.

关键词： control     irradiation     apoptotic     progression     3-AB    

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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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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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标题 作者 时间 类型 操作

Functional role of ATM in the cellular response to DNA damage

Ming LIU, Wenxiang HU

期刊论文

Analysis on carbon emission reduction intensity of fuel cell vehicles from a life-cycle perspective

期刊论文

Innate immune checkpoint Siglec10 in cancers: mining of comprehensive omics data and validation in patient

期刊论文

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

期刊论文

Immunometabolism: a new dimension in immunotherapy resistance

期刊论文

Challenges of NK cell-based immunotherapy in the new era

null

期刊论文

Discovery of small molecule degraders for modulating cell cycle

期刊论文

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,

期刊论文

Impact of siRNA targeting pirh2 on proliferation and cell cycle control of the lung adenocarcinoma cell

SU Yuan, JIN Yang, ZHANG Xiaoju, ZHOU Qiong, BAI Ming, ZHU Liping

期刊论文

Effects of galectin-3 inhibition on endometrial cell cycle and adhesion

LEI Caixia, ZHANG Wei, SUN Xiaowei, DU Guoping, WANG Li, LIU Yinkun

期刊论文

Screening responsive or resistant biomarkers of immune checkpoint inhibitors based on online databases

Zhen Xiang, Yingyan Yu

期刊论文

Analysis of interactions of immune checkpoint inhibitors with antibiotics in cancer therapy

期刊论文

Effects of 3-aminobenzamide on poly (ADP-ribose) polymerase expression, apoptosis and cell cycle progression

DU Xiang, ZHAO Hongguang, GUO Wei, GONG Shouliang, WANG Wen

期刊论文

Monitoring checkpoint inhibitors: predictive biomarkers in immunotherapy

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

期刊论文

Molecular classification and precision therapy of cancer: immune checkpoint inhibitors

null

期刊论文