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Multi-target combinatory strategy to overcome tumor immune escape

《医学前沿（英文）》 2022年 第16卷 第2期   页码 208-215 doi: 10.1007/s11684-022-0922-5

摘要： Immune therapy has become the fourth approach after surgery, chemotherapy, and radiotherapy in cancer treatment. Many immune checkpoints were identified in the last decade since ipilimumab, which is the first immune checkpoint inhibitor to cytotoxic T-lymphocyte associated protein 4, had been approved by the US Food and Drug Administration (FDA) for the treatment of unresectable or metastatic melanoma in 2011. The use of several antibody drugs that target PD1/PD-L1 for various cancer treatments has been approved by the FDA. However, fewer people are benefitting from immune checkpoint inhibitor treatment in solid cancers. Approximately 80% of patients do not respond appropriately because of primary or acquired therapeutic resistance. Along with the characterization of more immune checkpoints, the combinatory treatment of multi-immune checkpoint inhibitors becomes a new option when monotherapy could not receive a good response. In this work, the author focuses on the combination therapy of multiple immune checkpoints (does not include targeted therapy of oncogenes or chemotherapy), introduces the current progression of multiple immune checkpoints and their related inhibitors, and discusses the advantages of combination therapy, as well as the risk of immune-related adverse events.

关键词： immune checkpoints     multi-target     immune escape     immune-related adverse events     combination therapy    

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Palmitoylation of GNAQ/11 is critical for tumor cell proliferation and survival in GNAQ/11-mutant uveal melanoma

《医学前沿（英文）》 2022年 第16卷 第5期   页码 784-798 doi: 10.1007/s11684-021-0911-0

摘要： More than 85% of patients with uveal melanoma (UM) carry a GNAQ or GNA11 mutation at a hotspot codon (Q209) that encodes G protein α subunit q/11 polypeptides (Gαq/11). GNAQ/11 relies on palmitoylation for membrane association and signal transduction. Despite the palmitoylation of GNAQ/11 was discovered long before, its implication in UM remains unclear. Here, results of palmitoylation-targeted mutagenesis and chemical interference approaches revealed that the loss of GNAQ/11 palmitoylation substantially affected tumor cell proliferation and survival in UM cells. Palmitoylation inhibition through the mutation of palmitoylation sites suppressed GNAQ/11Q209L-induced malignant transformation in NIH3T3 cells. Importantly, the palmitoylation-deficient oncogenic GNAQ/11 failed to rescue the cell death initiated by the knock down of endogenous GNAQ/11 oncogenes in UM cells, which are much more dependent on Gαq/11 signaling for cell survival and proliferation than other melanoma cells without GNAQ/11 mutations. Furthermore, the palmitoylation inhibitor, 2-bromopalmitate, also specifically disrupted Gαq/11 downstream signaling by interfering with the MAPK pathway and BCL2 survival pathway in GNAQ/11-mutant UM cells and showed a notable synergistic effect when applied in combination with the BCL2 inhibitor, ABT-199, in vitro. The findings validate that GNAQ/11 palmitoylation plays a critical role in UM and may serve as a promising therapeutic target for GNAQ/11-driven UM.

关键词： uveal melanoma     mutant GNAQ/11     palmitoylation     BCL2     combination target therapy    

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Silica-based nanoarchitecture for an optimal combination of photothermal and chemodynamic therapy functions

《化学科学与工程前沿（英文）》   页码 2144-2155 doi: 10.1007/s11705-023-2362-4

摘要： This study introduces multifunctional silica nanoparticles that exhibit both high photothermal and chemodynamic therapeutic activities, in addition to luminescence. The activity of the silica nanoparticles is derived from their plasmonic properties, which are a result of infusing the silica nanoparticles with multiple Cu2–xS cores. This infusion process is facilitated by a recoating of the silica nanoparticles with a cationic surfactant. The key factors that enable the internal incorporation of the Cu2–xS cores and the external deposition of red-emitting carbon dots are identified. The Cu2–xS cores within the silica nanoparticles exhibit both self-boosting generation of reactive oxygen species and high photothermal conversion efficacy, which are essential for photothermal and chemodynamic activities. The silica nanoparticles’ small size (no more than 70 nm) and high colloidal stability are prerequisites for their cell internalization. The internalization of the red-emitting silica nanoparticles within cells is visualized using fluorescence microscopy techniques. The chemodynamic activity of the silica nanoparticles is associated with their dark cytotoxicity, and the mechanisms of cell death are evaluated using an apoptotic assay. The photothermal activity of the silica nanoparticles is demonstrated by significant cell death under near-infrared (1064 nm) irradiation.

关键词： copper sulfide nanoparticles     chemodynamic therapy     photothermal therapy     carbon dots     silica nanoparticles    

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Immunotherapy-based combination strategies for treatment of gastrointestinal cancers: current status

Chenfei Zhou, Jun Zhang

《医学前沿（英文）》 2019年 第13卷 第1期   页码 12-23 doi: 10.1007/s11684-019-0685-9

摘要：

Strategies in comprehensive therapy for gastrointestinal (GI) cancer have been optimized in the last decades to improve patients’ outcomes. However, treatment options remain limited for late-stage or refractory diseases. The efficacy of immune checkpoint inhibitors (ICIs) for treatment of refractory GI cancer has been confirmed by randomized clinical trials. In 2017, pembrolizumab was approved by the US Food and Drug Administration as the first agent for treatment of metastatic solid tumors with mismatch repair deficiency, especially for colorectal cancer. Given the different mechanisms, oncologists have focused on determining whether ICIs-based combination strategies could achieve higher efficacy than conventional therapy alone in late-stage or even front-line treatment of GI cancer. This review discusses the current status of combining immune checkpoint inhibitors with molecular targeted therapy, chemotherapy, or radiotherapy in GI cancer in terms of mechanisms, safety, and efficacy to provide basis for future research.

关键词： gastrointestinal cancer     immune checkpoint inhibitor     combination therapy    

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mTOR-targeted cancer therapy: great target but disappointing clinical outcomes, why?

Shi-Yong Sun

《医学前沿（英文）》 2021年 第15卷 第2期   页码 221-231 doi: 10.1007/s11684-020-0812-7

摘要： The mammalian target of rapamycin (mTOR) critically regulates several essential biological functions, such as cell growth, metabolism, survival, and immune response by forming two important complexes, namely, mTOR complex 1 (mTORC1) and complex 2 (mTORC2). mTOR signaling is often dysregulated in cancers and has been considered an attractive cancer therapeutic target. Great efforts have been made to develop efficacious mTOR inhibitors, particularly mTOR kinase inhibitors, which suppress mTORC1 and mTORC2; however, major success has not been achieved. With the strong scientific rationale, the intriguing question is why cancers are insensitive or not responsive to mTOR-targeted cancer therapy in clinics. Beyond early findings on induced activation of PI3K/Akt, MEK/ERK, and Mnk/eIF4E survival signaling pathways that compromise the efficacy of rapalog-based cancer therapy, recent findings on the essential role of GSK3 in mediating cancer cell response to mTOR inhibitors and mTORC1 inhibition-induced upregulation of PD-L1 in cancer cells may provide some explanations. These new findings may also offer us the opportunity to rationally utilize mTOR inhibitors in cancer therapy. Further elucidation of the biology of complicated mTOR networks may bring us the hope to develop effective therapeutic strategies with mTOR inhibitors against cancer.

关键词： mTOR     cancer therapy     resistance     GSK3     protein degradation     E3 ubiquitin ligase     PD-L1    

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Molecular targeted therapy of gynecological malignant tumors: the development and challenge, from laboratory

Pengming SUN PhD, MD , Jalid SEHOULI PhD, MD , Lihui WEI BM ,

《医学前沿（英文）》 2009年 第3卷 第3期   页码 256-264 doi: 10.1007/s11684-009-0052-3

摘要： More and more molecular drugs based on targeted therapy have been utilized in the treatment of gynecologic cancer, especially in ovarian cancer. In this article, we systematically review the current targeted therapeutic trials running in clinic. Large, randomized trials have been conducted in the treatment of ovarian cancer, endometrial cancer and cervical cancer by using small molecule, antisense, mutational gene as well as antibodies. Other planned or ongoing trials currentlytargeted at molecular markers which may play important roles in gynecological carcinogenesis andprogression suggest that combination chemotherapy with molecular targeted therapy will ultimately be an importantoption.

关键词： target therapy     gynecologic malignant tumors     clinical trail     molecular medicine    

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A small-molecule pan-HER inhibitor alone or in combination with cisplatin exerts efficacy against nasopharyngeal

《医学前沿（英文）》 2023年 第17卷 第2期   页码 275-289 doi: 10.1007/s11684-022-0945-y

摘要： The abnormal activation of HER family kinase activity is closely related to the development of human malignancies. In this study, we used HER kinases as targets for the treatment of nasopharyngeal carcinoma (NPC) and explored the anti-tumor effects of the novel pan-HER inhibitor HM781-36B, alone or in combination with cisplatin. We found that HER family proteins were positively expressed in tumor tissues of some NPC patients, and the high levels of those proteins were significantly related to poor prognosis. HM781-36B inhibited NPC in vitro and in vivo. HM781-36B exerted synergistic effects with cisplatin on inhibiting proliferation and promoting apoptosis of NPC cells. In NPC xenograft models in nude mice, HM781-36B and cisplatin synergistically inhibited tumor growth. Downregulating the activity of HER family proteins and their downstream signaling pathways and regulating tumor microenvironment may explain the synergistic anti-tumor effects of HM781-36B and cisplatin. In conclusion, our study provides evidence for HER family proteins as prognostic biomarkers and potential therapeutic targets for NPC. The pan-HER inhibitor HM781-36B alone or in combination with cisplatin represents promising therapeutic effects for the treatment of NPC patients, which provides a new idea for the comprehensive treatment of NPC.

关键词： epidermal growth factor receptor     ErbB receptors     HM781-36B     nasopharyngeal carcinoma     molecular targeted therapy     cisplatin    

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Protein phosphatase magnesium-dependent 1δ is a novel tumor marker and target in hepatocellular carcinoma

null

《医学前沿（英文）》 2016年 第10卷 第1期   页码 52-60 doi: 10.1007/s11684-016-0433-3

摘要：

Hepatocellular carcinoma (HCC) is a lethal liver malignancy worldwide. In this study, we reported that protein phosphatase magnesium-dependent 1δ (PPM1D) was highly expressed in the majority of HCC cases (approximately 59%) and significantly associated with high serum α-fetoprotein (AFP) level (P= 0.044). Kaplan-Meier and Cox regression data indicated that PPM1D overexpression was an independent predictor of HCC-specific overall survival (HR, 2.799; 95% CI, 1.346–5.818, P = 0.006). Overexpressing PPM1D promoted cell viability and invasion, whereas RNA interference-mediated knockdown of PPM1D inhibited proliferation, invasion, and migration of cultured HCC cells. In addition, PPM1D suppression by small interfering RNA decreased the tumorigenicity of HCC cells in vivo. Overall, results suggest that PPM1D is a potential prognostic marker and therapeutic target for HCC.

关键词： PPM1D     hepatocellular carcinoma     prognosis     target therapy    

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Curcumin based combination therapy for anti-breast cancer: from

Sunhui Chen,Qiuling Liang,Shuping Xie,Ergang Liu,Zhili Yu,Lu Sun,Meong Cheol Shin,Seung Jin Lee,Huining He,Victor C. Yang

《化学科学与工程前沿（英文）》 2016年 第10卷 第3期   页码 383-388 doi: 10.1007/s11705-016-1574-2

摘要： While drug resistance appears to be an inevitable problem of an increasing number of anticancer drugs in monotherapy, combination drug therapy has become a prosperous method to reduce the administered total drug dosages as well as overcome the drug resistance of carcinoma cells. Curcumin, considered to possess multi-faceted roles in cancer treatment according to its multiple anti-neoplastic mechanisms as a depressor of chemo-resistance, can significantly facilitate its anti-cancer functions and improve therapeutic effects via combination usage with a variety of other drugs with different reaction mechanisms. To explore this possibility, four anti-cancer chemotherapeutic agents that all possess a certain degree of drug resistance problems, including three tyrosine kinase inhibitors (erlotinib, sunitinib and sorafenib) that are acting on different cell pathways and a typical anticancer drug doxorubicin, were combined with curcumin individually to examine the synergistic anti-tumor effect both and . Results revealed that sunitinib combined with curcumin at the molar ratio of 0.46 yielded the most potent synergistic effect , and was therefore chosen for further animal evaluation. To further enhance the anti-cancer effect, bovine serum albumin (BSA) nanoparticles were utilized as a carrier to deliver the selected drug combination . Preliminary findings confirmed our hypothesis of being able to maintain a similar injected drug ratio for prolonged time periods in tested animals by our approach, thereby maximizing the therapeutic potency yet minimizing the toxicity of these drugs. This work could open up a new avenue on combination drug therapy and realization the clinical utility of such drugs.

关键词： curcumin     sunitinib     synergistic effect     bovine serum albumin (BSA)     nano-carriers    

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Probes and nano-delivery systems targeting NAD(P)H:quinone oxidoreductase 1: a mini-review

《化学科学与工程前沿（英文）》 2023年 第17卷 第2期   页码 123-138 doi: 10.1007/s11705-022-2194-7

摘要： The two-electron cytoplasmic reductase NAD(P)H:quinone oxidoreductase 1 is expressed in many tissues. NAD(P)H:quinone oxidoreductase 1 is well-known for being highly expressed in most cancers. Therefore, it could be a target for cancer therapy. Because it is a quinone reductase, many bioimaging probes based on quinone structures target NAD(P)H:quinone oxidoreductase 1 to diagnose tumours. Its expression is higher in tumours than in normal tissues, and using target drugs such as β-lapachone to reduce side effects in normal tissues can help. However, the physicochemical properties of β-lapachone limit its application. The problem can be solved by using nanosystems to deliver β-lapachone. This mini-review summarizes quinone-based fluorescent, near-infrared and two-photon fluorescent probes, as well as nanosystems for delivering the NAD(P)H:quinone oxidoreductase 1-activating drug β-lapachone. This review provides valuable information for the future development of probes and nano-delivery systems that target NAD(P)H:quinone oxidoreductase 1.

关键词： NAD(P)H:quinone oxidoreductase 1     cancer therapy     target     probe     nanosystem    

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New method for efficient control of hydrogen sulfide and methane in gravity sewers: Combination of NaOH

《环境科学与工程前沿（英文）》 2022年 第16卷 第6期 doi: 10.1007/s11783-021-1509-0

摘要：

• The combination of NaOH and nitrite was used to control harmful gas in sewers.

关键词： Sewer corrosion     Sulfide control     Combination treatment     NaOH     Nitrite    

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How to judge the association of postmenopausal hormone therapy and the risk of breast cancer

Ling XU

《医学前沿（英文）》 2010年 第4卷 第3期   页码 290-293 doi: 10.1007/s11684-010-0093-7

摘要： The relevance of postmenopausal hormone therapy (HT) for breast cancer risk has been long debated, although it is one of the most important barriers for women to accept HT. Various opinions have been reported from recent randomized clinical trials and epidemiological studies. These unanswered questions include: whether HT has a positive impact on breast cancer; whether risks of therapy with unopposed estrogen and combined estrogen-progestin are different; and whether different types and routes of estrogen and progestogens, as well as the duration and cessation of HT use, have different impacts on this disorder. Recently, there has been some good news such as the following: the currently available data do not provide sufficient evidence to prove a causal relationship between postmenopausal HT and breast cancer; breast cancer in postmenopausal women using HT usually has better prognosis than that of nonusers. In conclusion, HT is still the most effective method of relieving climacteric symptoms for many postmenopausal women. However, a possible risk of breast cancer associated with long-term HT usage should not be ignored. With respect to prevention of breast cancer, regular evaluation of individual breast cancer susceptibility and close follow-up through mammography and/or breast sonography are necessary strategies for the safety of HT use.

关键词： breast cancer     postmenopausal hormone therapy     unopposed estrogen therapy     combined estrogen-progestin therapy    

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Removal of virus aerosols by the combination of filtration and UV-C irradiation

《环境科学与工程前沿（英文）》 2023年 第17卷 第3期 doi: 10.1007/s11783-023-1627-y

摘要：

● The removal of virus aerosols by filtration and UV-C irradiation was proposed.

关键词： Filtration system     UV-C irradiation     Virus aerosol     Public health     COVID-19    

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Particle therapy for cancers: a new weapon in radiation therapy

null

《医学前沿（英文）》 2012年 第6卷 第2期   页码 165-172 doi: 10.1007/s11684-012-0196-4

摘要：

Particle irradiation started to draw attention in the past decade and has now become a hotspot in the radiation oncology community. This article reviews the most advanced developments in particle irradiation, focusing on the characteristics of proton and carbon ions in radiation physics and radiobiology. The Bragg peak of physical dose distribution causes proton and carbon beams to optimally meet the requirement for cancer irradiation because the Bragg peak permits the accurate concentration of the dose on the tumor, thus sparing the adjacent normal tissues. Moreover, carbon ion has more radiobiological benefits than photon and proton beams. These benefits include stronger sterilization effects on intrinsic radio-resistant tumors and more effective killing of hypoxic, G0, and S phase cells. Compared with the most advanced radiation techniques using photon, such as three-dimensional conformal radiation therapy and intensity-modulated radiation therapy, proton therapy has yielded more promising outcomes in local control and survival for head and neck cancers, prostate carcinoma, and pediatric cancers. Carbon therapy in Japan showed even more promising results than proton therapy. The local controls and overall survivals were as good as that treated by surgery in early stages of non-small cell lung cancer, hepatocellular carcinoma, prostate carcinoma, and head and neck cancers, especially for such highly resistant tumors as melanoma. The non-invasive nature of particle therapy affords more patients with chances to receive and benefit from treatment. Particle therapy is gradually getting attention from the oncology community. However, the cost of particle therapy facilities has limited the worldwide use of this technology.

关键词： radiation therapy     particle therapy     proton     carbon     cancer    

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基于评价方法属性层次的组合评价研究

陈衍泰,陈国宏,李美娟

《中国工程科学》 2005年 第7卷 第8期   页码 56-59

摘要：

针对现存的多种单一综合评价方法机理、属性层次相异引起的对同一个对象评价结论不相容的问题，提出一种新的组合评价方法。定义了“具有相容性”与“特殊属性”的两类综合评价方法；建立了两个组合评价模型，分别将这两个属性层次方法所得的不一致的评价值与排序结论进行组合；在此基础上提出“复组合”的概念。并应用此模型对我国欠发达地区15个城市的综合实力进行评价，使得系统评价更具有科学性和实用性，为欠发达地区开发战略制订宏观经济政策提供实证基础。

关键词： 评价方法的属性层次     组合模型     复组合    

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标题 作者 时间 类型 操作

Multi-target combinatory strategy to overcome tumor immune escape

期刊论文

Palmitoylation of GNAQ/11 is critical for tumor cell proliferation and survival in GNAQ/11-mutant uveal melanoma

期刊论文

Silica-based nanoarchitecture for an optimal combination of photothermal and chemodynamic therapy functions

期刊论文

Immunotherapy-based combination strategies for treatment of gastrointestinal cancers: current status

Chenfei Zhou, Jun Zhang

期刊论文

mTOR-targeted cancer therapy: great target but disappointing clinical outcomes, why?

Shi-Yong Sun

期刊论文

Molecular targeted therapy of gynecological malignant tumors: the development and challenge, from laboratory

Pengming SUN PhD, MD , Jalid SEHOULI PhD, MD , Lihui WEI BM ,

期刊论文

A small-molecule pan-HER inhibitor alone or in combination with cisplatin exerts efficacy against nasopharyngeal

期刊论文

Protein phosphatase magnesium-dependent 1δ is a novel tumor marker and target in hepatocellular carcinoma

null

期刊论文

Curcumin based combination therapy for anti-breast cancer: from

Sunhui Chen,Qiuling Liang,Shuping Xie,Ergang Liu,Zhili Yu,Lu Sun,Meong Cheol Shin,Seung Jin Lee,Huining He,Victor C. Yang

期刊论文

Probes and nano-delivery systems targeting NAD(P)H:quinone oxidoreductase 1: a mini-review

期刊论文

New method for efficient control of hydrogen sulfide and methane in gravity sewers: Combination of NaOH

期刊论文

How to judge the association of postmenopausal hormone therapy and the risk of breast cancer

Ling XU

期刊论文

Removal of virus aerosols by the combination of filtration and UV-C irradiation

期刊论文

Particle therapy for cancers: a new weapon in radiation therapy

null

期刊论文

基于评价方法属性层次的组合评价研究

陈衍泰,陈国宏,李美娟

期刊论文