基于有监督的多视角图神经网络的药物组合协同预测算法

药物组合疗法在癌症治疗中具有重要应用价值。通过算法预测药物协同组合,可为生物学研究提供靶向指导,从而提高研究效率,降低实验成本。针对现有算法缺乏有效的药物互相作用建模方法、无法考虑细胞系之间的关系等问题,提出了一种基于多视角图神经网络的药物协同预测算法。首先,采用变分图自编码器来学习特定细胞系药物的向量表示;然后,通过多视角框架整合同一组织内其他细胞系的药物信息,提升药物表示向量的可靠性;最后通过引入已知的药物组合得分作为监督信号对模型进行监督训练,实现可靠的药物协同效果预测。在DrugComb数据集上的实验结果验证了本方法的有效性。

基于多种基因数据库分析乳清酸性蛋白4-二硫键核心结构域2(WFDC2)在卵巢癌中表达及意义

目的研究乳清酸性蛋白4-二硫键核心结构域2(WFDC2)在卵巢癌中的表达及临床意义。方法分别利用Bio GPS数据库、Oncomine数据库以及癌症细胞系百科全书(CCLE)和Kaplan-Meier Plotter数据库分析WFDC2基因在正常人体组织中的表达、卵巢癌组织中表达以及卵巢癌细胞系中的表达和卵巢癌患者预后生存分析。结果 Bio GPS数据库分析结果显示WFDC2在正常卵巢组织不表达; Oncomine数据库检索出417例样本,WFDC2表达水平有差异意义的结果 34项,其中WFDC2表达增高19项,WFDC2表达降低15项;对符合设定条件的7项研究进行Meta分析发现,WFDC2在卵巢癌组织中呈高表达状态; CCLE分析结果显示WFDC2在卵巢癌细胞系中也呈高表达状态; Kaplan-Meier Plotter数据库结果显示WFDC2高表达组的卵巢癌患者总生存时间较低表达组显著延长。结论 WFDC2在卵巢癌组织高表达,且与卵巢癌患者预后生存显著相关。

ST3GAL5通过激活PPAR和抑制PI3K/AKT途径抑制膀胱癌的恶性生物学行为

目的研究ST3β-半乳糖苷α-2,3-半乳糖基转移酶5(ST3GAL5)对膀胱尿路上皮癌(BLCA)生物学行为的影响和潜在机制。方法利用生物信息分析确定与膀胱癌相关的差异表达基因。然后筛选出合适的膀胱癌细胞系。体外实验通过细胞计数盒-8(CCK-8)、5-乙炔基-2′脱氧尿嘧啶核苷(EdU)、菌落形成实验、转孔迁移、流式细胞仪凋亡实验和划痕实验评估ST3GAL5对膀胱癌生物行为的影响。使用癌症基因组图谱(TCGA)数据库对ST3GAL5基因进行了京都基因和基因组百科全书(KEGG)、基因集富集分析(GSEA)。最后,使用Western-blot技术验证其增殖和转移的相关通路。结果生物信息学分析和实验测量的结合表明,ST3GAL5的表达在人类的BLCA细胞系中是异常下调的。通过癌症细胞系百科全书(CCLE)数据库,成功筛选出HT-1376细胞系进行体外实验。实验结果发现上调ST3GAL5后膀胱癌的恶性生物学行为被抑制。GSEA富集分析显示,ST3GAL5及其共表达的基因通过激活PPAR途径和抑制PI3K/AKT途径抑制了膀胱癌的细胞增殖、侵袭和转移。Western-blot实验结果验证了ST3GAL5在膀胱癌中过表达后,PPAR信号通路的关键蛋白出现了明显的增加,PI3K/AKT信号通路的关键蛋白出现了明显的减少(P<0.05)。结论ST3GAL5基因可能作为膀胱癌的致癌抑制基因,可能通过激活PPAR信号通路和抑制PI3K/AKT信号通路的相关分子来抑制膀胱癌细胞的增殖、侵袭和转移。

基于矩阵填充算法的抗癌药物敏感性预测

在已有矩阵填充模型的基础上,融入癌细胞系的相似性信息与抗癌药物的相似性信息,提出了一种低秩矩阵填充模型,用于预测因受试验条件等影响而缺失的抗癌药物敏感性数据。将模型应用在CGP数据库中有缺失值的抗癌药物敏感性数据中,利用已有数据训练新模型的参数,并利用训练得到的最优参数对CGP数据库中的数据进行预测,得到最优近似值。结果表明,相较于其他模型,该模型能有效提高对缺失数据的填充效果。

抗癌药物作用预测计算方法的研究现状与展望

对精准医疗即个体化医疗理念的探讨与实践是当下医学研究的热门课题,如果精准医疗的设想实现可为患者提供更加精确有效的治疗方案,而对癌症的研究是医学界尚未攻破且意义重大的研究课题,也是和精准医疗结合最密切的课题之一。应用生物信息学的计算方法可以通过分析患者的概况来为癌症患者的药物选择提供有效方案,从而提高癌症患者的生存率。通过参考多篇使用计算方法研究抗癌药物作用的研究成果,从数据源和网络分析、机器学习和深度学习等计算方法两个方面总结了当前的研究成果,并对该课题存在的问题与未来发展趋势做出了分析与展望。

Texosome-based drug delivery system for cancer therapy: from past to present

Rising worldwide cancer incidence and resistance to current anti-cancer drugs necessitate the need for new pharmaceutical compounds and drug delivery system. Malfunction of the immune system, particularly in the tumor microenvironment, causes tumor growth and enhances tumor progression. Thus, cancer immunotherapy can be an appropriate approach to provoke the systemic immune system to combat tumor expansion. Texosomesj which are endogenous nanovesicles released by all tumor cells, contribute to cell-cell communication and modify the phenotypic features of recipient cells due to the texosomes＇ ability to transport biological components. For this reason, texosome-based delivery system can be a valuable strategy for therapeutic purposes. To improve the pharmaceutical behavior of this system and to facilitate its use in medical applications, biotechnology approaches and mimetic techniques have been utilized. In this review, we present the development history oftexosome-based delivery systems and discuss the advantages and disadvantages of each system.

Myo-inositol reduces β-catenin activation in colitis

To assess dietary myo-inositol in reducing stem cell activation in colitis, and validate pβ-cateninS552 as a biomarker of recurrent dysplasia.METHODSWe examined the effects of dietary myo-inositol treatment on inflammation, pβ-cateninS552 and pAkt levels by histology and western blot in IL-10-/- and dextran sodium sulfate-treated colitic mice. Additionally, we assessed nuclear pβ-cateninS552 in patients treated with myo-inositol in a clinical trial, and in patients with and without a history of colitis-induced dysplasia.RESULTSIn mice, pβ-cateninS552 staining faithfully reported the effects of myo-inositol in reducing inflammation and intestinal stem cell activation. In a pilot clinical trial of myo-inositol administration in patients with a history of low grade dysplasia (LGD), two patients had reduced numbers of intestinal stem cell activation compared to the placebo control patient. In humans, pβ-cateninS552 staining discriminated ulcerative colitis patients with a history of LGD from those with benign disease.CONCLUSIONEnumerating crypts with increased numbers of pβ-cateninS552 - positive cells can be utilized as a biomarker in colitis-associated cancer chemoprevention trials.

Role of nuclear receptor NR4A2 in gastrointestinal inflammation and cancers

NR4A2 is a transcription factor belonging to the steroid orphan nuclear receptor superfamily.It was originally considered to be essential in the generation and maintenance of dopaminergic neurons,and associated with neurological disorders such as Parkinson's disease.Recently,NR4A2 has been found to play a critical role in some inflammatory diseases and cancer.NR4A2 can be efficiently trans-activated by some proinflammatory cytokines,such as tumor necrosis factor-α,interleukin-1β,and vascular endothelial growth factor(VEGF).The nuclear factor-κB signaling pathway serves as a principal regulator of inducible NR4A expression in immune cells.NR4A2 can trans-activate Foxp3,a hallmark specifically expressed in regulatory T(Treg) cells,and plays a critical role in the differentiation,maintenance,and function of Treg cells.NR4A2 in T lymphocytes is pivotal for Treg cell induction and suppression of aberrant induction of Th1 under physiological and pathological conditions.High density of Foxp3 + Treg cells is significantly associated with gastrointestinal inflammation,tumor immune escape,and disease progression.NR4A2 is produced at high levels in CD133 + colorectal carcinoma(CRC) cells and significantly upregulated by cyclooxygenase-2-derived prostaglandin E 2 in a cyclic adenosine monophosphate(cAMP)/protein kinase A(PKA)-dependent manner in CRC cells.The cAMP/PKA signaling pathway is the common pathway of NR4A2-related inflammation and cancer.NR4A2 trans-activates osteopontin,a direct target of the Wnt/β-catenin pathway associated with CRC invasion,metastasis,and poor prognosis.Knockdown of endogenous NR4A2 expression attenuates VEGF-induced endothelial cell proliferation,migration and in vivo angiogenesis.Taken together,NR4A2 emerges as an important nuclear factor linking gastrointestinal inflammation and cancer,especially CRC,and should serve as a candidate therapeutic target for inflammation-related gastrointestinal cancer.

Antiproliferative Activity of Kappaphycus Alvarezii Extract on Three Cancer Cell Lines （NCIH 460, HCT 116 and U 251）

The methanolic extract of red seaweed Kappaphycus alvarezii was evaluated against three different cancer cell lines to study for its antiproliferative effect. Lung cancer cell line （NCIH 460）, Colon cancer cell line （HCT 116） and Glial cell carcinoma （U 251） are the three selected cell lines investigated in this study. Different concentrations of methanol extract （0.01, 0.10, 1.00, 10.00 and 100.00 lag/mL respectively） of Kappaphycus alvarezii were prepared and screened by quantitative MTT （Microculture Tetrazolium） （3-（4, 5-dimethylthiazol）-2, 5-diphenyltetrazolium bromide） assay. MTT assay are the colorimetric assay which was applied to assess the viability and proliferation of cancer cells to determine the cytotoxicity of methanol extract ofK. alvarezii. The MTT test is based on the enzymatic reduction of the tetrazolium salt （MTT） to formazon crystals exclusively in living metabolically active cells developed purple color complex which was directly proportional to the viability of cells. To elucidate the in-vitro anticancer activity the Lethal Concentration （LC50）, Growth Inhibition （GI50） and Total Growth Inhibition （TGI） of the extract were investigated individually for each cancer celt line. Analysis of the extract has shown good cytotoxicity in all tested cancer cell lines, with an IC50 of 55 μg/mL against NCIH460 and U251, 65 μg/mL for HCT116 respectively. GI50 was found to be 5 μg/mL for NCIH 460 and 10 μg/mL for HCT 116 and U251 cell lines. TGI was 19 μg/mL for NCIH 460, 29 μg/mL for HCT 116 and 25 μg/mL for U 251 cell lines. The cytotoxicity of the extract were significantly high in Lung Cancer Cell line （NCIH 460） when compared to Colon Cancer Cell line （HCT 116） and Glial Cell Carcinoma （U251） in the following order NCIH 460 〉 HCT 116 〉 U251.

Determination of Antioxidant and Cytotoxic Activities of Red Seaweed, （Gracilaria manilaensis） against Different Cancer Cell Lines

Antioxidants play an important role in inhibiting and scavenging free radicals in human, providing protection against cellular damage in relation to cancer initiation. Seaweeds have been proved to have high antioxidant activity. Thus, this research was carried out to determine the antioxidant and anticancer properties of edible red seaweed, Gracilaria manilaensis （Gracilariales, Rhodophyta）. The extracts were prepared by Soxhlet extraction using organic solvents with different polarities. The antioxidant activities of extracts were determined in terms of their flee radical scavenging activity （RSA IC50） and total phenolic content （TPC）. The cytotoxic activity of extracts were tested against human ovarian cancer cell line （Caov-3）, human breast cancer cell line （MDA-MB-231 and MCF-7）, human cervical cell line （HeLa）, mouse fibroblast cell line （L929） and Madin-Darby canine kidney （MDCK） and the cell viability after 72 h incubation was determined by methylene blue assay. The findings showed that acetone extract has the lowest DPPH IC50 value followed by ethyl acetate extract. Both extracts also showed high values of TPC. Dichloromethane extract had the strongest cytotoxic on MDA-MB-231 （53.90 μg/mL ± 5.59 μg/mL） and HeLa （95.50 μg/mL）. While, acetone and ethyl acetate extracts were cytotoxic on MCF-7 （66.07 μg/mL） and Caov-3 （69.67 μg/mL ± 13.94 μg/mL）. It could be concluded that the antioxidant and cytotoxic activities of G. manilaensis were influenced by the types of solvents used and thus had a potential to develop as a cancer chemoprevention or anticancer agent against selected cancer.

基于ONCOMINE数据库荟萃分析BRCA1基因在肺癌中的表达及意义

为探讨BRCA1基因在肺癌中的表达及对肺癌患者预后生存意义,本研究利用(BioGPS,Oncomine,Kaplan-Meier Plotter)基因数据库和癌症细胞系百科全书(CCLE),分析BRCA1基因在正常人体组织中的表达以及差异表达情况,并对符合条件的研究进行Meta分析,同时分析BRCA1基因在肺癌组织细胞系中的表达和对肺癌患者预后生存意义。研究发现,BioGPS数据库显示BRCA1在正常肺癌组织中低表达(3.65±0.035);同时Oncomine数据库检索BRCA1基因有453项不同种类结果,35项结果表达有统计学差异意义,其中28项显示表达增高,7项显示表达降低,共有研究样本量229例;并对符合条件的5项研究进行Meta分析,发现BRCA1基因差异表达中位数值排名为34.0,p=2.51×10^-5;与CCLE检索BRCA1基因在肺癌组织细胞系中高表达的结果一致;Kaplan-Meier Plotter数据库检索结果表明BRCA1表达水平与患者的总生存预后周期相关(p=9.5×10^-6);并且BRCA1高表达组相对于低表达组的肺癌患者总体生存周期明显降低(p<0.05)。因此,通过深入挖掘Oncomine等数据库中BRCA1基因芯片信息,证实BRCA1基因在肺癌组织中呈现高表达状态,且与肺癌患者预后生存周期相关,为临床肺癌的治疗及基因靶向药物的研制提供重要依据。

Characterization of cancer stem-like cells in the side population cells of human gastric cancer cell line MKN-45

Objective:Side population(SP) cells may play a crucial role in tumorigenesis and the recurrence of cancer.Many kinds of cell lines and tissues have demonstrated the presence of SP cells,including several gastric cancer cell lines.This study is aimed to identify the cancer stem-like cells in the SP of gastric cancer cell line MKN-45.Methods:We used fluorescence activated cell sorting(FACS) to sort SP cells in the human gastric carcinoma cell line MKN-45(cells labeled with Hoechst 33342) and then characterized the cancer stem-like properties of SP cells.Results:This study found that the SP cells had higher clone formation efficiency than major population(MP) cells.Five stemness-related gene expression profiles,including OCT-4,SOX-2,NANOG,CD44,and adenosine triphosphate(ATP)-binding cassette transporters gene ABCG2,were tested in SP and MP cells using quantitative real-time reverse transcription polymerase chain reaction(RT-PCR).Western blot was used to show the difference of protein expression between SP and MP cells.Both results show that there was significantly higher protein expression in SP cells than in MP cells.When inoculated into non-obese diabetic/severe combined immunodeficiency(NOD/SCID) mice,SP cells show higher tumorigenesis tendency than MP cells.Conclusions:These results indicate that SP cells possess cancer stem cell properties and prove that SP cells from MKN-45 are gastric cancer stem-like cells.

Proteomic analysis of primary colon cancer-associated fibroblasts using the SELDI-ProteinChip platform

Objective： Cancer-associated fibroblasts （CAFs） are one of the hallmarks of the cancer microenvironment. Recent evidence has indicated that CAFs are more competent in enhancing cancer cell growth and migration than normal fibroblasts. However, the unique protein expression of CAFs has not been fully elucidated. This study aims to investigate the characterizations of colon CAFs by comparing the differential protein expression between CAFs and normal fibroblasts. Methods： Primary fibroblasts were isolated from surgical specimen of human colon cancer and matched normal colonic tissue. Purity of the cell population was verified through immunostain analysis. Total cell lysates and conditioned media from each group of cells were extracted, and protein expression analysis was con- ducted using the surface-enhanced laser desorption/ionization time-of-flight mass spectrometry （SELDI-TOF-MS） ProteinChip platform. Results： Most primary cells showed typical fibroblast-like features after two weeks. Increased proportion of a-smooth muscle actin-positive myofibroblasts was detected within the CAFs in four of the six pairs of primary cells. Fibroblast activation protein was weakly expressed in most cells without differences. Using SELDI-TOF-MS ProteinChip platform, four protein peaks mass over charge ratio （m/z） 1142, 3011, 4035, and 4945 were detected in the total cell lysates, and two protein peaks m/z 1368 and 1389 were detected in the conditioned media. The potential candidate proteins found in the Swiss-Prot database include morphogenetic neuropeptides, FMRFamide-related peptides, insulin-like growth factor II, thymosin 13-4-like protein 3, and tight junction-associated protein 1. Conclusions： Using the SELDI-ProteinChip platform, differential protein expressions were identified in colon CAFs compared with normal colonic stromal fibroblasts. The complex proteomic alternations in colon CAFs may play important roles related to the colon cancer microenvironment.

Complex roles of necroptosis in cancer

Necroptosis is a tightly regulated form of necrosis that requires the activation of receptor-interacting protein(RIP)kinases RIPK1 and RIPK3,as well as the RIPK3 substrate mixed lineage kinase domain-like protein(MLKL).Because of membrane rupture,necroptotic cells release damage-associated molecular patterns(DAMPs)that evoke immune responses.Necroptosis is emerging as an important cellular response in the modulation of cancer initiation,progression,and metastasis.Necroptosis of cancer cells is considered to be an immunogenic cell death capable of activating anti-tumor immunity.Necroptosis also participates in the promotion of myeloid cell-induced adaptive immune suppression and thus contributes to oncogenesis.In addition,necroptosis of endothelial cells and tumor cells is conducive to tumor metastasis.In this review,we summarize the current knowledge of the complex role of necroptosis in cancer and discuss the potential of targeting necroptosis components for cancer therapies.

Engineering a customized nanodrug delivery system at the cellular level for targeted cancer therapy

Drug administration customized to individual cells could intrinsically address cancer heterogeneity and provide a safe and effective method for delivering personalized treatment. To accomplish this, we developed a smart nanodrug delivery system characterized by cancer cell-targeted drug delivery and intracellular biomarker-responsive drug activation. This system was composed of a long-nicked DNA duplex formed by tandem hybridization of two extended antisense oligonucleotides whose ends were separately blocked with a cancer cell-specific aptamer, AS1411,and a replaceable anti-biomarker probe(ABP). We demonstrated that this DNA nanodrug was directed to cancer cells with the guidance power of AS 1411 and then activated by the presence of a given intracellular biomarker. By using such a belt-and-braces strategy, this DNA nanodrug system could safely and efficiently accelerate apoptosis of target cancer cells. Moreover, since the expression level of biomarkers tends to indicate the specific physiological state of individual cells, biomarker-responsive activation of the nanodrug is expected to enable customized drug administration at the cellular level.