• 【对人结肠癌细胞和神经细胞的苏拉明衍生物的双重筛选提供了具有降低毒性的新治疗剂。】 复制标题 收藏 收藏
    DOI:10.1016/0304-3835(91)90116-y 复制DOI
    作者列表:Baghdiguian S,Nickel P,Fantini J
    BACKGROUND & AIMS: :Suramin is a polyanionic compound currently used under evaluation for antineoplastic activity. One of the main problems encountered during clinical trials was an adverse neurotoxic effect, probably due to a direct cytotoxic effect on neural cells. Suramin is also known to trigger differentiation of human colon cancer cells, yet a chronic treatment induces a lysosomal storage disorder. The aim of this study was to evaluate suramin analogs for their effect: (i) on the lysosomal system of the human colon cancer cell clone HT29-D4; and (ii) on C6 glioma cell growth and morphology. One of the derivatives tested, NF036, induced terminal differentiation of HT29-D4 cells without any impairment of the lysosomal system. Furthermore, in contrast to suramin, NF036 did not alter C6 cell growth and morphology. We conclude that there is a relationship between the ability of a suramin derivative to induce a lysosomal storage disorder in human colon cancer cells and its neurotoxic effect. A double screening of suramin analogs on HT29-D4 and C6 cells allowed us to identify a new candidate antineoplastic drug: NF036.
    背景与目标: : 苏拉明是目前用于抗肿瘤活性评估的聚阴离子化合物。在临床试验中遇到的主要问题之一是不良的神经毒性作用,可能是由于对神经细胞的直接细胞毒性作用所致。苏拉明还已知会触发人结肠癌细胞的分化,但长期治疗会导致溶酶体贮积障碍。这项研究的目的是评估苏拉明类似物的作用 :( i) 对人结肠癌细胞克隆HT29-D4的溶酶体系统; (ii) 对C6神经胶质瘤细胞的生长和形态。测试的衍生物之一NF036诱导了HT29-D4细胞的终末分化,而溶酶体系统没有任何损伤。此外,与苏拉明相反,NF036没有改变C6细胞的生长和形态。我们得出的结论是,苏拉明衍生物在人结肠癌细胞中诱导溶酶体贮积障碍的能力与其神经毒性作用之间存在关系。苏拉明类似物在HT29-D4和C6细胞上的双重筛选使我们能够鉴定一种新的候选抗肿瘤药物: nf036。
  • 【结肠腺癌患者由胸膜炎引起的胸膜炎。】 复制标题 收藏 收藏
    DOI:10.1111/j.1439-0507.2008.01517.x 复制DOI
    作者列表:Koç AN,Mutlu Sarigüzel F,Artiş T
    BACKGROUND & AIMS: :Although Acremonium strictum is environmentally widespread as opportunistic mold, it may cause infection in patients who have immunodeficiency problems. In this study, Staphylococcus aureus and A. strictum were isolated from the pleural fluid of a patient with colon adenocarcinoma. The patient did not receive antifungal therapy because the patient died after the isolation of mold. The minimal inhibitory concentrations of amphotericin B, fluconazole, ketoconazole, itraconazole, voriconazole for the A. strictum strain isolated from pleural fluid were 0.125, 256, 2 and 1.5, 0.25 mug ml(-1) respectively. In conclusion, bacteria and fungus, especially opportunistic mold, should be taken into consideration in developing pleuritis in the patients with immune-deficiency.
    背景与目标: : 尽管在环境上广泛存在于条件性霉菌中,但它可能会导致有免疫缺陷问题的患者感染。在这项研究中,从结肠腺癌患者的胸膜液中分离出金黄色葡萄球菌和A. strictum。患者未接受抗真菌治疗,因为隔离分离霉菌后死亡。两性霉素b,氟康唑,酮康唑,伊曲康唑,伏立康唑对从胸腔积液中分离的A. strictum菌株的最小抑菌浓度分别为0.125,256,2和1.5,0.25 mug ml(-1)。总之,在免疫缺陷患者发生胸膜炎时应考虑细菌和真菌,尤其是机会性霉菌。
  • 【六磷酸肌醇对HT-29人结肠癌细胞系增殖的影响。】 复制标题 收藏 收藏
    DOI:10.3748/wjg.v12.i26.4137 复制DOI
    作者列表:Tian Y,Song Y
    BACKGROUND & AIMS: AIM:To investigate the effects of inositol hexaphosphate (IP(6)) on proliferation of HT-29 human colon carcinoma cell line. METHODS:Cells were exposed to various concentrations (0, 1.8, 3.3, 5.0, 8.0, 13.0 mmol/L) of IP(6) for a certain period of time. Its effect on growth of HT-29 cells was measured by MTT assay. The expressions of cell cycle regulators treated with IP(6) for 2 d were detected by immunocytochemistry. RESULTS:IP(6) inhibited the HT-29 cell growth in a dose- and time-dependent manner. Analysis of cell cycle regulator expression revealed that IP(6) reduced the abnormal expression of P53 and PCNA and induced the expression of P21. CONCLUSION:IP(6) has potent inhibitory effect on proliferation of HT-29 cells by modulating the expression of special cell cycle regulators.
    背景与目标:
  • 【无论p53状态如何,慢病毒短发夹RNA沉默胸苷酸激酶和阿霉素在结肠癌细胞中的合成致死率。】 复制标题 收藏 收藏
    DOI:10.1158/0008-5472.CAN-07-3069 复制DOI
    作者列表:Hu CM,Chang ZF
    BACKGROUND & AIMS: :Intracellular supply of dTTP is a highly regulated process and has been a key target for chemotherapeutic drug development. Thymidylate kinase (TMPK) is the key enzyme for dTTP formation in both de novo and salvage pathways. In this study, we used lentiviral-based small hairpin RNA to silence TMPK expression in p53(+/+) and p53(-/-) HCT-116 colon cancer cells. This approach was sufficient to decrease the dTTP pool gradually without affecting p53 expression and generating cytotoxicity. TMPK knockdown significantly increased doxorubicin sensitivity dramatically in p53-proficient, p53-null HCT-116, and LoVo colon cancer cells. The decrease in the dTTP pool using this approach augmented the DNA damage response and enhanced apoptotic induction after exposure to low-dose doxorubicin, leading to cell death. In contrast, silencing of thymidylate synthase which blocks the de novo pathway was incapable of sensitizing p53-null HCT-116 cells to doxorubicin-induced apoptosis because of the compensation by the salvage pathway. Our results suggest the lentiviral delivery of small hairpin RNA targeting TMPK in combination with a low dose of doxorubicin as a new approach to kill colon cancer cells regardless of p53 status.
    背景与目标: : dTTP的细胞内供应是一个高度调节的过程,并且一直是化学治疗药物开发的关键目标。胸苷酸激酶 (TMPK) 是从头和挽救途径中dTTP形成的关键酶。在这项研究中,我们使用基于慢病毒的小发夹RNA来沉默结肠癌细胞中p53 (/) 和p53(-/-) HCT-116 TMPK的表达。这种方法足以逐渐减少dTTP库,而不会影响p53表达并产生细胞毒性。TMPK敲低显着提高了p53-proficient,p53-null HCT-116和LoVo结肠癌细胞中阿霉素的敏感性。使用这种方法减少的dTTP库增加了DNA损伤反应,并增强了低剂量阿霉素暴露后的凋亡诱导,导致细胞死亡。相反,由于挽救途径的补偿,阻断从头途径的胸苷酸合酶的沉默不能使p53-null HCT-116细胞对阿霉素诱导的凋亡敏感。我们的结果表明,靶向TMPK的小发夹RNA的慢病毒递送与低剂量的阿霉素相结合,是一种杀死结肠癌细胞的新方法,而与p53状态无关。
  • 【CD44通过Lyn激酶和AKT磷酸化调节人结肠癌细胞中的细胞迁移。】 复制标题 收藏 收藏
    DOI:10.1016/j.yexmp.2007.04.008 复制DOI
    作者列表:Subramaniam V,Vincent IR,Gardner H,Chan E,Dhamko H,Jothy S
    BACKGROUND & AIMS: :Colon cancer is among the leading causes of cancer death in North America. CD44, an adhesion and antiapoptotic molecule is overexpressed in colon cancer. Cofilin is involved in the directional motility of cells. In the present study, we looked at how CD44 might modulate cell migration in human colon cancer via cofilin. We used a human colon cancer cell line, HT29, which expresses CD44, HT29 where CD44 expression was knocked down by siRNA, SW620, a human colon cancer cell line which does not express CD44, stably transfected exons of CD44 in SW620 cells and the colon from CD44 knockout and wild-type mouse. Western blot analysis of siRNA CD44 lysates showed increased level of AKT phosphorylation and decreased level of cofilin expression. Similar results were also observed with SW620 cells and CD44 knockout mouse colon lysates. Experiments using the AKT phosphorylation inhibitor LY294002 indicate that AKT phosphorylation downregulates cofilin. Immunoprecipitation studies showed CD44 complex formation with Lyn, providing an essential link between CD44 and AKT phosphorylation. LY294002 also stabilized Lyn from phosphorylated AKT, suggesting an interaction between Lyn and AKT phosphorylation. Immunocytochemistry showed that cofilin and Lyn expression were downregulated in siRNA CD44 cells and CD44 knockout mouse colon. siRNA CD44 cells had significantly less migration compared to HT29 vector. Given the well-defined roles of CD44, phosphorylated AKT in apoptosis and cancer, these results indicate that CD44-induced cell migration is dependent on its complex formation with Lyn and its consequent regulation of AKT phosphorylation and cofilin expression.
    背景与目标: : 结肠癌是北美癌症死亡的主要原因之一。CD44是一种粘附和抗凋亡分子,在结肠癌中过度表达。Cofilin参与细胞的定向运动。在本研究中,我们研究了CD44如何通过cofilin调节人结肠癌中的细胞迁移。我们使用了表达CD44,HT29的人结肠癌细胞系HT29,其中CD44表达被不表达CD44的人结肠癌细胞系siRNA SW620下调,SW620细胞和结肠中CD44的稳定转染外显子来自CD44基因敲除和野生型小鼠。siRNA CD44裂解物的Western印迹分析显示AKT磷酸化水平升高,cofilin表达水平降低。SW620细胞和CD44敲除小鼠结肠裂解物也观察到类似的结果。使用AKT磷酸化抑制剂LY294002的实验表明,AKT磷酸化下调了cofilin。免疫沉淀研究表明,与Lyn形成CD44复合物,在CD44和AKT磷酸化之间提供了重要的联系。LY294002还使Lyn从磷酸化的AKT中稳定下来,表明Lyn和AKT磷酸化之间存在相互作用。免疫细胞化学显示cofilin和Lyn在siRNA CD44细胞和CD44基因敲除小鼠结肠中的表达下调。与HT29载体相比,siRNA CD44细胞的迁移明显减少。鉴于CD44,磷酸化的AKT在细胞凋亡和癌症中的明确定义的作用,这些结果表明CD44-induced细胞迁移取决于其与Lyn的复合物形成及其对AKT磷酸化和cofilin表达的调节。
  • 【链球菌制剂 (OK-432) 增强NCC-ST-421对人结肠癌的细胞毒性的单克隆抗体。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Kawano Y,Watanabe M,Kubota T,Nishibori H,Kurihara N,Teramoto T,Kitajima M
    BACKGROUND & AIMS: The murine IgG3 monoclonal antibody NCC-ST-421 (ST-421), raised against human gastric cancer, shows strong reactivity with the Le(a)/Le(a) (al-fucosylated extended type 1 chain) antigen expressed on gastrointestinal (GI) cancer cells. ST-421 is capable of mediating both antibody-dependent cellular cytotoxicity (ADCC) by human peripheral blood lymphocytes (PBL), and complement dependent cytotoxicity (CDC). We investigated combination immunotherapy with OK-432, a streptococcal preparation, and ST-421 in vitro and in vivo. ADCC against Colo 205 (a human colon cancer cell line) was enhanced 2 to 3 fold after preincubation of PBL with OK-432 in vitro. These effect's were strongest when PBL were preincubated with OK-432 at a concentration of 0.5 ng/ml for 24 hours. In vivo, a human colon cancer xenograft model exhibited significant growth suppression after combined treatment with ST-421 and OK-432. Such combination immunotherapy may therefore be clinically useful in GI cancer.

    背景与目标: 抗人胃癌的鼠IgG3单克隆抗体NCC-ST-421 (ST-421) 与在胃肠道 (GI) 癌细胞上表达的Le(a)/Le(a) (al-岩藻糖基化的延伸1型链) 抗原显示出强反应性。ST-421能够介导人外周血淋巴细胞 (PBL) 的抗体依赖性细胞毒性 (ADCC) 和补体依赖性细胞毒性 (CDC)。我们研究了与OK-432 (一种链球菌制剂) 的联合免疫疗法,并在体外和体内ST-421。在体外用OK-432预孵育PBL后,针对Colo 205 (人结肠癌细胞系) 的ADCC增强2至3倍。当PBL与0.5 ng/ml浓度的OK-432预孵育24小时时,这些作用最强。在体内,人结肠癌异种移植模型在用ST-421和OK-432联合治疗后表现出显著的生长抑制。因此,这种联合免疫疗法可能在胃肠道癌症中具有临床意义。
  • 【天然化合物通过调节信号转导和miRNA表达在人结肠癌细胞中的抗癌作用。】 复制标题 收藏 收藏
    DOI:10.1016/j.jnutbio.2013.04.006 复制DOI
    作者列表:Kumazaki M,Noguchi S,Yasui Y,Iwasaki J,Shinohara H,Yamada N,Akao Y
    BACKGROUND & AIMS: :Much evidence indicates that various naturally occurring compounds have an anti-cancer effect, but the detailed mechanisms are not well understood. In this study, we selected anti-cancer phytochemicals such as epigallocatechin-3-gallate (EGCG), resveratrol (RES) and α-mangostin (α-M), all of which are well-characterized chemopreventive agents. We sought to elucidate the mechanism of their anti-cancer effects and the synergistic effects obtained by combined treatment with the anti-cancer drug 5-fluorouracil (5-FU) in three human colon cancer cell lines. The numbers of viable cells were consistently decreased by the treatment with EGCG, RES or α-M at more than 10 μM in all three cell lines tested. All compounds mainly induced apoptosis and suppressed the PI3K/Akt signaling pathway. Additionally, α-M, which had the greatest PI3K/Akt-suppressing activity, also suppressed MAP kinase (MAPK)/Erk1/2 signaling. Importantly, the combination treatment with RES and 5-FU induced a remarkably synergistic enhancement of growth inhibition and apoptosis through the additional suppression of the MAPK/Erk1/2 signaling pathway in colon cancer DLD-1 cells. Interestingly, RES increased the intracellular expression level of miR-34a, which down-regulated the target gene E2F3 and its downstream Sirt1, resulting in growth inhibition. These findings indicate that these compounds functioned as chemosensitizers when combined with anti-cancer drugs through the modulation of apoptotic and growth-related signaling pathways. Also, RES exerted its anti-cancer activity in part through a newly defined mechanism, i.e., the miR-34a/E2F3/Sirt1 cascade.
    背景与目标: : 许多证据表明,各种天然存在的化合物具有抗癌作用,但详细的机制尚不清楚。在这项研究中,我们选择了抗癌植物化学物质,例如epigallocatechin-3-gallate (EGCG),白藜芦醇 (RES) 和 α-甘露素 (α-M),它们都是特征良好的化学预防剂。我们试图阐明其抗癌作用的机制以及通过与抗癌药物5-氟尿嘧啶 (5-FU) 联合治疗在三种人结肠癌细胞系中获得的协同作用。在所有测试的三种细胞系中,通过使用超过10μm的EGCG,RES或 α-M处理,活细胞的数量持续减少。所有化合物均主要诱导细胞凋亡并抑制PI3K/Akt信号通路。此外,具有最大PI3K/Akt抑制活性的 α-M也抑制了MAP激酶 (MAPK)/Erk1/2信号传导。重要的是,RES和5-FU的联合治疗通过额外抑制结肠癌DLD-1细胞中的MAPK/Erk1/2信号通路,诱导生长抑制和凋亡的显著协同增强。有趣的是,RES增加了miR-34a的细胞内表达水平,从而下调了靶基因E2F3及其下游Sirt1,从而导致生长抑制。这些发现表明,当这些化合物与抗癌药物结合时,通过调节凋亡和与生长相关的信号通路发挥化学增敏作用。此外,RES部分地通过新定义的机制,即miR-34a/E2F3/Sirt1级联发挥其抗癌活性。
  • 【大肠异时性腺瘤的化学预防: 钙和纤维随机试验的设计和中期结果。ECP结肠组。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Faivre J,Couillault C,Kronborg O,Rath U,Giacosa A,De Oliveira H,Obrador T,O'Morain O
    BACKGROUND & AIMS: A European multicentric intervention study, led by the colon group of the European Cancer Prevention Organization, is under way. The main aim of the study is to test the efficacy of oral calcium supplementation with 2 g calcium per day and oral dietary supplementation with mucilaginous substances (as 3.8 g of ispaghula husk) on adenoma recurrence. Secondary aims are the study of treatment efficacy on colonic cell proliferation and on stool bile acid and sterol concentration. Serum and plasma samples are also collected. To better interpret the effect of the intervention, a diet history questionnaire and an aspirin and anti-inflammatory drug questionnaire are administered. The aim will be achieved through a randomized placebo-controlled clinical trial using a parallel design in patients aged 35 to 75 at entry with a complete colonoscopy and a clean colon. Overall, 655 subjects have been included. All randomized patients are followed up every six months for 3 years. If one of the evaluated interventions proves efficient, the benefits of a simple, safe and inexpensive prophylaxy for a very common cancer will be clear.

    背景与目标: 由欧洲癌症预防组织的结肠小组领导的一项欧洲多中心干预研究正在进行中。该研究的主要目的是测试每天口服2g钙的钙补充剂和口服饮食中粘液物质 (如3.8g ispaghula壳) 对腺瘤复发的疗效。次要目的是研究对结肠细胞增殖以及粪便胆汁酸和固醇浓度的治疗效果。还收集血清和血浆样品。为了更好地解释干预的效果,我们使用了饮食史问卷和阿司匹林和抗炎药问卷。该目标将通过一项随机安慰剂对照临床试验来实现,该试验使用平行设计对35至75岁的患者进行完整的结肠镜检查和清洁的结肠。总体而言,已包括655个主题。所有随机患者每6个月随访3年。如果评估的干预措施之一被证明是有效的,那么简单,安全和廉价的预防疗法对非常常见的癌症的好处将是显而易见的。
  • 【性腺激素和年龄对1,2-二甲基肼诱导的结肠癌发生的影响。】 复制标题 收藏 收藏
    DOI:10.1002/1097-0142(197711)40:5+<2502::aid-cncr28204 复制DOI
    作者列表:Moon RC,Fricks CM
    BACKGROUND & AIMS: :BD-II and BD-IX male and female rats received weekly subcutaneous (s.c.) injections of 15 mg/kg 1,2-dimethylhydrazine dihydrochloride (DMH) beginning at either 35, 120 or 210 days of age and continuing for 20 weeks. Control animals received only the DMH vehicle. Additional BD-II and BD-IX male and female rats of the three age groups were gonadectomized at 21, 106 and 196 days. Beginning 14 days after gonadectomy, the rats received 15 mg/kg of DMH by s.c. injection once a week for 20 weeks. Animals were sacrificed 35 weeks after the initial DMH injection. Control rats of the appropriate age and sex did not develop colon tumors. BD-IX rats are apparently more sensitive to DMH than BD-II rats. The incidence of DMH-induced cancer is less in females than in males in both the BD-II and BD-IX animals. Gonadectomy does not affect cancer incidence in either BD-II males or females nor in the BD-IX females but reduced the incidence in BD-IX males exposed initially at either 120 or 210 days. Administration of androgen to castrate BD-IX males (120-day-old group) increases the incidence of colon cancer to that approaching the intact animal but has little effect in the BD-II castrate male. These data suggest a genetically influenced susceptibility to DMH-induced colon carcinogenesis between BD-II and BD-IX rats. Furthermore, a sex difference is evident in both BD lines but age appears to be a factor only in older BD-IX females. Apparently, androgens influence DMH-induced tumorigenesis in BD-IX males only if the initial exposure of DMH occurs after sexual maturity.
    背景与目标: : bd-ii和bd-ix雄性和雌性大鼠每周接受15 mg/kg 1,2-二甲基肼二盐酸盐 (DMH) 的皮下 (s.c.) 注射,从35、120或210日龄开始,持续20周。对照动物仅接受DMH运载工具。在21、106和196天时对三个年龄组的其他bd-ii和bd-ix雄性和雌性大鼠进行性腺切除。从性腺切除术后14天开始,大鼠接受了15 mg/kg的DMH。每周注射一次,持续20周。在最初的DMH注射后35周处死动物。适当年龄和性别的对照大鼠没有发展为结肠肿瘤。Bd-ix大鼠显然比bd-ii大鼠对DMH更敏感。在bd-ii和bd-ix动物中,女性中DMH诱发的癌症的发生率均低于男性。性腺切除术不影响bd-ii男性或女性或bd-ix女性的癌症发病率,但降低了最初在120天或210天暴露的bd-ix男性的发病率。对去势的bd-ix雄性 (120天大组) 施用雄激素可增加结肠癌的发生率,使其接近完整动物,但对bd-ii去势的雄性几乎没有影响。这些数据表明,在BD-II和BD-IX大鼠之间,对DMH诱导的结肠癌发生的遗传易感性受到影响。此外,两个BD系的性别差异都很明显,但年龄似乎仅是年龄较大的bd-ix女性的一个因素。显然,只有当DMH的初次暴露发生在性成熟后,雄激素才会影响bd-ix男性中DMH诱导的肿瘤发生。
  • 【人参皂苷Rk3通过保护结肠屏障和抑制NLRP3炎症小体途径减轻DSS诱导的溃疡性结肠炎。】 复制标题 收藏 收藏
    DOI:10.1016/j.intimp.2020.106645 复制DOI
    作者列表:Tian M,Ma P,Zhang Y,Mi Y,Fan D
    BACKGROUND & AIMS: :Ginsenosides have a variety of pharmacological activities, including immunomodulatory, antitumor and anti-inflammatory activities. However, the effect of Rk3 on ulcerative colitis has rarely been reported. This study evaluated the effect of Rk3 on DSS-induced ulcerative colitis and preliminarily explored the anti-inflammatory mechanisms. Rk3 administration significantly attenuated the weight loss, increased DAI scores, colonic shortening, and increased MPO and iNOS activities caused by DSS in mice. Histological improvement was apparent, tight junctions in the colon were restored, and the levels of short-chain fatty acids (acetic acid, butyric acid and isovaleric acid) were increased. In addition, Rk3 reduced the expression of proinflammatory factors (TNF-α, IL-1β and IL-6), NLRP3, ASC, and Caspase-1, indicating blockade of the NLRP3 inflammasome pathway. These results show that Rk3 can improve DSS-induced ulcerative colitis by protecting intestinal barrier function and inhibiting NLRP3 inflammasome expression, indicating that Rk3 could be used as a potential drug for treating ulcerative colitis.
    背景与目标: : 人参皂苷具有多种药理活性,包括免疫调节,抗肿瘤和抗炎活性。然而,Rk3对溃疡性结肠炎的作用很少报道。本研究评估了Rk3对DSS诱导的溃疡性结肠炎的作用,并初步探讨了其抗炎机制。Rk3给药可显着减轻小鼠的体重减轻,DAI评分增加,结肠缩短以及DSS引起的MPO和iNOS活性增加。组织学改善明显,结肠中的紧密连接恢复,短链脂肪酸 (乙酸,丁酸和异戊酸) 的水平增加。此外,Rk3降低了促炎因子 (TNF-α,IL-1β 和IL-6),NLRP3,ASC和Caspase-1的表达,表明NLRP3炎症小体途径被阻断。这些结果表明,Rk3可以通过保护肠屏障功能和抑制NLRP3炎症小体表达来改善DSS诱导的溃疡性结肠炎,表明Rk3可以作为治疗溃疡性结肠炎的潜在药物。
  • 【通过MICA的HSF1-mediated表达来调节轻度热应激后结肠肿瘤细胞对自然杀伤细胞细胞毒性的敏感性。】 复制标题 收藏 收藏
    DOI:10.3109/02656736.2013.821526 复制DOI
    作者列表:Dayanc BE,Bansal S,Gure AO,Gollnick SO,Repasky EA
    BACKGROUND & AIMS: PURPOSE:Previously we showed that mild thermal stress increased natural killer (NK) cell-mediated tumour cytotoxicity and that this could be blocked by anti-NKG2D or anti-MICA (major histolocompatability complex (MHC) class I related chain A) antibodies. Here, we investigated the role of the transcription factor heat shock factor 1 (HSF1) in thermal regulation of MICA expression in tumour cells in vitro and in vivo. MATERIALS AND METHODS:Hyperthermia experiments were conducted in vitro and in mice using a target temperature of 39.5 °C. Apoptotic cells and NK cells in situ were visualised by use of the TUNEL assay or expression of NKp46 respectively. Using Colo205 cells, HSF1 message was blocked utilising siRNA while luciferase reporter assays were used to measure the activity of the MICA promoter in vitro. Cell surface MICA was measured by flow cytometry. RESULTS:Following whole body hyperthermia (WBH), tumour tissues showed an increase in NK cells and apoptosis. Mild thermal stress resulted in a transient increase in surface MICA and enhanced NK cytotoxicity of the Colo205 colon cancer cell line. Silencing (mRNA) HSF1 expression in Colo205 cells prevented the thermal enhancement of MICA message and surface protein levels, with partial loss of thermally enhanced NK cytotoxicity. Mutations of the HSF1 binding site on the MICA promoter implicated HSF1 in the thermal enhancement of MICA. Some, but not all, patient-derived colon tumour derived xenografts also exhibited an enhanced MICA message expression after WBH. CONCLUSIONS:Up-regulation of MICA expression in Colo205 cells and enhanced sensitivity to NK cell killing following mild thermal stress is dependent upon HSF1.
    背景与目标:
  • 【使用机器学习构建转移性结肠癌患者的列线图。】 复制标题 收藏 收藏
    DOI:10.1111/codi.14991 复制DOI
    作者列表:Zhao B,Gabriel RA,Vaida F,Eisenstein S,Schnickel GT,Sicklick JK,Clary BM
    BACKGROUND & AIMS: AIM:Patients with synchronous colon cancer metastases have highly variable overall survival (OS), making accurate predictive models challenging to build. We aim to use machine learning to more accurately predict OS in these patients and to present this predictive model in the form of nomograms for patients and clinicians. METHODS:Using the National Cancer Database (2010-2014), we identified right colon (RC) and left colon (LC) cancer patients with synchronous metastases. Each primary site was split into training and testing datasets. Nomograms predicting 3- year OS were created for each site using Cox proportional hazard regression with lasso regression. Each model was evaluated by both calibration (comparison of predicted vs observed OS) and validation (degree of concordance as measured by the c-index) methodologies. RESULTS:A total of 11 018 RC and 8346 LC patients were used to construct and validate the nomograms. After stratifying each model into five risk groups, the predicted OS was within the 95% CI of the observed OS in four out of five risk groups for both the RC and LC models. Externally validated c-indexes at 3 years for the RC and LC models were 0.794 and 0.761, respectively. CONCLUSIONS:Utilization of machine learning can result in more accurate predictive models for patients with metastatic colon cancer. Nomograms built from these models can assist clinicians and patients in the shared decision-making process of their cancer care.
    背景与目标:
  • 【通过单克隆抗体组合在新的人结肠癌细胞系 (LIM1899) 中的肿瘤定位。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Andrew SM,Teh JG,Johnstone RW,Russell SM,Whitehead RH,McKenzie IF,Pietersz GA
    BACKGROUND & AIMS: :One of the problems of in vivo diagnosis and therapy of tumors with monoclonal antibodies is their heterogeneity with respect to antigen expression, with some cells expressing no antigen and others being weakly or strongly positive. Selected mixtures of antibodies to different antigens are therefore likely to react with more cells than single antibodies and be more effective for imaging and therapy. With this in mind, we have examined a new human colon cancer cell line (LIM1899) which has a heterogeneous expression of several cell surface molecules: by flow cytometry 38% were carcinoembryonic antigen positive; 64%, human milk fat globule positive, and 73%, CD46 positive; 87% of tumor cells bound a mixture of all three antibodies in vitro. Some blocking of the binding of anti-human milk fat globule antibody by the anti-CD46 antibody was noted. LIM1899 was established as a xenograft in nude mice and in vivo biodistribution studies performed using antibodies alone or in combination. Mixtures of antibodies clearly showed a higher percentage of injected dose of antibody in the tumor than did single antibodies: one antibody gave 10%; two together, 17 to 21%; and all three together gave 29% of the injected dose in the tumor. Tumor:blood ratios were also superior for combinations of antibodies, provided that low doses of the antibodies were used; at higher doses the effect was lost. The study demonstrates that combinations of antibodies are better than single antibodies for localization, provided that the dose used is carefully selected.
    背景与目标: : 用单克隆抗体对肿瘤进行体内诊断和治疗的问题之一是它们在抗原表达方面的异质性,其中一些细胞不表达抗原,而另一些细胞则呈弱阳性或强阳性。因此,针对不同抗原的抗体的选定混合物可能比单个抗体与更多的细胞反应,并且对成像和治疗更有效。考虑到这一点,我们检查了一种新的人结肠癌细胞系 (LIM1899),该细胞系具有几种细胞表面分子的异质表达: 通过流式细胞术,38% 为癌胚抗原阳性; 64%,人乳脂肪球阳性,73%,CD46阳性; 肿瘤细胞的87% 在体外结合所有三种抗体的混合物。注意到anti-CD46抗体对抗人乳脂肪球抗体结合的一些阻断。LIM1899被建立为裸鼠异种移植物,并单独或组合使用抗体进行体内生物分布研究。抗体混合物清楚地显示出肿瘤中注射抗体剂量的百分比高于单个抗体: 一种抗体产生10%; 两种在一起,17至21%; 并且所有三种一起产生肿瘤中注射剂量的29%。肿瘤: 如果使用低剂量的抗体,血液比率也优于抗体组合; 在较高剂量下,效果消失。研究表明,只要仔细选择使用的剂量,抗体的组合在定位方面优于单一抗体。
  • 【用于确定结肠腺癌诊断和预后生物标志物的综合分析。】 复制标题 收藏 收藏
    DOI:10.1089/dna.2019.5215 复制DOI
    作者列表:Liu Z,Bai Y,Xie F,Miao F,Du F
    BACKGROUND & AIMS: :Colon adenocarcinoma (COAD) is a common noncutaneous carcinoma worldwide with high morbidity and mortality. Effective prevention methods are far from being met. Both diagnostic and prognostic models that can precisely and accurately predict the status and survival time of COAD are urgently needed. In the field of COAD, there have been limited studies on molecular biomarkers that can predict disease status and prognosis. Hence, an important task is to identify these biomarkers. We aimed to identify important risk genes that have the ability not only to diagnose tumors but also to predict overall survival. A comprehensive analysis was performed in this study. Finally, carbonic anhydrase 1 (CA1) and CA4 were identified as potential biomarkers due to their predictive roles in diagnosis and prognosis, and the results were further confirmed by a series of analyses. Overall, these findings are of great importance and may facilitate individualized treatment in diagnosis and prognosis.
    背景与目标: 结肠腺癌 (COAD) 是世界范围内常见的非皮肤癌,具有很高的发病率和死亡率。有效的预防方法远未得到满足。迫切需要能够准确,准确地预测COAD状态和生存时间的诊断和预后模型。在COAD领域,关于可预测疾病状态和预后的分子生物标志物的研究有限。因此,一个重要的任务是识别这些生物标志物。我们旨在确定重要的风险基因,这些基因不仅具有诊断肿瘤的能力,而且还具有预测总体生存率的能力。本研究进行了全面分析。最后,碳酸酐酶1 (CA1) 和CA4被确定为潜在的生物标志物,因为它们在诊断和预后中的预测作用,并通过一系列分析进一步证实了结果。总体而言,这些发现非常重要,可能有助于诊断和预后的个体化治疗。
  • 【弓形虫引起的回肠和降结肠肌间神经丛的改变 (基因型III)。】 复制标题 收藏 收藏
    DOI:10.1590/s0004-282x2008000400015 复制DOI
    作者列表:Sugauara EY,Sant'Ana Dde M,Almeida EC,Reis AB,Silva AV,Araújo EJ
    BACKGROUND & AIMS: :Alterations caused by a genotype III strain of Toxoplasma gondii were assessed with respect to the number and the morphometry of the myenteric neurons in the terminal ileum and the descending colon. Eighteen rats were divided into four groups: Acute Control Group (ACG, n=4); Acute Experimental Group (AEG, n=4); Chronic Control Group (CCG, n=5) and Chronic Experimental Group (CEG, n=5). NaCl solution was administered through gavage to the animals in the ACG and CCG. Toxoplasma gondii tachyzoites (10(4)) from a genotype III strain were orally administered to the AEG and CEG. Acute Groups were died after 24 hours, and the Chronic Groups after 30 days. Neuronal loss was not observed in both organs. The neurons atrophied in the terminal ileum as the opposite occurred with the neurons at the descending colon during the chronic phase of infection. In the terminal ileum, the neurons atrophied during the chronic phase of the infection as no alteration was found during the acute phase. For the descending colon, the neurons became hypertrophic during the chronic infection in opposition to the atrophy found during the acute phase.
    背景与目标: : 根据回肠末端和降结肠中肌间神经元的数量和形态,评估了弓形虫III型菌株引起的改变。将18只大鼠分为四组: 急性对照组 (ACG,n = 4); 急性实验组 (AEG,n = 4); 慢性对照组 (CCG,n = 5) 和慢性实验组 (CEG,n = 5)。通过灌胃将NaCl溶液施用于ACG和CCG中的动物。将来自基因型III菌株的弓形虫速殖子 (10(4)) 口服给AEG和CEG。急性组在24小时后死亡,慢性组在30天后死亡。两个器官均未观察到神经元丢失。在感染的慢性阶段,降结肠的神经元在回肠末端萎缩,相反。在回肠末端,由于在急性期未发现任何改变,因此在感染的慢性期神经元萎缩。对于降结肠,神经元在慢性感染期间变得肥厚,与急性期发现的萎缩相反。

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