肠道具核梭杆菌与结直肠癌的关系及其致病机制的研究进展

结直肠癌(colorectal cancer, CRC)为全球第三大常见癌症,死亡率位居第二。随着微生物组学技术的发展,近年来,研究发现,具核梭杆菌(Fusobacterium nucleatum,Fn)不仅参与口腔疾病和脑膜炎、心内膜炎、化脓性关节炎等口腔外感染性疾病的发生、发展,还可能通过促进结直肠上皮细胞增殖、促进机体炎症微环境、免疫调节等多种机制参与CRC的发生、发展,但具体致病机制还亟待阐明。基于此,现就Fn与CRC的关系和相关致病机制作一概述,为未来深入探究CRC生物预防及治疗提供理论依据。     

TWEAK/Fn14信号调控干细胞增殖与分化的作用与机制

肿瘤坏死因子样弱凋亡诱导蛋白(TWEAK)是肿瘤坏死因子(TNF)超家族成员,通过作用于唯一受体成纤维细胞生长因子14(Fn14)调控细胞的增殖、分化和迁移等多种生命活动。近来研究表明,TWEAK/Fn14信号可以作用于多种干细胞,如肝干细胞、神经干细胞和间充质干细胞等,通过影响其增殖与分化的能力,干预组织的修复与再生。对该领域的研究进行综述,将有助于揭示TWEAK/Fn14信号调控干细胞增殖与分化的作用与机制,并为干细胞在疾病发生机制等基础研究、细胞治疗和组织工程等临床医学研究提供新的方向。     

CRC中EMT的作用及靶向治疗研究进展

结直肠癌(colorectal cancer, CRC)是世界第三大常见的癌症。上皮间质转化(epithelial-mesenchymal transition, EMT)在肿瘤迁移和侵袭中起着非常重要的作用。本文主要总结了EMT在CRC进展中的作用及针对EMT的靶向治疗,对EMT的特点、EMT在结直肠癌转移侵袭中的作用以及EMT的临床应用进行了探讨和分析,同时对一些针对EMT的治疗靶点在CRC中的应用进行了评述,以期为深入理解CRC中EMT的作用和相关治疗研究提供新的视角。     

肿瘤标志物在结直肠癌诊疗应用中的研究进展

结直肠癌(colorectal cancer, CRC)是世界第三大常见恶性肿瘤,也是全球癌症相关死亡的主要原因之一。近年来,随着各种新兴组学测序技术和人工智能的发展,肿瘤标志物在临床肿瘤学中的应用研究不断拓宽。以DNA甲基化、非编码RNA、循环肿瘤细胞、肠道菌群及代谢物为主的新型标志物逐渐成为肿瘤诊疗研究中的重点方向,在CRC的早筛早诊、病情监测及预后评估等方面起着重要的指导作用。该文就近年来临床常用肿瘤标志物和新型肿瘤标志物在CRC诊疗中的应用及进展进行了综述,并对检验大数据和人工智能在肿瘤临床诊疗中的潜在应用前景进行了讨论,以期为CRC的诊疗应用研究提供借鉴。     

结直肠癌原发与配对转移肿瘤遗传异质性研究进展

结直肠癌(colorectal cancer, CRC)是我国常见的致死性肿瘤类型之一。根据体细胞突变谱预测抗EGFR单抗治疗疗效已成为转移性结直肠癌(metastatic colorectal cancer, mCRC)治疗的标准步骤。由于临床上转移样本难以获得,只能采用原发肿瘤替代进行检测。原发和配对转移肿瘤间的遗传异质性会导致原发灶取样无法代表转移灶突变谱。目前CRC原发和配对转移肿瘤间遗传异质性程度仍存在争议。本文就CRC原发和配对转移基因组谱的对比研究进行了综述,并讨论了原发与配对转移肿瘤遗传异质性形成的原因及应对策略。     

RhoGDI2 在结直肠癌组织中的表达及其与临床侵袭转移的关系

目的:研究鸟嘌呤核苷酸解离抑制因子2(Rho GDI2)在结直肠癌(CRC)组织中的表达及其与临床侵袭转移的关系。方法:收集本院于2015年1月至2015年12月收治的80例CRC患者手术切除的原发灶组织和正常癌旁组织。采用免疫组化法检测各组织标本中Rho GDI2的表达情况,并分析其表达量与临床病理特征的相关性。结果:(1)Rho GDI2主要表达于CRC癌细胞胞浆中,在肿瘤原发灶和正常癌旁组织中的阳性表达率分别为26.25%和0.00%,差异具有统计学意义(P0.05);(2)肿瘤原发灶中Rho GDI2的阳性表达率与患者的性别、年龄、肿瘤位置、大小、数量、组织学分级、原发灶分期、血管浸润、神经浸润间均不存在相关关系(P0.05),而与淋巴结转移及远端转移有关(P0.05)。结论:Rho GDI2在CRC肿瘤原发灶中呈阳性表达,且其高表达可促进CRC的侵袭转移,可作为CRC治疗的作用靶点。     

核酸适配子结合无机纳米材料在肿瘤研究中的应用

在倡导精准医疗的今日,在基本掌握与肿瘤发生密切相关的靶点的机理后,如何实现肿瘤靶向治疗,尽量消减由治疗带来的不良反应显得尤为关键。核酸适配子是能与靶标以高亲和力、高特异性结合的寡核苷酸;无机纳米材料是纳米材料作为医学领域诊疗制剂中重要的组成部分;利用核酸适配子与靶标结合的特性将其与无机纳米材料结合后,可将靶向结合、生物成像及药物递送等特点集于一体,综合应用于肿瘤研究,同时有力于促进核酸纳米技术的发展。综述了近年不同无机纳米材料结合核酸适配子在肿瘤研究领域中的研究进展,以及对无机纳米材料在医学应用的安全性思考,以期早日实现新型靶向肿瘤治疗策略的开发。     

肠道微生态在结直肠癌诊断中的研究进展

近年来，肠道微生态学已经成为众学者的研究热点，肠道微生态平衡影响人体健康，尤其与结直肠癌（colorectal cancer,CRC）关系密切。许多CRC患者在早期并无明显症状，在进入中晚期时才被确诊，因错过早期治疗的机会而导致治疗效果欠佳，目前亟需更新更优的CRC早期诊断方法。基于肠道微生态与CRC的密切关系，肠道微生态已成为CRC新诊断方法的主要选择之一，主要研究方向是肠道中的细菌、病毒及其代谢产物的种类与数量的检测。本文就近年来关于肠道微生态对CRC诊断作用的相关热点问题进行概述，并展望肠道微生态在CRC诊断作用研究的主要方向及预期进展，旨在为通过肠道微生态诊断CRC提供理论依据。     

γ-谷胱甘肽环酰基转移酶在结直肠癌中的表达及临床意义

目的检测γ-谷胱甘肽环酰基转移酶(γ-glutamyl cyclotransferase,GGCT)在结直肠癌(colorectal cancer, CRC组织中的表达,探讨GGCT表达与患者临床病理特征、结直肠肿瘤细胞增殖的关系,进一步探究GGCT表达与CRC患者预后的相关性。方法采用免疫组织化学方法检测229例结直肠肿瘤组织和其中能收集到的167例癌旁正常组织中GGCT、Ki-67和细胞周期蛋白D1 (cyclin D1)的表达水平,应用SPSS 26.0软件对实验数据进行统计学处理。结果 GGCT在CRC和癌旁组织的胞质阳性表达率分别为83.4%和75.4%(P=0.792),而在胞核的阳性表达率分别为36.7%和74.3%(P=0.045);Ki-67在CRC和癌旁正常组织阳性表达率分别为77.7%和60.5%(P=0.040);cyclin D1在CRC和癌旁正常组织阳性表达率分别为43.2%和12.0%(P=0.030)。GGCT在细胞核中阳性表达与肿瘤大小、淋巴结转移、TNM分期呈负相关,GGCT在CRC组织中的表达与Ki-67、cyclin D1呈负相关。CRC患者中GGCT核阴性表达组生存期低于阳性表达组。结论 GGCT在CRC和癌旁正常组织细胞中的定位存在差异,这一差异主要体现在细胞核上。GGCT在CRC胞核中低表达,癌旁正常组织中高表达。GGCT在CRC细胞中的定位不同,发挥功能不同,胞核上GGCT表达的降低可能与肿瘤细胞增殖活性增加有关,与CRC患者生存预后有关,参与了CRC的发生与发展。     

Fn14 在 EGFR 外显子 19 缺失突变的非小细胞肺癌中的表达及其临床意义

目的:探讨成纤维细胞生长因子诱导14(Fn14)在表皮生长因子受体(EGFR)外显子19缺失的非小细胞肺癌(NSCLC)组织中的表达及其临床意义。方法:选择2010年9月至2013年11月第四军医大学唐都医院收治的125例原发性EGFR外显子19缺失的NSCLC组织及与之相对应的30例正常肺组织为研究对象,应用免疫组化法检测和比较其Fn14的表达,分析Fn14的表达与原发性EGFR外显子19缺失的的NSCLC临床病理特征的关系。结果:Fn14阳性表达主要定位于胞膜和胞质中。在125例原发性EGFR外显子19缺失的NSCLC组织中,Fn14的阳性表达率为100%,显著高于正常肺组织(P<0.001)。鳞癌和腺癌NSCLC组织中Fn14的阳性表达率比较无统计学差异(P=0.106);不同病理分化程度、不同TNM分期的NSCLC组织中Fn14的阳性表达率比较均具有显著性差异(P=0.000、P=0.000)。Fn14蛋白的表达与EGFR外显子19缺失的NSCLC的淋巴结转移状态、肿瘤大小以及肿瘤解剖学分类均显著相关(P=0.000、P=0.029、P=0.000、P=0.026),而与患者的性别、年龄、吸烟史均无关(P=0.816、P=0.122、P=0.816)。结论:Fn14在原发性EGFR外显子19缺失的NSCLC中呈异常高表达,EGFR外显子19缺失突变很可能通过上调Fn14通路,促进NSCLC的发生和发展。     

Polymorphisms of CYP1B1 and COMT in Breast and Endometrial Cancer

CYP1B1 and COMT code for the key enzymes of catecholestrogen biosynthesis and metabolism, and their polymorphisms determine the variation of enzyme activities. RFLP analysis was used to study the allele and genotype frequency distributions of CYP1B1 polymorphisms Arg48Gly, Ala119Ser, and Val432Leu, and COMT polymorphism Val158Met among 210 breast cancer patients, 138 endometrial cancer patients, and 152 healthy women. The COMT polymorphism showed no significant association with breast or endometrial cancer. For the first time, such association was observed for the CYP1B1 polymorphisms. CYP1B1 allele C (Arg48), which codes for the enzyme more active in estradiol 4-hydroxylation, was associated with higher risk of breast (OR = 3.22, CI 2.34–4.43, P = 0.000) and endometrial (OR = 2.43, CI 1.72–3.44, P = 0.000) cancer. Similar data were obtained for CYP1B1 allele G (Ala119): OR = 2.18, CI 1.58–3.01, P = 0.000 in breast cancer and OR = 2.52, CI 1.78–3.56, P = 0.000 in endometrial cancer. Risk of endometrial but not breast cancer was significantly higher in carriers of CYP1B1 genotype Val432/Val. This was explained by stronger estrogen dependence and, consequently, higher estrogen responsiveness of the endometrium as compared with the mammary gland.     

Glutathione S-Transferase M1, T1, P1 Genotypes and Risk for Development of Colorectal Cancer

The glutathione S-transferase (GST) supergene family is an important part of cellular enzyme defense against endogenous and exogenous chemicals, many of which have carcinogenic potential. The present investigation was conducted to detect a possible association between polymorphisms at the GSTM1, GSTT1, and GSTP1 genes and the interaction with cigarette smoking and colorectal cancer incidence. We examined 181 patients with colorectal cancer and 204 controls. DNA was extracted from whole blood, and the GSTM1, GSTT1, and GSTP1 polymorphisms were determined using a real-time polymerase chain reaction and fluorescence resonance energy transfer with a Light-Cycler instrument. Associations between specific genotypes and the development of colorectal cancer were examined by use of logistic regression analysis to calculate odds ratios (OR) and 95% confidence intervals (CI). The GSTM1 polymorphism was associated with an increased risk of developing colorectal cancer (OR = 1.62, 95% CI: 1.06–2.46). Also the risk of colorectal cancer associated with the GSTT1 null genotype was 1.64 (95% CI: 1.10–2.59). Statistically no differences were found between patients with colorectal cancer and control groups for the GSTP1 Ile/Ile, Ile/Val and Val/Val genotypes. In addition, the frequencies of the GSTM1 and GSTT1 deletion genotypes differed significantly between the cases and controls for current smokers; the GSTT1 null genotype especially is associated with a greater risk of colorectal cancer (OR = 2.44, 95% CI: 1.24–4.81). The GSTM1 and GSTT1 deletions were associated with an increased risk of developing a transverse or rectal tumor (OR = 1.86, 95% CI: 1.15–3.00; OR = 1.70, 95% CI: 1.02–2.84; respectively). The glutathione S-transferase polymorphisms were not associated with risk in patients stratified by age. The risk of colorectal cancer increased as putative high-risk genotypes increased for the combined genotypes of GSTM1 null, GSTT1 null, and either GSTP1 valine heterozygosity or GSTP1 valine homozygosity (OR = 2.69, 95% CI: 1.02–7.11). In conclusion, the results obtained in this study clearly suggest that those susceptibility factors related to different GST polymorphic enzymes are predisposing for colorectal cancer.     

结直肠癌相关致病菌的研究进展

肠道微生物群落与结直肠癌（Colorectal Cancer,CRC）有着十分密切的关系。肠道微生物的群落变化可能会伴随着CRC的发生,而一些有害菌的出现可能是导致CRC的直接原因。其中,具核梭杆菌（Fusobacterium nucleatum）、产肠毒素脆弱拟杆菌（Enterotoxigenic Bacteroides fragilis,ETBF）和pks阳性大肠杆菌（pks⁺ Escherichia coli）与CRC的发生最密切。本综述着重介绍了pks⁺ E. coli及Colibactin的致病原因、对肠道微生物组成的影响、Colibactin的合成及怎样抑制或促进pks⁺ E. coli。同时也对ETBF和F. nucleatum可能的致癌原因、对肠道微生物组成的影响及对二者的促进或抑制做出了介绍。     

The Association of the CYP19 and CYP17 Polymorphic Markers with Sporadic Breast Cancer

Polymorphic alleles of CYP17 and CYP19, which are involved in estrogen biosynthesis, were tested for association with breast cancer (BC). Microsatellite (TTTA)_n and 3-bp deletion of CYP19 and single-nucleotide polymorphism T27C of CYP17 were analyzed in 123 BC patients and 119 healthy women. Of the six (TTTA)_n alleles observed, allele (TTTA)₈ proved to be associated with BC (11.8% vs. 6.3%, P = 0.04). Genotype A2/A2 of CYP17 was also associated with BC (32.5% vs. 20.2%, P = 0.04). Risk of BC was especially high in the presence of both factors (7.3% vs. 0%, P < 0.01). Allele (TTTA)₈ and genotype A2/A2 were assumed to be risk factors of BC.     

Prevalence of Helicobacter pylori genotypes (vacA, cagA, cagE and virB11) in gastric cancer in Brazilian's patients: an association with histopathological parameters

Purpose: To investigate the frequency and the association of vacA alleles, cagA, cagE and virB11 genes of Helicobacter pylori from patients with gastric cancer, considering the clinic histopathological parameters. Methods: One hundred and one gastric adenocarcinoma tissues were assessed by PCR to detect H. pylori and vacA alleles, cagA, cagE and virB11. Results: The distribution of cases according to the presence of the genes studied showed that the group containing vacA s1m1, cagA, cagE and virB11 H. pylori genes was significantly more frequent, followed by the group with at least one marker on the right side and left of the island. They were also present in the early stages and were the most frequent in nearly all histopathological grades. Conclusions: This study verified that vacAs1m1 and cag-PAI genes, cagA, cagE and virB11 are important H. pylori markers for gastric cancer development. Also, this study corroborates the importance of cagE and cagA together as cag-PAI marker.     

Foreign exploration for Scirtothrips perseae Nakahara (Thysanoptera: Thripidae) and associated natural enemies on avocado (Persea americana Miller)

Scirtothrips perseae Nakahara was discovered attacking avocados in California, USA, in 1996. Host plant surveys in California indicated that S. perseae has a highly restricted host range with larvae being found only on avocados, while adults were collected from 11 different plant species. As part of a management program for this pest, a “classical” biological control program was initiated and foreign exploration was conducted to delineate the home range of S. perseae, to survey for associated natural enemies and inventory other species of phytophagous thrips on avocados grown in Mexico, Guatemala, Costa Rica, the Dominican Republic, Trinidad, and Brazil. Foreign exploration efforts indicate that S. perseae occurs on avocados grown at high altitudes (>1500 m) from Uruapan in Mexico south to areas around Guatemala City in Guatemala. In Costa Rica, S. perseae is replaced by an undescribed congener as the dominant phytophagous thrips on avocados grown at high altitudes (>1300 m). No species of Scirtothrips were found on avocados in the Dominican Republic, Trinidad, or Brazil. In total, 2136 phytophagous thrips were collected and identified, representing over 47 identified species from at least 19 genera. The significance of these species records is discussed. Of collected material 4% were potential thrips biological control agents. Natural enemies were dominated by six genera of predatory thrips (Aeolothrips, Aleurodothrips, Franklinothrips, Leptothrips, Scolothrips, and Karnyothrips). One genus each of parasitoid (Ceranisus) and predatory mite (Balaustium) were found. Based on the results of our sampling techniques, prospects for the importation of thrips natural enemies for use in a “classical” biological control program in California against S. perseae are not promising.     

Structural Peculiarities of Na+,K+-ATPase Isozymes from the Calf Brain

Functionally active preparations of Na⁺,K⁺-ATPase isozymes from calf brain that contain catalytic subunits of three types (1, 2, and 3) were obtained using two approaches: a selective removal of contaminating proteins by the Jorgensen method and a selective solubilization of the enzyme with subsequent reconstitution of their membrane structure by the Esmann method. The ouabain inhibition constants were determined for the isozymes. The real isozyme composition of the Na⁺ pump from the grey matter containing glial cells and the brain stem containing neurons was determined. The plasma membranes of glial cells were shown to contain mainly Na⁺,K⁺-ATPase of the 11 type and minor amounts of isozymes of the 22(1) and the 31(2) type. The axolemma contains 21 and 31 isozymes. A carbohydrate analysis indicated that 11 enzyme preparations from the brain grey matter substantially differ from the renal enzymes of the same composition in the glycosylation of the 1 isoform. An enhanced sensitivity of the 3 catalytic subunit of Na⁺,K⁺-ATPase from neurons to endogenous proteolysis was found. A point of specific proteolysis in the amino acid sequence PNDNR⁴⁹² Y⁴⁹³ was localized (residue numbering is that of the human 3 subunit). This sequence corresponds to one of the regions of the greatest variability in 1-, 2-, 3-, and 4-subunits, but at the same time, it is characteristic of the 3 isoforms of various species. The presence of the 3 isoform of tubulin (cytoskeletal protein) was found for the first time in the high-molecular-mass Na⁺,K⁺-ATPase 31 isozyme complex isolated from the axolemma of brain stem neurons, and its binding to the 3 catalytic subunit was shown.     

Characterization of SSEA-1 glycolipids from the brain of a patient with fucosidosis

Neutral glycolipids from the brain of a patient with Fucosidosis were analyzed and two complex glycolipids containing five and eight sugars were isolated from the cortical grey matter. These two glycolipids reacted with antibodies recognizing the SSEA-1 [Le^x(X)] carbohydrate determinant. SSEA-1 glycolipids are normally expressed in human embryonic brain but are found in only small amounts in postnatal human brain. The accumulation of the two SSEA-1 glycolipids in Fucosidosis brain thus represents a defect which affects the normal developmentally regulated decrease in postnatal, expression of these glycolipids, and may be a contributing factor in the abnormal brain development associated with the disease. Chemical characterization of the two isolated glycolipids by gas chromatographic and mass spectrometric analyses has identified the two glycolipids as lacto-N-fucopentaosylceramide (III) and difucosyl-neolactonorhexaosylceramide.Abbreviations DCl direct chemical ionization - FAB tastatiom bombardment - GC gas chromatography - GSLs glycosphingolipids - MS mass spectrometry - SSEA-1 stage specific embryonic antigen-1 - TLC thin layer chromatographys