程序性死亡受体1/程序性死亡受体配体1抑制剂在三阴性乳腺癌治疗中的研究进展

三阴性乳腺癌（TNBC）是一种侵袭性乳腺癌亚型,具有较高的免疫原性、肿瘤浸润淋巴细胞（TIL）富集及程序性死亡受体配体1(PD-L1)表达的特点,其比多数其他类型的乳腺癌亚型患者可能更早开始受益于免疫检查点的封锁和治疗。目前,程序性死亡受体1(PD-1)/PD-L1已被批准作为一种辅助诊断指标。但PD-1/PD-L1抑制剂在TNBC治疗中的安全性、有效性、稳定性尚不明确。本文就免疫检查点抑制剂（ICI）单药及与化疗、分子靶向治疗和放疗联合治疗在TNBC中的研究进展进行综述。     

程序性死亡蛋白1及其配体在结直肠癌中的临床研究现状

程序性死亡蛋白-1(Programmed cell death protein-1,PD-1)通过与程序性死亡蛋白配体-1(Programmed cell death protein ligand-1,PD-L1)相互作用进而发挥负向调节机体免疫反应机制,促使肿瘤细胞发生免疫逃逸。以PD-1/PD-L1为靶点的免疫治疗已成为肿瘤治疗的新模式。目前,手术和放化疗仍然是结直肠癌的主要治疗手段,但生存率没有明显的改善。研究显示PD-1/PD-L1抑制剂单药治疗或与放化疗和手术联合治疗在结直肠癌中取得了可观的效果,且相关的临床试验正在进行。本文阐述了PD-1/PD-L1信号通路相关的分子生物学机制及PD-L1的表达与结直肠癌放化疗和预后的关系,并介绍了PD-1/PD-L1抑制剂在结直肠癌中的临床研究进展。     

PD-1/PD-L1抑制剂在外周T细胞淋巴瘤治疗中的研究进展#br#

外周T细胞淋巴瘤（peripheral T-cell lymphoma, PTCL）是一组高度异质性和侵袭性的非霍奇金淋巴瘤（non-Hodgkin’s lymphoma,NHL）。在目前化疗为主的治疗下,PTCL患者通常预后差,复发率高,因此需要积极探索新药来改善预后。肿瘤微环境（tumor microenvironment,TME）在多种肿瘤中发挥重要作用,程序性死亡［蛋白］-1（programmed death-1,PD-1）/程序性死亡［蛋白］配体-1（programmed death ligand-1,PD-L1）信号通路是参与肿瘤免疫逃逸的重要途径之一,针对PD-1/PD-L1通路的抑制剂在多种肿瘤中疗效显著,在PTCL的治疗上也有广阔的应用前景。研究表明在PTCL多种亚型中均有不同程度PD-1/PD-L1的表达,且PD-1单抗在部分亚型中疗效显著。现就PD-1/PD-L1在PTCL中的表达情况和其抑制剂的治疗进展作一综述。     

PD-1/PD-L1在结直肠癌中的研究进展

程序性死亡受体-1 (programmed death 1,PD-1)与其配体(programmed death-ligand l,PD-L1)是目前免疫治疗中关注的焦点.PD-1与其配体PD-L1结合导致肿瘤微环境中T细胞衰竭及免疫逃逸,阻断PD-1与PD-L1结合是有效的治疗靶点.针对阻断PD-1/PD-L1通路的单克隆抗体通过美国FDA的审批己应用于临床,并已证实在恶性黑色素瘤、肺癌、膀胱癌、胃癌、霍奇金淋巴瘤、乳腺癌等多种恶性肿瘤的治疗中取得了显著效果,目前该疗法在结直肠癌(colorectal cancer,CRC)的治疗研究中也显示出了良好的疗效.本文对当前PD-1/PD-L1的分子结构、肿瘤免疫中的生物学功能和在结直肠癌微环境中的特点、临床病理分子特点、PD-1/PD-L1抑制剂治疗与耐药及预后方面的研究进展作一综述.     

PD-1/PD-L1抑制剂与多药联合治疗三阴性乳腺癌的研究进展

因缺乏明确的分子靶点,三阴性乳腺癌（TNBC）与其他乳腺癌亚型相比是较难治疗以及预后较差的乳腺癌亚型。程序性死亡受体-配体1（PD-L1）在TNBC中表达明显增加,其免疫逃逸机制使其更适用于免疫检查点阻断治疗。然而,临床试验中TNBC对抗PD-L1或抗程序性死亡受体1（PD-1）治疗的反应率并不令人满意,客观反应率只有10%~20％,可能与TNBC具有免疫沉默效应有关,因此免疫检查点阻断剂与其他药物的联合策略可能会增加TNBC的临床获益率。本文综述TNBC中PD-1/PD-L1抑制剂联合其他药物的研究进展,为临床医生设计多药联合策略提供依据。     

PD-1/PD-L1抑制剂在膀胱癌新辅助治疗中的应用进展

膀胱癌是一种泌尿系统常见的肿瘤,单纯根治切除手术治疗的患者面临较高复发和转移风险,5年生存率为60~80%。在减少复发、转移和延长生存期的探索中,指南推荐以顺铂为基础的化疗作为标准新辅助治疗。但部分患者无法耐受化疗或对化疗不敏感,新辅助治疗应用率较低,未广泛开展。程序性死亡因子1(PD-1)和程序性死亡因子配体1(PD-L1)是重要的免疫检验点共抑制分子,通过抑制T细胞的激活和增殖通路参与肿瘤的免疫逃逸。近年来一批PD-1/PD-L1抑制剂被批准用于局晚期膀胱癌的一线、二线治疗,疗效及安全性得到证实,因此一些最新的研究探索将PD-1/PD-L1抑制剂运用于新辅助治疗。本文主要对近年来相关研究进行了回顾与总结,探讨PD-1/PD-L1抑制剂在膀胱癌新辅助治疗应用的前景和可能发展的方向。     

胸腺上皮肿瘤中程序性死亡蛋白1及其配体的临床研究进展

近年来,随着免疫治疗及肿瘤微环境概念的广泛普及,许多肿瘤靶向位点被人们关注并投以大量的实验研究。程序性死亡蛋白1及其配体（PD-1/PD-L1）作为目前最热门的一个免疫靶点通路,其抑制剂已经应用于多种恶性肿瘤的治疗当中。胸腺上皮肿瘤（TETs）是一种较为少见的肿瘤,目前已有证据表明PD-L1在TETs中存在高表达水平并且其与疾病的预后相关,因此本文针对PD-1/PD-L1在TETs中的临床研究进展作一综述。     

PD-1/PD-L1治疗非小细胞肺癌的研究进展

程序性死亡受体-1（programmed cell death-1,PD-1）/程序性死亡配体-1（programmed cell death-ligand 1,PD-L1）信号通路与肿瘤免疫逃逸密切相关,针对PD-1/PD-L1通路的免疫检查点抑制剂为非小细胞肺癌（non-small cell lung cancer,NSCLC）患者提供了一种新的治疗选择,并且显示出良好的疗效和安全性。本文对PD-1/PD-L1抑制剂治疗NSCLC的临床研究进展进行综述。      

PD-1/PD-L1抑制剂在淋巴瘤治疗中的研究进展

近年来,肿瘤生物免疫治疗因其显著的疗效而迅速发展为肿瘤研究领域的热点。程序性死亡受体-1（programmed death-1,PD-1）与其配体（programmed death ligand-1,PD-L1）在多种肿瘤细胞中过表达,参与肿瘤的发生、发展及侵袭转移。因此,PD-1/PDL1信号通路成为了肿瘤免疫治疗的有效新靶点。目前,PD-1/PD-L1抑制剂在淋巴瘤治疗研究中取得了较好的疗效。本文将对该类药物的相关临床研究现状进行综述,旨在加深对PD-1/PD-L1信号通路的作用机制及相关抗体应用于淋巴瘤治疗的认识。      

PD-1/PD-L1抑制剂治疗晚期肝细胞癌的机制及研究进展

原发性肝癌起病隐匿,恶性程度高,易发生进展及转移,往往发现疾病时已是肝癌中晚期。较长一段时间内,对于肝癌的主要治疗手段包括手术、放化疗、介入治疗及靶向治疗。但传统治疗方法疗效有限,近年来,随着对原发性肝癌的免疫系统研究逐步深入,免疫治疗已然成为一种新兴的治疗手段,其中以程序性死亡蛋白-1（PD-1）/程序性死亡蛋白配体-1（PD-L1）为靶点的免疫疗法在非小细胞肺癌及肾细胞癌的临床应用中取得了明显疗效。因此,许多研究者开始进一步探索PD-1/PD-L1抑制剂在肝癌中的治疗效果。本文将对PD-1/PD-L1抑制剂治疗肝癌的机制及现阶段国内外多项免疫治疗取得的成效作一综述。     

HDAC1-mSin3a-NCOR1, Dnmt3b-HDAC1-Egr1 and Dnmt1-PCNA-UHRF1-G9a regulate the NY-ESO1 gene expression

The NY-ESO1 gene is a cancer/testis antigen considered to be suitable target for the immunotherapy of human malignancies. Despite the identification of the epigenetical silencing of the NY-ESO1 gene in a large variety of tumors, the molecular mechanism involved in this phenomenon is not fully elucidated. In two non epithelial cancers (glioma and mesothelioma), we found that the epigenetic regulation of the NY-ESO1 gene requires the sequential recruitment of the HDAC1-mSin3a-NCOR, Dnmt3b-HDAC1-Egr1 and Dnmt1-PCNA-UHRF1-G9a complexes. Thus, our data illustrate the orchestration of a sequential epigenetic mechanism including the histone deacetylation and methylation, and the DNA methylation processes.     

CYP1A1, SULT1A1, and SULT1E1 polymorphisms are risk factors for endometrial cancer susceptibility

BACKGROUND: In estrogen biosynthetic pathways, many enzymes are important for metabolism, detoxification, and bioavailability. Polymorphisms in these genes may have an effect on the enzymes' function. For example, higher expression and activation of biosynthetic enzymes and lower expression and activation of conjugation enzymes may lead to high toxicity or carcinogenesis. The authors hypothesized that single nucleotide polymorphisms (single nucleotide polymorphisms) of CYP1A1, CYP1A2, CYP1B1, CYP17, SULT1A1, SULT1E1, and SHBG genes may be risk factors for endometrial cancer. METHODS: DNA samples from 150 cases of endometrial cancer and healthy controls (n = 165) were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to determine the genotypic frequency of 13 different polymorphic loci on the CYP1A1 (m1, m2, m3, m4), CYP1A2 1F, CYP1B1 codon432, COMT codon158, CYP17, SULT1A1 (Arg213His, 14A/G, 85C/T in the 3' flanking region), SULT1E1-64G/A promoter region, and SHBG genes. Genotyping was validated by direct DNA sequencing. The authors also investigated the relation between expression of CYP1A1 in endometrial cancer tissues and genotypes of CYP1A1 m1. RESULTS: A decreased frequency of TC + CC genotype of the CYP1A1 m1 (T/C) polymorphism was observed in endometrial cancer patients compared with controls (OR = 0.42; 95% CI, 0.27-0.69). The T-A haplotype of CYP1A1 m1 and m2 was increased in endometrial cancer patients (P = .017). The frequency of CYP1A1 m1 T/C + C/C was higher in a high CYP1A1 expression group (P = .009). The authors also found that individuals carrying the variants of SULT1A1 codon213 and 2 single nucleotide polymorphisms in the 3' flanking region (14A/G and 85C/T) had an increased risk for endometrial cancer. The frequencies of G-A-C and A-G-T haplotypes of these 3 variants were higher in endometrial cancer patients (P < .0001; P = .0002). In addition, the frequency of combined genotypes (SULT1A1 213 GA + AA and CYP1A1 m1 TT) was higher in endometrial cancer patients. (OR, 4.58; 95% CI, 2.35-8.93). CONCLUSIONS: This is the first report on the combined association of CYP1A1 and SULT gene polymorphisms in endometrial cancer that suggests a decreased single nucleotide polymorphism of CYP1A1 and an increased single nucleotide polymorphism for SULT1A1 and SULT1E1 genes may be risk factors for endometrial cancer in Caucasians.     

CYP1A1.

CYP1A1 plays an important role in the metabolism of polycyclic hydrocarbons that occur in the environment and several studies suggest that the genetic polymorphism of the gene may play a role in the predisposition to cancer. In order to evaluate the function of CYP1A1 in vivo as a host factor determinant of environmentally-caused cancers in humans, additional investigations are needed involving not only molecular epidemiological approaches in different ethnic populations but also more direct approaches such as the use of gene-targeted mice as a model system.     

DNA切除修复交叉互补基因1、乳腺癌易感基因、核苷酸还原酶1与非小细胞肺癌

 阐述了近年来非小细胞肺癌（NSCLC）化疗敏感性与DNA 切除修复交叉互补基因1 （ERCC1）、乳腺癌易感基因（BRCA1）、核苷酸还原酶1（RRM1）基因表达关系的研究进展，分析3个基因对NSCLC个体化化疗潜在的指导意义     

Methoxyestrogens exert feedback inhibition on cytochrome P450 1A1 and 1B1

Cytochrome P450 1A1 (CYP1A1) and 1B1 (CYP1B1) catalyze the oxidative metabolism of 17 beta-estradiol (E2) to catechol estrogens (2-OHE2 and 4-OHE2) and estrogen quinones, which may lead to DNA damage. Catechol-O-methyltransferase catalyzes the methylation of catechol estrogens to methoxyestrogens (2-MeOE2, 2-OH-3-MeOE2, and 4-MeOE2), which simultaneously lowers the potential for DNA damage and increases the concentration of 2-MeOE2, an antiproliferative metabolite. In this study, we showed that CYP1A1 and CYP1B1 recognized as substrates both the parent hormone E2 and the methoxyestrogens. Using purified recombinant enzymes, we demonstrated that CYP1A1 and CYP1B1 O-demethylated the methoxyestrogens to catechol estrogens according to Michaelis-Menten kinetics. Both CYP1A1 and CYP1B1 demethylated 2-MeOE2 and 2-OH-3-MeOE2 to 2-OHE2, whereas CYP1B1 additionally demethylated 4-MeOE2 to 4-OHE2. Because the P450-mediated oxidation of E2 and the O-demethylation of methoxyestrogens both yielded identical catechol estrogens as products, we used deuterated E2 (E2-d4), unlabeled methoxyestrogens, and gas chromatography/mass spectrometry to examine both reactions simultaneously. Kinetic analysis revealed that methoxyestrogens acted as noncompetitive inhibitors of E2 oxidation with K(i) ranging from 27 to 153 micro M. For both enzymes, the order of inhibition by methoxyestrogens was 2-OH-3-MeOE2 > or = 2-MeOE2 > 4-MeOE2. Thus, methoxyestrogens exert feedback inhibition on CYP1A1- and CYP1B1-mediated oxidative estrogen metabolism, thereby reducing the potential for estrogen-induced DNA damage.     

CYP1A1 and GSTM1 polymorphisms affect urinary 1-hydroxypyrene levels after PAH exposure

Certain human biotransformation enzymes have been implicated in the formation and scavenging of the ultimate reactive metabolites, the diolepoxides, from polycyclic aromatic hydrocarbons (PAHs). In the present study, performed on aluminum smelter workers, we have analyzed airborne PAH, the pyrene metabolite 1-hydroxypyrene (1-OHP) in urine, and genotypes for biotransformation enzymes involved in PAH metabolism. The aim was to evaluate the correlation between external exposure and biomarkers of exposure and to investigate to what extent genetic polymorphism in metabolic enzymes can explain interindividual variation in urinary 1-OHP levels. DNA was prepared from blood samples from 98 potroom workers and 55 controls and altogether eight polymorphisms in the CYP1A1, mEH, GSTM1, GSTP1 and GSTT1 genes were analyzed. The 1-OHP excretion was found to correlate significantly (P 100-fold) and univariate and multivariate regression analyses were used to find the variables that could determine differences in excretion. The variation could, to some degree, be explained by differences in exposure to airborne particulate-associated PAHs, the use of personal respiratory protection devices, smoking habits and genetic polymorphisms in the cytochrome P450 1A1, GSTM1 and GSTT1 enzymes. The part of the variance that could be explained by differences in biotransformation genotypes seemed to be of the same order of magnitude as the variance explained by differences in exposure. In the control group as well as in the occupationally exposed group, the highest 1-OHP levels were observed in individuals carrying the CYP1A1 Ile/Val genotype who were also of the GSTM1 null genotype. The results show that urinary 1-OHP is a sensitive indicator of recent human exposure to PAHs and that it may also to some extent reflect the interindividual variation in susceptibility to PAHs.     

Polymorphisms in CYP1B1, GSTM1, GSTT1 and GSTP1, and susceptibility to breast cancer

Polymorphisms in the cytochrome P450 1B1 (CYP1B1) and glutathione S-transferase (GST) drug metabolic enzymes, which are responsible for metabolic activation/detoxification of estrogen and environmental carcinogens, were analyzed for their association with breast cancer risk in 541 cases and 635 controls from a North Carolina population. Each polymorphism, altering the catalytic function of their respective enzymes, was analyzed in Caucasian and African-American women. As reported in previous studies, individual polymorphisms did not significantly impact breast cancer risk in either Caucasian or African-American women. However, African-American women exhibited a trend towards a protective effect when they had at least one CYP1B1 119S allele (OR=0.53; 95% CI=0.20-1.40) and increased risk for those women harboring at least one CYP1B1 432V allele (OR=5.52; 95% CI=0.50-61.37). Stratified analyses demonstrated significant interactions in younger (age < or =60) Caucasian women with the CYP1B1 119SS genotype (OR=3.09; 95% CI=1.22-7.84) and younger African-American women with the GSTT1 null genotype (OR=4.07; 95% CI=1.12-14.80). A notable trend was also found in Caucasian women with a history of smoking and at least one valine allele at GSTP1 114 (OR=2.12; 95% CI=1.02-4.41). In Caucasian women, the combined GSTP1 105IV/VV and CYP1B1 119AA genotypes resulted in a near 2-fold increase in risk (OR=1.96; 95% CI=1.04-3.72) and the three way combination of GSTP1 105IV/VV, CYP1B1 119AS/SS and GSTT1 null genotypes resulted in an almost 4-fold increase in risk (OR=3.97; 95% CI=1.27-12.40). These results suggest the importance of estrogen/carcinogen metabolic enzymes in the etiology of breast cancer, especially in women before the age of 60, as well as preventative measures such as smoking cessation.