The Relationship <i>BRCA1/2</i> Genes and Family History in Ovarian Cancers

BRCA1/2 genes are responsible for the hereditary breast and ovarian cancer syndrome. In this study, Turkish women with ovarian cancer were investigated in terms of demographic, clinicopathologic and family cancer stories according to their condition of the BRCA1/2 genes mutation carrier. During 2011 to 2017 in Turkey, BRCA1 and BRCA2 genes were analyzed in 38 women, who were diagnosed with cancer using Next Generation Sequencing technique. Pathogenic mutations were detected in 9 (23.7%) of patients. The diagnosis age for Ovarian cancer patients for BRCA1/2 mutation carriers was found higher. It was seen that mutations mostly occurred in the BRCA2 gene and frameshift mechanism and they were located in exon10 in the BRCA1 gene and especially in exon11 in the BRCA2 gene. According to the applied logistic regression model, it was found that patients with more than two relatives having cancer would have a 12.844 fold and high risk of being a BRCA1/2 mutation carrier. In women with ovarian cancer, BRCA1/2 gene mutations are observed more frequently in certain exons of these genes. BRCA1 mutation carriers are diagnosed with ovarian cancer earlier than BRCA2 mutation carriers. In hereditary ovarian cancers, besides BRCA1/2, many identified genes and many modifier candidate genes that are waiting to be discovered can cause this condition. In the family history, the numerical increase of cancerous relatives significantly increases the risk of BRCA1/2 carrying mutation.     

Evaluation of <i>MGMT</i> Gene Methylation in Neuroendocrine Neoplasms

Unresectable neuroendocrine neoplasms (NENs) often poorly respond to standard therapeutic approaches. Alkylating agents, in particular temozolomide, commonly used to treat high-grade brain tumors including glioblastomas, have recently been tested in advanced or metastatic NENs, where they showed promising response rates. In glioblastomas, prediction of response to temozolomide is based on the assessment of the methylation status of the MGMT gene, as its product, O6 -methylguanine-DNA methyltransferase, may counteract the damaging effects of the alkylating agent. However, in NENs, such a biomarker has not been validated yet. Thus, we have investigated MGMT methylation in 42 NENs of different grades and from various sites of origin by two different approaches: in contrast to methylation-specific PCR (MSP), which is commonly used in glioblastoma management, amplicon bisulfite sequencing (ABS) is based on high-resolution, next-generation sequencing and interrogates several additional CpG sites compared to those covered by MSP. Overall, we found MGMT methylation in 74% (31/42) of the NENs investigated. A higher methylation degree was observed in welldifferentiated tumors and in tumors originating in the gastrointestinal tract. Comparing MSP and ABS results, we demonstrate that the region analyzed by the MSP test is sufficiently informative of the MGMT methylation status in NENs, suggesting that this predictive parameter could routinely be interrogated also in NENs.     

<i>In vivo</i> Effects of Aqueous Extract of <i>Gongronema latifolium</i> Benth on the Tumor Necrosis Factor-α, Transforming Growth Factor-β, and Hepatic Enzymes

Nonsteroidal anti-inflammatory drugs have a number of side effects. However, some medicinal herbs have anti-inflammatory properties with few side effects. This study aimed to determine the effect of the aqueous extract of Gongronema latifolium (AEGL) leaves on the level of tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) in rabbits. Enzyme-linked immunosorbent assay (ELISA) was performed to determine the effect of the AEGL on the activities of pro-inflammatory cytokine (TNFα), and regulatory cytokine (TGF-β) in rabbits. Also, a colorimetric method was performed to evaluate the levels of AST and ALT. Overall, the weight of the animals increased until the 21st day and then slightly decreased in the last week of treatment. AEGL showed significant (p < 0.05) inhibitory activity against pro-inflammatory and regulatory cytokines. The greatest inhibitory activities against TNF-α (21 days) and TGF-β (14 days) were obtained at a dose of 400 mg/kg of AEGL. No hepatotoxicity was observed within a 28-day period. This study showed that AEGL can be used as a safe herbal anti-inflammatory and immunomodulatory treatment. Further clinical trials are needed to approve this potential.     

Double Heterozygosity in the <i>BRCA1/2</i> Genes in a Turkish Patient with Bilateral Breast Cancer: A Case Report

BRCA1 and BRCA2 tumor suppressor genes are responsible for a quarter of hereditary breast cancers. Double heterozygous (DH) pathogenic variant carrier status in these genes is an extremely rare condition, especially in non-Askenazi individuals. We report a woman patient with bilateral breast cancer that carries DH disease-causing variants in BRCA1/2 genes. The 45-year-old patient who was followed up with the diagnosis of metachronous bilateral breast cancer was diagnosed with cancer at the age of 39 and 43, respectively. BRCA1/2 genes of the patient were evaluated using Next-Generation Sequencing. In the patient, the c.2800C>T (p.Gln934Ter) pathogenic variant in BRCA1 and the c.9648+1G>C likely pathogenic variant in BRCA2 were detected as DH. Segregation analysis in family members revealed that her two healthy siblings available for testing were heterozygous for either BRCA1 or BRCA2 variants, but her mother, who had a past diagnosis of ovarian cancer, was heterozygous for both BRCA1 and BRCA2 variants. Germline double heterozygosity in inherited cancer is a rare condition, and as far as we know it is reported for the first time from patient population in Turkey. Large-scale patient series are needed to determine the impact of double heterozygosity on diseases course, such as prognosis and treatment responses.     

Analysis of Antioxidant Potential of <i>Trigonella foenum-graecum</i> (L.) Extract Against Tumorigenesis

Background: Trigonella foenum-graecum Linn. has been extensively used for medicinal purposes. The current study deals with in vitro and in vivo correlation of free radical quenching activity and anticancer potential of seed extracts of Trigonella. Materials and methods: Antioxidant activity was evaluated against DPPH, NO and ABTS via in vitro radical scavenging assay. Cytotoxicity effect of Trigonella seed extract was studied in human embryonic kidney HEK 293 cell line by alamar blue assay. In vivo antioxidant activity in Swiss albino mice model was assessed by studying endogenous antioxidant enzymes such as GSH, GPx, SOD and LPO. Antitumor effect was observed by studying parameters like total number of tumors, tumor size in mice. Further, expression of tumor suppressor gene, p53 in treated mice was investigated. Results: In vitro antioxidant assays had shown methanolic extract to possess higher radical scavenging activity than aqueous and to be minimal cytotoxic. In vivo study has shown a significant reduction in total number of tumors and tumor size for the mice group treated with extract in comparison to DMBA-TPA treated group. An increase in the levels of GSH, SOD and GPx was observed with a significant reduction in LPO levels. Expression of p53 was found to be upregulated in Swiss albino mice treated with extract emphasizing possible antitumor effect of Trigonella. Conclusion: The present study helped in understanding the reducing potential and antitumorigenic activity of Trigonella seed extract and its probable therapeutic effect in skin papillomagenesis.     

Anticancer and Antioxidant Activities of Aqueous and Ethanolic Bark Extracts of <i>Acer Tegmentosum</i> Maxim (Aceaceae) on Tumor Cell Lines

The medicinal plant of Acer tegmentosum Maxim is traditionally used in the southern part of Asia to treat oxidative stress-related diseases, including cancer, diabetes mellitus , wounds, infections, etc. Based on this, the current study was designed to investigate the phytochemical analysis, antioxidants and anti-cancer activities of Acer tegmentosum Maxim (AT). The total phenolic content (TPC), total flavonoid content (TFC), free radicals scavenging (DPPH and ABTS), chemical constituents as well as cytotoxicity potential ATWE (Acer tegmentosum Maxim water extracts) and ATEE (Acer tegmentosum Maxim ethanolic extracts) were tested. The cytotoxic efficacy ATWE and ATEE were studied in Human embryonic kidney 293 cells (HEK 293), human lung cancer cell lines (A549), prostate cancer cells (PC3) and breast cancer cells (MDA-MB 231). The results revealed that, TPC ranged between in 199.97 ± 0.09 mg GAR/g extract in ATWE and 103.48 ± 0.82 mg GAR/g extract in ATEE, TFC were 72.10 ± 0.07 mg RE/g extract in ATWE, and 47.28 ± 0.55 mg RE/g extract in ATEE. Aside it showed a promising antioxidant scavenging activity against DPPH and ABTS radicals. The antioxidant capacity of the two extracts increased in a dose-dependent manner. ATEE and ATWE had little difference in the scavenging rate of DPPH free radicals, and its radical scavenging activity were reached about 70% at 1000 μg/mL. ATWE had significant cytotoxicity to all the tested cancer cell lines of A549, PC3, and MDA-MB 231. The anti-cancer activity of ATWE was better than ATEE, and the IC₅₀ value for A549 cells, PC3 cells, and MDA-MB cells were 96.32 ± 5.96, 198.58 ± 10.35 and 365.27 ± 19.72 μg/mL, respectively. The fluorescent staining (AO/EB, PI, Rh123, ROS) studies explored that ATWE could target the cancer cell via nuclear damage, excessive production of ROS and loss of mitochondrial membrane potential, suggesting that activation of endogenous apoptosis pathways. These results proved that AT extracts (especially ATWE) had significant antioxidants and anti-cancer activities, implying a possible pharmacological application of AT.     

Comparison of <i>UGT1A1</i> Polymorphism as Guidance of Irinotecan Dose Escalation in RAS Wild-Type Metastatic Colorectal Cancer Patients Treated With Cetuximab or Bevacizumab Plus FOLFIRI as the First-Line Therapy

Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) polymorphism plays a crucial role in the increased susceptibility and toxicity of patients to irinotecan. This retrospective, observational study compared the clinical outcomes and adverse events (AEs) in RAS wild-type metastatic colorectal cancer (mCRC) patients treated with cetuximab or bevacizumab plus FOLFIRI with UGT1A1 genotyping and irinotecan dose escalation as the first-line therapy. In total, 173 patients with mCRC with RAS wild-type were enrolled. Among them, 98 patients were treated with cetuximab, whereas 75 patients were treated with bevacizumab. All patients received irinotecan dose escalation based on UGT1A1 genotyping. We compared the progression-free survival (PFS), overall survival (OS), objective response rates (ORRs), disease control rates (DCRs), metastatectomy, and severe adverse events (SAEs) between the two groups. The clinical effects of primary tumor sidedness and target therapy crossover were further analyzed. Over a median follow-up of 23.0 months [interquartile range (IQR), 15.0–32.5 months], no significant differences were observed between the cetuximab and bevacizumab groups in PFS [18.0 months vs. 14.0 months; 95% confidence interval (CI), 0.517–1.027; hazard ratio (HR), 0.729; p = 0.071], OS (40.0 months vs. 30.0 months; 95% CI, 0.410–1.008; HR, 0.643; p = 0.054), ORR (65.3% vs. 62.7%; p = 0.720), DCR (92.8% vs. 86.7%; p = 0.175), metastatectomy (36.7% vs. 29.3%; p = 0.307), and SAEs (p = 0.685). Regardless of primary tumor sidedness and target therapy crossover, no significant differences were noted in efficacy and safety between the two groups (all p > 0.05). Our results revealed that patients with wild-type RAS mCRC, regardless of biologics, with UGT1A1 genotyping can tolerate escalated doses of irinotecan and potentially achieve a more favorable clinical outcome without significantly increased toxicity.     

Anticancer Effects of <i>Gleditsia sinensis</i> Extract in Rats Transplanted With Hepatocellular Carcinoma Cells

The thorns of Gleditsia sinensis have been historically used in Chinese medicine and are considered one of the fundamental therapeutic herbs. Its anticancer effects are currently being explored. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and still requires the development of new drugs with higher efficiency. By using a rat HCC model implanted with cancerous Walker-256 cells, the therapeutic effects of G. sinensis extract (GSE) were assessed, as well as its regulatory effects on miRNAs. GSE significantly restored liver morphology and dramatically induced cell apoptosis in HCC rats. In addition, miR-21/181b/183 was upregulated in the HCC liver, and the elevation of these miRNAs could be alleviated by both GSE and sorafenib. PTEN/TIMP3/PDCD4 downregulation was consistent with the targets of miR-21/181b/183 in the HCC liver, and the alteration of these target genes was restored by both GSE and sorafenib. TIMP3 effects on MMP-2/9 expression were also determined. Our present findings indicate the potential of GSE in HCC treatment, and expand the understanding of miRNA-related mechanisms in the anticancer effects of GSE.     

Computational high-throughput screening and <i>in vitro</i> approaches identify CB-006-3; A novel PI3K-BRAF^V600E dual targeted inhibitor against melanoma

Malignant melanoma is characterized by both genetic and molecular alterations that activate phosphoinositide 3-kinase (PI3K), and RAS/BRAF pathways. In this work, through diversity-based high-throughput virtual screening we identified a lead molecule that selectively targets PI3K and BRAF^V600E kinases. Computational screening, Molecular dynamics simulation and MMPBSA calculations were performed. PI3K and BRAF^V600E kinase inhibition was done. A375 and G-361 cells were used for in vitro cellular analysis to determine antiproliferative effects, annexin V binding, nuclear fragmentation and cell cycle analysis. Computational screening of small molecules indicates compound CB-006-3 selectively targets PI3KCG (gamma subunit), PI3KCD (delta subunit) and BRAF^V600E. Molecular dynamics simulation and MMPBSA bases binding free energy calculations predict a stable binding of CB-006-3 to the active sites of PI3K and BRAF^V600E. The compound effectively inhibited PI3KCG, PI3KCD and BRAF^V600E kinases with respective IC₅₀ values of 75.80, 160.10 and 70.84 nM. CB-006-3 controlled the proliferation of A375 and G-361 cells with GI₅₀ values of 223.3 and 143.6 nM, respectively. A dose dependent increase in apoptotic cell population and sub G₀/G₁ phase of cell cycle were also observed with the compound treatment in addition to observed nuclear fragmentation in these cells. Furthermore, CB-006-3 inhibited BRAF^V600E, PI3KCD and PI3KCG in both melanoma cells. Collectively, based on the computational modeling and in vitro validations, we propose CB-006-3 as a lead candidate for selectively targeting PI3K and mutant BRAF^V600E to inhibit melanoma cell proliferation. Further experimental validations, including pharmacokinetic evaluations in mouse models will identify the druggability of the proposed lead candidate for further development as a therapeutic agent for treating melanoma.     

肺结核合并肺癌患者的临床特点及影响预后的相关因素分析

目的 分析肺结核合并肺癌患者的临床特征及影响患者5年生存率的因素.方法 选择收治的肺结核合并肺癌患者76例的临床资料.分析患者的临床症状及影响学特征;采用Kaplan-Meier生存分析法分析患者生存率,对影响患者预后的因素进行回归分析.结果 患者首发症状依次为咳嗽36例(47.4％),胸闷22例(28.9％),发热20例(26.3％),咯血咯痰18例(23.7％),胸背部疼痛17例(22.4％).影像学和病理学检查显示肿瘤位于左肺32例(42.1％),右肺35例(46.1％),全肺9例(11.8％);中央型肺癌26例(34.2％),周围型肺癌50例(65.8％);鳞癌45例(59.2％),腺癌21例(27.6％),小细胞肺癌8例(10.5％),未定型2例(3.9％);肿瘤TNM分期Ⅰ期16例(21.1％),Ⅱ期29例(38.2％),Ⅲ期21例(27.6％),Ⅳ期10例(13.2％).患者中位生存期为26个月,累积1年、3年、5年生存率分别为77.6％,35.5％,17.7％.单因素分析结果显示肿瘤病理类型、TNM分期和肺结核活动状态与患者预后显著相关.多因素分析结果显示:病理类型、TNM分期和肺结核活动状态是预后的独立影响因素.结论 肺结核合并肺癌患者无典型的临床表现,应避免漏诊误诊.肿瘤病理类型、TNM分期和肺结核活动状态是影响预后的独立危险因素.     

558例维吾尔族肺癌患者的临床病理特征及预后分析

目的 分析新疆本地维吾尔族肺癌患者的临床病理特征,了解该民族肺癌的分布特点及差异。方法 收集新疆医科大学附属肿瘤医院2005年1月1日至2014年12月31日就诊的558例维吾尔族肺癌患者,对患者的临床分期、病理类型、驱动基因等临床资料进行对比分析及随访。结果 男女比例1.37:1,女性和城市维吾尔族肿瘤患者中腺癌最多,而男性、有吸烟史和乡镇患者中鳞癌和小细胞肺癌居多;小细胞肺癌患者3年生存率最低,腺癌最高;21.8%（65/298）患者存在EGFR基因突变,多见于不吸烟、腺癌、女性患者;6.9%（11/159）患者存在EML4-AL基因融合,多表达于腺癌、不吸烟或既往有吸烟史,同时无EGFR突变患者;Ⅳ期EGFR基因突变患者与EGFR野生型患者总生存期（OS）差异无统计学意义（P=0.597）。Ⅳ期EML4-ALK基因融合患者与EML4-ALK基因未融合患者总生存期差异无统计学意义（P=0.941）。结论 维吾尔族肺癌患者在临床特征、病理类型、流行病学分布及驱动基因方面有其特点。病理类型和分期是影响维吾尔族NSCLC患者预后的独立因素。     

女性肺癌237例临床分析

目的 探讨女性肺癌的临床病理学特征及生存状况.方法 回顾性分析237例女性肺癌的临床资料,单因素分析采用Kaplan-Meier生存分析,并进行Log-rank时序检验.结果 ①女性肺癌好发年龄为40~69岁,首发症状以咳嗽咳痰为主,病理类型多为腺癌.②确诊方法为开胸、胸腔镜手术及支气管镜.肿瘤TNM分期以晚期为主,无症状患者ⅠA~ⅢA期居多.③无症状患者中位生存期更长.④确诊时血清CEA水平与预后相关.⑤接受表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor tyrosine kinase inhibitor,EGFR-TKI)的EGFR突变患者有生存优势.结论 女性肺癌以腺癌为主,确诊时多已是晚期,无症状患者以早期为主.定期体检、早期发现和诊断可提高生存.女性是EGFR高突变人群,突变患者靶向治疗可获益.     

肺癌分子生物学研究进展

肺癌是世界上最常见的恶性肿瘤之一,其发病率和死亡率都非常高。高通量二代测序技术的发展推动了肺癌分子生物学的研究。近年来针对肺癌的基因组及转录组变异特征的研究取得了很大的进步,然而尚缺乏对肺癌发生发展过程的多组学分子机制的研究。本文通过对近年来肺癌分子生物学研究成果进行综述,希望为今后的研究提供方向和依据。     

RKIP PTEN基因启动子区甲基化与肺癌的关系

探讨RKIP基因和PTEN基因启动子区甲基化与肺癌及其临床病理特征的关系。方法：采用甲基化特异性PCR（MSP）法,分析肺癌组织及相应癌旁正常肺组织中RKIP和PTEN启动子区甲基化表达情况。结果：45.8%（38/83）的肺癌组织和13.3%（11/83）的癌旁肺组织RKIP基因启动子区发生甲基化,51.8%（43/83）的肺癌组织和15.7%（13/83）的癌旁肺组织PTEN基因启动子区发生甲基化,癌组织中RKIP和PTEN启动子区甲基化率显著增高（P<0.05）;发生淋巴结转移的43例肺癌组织中,27例RKIP基因启动子区发生甲基化,30例PTEN基因启动子区发生甲基化,淋巴结转移组RKIP及PTEN基因启动子区甲基化均显著高于无淋巴结转移组（P<0.05）。结论：肺癌中RKIP和PTEN基因启动子区甲基化,可能是肺癌发生、发展及转移的重要原因之一。     

肺结核合并肺癌的临床特点及影像学检查在其诊断中的应用价值

目的 探讨肺结核合并肺癌的临床特点,并通过分析研究影像学检查在该疾病诊断中的应用价值.方法 选取60例肺结核合并肺癌的患者作为观察组,同时选取同期收治的单纯肺结核患者60例为对照组,分析2组患者在临床特征、实验室检查和CT影像学检查中的差异.结果 肺结核结合肺癌患者的吸烟史、胸痛、声音嘶哑和消瘦的比例均明显高于单纯肺结核组(P＜0.05);同时,其CEA、CA125及非小细胞肺癌抗原的指标值也显著高于单纯肺结核组.2组患者的各项影像学特征均有统计学差异(P＜0.05).结论 患者的吸烟史、胸痛、声音嘶哑和消瘦等临床特征,以及CEA、CA125和非小细胞肺癌抗原3种血清癌抗原在诊断肺结核合并肺癌中有参考价值;CT影像学检查在诊断该疾病中有较高的应用价值,值得在临床推广应用.     

检测肺癌患者血清p53抗体的临床意义

目的:探讨检测肺癌患者血清p53抗体的临床意义。方法:采用酶联免疫吸附法检测120例肺癌患者血清p53抗体,并以30例肺部良性疾病患者和120例正常健康人作对照。结果:肺癌患者血清p53抗体水平明显高于肺部良性疾病患者和正常人(P<0.05),而正常人与肺部良性疾病患者间无显著性差异(P>0.05)。120例肺癌中26例p53抗体阳性,阳性率为21.7%,而30例肺部良性疾病患者和120例正常人无1例阳性。肺癌者血清p53抗体与肺癌细胞分化程度和临床分期有密切关系(P<0.01)。结论:检测血清p53抗体水平有助于肺部良恶性疾病的诊断及鉴别诊断。     

肺癌患者化疗前后外周血肿瘤标志物水平变化的临床价值

目的 对肺癌患者化疗前后外周血内肿瘤标志物水平改变进行分析.方法 随机选取50例肺癌患者,给予紫杉醇类或联合顺铂方案化疗2个周期,采用放射免疫技术对不同病理类型组化疗前后外周血内肿瘤标志物CEA、NSE、CYFRA 21-1水平进行监测,并结合化疗前后肺部CT影像学变化分析化疗前各病理类型血清肿瘤外周血内肿瘤标志物水平.结果 50例患者经2个周期化疗后,行CT影像学检测评估,肿块PR+ CR者38例,NC+ PD者12例.化疗前,腺癌组血清CEA水平显著高于鳞癌组和小细胞肺癌组;鳞癌组CYFRA 21-1水平显著高于腺癌组和小细胞肺癌;小细胞肺癌组NSE水平显著高于腺癌组和鳞癌组,数据对比差异均具有统计学意义(P＜0.05).腺癌组(CR+ PR)化疗后CEA水平显著低于化疗前;鳞癌组(CR+ PR)化疗后CYFRA 21-1水平显著低于化疗前;小细胞肺癌组(CR+ PR)化疗后NSE水平显著低于化疗前,数据对比差异均具有统计学意义(P＜0.05).结论 通过检测外周血内肿瘤标志物CEA、NSE、CYFRA 21-1水平改变可用于化疗疗效判定,具有简便、经济的特点.     

以脑转移为首发的肺癌患者的临床特点及预后影响因素分析

目的分析以脑转移为首发的肺癌患者的临床特点,探究影响其预后效果的因素。方法选取以脑转移为首发的肺癌患者500例,通过分析患者临床特征,用Kaplan-Meier计算患者生存率、中位生存期、绘制患者累积生存函数曲线,用Log-rank对相关因素行单因素分析,用Cox回归模型对单因素分析后有统计学意义的因素进行多因素预后分析。结果 500例患者中有438例患者经过随访收集到完整资料,总随访率为87.6%,患者发病时最常见的神经系统症状为颅高压症状,病理类型主要以腺癌为主,占总患者的55.7%,肺癌脑转移部位主要以大脑幕上为主,占总患者的55.9%,438例患者中位随访时间为16个月,中位生存期为15个月,1年、2年、3年、4年、5年生存率分别为53.7%、32.6%、21.3%、13.9%、9.4%,单因素分析患者的年龄是否>60岁、发病急缓、病理类型是否为腺癌、病理类型是否为低分化癌,肺部原发病灶是否放疗,手术治疗是否联合SRS技术6个因素对患者生存率有影响,多因素分析显示患者的年龄是否>60岁、发病急缓、病理类型是否为腺癌,有无靶向治疗既往史4个因素是影响患者生存率的独立预后影响因素。结论脑转移首发表征肺癌患者颅高压症状颅内转移灶多发于大脑半球,患者年龄>60、发病急骤、非腺癌、未行靶向治疗其独立不良预后影响因素。