苯丙(a)蒽的毒性研究进展

苯丙（a）蒽（BaA）是一种四环结构的多环芳烃（PAH）类物质,是化石燃料不完全燃烧的副产物,与其他的PAHs以混合物的形式存在。BaA可通过口腔、鼻腔及皮肤等多种途径暴露于人类,对人的主要危害是致癌性。国际癌症研究机构（IARC）根据其分类标准将BaA归为2B类（对人可能致癌）。目前尚无充足数据支持通过计算剂量外推斜率因子（slope factor）来完成动物致癌系数与人体致癌系数之间的推导。本文对BaA的致癌性等毒性研究进行系统文献检索与综述,以期为今后进行BaA的健康风险评估提供可靠的毒理学数据基础。     

癌肿病人血浆阿朴脂蛋白(a)水平升高

癌肿病人脂蛋白代谢的变化早已报道,并建议将特定脂蛋白作为恶性肿瘤的潜在标记。Skipski从癌肿病人血清中,分离出在脂质构成和漂浮特性上类似于高密度脂蛋白(HDL)的糖基脂蛋白,称之为新蛋白质w和s(neopr-oteolipids W和s)。Wieczorek等描述了类似脂蛋白的颗粒,称之为含mRNA的脂蛋白,其某些特性类似于HDL。Mountford和Wright检测到癌肿病人的血浆脂蛋白并称之为恶性相关脂蛋白(MAL)。在这些研究中,作者分析     

Docetaxel (Taxotere) in the treatment of non-small cell lung cancer (NSCLC)--is there a role for a new chemotherapy programme?

Phase II with single-agent docetaxel, in second-line NSCLC, demonstrated an overall response rate of 20%, with a median response duration of 7 months and a median survival time of 9 months. These results suggested that docetaxel had promising activity in patients with platinum-resistant or refractory NSCLC. Phase III studies in this patient population subsequently confirmed this activity; docetaxel prolonged survival when compared to either vinorelbine/ifosfamide or the best supportive care. The phase II studies with docetaxel in first-line NSCLC produced an overall response rate of 30% in evaluable patients, with a median response duration of 6 months and a median survival time of 9 months. A phase III randomized study demonstrated a significant improvement in survival and time to progression with docetaxel, compared to the best supportive care. Based on the activity observed with single-agent docetaxel, combination and multimodality studies with docetaxel have also been conducted. Docetaxel is an active agent in first- and second-line NSCLC. Ongoing studies in the front-line treatment of NSCLC will further define the role of docetaxel in the neo-adjuvant setting.     

Poly(ADP-ribose): a co-regulator of DNA methylation?

The formation of multiprotein complexes is l'ordre du jour in regulatory pathways. In this issue of Oncogene, Reale et al. report the formation of a particularly sophisticated complex of two important regulatory enzymes, DNMT1 (DNA methyltransferase-1) and PARP-1 (poly(ADP-ribose)polymerase-1). The former evolved with a specific sequence motif binding the enzymatic product of the latter. The product, poly(ADP-ribose), bonds the two partners into a heterodimeric complex and, as a consequence, the catalytic function of DNMT1 is silenced. Thus, PARP-1 becomes a conditional negative regulator of DNMT1. In a larger perspective, Reale et al. highlight the potential role of PARP-1 as a co-regulator of DNA methylation leading to epigenetic reprogramming of cancer cells.     

Does cisplatin (CDDP) function as a modulator of 5-fluorouracil (5-FU) antitumor action? A study based on a clinical trial

Objective To clarify whether CDDP acts as a modulator of 5-FU antitumor action in gastric cancer, patients were treated preoperatively with 5-FU+CDDP (FP) chemotherapy.Patients and methods From September 2000 to November 2001 at Takarazuka Municipal Hospital, 29 patients preoperatively diagnosed with stages II–IV gastric cancer were enrolled. Written informed consent was obtained from all patients. The patients were randomly assigned to two groups: the FU group, in which patients received a continuous intravenous infusion of 5-FU 320 mg/m² per day over 24 h a day for 5 days beginning 5 days prior to surgery, and the FP group, in which patients received bolus intravenous injections of CDDP 3.5 mg/m² per day for 5 days prior to surgery in addition to the same infusion of 5-FU as the FU group. As indicators of the intracellular effect of 5-FU treatment, thymidylate synthase (TS) inhibition rates, TS protein levels, TS and dihydropyrimidine dehydrogenase (DPD) activity, and F-RNA concentrations were measured.Results Using Scheffes multiple comparison test, in both treatment groups the tumor regions were found to have significantly higher TS inhibition rates than the nontumor regions (P<0.05). No significant differences in TS protein levels, TS activity, DPD activity or F-RNA concentrations were found between the four regions.Conclusions Our results show that CDDP clinically may act to enhance the antitumor effects of 5-FU in terms of the inhibition of DNA synthesis and could therefore act as a modulator of 5-FU.     

Lysophosphatidic acid (LPA)—a perspective marker in ovarian cancer

To compare plasma lysophosphatidic acid (LPA) levels in ovarian cancer patients in women with benign ovarian tumors and in women with no ovarian pathology. We correlated clinico-pathological parameters with plasma LPA levels. Capillary electrophoresis with indirect ultraviolet detection was used to analyze the plasma LPA levels of 159 patients (81 patients with ovarian cancer, 27 women without ovarian or uterine pathologies, and 51 patients with benign ovarian tumors) during a 5-year period. Patients with ovarian cancer had a significantly higher plasma LPA level (n = 81; median (med), 11.53 μmol/l; range, 1.78–43.21 μmol/l) compared with controls with no ovarian pathology (n = 27; med, 1.86 μmol/l; range, 0.94–9.73 μmol/l), and patients with benign ovarian tumor (n = 51; med, 6.17 μmol/l; range, 1.12–25.23 μmol/l; P < 0.001). We found that plasma LPA levels were associated with the International Federation of Gynecology and Obstetrics stage. The histological subtype and grade of ovarian cancer did not influence the plasma LPA levels in this study. The plasma LPA level can be a useful marker for ovarian cancer, particularly in the early stages of the disease.     

难治性急性髓系白血病(M2a)的基因表达谱

背景与目的:复发是急性髓系白血病(acutemyeloidleukemia,AML)治疗失败的主要原因,部分AML复发时其免疫表型和细胞遗传学已发生了改变。耐药是AML难治的主要原因,AML耐药与基因的异常表达有关,目前对AML复发/难治或耐药相关基因及其表达所知甚少。本研究检测AML初诊与复发/难治之间的基因表达差异,为阐明AML复发/难治的可能机制提供依据。方法:应用基因芯片技术,对5例自身配对初诊与复发/难治AML鄄M2a患者之间骨髓单个核细胞的基因表达差异进行了检测。结果:在检测的925个基因中,14个基因在初诊与复发/难治AML鄄M2a之间差异表达,其中12个基因(涉及细胞信号转导、DNA复制、转录调节和RNA加工以及细胞循环等相关基因)在复发时明显上调,参与DNA复制过程的RRM1基因上调最显著。结论:在AML鄄M2a复发/难治的发生过程中有多个基因共同参与,这些基因的高表达提示复发/难治AML细胞增殖能力可能更强。     

Dendritic cells and HNSCC: a potential treatment option? (Review)

Patient survival in head and neck squamous cell cancer (HNSCC) has not changed significantly in many years, despite progress in surgical, radiotherapy and chemotherapy techniques. Immunotherapy, a rapidly progressing alternative cancer treatment, aims to prompt or assist the body's immune system to combat the disease itself. A number of strategies exist including the use of dendritic cells, natural antigen presenting cells capable of stimulating an anti-tumor immune response. Encouraging work has been performed using these cells as vaccines against a number of tumors especially melanoma. Work with head and neck cancer is also encouraging, but less advanced. Dendritic cell presence in head and neck squamous cell cancers is associated with an improved prognosis, however due to immunosuppression, the exact mechanism of which remains poorly understood, these cells do not function efficiently. This prevents the stimulation of an effective anti-tumor immune response by the patient and allows tumor growth to continue. This review summarises the current level of understanding of dendritic cells and their relationship with HNSCC. It briefly summarises work with dendritic cells and other cancers where relevant to HNSCC; dendritic cells and head and neck cancer; the possible causes of dendritic cell impairment; the techniques used to restore their function and the methods used to prime the dendritic cells prior to their use as vaccines for the stimulation of an anti-tumor response.     

Is placental alkaline phosphatase (PLAP) a useful marker for seminoma?

The usefulness of placental alkaline phosphatase (PLAP) as a tumour marker was assessed in 1578 serum samples from 236 patients with seminoma. Smoking habits were known for all but 7 patients (22 samples). Smoking was associated with significantly higher mean levels of PLAP in disease-free patients (28.8[S.E. 2.1]U/l vs. 15.9[1.3] U/l in non-smokers). Mean PLAP levels were higher in patients with active disease (78.6 [23.5] U/l in non-smokers and 47.2 [18.5] U/l in smokers). The median values showed a similar trend. However, there was considerable overlap between the various groups and differences between mean and median values indicated that PLAP values were distributed asymmetrically. The predictive value of PLAP as a tumour marker was consequently much less than superficial inspection of these values might suggest. In 97 patients on surveillance, only 2 out of 11 patients who relapsed had elevated PLAP at the time of clinically detectable relapse. With the upper limit of normal PLAP quoted by our laboratory (35 U/l), specificity and sensitivity were, respectively, 88% and 45% (all patients) and 96% and 47% (non-smokers). The sensitivity and specificity of PLAP were assessed in more detail for a series of threshold values (normal vs. abnormal) with a graphical method. Only in non-smokers did PLAP seem useful and even in this group the positive predictive value of an “abnormal” test may be low; less than 50% in clinically relevant circumstances. Serum PLAP assay cannot usefully stand alone as a marker for seminoma and its routine estimation contributes little to follow-up.     

Large Vessel (Takayasu's) Arteritis in a Patient With Myelodysplastic Syndrome: Is There a Common Pathogenesis?

Autoimmune phenomena may complicate the course of myelodysplastic syndromes (MDS) but large vessel arteritis is a rare event. We report a case of large vessel arteritis in a patient with MDS. A 62-year-old male presented with thrombocytopenia and was diagnosed with low-risk MDS, (<5% blasts in his bone marrow and a normal karyotype). Shortly thereafter he developed large vessel (Takayasu's) arteritis (TA) that responded well to oral corticosteroid and methotrexate therapy. Ten months later the MDS transformed into acute myeloid leukemia (AML). After a successful induction course with cytarabine and daunorubicin he underwent allogeneic transplantation from a matched unrelated donor with reduced-intensity conditioning. The transplantation was complicated by systemic cytomegalovirus (CMV) disease and he died 6 weeks post transplantation. Takayasu's arteritis is an uncommon form of vasculitis affecting primarily young women and is atypical for elderly males. Though autoimmune manifestations in MDS occur in 10%-18.5% of patients, usually large vessels are spared. In MDS, activated T cells are thought to mediate bone marrow failure via overproduction of proinflammatory cytokines that cause stem cell apoptosis. These T cells may also mediate the autoimmune phenomena in MDS. The prognostic significance of autoimmunity in the course of MDS is not yet determined. Some reports suggest worse prognosis. The case illustrates a possible association between MDS and large vessel vasculitis and suggests a possible relationship between the presence of autoimmune syndromes and the outcome of patients with MDS.     

Methylenetetrahydrofolate reductase (MTHFR) and breast cancer risk: a nested-case–control study and a pooled meta-analysis

Encouraged by recent studies on the MTHFR 677C>T polymorphism and breast cancer risk that suggested an association of the 677 TT genotype with increased breast cancer susceptibility in premenopausal women, we performed an analysis of the relationship between breast cancer risk and the MTHFR 677C>T polymorphism in 210 premenopausal breast cancer patients and sex- and agematched healthy control subjects. Our data show a trend for a higher MTHFR 677T allele frequency in breast cancer cases (61.9%) than in controls (51.5%, P = 0.082) supporting the results of previous studies.     

Non-Small-Cell Lung Cancer (NSCLC) Harboring ALK Translocations: Clinical Characteristics and Management in a Real-Life Setting: a French Retrospective Analysis (GFPC 02–14 Study)

Background

Chromosomal translocations involving the anaplastic lymphoma kinase gene (ALK) are rare oncogenic events found in 3–5% of non-small-cell lung cancers (NSCLC). Limited data have been published on the management of these patients outside clinical trials.

Objective

To investigate the clinical characteristics and management of patients with NSCLC harboring ALK translocations (ALK+) in a real-life setting in France.

Methods

This multicenter, observational, retrospective study included all NSCLC patients harboring ALK translocations diagnosed in participating centers between January 2012 and December 2014. Patient data include clinical characteristics, disease management, and outcomes [progression-free survival (PFS) and overall survival (OS)].

Results

The 31 participating centers reported data on 132 patients, of whom 51% (n = 67) were male. The median age was 60.1 ± 14.5 (standard deviation) years; 89% (n = 106/119) had performance status 0/1 at diagnosis; 79% (n = 103/130) were non- or former smokers; 93% (n = 120/129) had adenocarcinomas and 74%(n = 97)/19%(n = 25)/7%(n = 10) had disease stages IV/III/I-II at diagnosis, respectively; co-mutations included EGFR (n = 2), BRAF (n  = 2), KRAS (n = 1), and HER2 (n = 1). Of the patients with stage IV NSCLC (n = 97), 96% received first-line treatment [75% chemotherapy-based, 21% ALK tyrosine kinase inhibitor (TKI)], with an associated response rate (RR), disease-control rate (DCR), and PFS of 42%, 64%, and 7.5 [95% confidence interval (CI) 5.9–9.5] months, respectively; 62% received second-line treatment (28% chemotherapy, 72% ALK TKI) with an associated RR, DCR, and PFS of 43.4%, 70%, and 4.7 (95% CI 4.0–8.1) months, respectively. The 2-year OS was 56.7% (95% CI 45.5–70.4%); median OS was not reached.

Conclusion

The results of this real-life analysis suggest that the prognosis of NSCLC patients with theALK translocation may be better than that of the overall NSCLC population, but the outcomes were poorer than those of ALK+ NSCLC patients included in clinical studies.

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Interaction of folliculin (Birt-Hogg-Dubé gene product) with a novel Fnip1-like (FnipL/Fnip2) protein

Birt-Hogg-Dubé (BHD) syndrome is characterized by the development of pneumothorax, hair folliculomas and renal tumors and the responsible BHD gene is thought to be a tumor suppressor. The function of folliculin (Flcn), encoded by BHD, is totally unknown, although its interaction with Fnip1 has been reported. In this study, we identified a novel protein binding to Flcn, which is highly homologous to Fnip1, and which we named FnipL (recently reported in an independent study as Fnip2). The interaction between FnipL/Fnip2 and Flcn may be mediated mainly by the C-terminal domains of each protein as is the case for the Flcn-Fnip1 interaction. FnipL/Fnip2 and Flcn were located together in the cytoplasm in a reticular pattern, although solely expressed Flcn was found mainly in the nucleus. Cytoplasmic retention of Flcn was canceled with C-terminal truncation of FnipL/Fnip2, suggesting that FnipL/Fnip2 regulates Flcn distribution through their complex formation. By the employment of siRNA, we observed a decrease in S6K1 phosphorylation in the BHD-suppressed cell. We also observed a decrease in S6K1 phosphorylation in FNIP1- and, to a lesser extent, in FNIPL/FNIP2-suppressed cells. These results suggest that Flcn-FnipL/Fnip2 and Flcn-Fnip1 complexes positively regulate S6K1 phosphorylation and that FnipL/Fnip2 provides an important clue to elucidating the function of Flcn and the pathogenesis of BHD.