应用遗传毒理学方法对表皮生长素的致突变性和皮肤毒性研究

目的 为临床安全使用表皮生长素药物提供科学参考依据。方法 应用Ames试验、CHL细胞染色体畸变试验、小鼠骨髓细胞微核试验、小鼠精子畸形试验、豚鼠皮肤致敏试验及家兔皮肤、眼刺激试验等方法评价表皮生长素的致突变性和皮肤毒性。结果 以上测试方法均呈现阴性结果。结论 通过遗传毒理学和皮肤毒性测试方法未观察到表皮生长素的致突变性和皮肤毒性效应。

Reduced secretion of epidermal growth factor in duodenal ulcer patients with Helicobacter pylori infection

AIM To investigate the concentration changes of epidermal growth factor (EGF) in duodenal ulcer patients with H. pylori infection.

生物剪刀

到目前为止,科学对剪羊毛工作者的帮助在于不断改进羊毛剪刀的质量。早期的羊毛剪刀是装有弹簧的,后来改用蒸气动力,最后发展成电动的。 每年,澳大利亚的13,500万只羊的毛仍然是用手剪的,每只羊的剪毛费高达一美元。现在他们已通过实验证明,如果把一种叫作表皮生长素的天然蛋白质注射进美利奴羊的肌体,就能使这些羊的毛完全脱落,而人们最多轻轻用手一捋,羊毛就会一把一把地脱下来。 从医学的角度说,使一只羊的毛完全脱光是不困难的。有消息说。

唾液保健的奥秘

唾液俗称口水,是人体之宝,祖国医学一向十分重视它的作用,有着“玉泉”、“甘露”、“金津玉液”等誉称。中医学认为唾液是由人体五脏精华上升而产生的。现代医学研究表明,人的唾液腺每天分泌的一至二升唾液中,含有球蛋白、粘蛋白、氨基酸、溶菌酶、淀粉酶、生长素甲、钠。

Genetic alterations in pancreatic cancer

The diagnosis of pancreatic patients and their relatives cancer is devastating for as the incidence rate is approximately the same as mortality rate. Only a small percentage, which ranges from 0.4% to 4% of patients who have been given this diagnosis, will be alive at five years. At the time of diagnosis, 80% of pancreatic cancer patients have unresectable or metastatic disease. Moreover, the therapeutic alternatives offered by chemotherapy or radiotherapy are few, if not zero. For all these reasons, there is an imperative need of analyzing and understanding the primitive lesions that lead to invasive pancreatic adenocarcinoma. Molecular pathology of these lesions is the key of our understanding of the mechanisms underlying the development of this cancer and will probably help us in earlier diagnosis and better therapeutic results. This review focuses on medical research on pancreatic cancer models and the underlying genetic alterations.

Trefoil factors:Tumor progression markers and mitogens via EGFR/MAPK activation in cholangiocarcinoma

AIM:To investigate trefoil factor(TFF) gene copy number,mRNA and protein expression as potential biomarkers in cholangiocarcinoma(CCA).METHODS:TFF mRNA levels,gene copy number and protein expression were determined respectively by quantitative reverse transcription polymerase chain reaction(PCR),quantitative PCR and immunohistochemistry in bile duct epithelium biopsies collected from individuals with CCA,precancerous bile duct dysplasia and from disease-free controls.The functional impact of recombinant human(rh) TFF2 peptide treatment on proliferation and epidermal growth factor receptor(EGFR) /mitogenactivated protein kinase(MAPK) signaling was assessed in the CCA cell line,KMBC,by viable cell counting and immunoblotting,respectively.RESULTS:TFF1,TFF2 and TFF3 mRNA expression was significantly increased in CCA tissue compared to disease-free controls,and was unrelated to gene copy number.TFF1 immunoreactivity was strongly increased in both dysplasia and CCA,whereas TFF2 immunoreactivity was increased only in CCA compared to diseasefree controls.By contrast,TFF3 immunoreactivity was moderately decreased in dysplasia and further decreased in CCA.Kaplan-Meier analysis found no association of TFF mRNA,protein and copy number with age,gender,histological subtype,and patient survival time.Treatment of KMBC cells with rhTFF2 stimulated proliferation,triggered phosphorylation of EGFR and downstream extracellular signal related kinase(ERK),whereas co-incubation with the EGFR tyrosine kinase inhibitor,PD153035,blocked rhTFF2-dependent proliferation and EGFR/ERK responses.CONCLUSION:TFF mRNA/protein expression is indicative of CCA tumor progression,but not predictive for histological sub-type or survival time.TFF2 is mitogenic in CCA via EGFR/MAPK activation.

High levels of serum platelet-derived growth factor-AA and human epidermal growth factor receptor-2 are predictors of colorectal cancer liver metastasis

AIM To develop predictive markers in blood for colorectal cancer liver metastasis.METHODS Twenty colorectal cancer patients were selected and divided into two groups. Group A consisted of 10 patients whose pathological TNM stage was ⅢC(T3-4N2M0), while another 10 patients with synchronous liver metastasis(TNM stage Ⅳ) were recruited for group B. During the surgical procedure, a 10-ml drainage vein(DV) blood sample was obtained from the DV of the tumor-bearing segment prior to the ligation of the DV. At the same time, a 10-ml peripheral vein(PV) blood sample was collected via peripheral venipuncture. The serum levels of 24 molecules that are potentially involved in the mechanism of liver metastasis in both DV blood and PV blood were analyzed by using high-throughput enzyme-linked immunosorbent assay technology.RESULTS Univariate analysis revealed that platelet-derivedgrowth factor AA(PDGFAA) in DV blood(d PDGFAA)(P = 0.001), PDGFAA in PV blood(p PDGFAA)(P = 0.007), and human epidermal growth factor receptor-2 in PV blood(p HER2)(P = 0.001), p MMP7(P = 0.028), pR ANTES(P = 0.013), and pE GF(P = 0.007) were significantly correlated with synchronous liver metastasis. Multivariate analysis identified d PDGFAA(HR = 1.001, P = 0.033) and p HER2(HR = 1.003, P = 0.019) as independent predictive factors for synchronous liver metastasis. Besides, high peripheral HER2 level may also be a risk factor for metachronous liver metastasis, although the difference did not reach statistical significance(P = 0.06). Significant correlations were found between paired DV and PV blood levels for PDGFAA(r = 0.794, P < 0.001), but not for HER2(r = 0.189, P = 0.424).CONCLUSION PDGFAA in tumor drainage and HER2 in PV blood may be useful predictive factors for synchronous liver metastasis of colorectal cancer.

Antitumor effect of Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, combined with cytotoxic agent on murine hepatocellular carcinoma

AIM: To investigate the inhibitory effect of gefitinib combined with cytotoxic agent cisplatin (CDDP) on hepatocellular carcinoma (HCC). METHODS: Female Kunming mice and H22 hepatocarcinoma cells were used. Gefitinib at daily dose of 100 mg/kg body weight (BW) or lecithin liquid was given by gastrogavage once a day for 5 or 10 successive days. CDDP or normal saline (NS) was administered intraperitoneally (i.p.) once a day for 5 successive days. Mice were randomly divided into control group (lecithin, or NS, i.p.), CDDP group (daily dose, 1.2 mg/kg BW; d1-5, or d6-10), Gefitinib (d1-5, or d6-10, or d1-10), and Gefitinib combined with CDDP groups. The inhibitory rate (IR) of tumor, net BW, spleen index (SI), thymus index (TI) and the amount of peripheral blood cells of mice were detected on the 12th experiment day. RESULTS: The growth of HCC in mice was inhibited by Gefitinib alone (IR: 41% in d1-10 group and 30% in d1-5 group, respectively) or CDDP alone (IR: 32-54% in d1-5 group or d6-10 group). The highest inhibitory effect (IR: 56%) on HCC growth was observed in Gefitinib (d1-10) combined with CDDP (d1-5) group. Higher inhibition was also observed in CDDP (d1-5) followed by Gefitinib (d6-10) group than that in Gefitinib (d1-5) followed by CDDP (d6-10) group (IR: 61% vs 36%, P<0.01) in the independent study. Net BW, SI, TI and the amount of blood cells of mice in Gefitinib alone group were not significantly different from those in control groups. CONCLUSION: Gefitinib can significantly inhibit the growth of murine H22 hepatocellular carcinoma. If Gefitinib is used after CDDP treatment in animal experiments, the inhibitory effect could be enhanced.

Efficacy of pemetrexed combined with erlotinib/gefitinib in advanced non-small cell lung cancer patients during tyrosine kinase inhibitor treatment

Objective We aimed to evaluate the efficacy and safety of pemetrexed combined with erlotinib/gefitinib in advanced non-small cell lung cancer(NSCLC) patients during tyrosine kinase inhibitor(TKI) treatment. Methods Thirty-two patients with advanced NSCLC were divided into two groups. Patients in the control group received continuous daily epidermal growth factor receptor tyrosine kinase inhibitor(EGFRTKI) treatment, and patients in the experimental group received continuous daily EGFR-TKI along with pemetrexed treatment, which was administered on day 1 at 500 mg/m2. Erlotinib(150 mg) or gefitinib(250 mg) was administered daily from day 1 to day 21, with a cycle of every 21 days. Dexamethasone, folic acid, and vitamin B12 were also administered during the treatment. The endpoint of the primary study was the disease control rate. Results The objective response rate was 21.9%(95% CI: 7.6% to 36.3%) in the control group, whereas the disease control rate was 84.4%(95% CI: 71.8% to 97.0%) in the experimental group. The median progression-free survival was 6.2(95% CI: 2.4 to 10.0). Grades 3 or 4 adverse effects of leucopenia(15.6%), neutropenia(12.5%), anemia(3.1%), and nausea or vomiting(3.1%) were found in the experimental group.Conclusion The administration of pemetrexed combined with erlotinib or gefitinib showed a higher efficacy in TKI-resistant NSCLC patients. Further, the adverse effects of this drug combination were well tolerated by the patients. Pemetrexed combined with TKI treatment might provide a satisfactory therapeutic strategy for advanced NSCLC patients after TKI treatment.

Pharmacokinetics Evaluation of Nimotuzumab in Combination with Doxorubicin and Cyclophosphamide in Patients with Advanced Breast Cancer

EGFr （Epidermal growth factor receptor） overexpression has been detected in many tumors of epithelial origin, specifically in breast cancer and it is often associated with tumor growth advantages and poor prognosis. The nimotuzumab is a genetically engineered humanized MAb （monoclonal antibody） that recognizes an epitope located in the extracellular domain of human EGFr. The aim of this study was to assess the pharmacokinetics of nimotuzumab in patients with locally advanced breast cancer who are receiving neoadyuvant therapy combined with the AC chemotherapy regimen （i.e., 60 mg/m2 of Doxorubicin and 600 mg/m2 of Cyclophosphamide in 4 cycles every 21 days）. A single center, non-controlled, open Phase I clinical trial, with histopathological diagnosis of locally advanced stage III breast cancer, was conducted in 12 female patients. Three patients were enrolled at each of the following fixed dose levels： 50, 100, 200 and 400 mg/week. Multiple intermittent short-term intravenous infusions of nimotuzumab were administered weekly, except on weeks 1 and 10, when blood samples were drawn for pharmacokinetic assessments. Nimotuzumab showed dose-dependent kinetics. No anti-idiotypic response against nimotuzumab was detected in blood samples of participants. There was not interaction between the administration of nimotuzumab and chemotherapy at the dose levels studied. The optimal biological doses ranging were estimated to be 200 mg/weekly to 400 mg/weekly.

Sixteen Years of Trastuzumab Use： Complete Response in Lung, Bone, and CNS Metastasis from Breast Cancer

Although metastatic breast cancer is considered as an incurable disease, various biological drivers influence the outcomes. The use of trastuzumab in patients overexpressing HER（human epidermal growth factor receptor 2）-2 increases long-term survival even in those patients who developed brain metastasis. Nevertheless, special attention must be paid to the risk of cardiotoxicity. We report the case of a young woman with HER-2-positive breast cancer with bone and lung disease who developed brain metastasis during treatment with trastuzumab. The treatment has been continued and she is alive and in complete remission after 16 years.

Effect of epidermal growth factor on follicle-stimulating hormone-induced proliferation of granulosa cells from chicken prehierarchical follicles

The development of ovarian follicular cells is controlled by multiple circulating and local hormones and factors, including follicle-stimulating hormone （FSH） and epidermal growth factor （EGF）. In this study, the stagespecific effect of EGF on FSH-induced proliferation of granulosa cells was evaluated in the ovarian follicles of egg-laying chickens. Results showed that EGF and its receptor （EGFR） mRNAs displayed a high expression in granulosa cells from the prehierarchical follicles, including the large white follicle （LWF） and small yellow follicle （SYF）, and thereafter the expression decreased markedly to the stage of the largest preovulatory follicle. SYF represents a turning point of EGF/EGFR mRNA expression during follicle selection. Subsequently the granulosa cells from SYF were cultured to reveal the mediation of EGF in FSH action. Cell proliferation was remarkably increased by treatment with either EGF or FSH （0.1-100 ng/ml）. This result was confirmed by elevated proliferating cell nuclear antigen （PCNA） expression and decreased cell apoptosis. Furthermore, EGF-induced cell proliferation was accompanied by increased mRNA expressions of EGFR, FSH receptor, and the cell cycle-regulating genes （cyclins D1 and El, cyclin-dependent kinases 2 and 6） as well as decreased expression of luteinizing hormone receptor mRNA. However, the EGF or FSH-elicited effect was reversed by simultaneous treatment with an EGFR inhibitor AG1478. In conclusion, EGF and EGFR expressions manifested stage-specific changes during follicular development and EGF mediated FSH-induced cell proliferation and retarded cell differentiation in the prehierarchical follicles. These expressions thus stimulated follicular growth before selection in the egg-laying chicken.

Curcumin co-treatment ameliorates resistance to gefitinib in drug-resistant NCI-H1975 lung cancer cells

OBJECTIVE: To examine whether a combinative treatment with curcumin enhances the effects of the epidermal growth factor receptor-tyrosine kinase inhibitor(EGFR-TKI) gefitinib on cell proliferation, clonogenic capacity and apoptosis in the drug-resistant lung cancer cell line NCI-H1975, and further investigate the molecular mechanisms involved.METHODS: NCI-H1975 cells were treated with curcumin and gefitinib alone or in combination, and cell proliferation, clonogenic capacity and apoptosis were examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) assay, clone forming experiments, and flow cytometry, respectively, while p38, extracellular regulated protein kinase(ERK)1/2, and protein kinase B(AKT)phosphorylation were examined using Western blotting.RESULTS: Compared with the effects of either agent alone, the combination of curcumin and gefitinib had a stronger suppressive effect on proliferation and the clonogenic capacity(P < 0.05), and showed an increased ability to promote apoptosis(P < 0.05) and reduce p38, ERK1/2, and AKT phosphorylation(P < 0.05).CONCLUSION: Co-treatment of curcumin and gefitinib significantly improves the ability of gefitinib to inhibit cell proliferation, suppress the clonogenic capacity and enhance apoptosis in NCI-H1975 cells,and these effects are possibly mediated via a decrease in phosphorylation of proteins in downstream pathways of the epidermal growth factor receptor.