表皮、真皮因素对创面愈合中成纤维细胞生物学行为的影响

成纤维细胞参与创面愈合的全过程，是创伤愈合中主要的修复细胞之一，创伤后成纤维细胞被激活，发生迁移、增殖，分泌包括胶原在内的细胞外基质，参与肉芽组织及疤痕形成。在这一过程中成纤维细胞的生物学行为受多种因素的调控。表皮成分、真皮模板通过对成纤维细胞生物学行为的影响，可减少创伤后伤口收缩以及疤痕增生，从而改善了创面愈合质量。

影响砂岩酸化措施成败的主要因素分析

酸化是油田普遍应用的增产措施之一。由于砂岩的基质酸化极其复杂,因而导致施工失败的因素很多。在总结国内外油田的实际经验和调研相关文献的基础上,对影响砂岩酸化措施效果的主要因素进行了分析,并为某些因素提出了选择标准,对以后的砂岩酸化施工提供参考。

表皮生长因子测定与妇科肿瘤关系初探

应用放射免疫分析法测定了32例肿瘤组织中表皮生长因子(EGF)含量,其中子宫内膜癌10例、子宫肌瘤22例和正常子宫内膜20例(对照组)。结果:子宫内膜癌的非肿瘤内膜组织中EGF含量明显高于对照组(P<0.05);其癌组织中EGF含量明显低于对照组(P<0.01);子宫肌瘤组织中EGF含量亦高于对照组(P<0.05)。提示EGF在促进肿瘤的发生和发展中可能起着重要作用,而癌组织分泌EGF的功能相对下降。

非小细胞肺癌中EGFR基因突变及靶向药物治疗研究进展

报道在非小细胞肺癌(NSCLC)中表皮生长因子受体(EGFR)基因突变与非小细胞肺癌发生的相关性,尤其在东方人群、女性、非吸烟者、腺癌的患者中突变率更高的现状。分别对EGFR基因突变与临床病理特征的关系、相关靶向药物治疗、检测方法等方面进展进行了综述,EGFR基因突变检测将会成为今后研究EGFR靶向药物治疗的热点。

肺耐药蛋白在乳腺浸润性导管癌中的表达及与EGFR、HER-2的相关性

目的探讨肺耐药蛋白(lung-resistance protein,LRP)与促瘤因素表皮生长因子受体(epidermal growth factor receptor,EGFR)和HER-2在乳腺浸润性导管癌中的表达及其临床意义。方法采用免疫组化EnVision法,检测76例乳腺癌组织中LRP、EGFR和HER-2的表达。结果1)在乳腺癌组织中,LRP、EGFR、HER-2的表达率分别为35.53%、15.79%和25%,它们相互之间表达相关性不明显。2)随着肿瘤组织恶性程度的增高,LRP的表达明显降低(P=0.039)。3)LRP、EGFR、HER-2在淋巴结非转移组与转移组中的表达差异无统计学意义。结论LRP的表达在乳腺癌的恶性进展过程中起重要作用,诊断过程中结合该指标可更准确判断肿瘤恶性程度。

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.

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.

乳腺癌患者行新辅助化疗前后其肿瘤组织ER、PR、Her-2的表达及临床意义

目的:探究乳腺癌接受新辅助化疗前后的肿瘤组织中ER、PR、Her-2等的表达和临床意义。方法:针对150名乳腺癌患者在新辅助化疗前后的ER、PR和Her-2的表达情况采用免疫组织化学染色法进行检测。结果:新辅助化疗前后的ER、PR和Her-2表达阳性率差异并不明显,无任何统计学意义(P>0.05);ER、PR和Her-2阳性和阴性表达转化率分别是26.0%、28.0%和31.0%,其中PR和Her-2丢失比较常见(P<0.05)。结论:ER、EP和Her-2表达变化可被当做乳腺癌新辅助化疗的重要指标。

Significance of glucocorticoid receptor expression in colonic mucosal cells of patients with ulcerative colitis

AIM: Glucocorticoid (GC) resistant ulcerative colitis (UC) remains a serious disease and is difficult to manage. Although the molecular basis of GC insensitivity is still unknown, GC receptors (GRAAA and GRp) may play an important role in it. This study was aimed to investigate the relationship between the expression of GRa and GRp in colonic mucosal cells of patients with UC, the efficacy of GC therapy and the intensity of inflammation. METHODS: Twenty-five cases of UC were classified into: GC sensitive (n = 16) and GC resistant (n - 9) cases. Patients consisted of mild (n = 6), moderate (n = 8) and severe (n = 11) cases. GRa and GRp expression in colonic mucosal specimens were investigated by immunohistochemistry, and compared between GC resistant and sensitive groups, and also among various degrees of inflammation. RESULTS: All cases were positive for GRa and GRp expression. Both positive association between GRa expression and the response of UC to GC and strong negative association between GRp expression and the response of UC to GC were identified. There was no significant association between GRa/GRp expression and the degree of inflammation of UC. CONCLUSION: These findings suggest that both GRa and GRp may play an important role in the action of GC, and that GRp functions as a dominant negative inhibitor of GRa. Expression of GRa and GRp in colonic mucosal cells of patients with UC may serve as predictors of glucocorticoid response, but can not function as markers of inflammatory intensity.

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.

EOTAXIN AND EOTAXIN-2 EXPRESSION IN HUMAN BRONCHIAL EPITHELIAL CELL

Objective To study the role of eotaxin and eotaxin-2 expression by Th2 cytokine and analyze their relationship in normal human bronchial epithelial cell line-BEAS-2B cell. Methods Levels of eotaxin mRNA and protein expression in the bronchial epithelial cell line BEAS-2B cell were determined with RT-PCR and ELISA. We also used RT-PCR to evaluate eotaxin-2 expression under the regulation of Th2 cytokine IL-4 and IL-13 as well as proinflammatory agent-TNFα. Results Eotaxin mRNA expression was the highest at the time point of 12h under the stimulation of TNF-α. While Th2 cytokine IL-4 and IL-13 had the amplification effect on the expression. Eotaxin protein was also elevated with the combination stimulation of proinflammatory agent TNF-α and IL-4 in dose and time dependent manner（ P 〈 0. 01 ）. These results were also seen when the cells were stimulated by TNF-α and 1L- 13. Eotaxin-2 mRNA expression was the highest at the time point of 8h. The expression evaluated by semi-quantitative RT-PCR also elevated under the co-stimulation of TNF-α and IL-4 or TNF-α and IL-13 and it should significantly correlate with Eotaxin （ P 〈 0. 05 ）. Conclusion This study demonstrated that Th2 cytokine like IL-4 and IL-13 enhances eotaxin and eotaxin-2 expression when co-stimulated with proinflammatory agent TNF-α. These results showed that Th2 cytokines existence is the strong evidence for bronchial epithelial cells taking part in the allergic inflammation especially in eosinophils recruitment.

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.

非小细胞肺癌EGFR突变状态与CT特征的相关性

目的 分析计算机断层扫描(CT)纹理特征与非小细胞肺癌(non-small cell lung cancer, NSCLC)表皮生长因素受体(EGFR)突变状态的相关性。方法 选择2018年1月至2022年1月我院收治的73例NSCLC患者为对象,根据EGFR突变状态分为突变组40例和未突变组33例。筛选NSCLC EGFR突变状态非0系数的CT纹理特征,构建Lasso-Logistics回归模型,绘制受试者工作特征曲线(ROC)分析诊断效能。结果 共筛选出能量、熵、均匀度、对比度4个非0系数的CT纹理特征及气管空气征、胸膜凹陷征2个CT形态特征。ROC曲线分析显示Lasso-Logistics回归模型诊断NSCLCEGFR突变状态的AUC为0.879(95%CI 0.872~0.926),敏感度90.00%,特异度82.50%。结论 CT纹理特征气管空气征、胸膜凹陷征、能量、熵、均匀度、对比度是NSCLC患者EGFR突变状态的诊断因素,建立的诊断模型能为临床识别NSCLC EGFR突变的高危患者提供参考。

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.

Expression of glucocorticoid receptor isoforms in cutaneous hemangiomas and vascular malformations

Background Hemangiomas are the most common tumors in children. Some hemangiomas may require intervention because of their location, size, behavior, or potential for important complications. Pharmacological therapy with glucocorticoids is the mainstay treatment, but there is no consensus on therapeutic regimens or candidate selection, therapeutic efficacy vaires, and the mechanism mediating the beneficial effects of glucocorticoids remains unclear. This study was performed to investigate the expression patterns of the glucocorticoid receptor (GR) and its α isoform (GRα) in cutaneous hemangiomas and vascular malformations.Methods SP immunohistochemical technique was used to examine the expression of GR(e-20) (GR) and GR (p-20) (GRα) on vascular endothelial cells in 80 specimens that included 33 proliferating hemangiomas, 32 involuting hemangiomas, 7 vascular malformations as well as 8 normal skin tissues, all obtained from infants and children. GR and GRα expression in prepared tissue slides were examined using automated computer-assisted microscopic analysis. Mean gray scale values were compared among the various tumor types.Results The mean gray scale values of GR were 127.0±6.4 and 121.4±6.6 in hemangiomas and vascular malformations respectively, but this difference was not statistically significant ( P =0.104). However, these values were all markedly higher than that of normal skin, which was only 108.6±6.8 ( P =0.001 and P =0.000 for comparison with hemangiomas and vascular malformations respectively). The gray scale of GR in proliferation and involuting hemangiomas were 127.9±4.8 and 126.0±5.8 respectively, but this difference was not significant ( P =0.146). However, GRα expression in hemangiomas, vascular malformations and normal skin declined gradually in stepwise fashion (127.3±5.4, 120.4±6.1 and 109.9±5.3 respectively; P <0.001). GRα expression was higher in proliferating hemangiomas than in involuting hemangiomas (127.2±6.3 and 122.5±6.3; P =0.004).Conclusions GR and GRα are strongly expressed in hemangiomas and vascular malformations. The expression of GRα is closely related to the phase of the hemangioma. Determination of GR and GRα may be a positive significance to understand the information of hemangiomas and vascular malformations and may further help determining proper strategies of steroid therapy for hemangiomas and vascular malformations.

新辅助化疗前后乳腺癌患者的临床病理特征变化

目的探讨乳腺癌患者新辅助化疗前后的临床病理特征变化及与临床疗效的关系。方法回顾性选取2017年5月至2019年10月间北京协和医院肿瘤医院深圳医院收治的39例行新辅助化疗的乳腺癌患者,分析患者原发灶、区域淋巴结转移灶、雌激素受体(ER)、孕激素受体(PR)、人表皮生长因子受体2(HER2)和增殖核抗原Ki-67等的变化,并探讨与临床疗效的相关性。结果20.5%的患者对新辅助化疗无反应(疾病进展和疾病稳定),12.8%的患者达病理完全缓解。新辅助化疗后,2.5%的患者ER表达阳性转阴性,20.5%的患者PR表达阳性转阴性,2.5%的患者阴性转阳性,7.7%的患者HER2表达阳性转阴性。Ki-67按照<15%、15%~30%和≥30%的范围分级,新辅助化疗后,51.3%的患者化疗前后处于同一范围,46.2%的患者由高一级降到低一级范围甚至更低一级。二元Logistics回归分析发现,患者Ki-67范围变化与疗效密切相关。新辅助化疗前后,69.2%的患者发生原发灶(T)降期,38.5%的患者发生区域淋巴结(N)降期。结论新辅助化疗可改变乳腺癌患者重要分子标记物的表达状态,但对治疗和预后的影响仍需进一步研究;Ki-67与新辅助化疗疗效相关,可能是新辅助化疗疗效的一个预测指标。