Combined effect of cabozantinib and gefitinib in crizotinib‐resistant lung tumors harboring ROS1 fusions

The ROS1 tyrosine kinase inhibitor (TKI) crizotinib has shown dramatic effects in patients with non‐small cell lung cancer (NSCLC) harboring ROS1 fusion genes. However, patients inevitably develop resistance to this agent. Therefore, a new treatment strategy is required for lung tumors with ROS1 fusion genes. In the present study, lung cancer cell lines, HCC78 harboring SLC34A2‐ROS1 and ABC‐20 harboring CD74‐ROS1, were used as cell line‐based resistance models. Crizotinib‐resistant HCC78R cells were established from HCC78. We comprehensively screened the resistant cells using a phosphor‐receptor tyrosine kinase array and RNA sequence analysis by next‐generation sequencing. HCC78R cells showed upregulation of HB‐EGF and activation of epidermal growth factor receptor (EGFR) phosphorylation and the EGFR signaling pathway. Recombinant HB‐EGF or EGF rendered HCC78 cells or ABC‐20 cells resistant to crizotinib. RNA sequence analysis by next‐generation sequencing revealed the upregulation of AXL in HCC78R cells. HCC78R cells showed marked sensitivity to EGFR‐TKI or anti‐EGFR antibody treatment in vitro. Combinations of an AXL inhibitor, cabozantinib or gilteritinib, and an EGFR‐TKI were more effective against HCC78R cells than monotherapy with an EGFR‐TKI or AXL inhibitor. The combination of cabozantinib and gefitinib effectively inhibited the growth of HCC78R tumors in an in vivo xenograft model of NOG mice. The results of this study indicated that HB‐EGF/EGFR and AXL play roles in crizotinib resistance in lung cancers harboring ROS1 fusions. The combination of cabozantinib and EGFR‐TKI may represent a useful alternative treatment strategy for patients with advanced NSCLC harboring ROS1 fusion genes.     

Synergistic anti‐tumor effect of paclitaxel with CRM197, an inhibitor of HB‐EGF,in ovarian cancer

Heparin‐binding EGF‐like growth factor (HB‐EGF) plays a pivotal role in tumor growth and clinical outcomes in patients with ovarian cancer, leading to the validation of HB‐EGF as a target for ovarian cancer therapy. In this study, we investigated the anti‐tumor effects of paclitaxel, as an anti‐cancer agent, and CRM197, as a specific inhibitor off HB‐EGF, in ovarian cancer. Paclitaxel induced transient ERK activation and sustained activation of JNK and p38 MAPK through the ectodomain shedding of HB‐EGF in SKOV3 cells. In addition, the overexpression of HB‐EGF in paclitaxel‐treated SKOV3 cells resulted in modulation of paclitaxel‐evoked MAPK signaling, including marked activation of ERK and Akt, and minimized activation of JNK and p38 MAPK, indicating that HB‐EGF is involved in drug sensitivity through the balance of anti‐apoptotic and pro‐apoptotic signals induced by paclitaxel. The combination of paclitaxel with CRM197 had an inhibitory effect on cell proliferation and enhanced apoptosis via the inhibition of ERK and Akt activation and the stimulation of p38 and JNK activation. More prominently, the administration of paclitaxel with CRM197 resulted in synergistic anti‐tumor effects in SKOV3 cells and in SKOV3 cells overexpressing HB‐EGF in xenografted mice. Accordingly, inhibitory agents against HB‐EGF, such as CRM197, represent possible chemotherapeutic and chemosensitizing agents for ovarian cancer. © 2008 Wiley‐Liss, Inc.     

Synergistic effect of lung tumor‐associated dendritic cell‐derived HB‐EGF and CXCL5 on cancer progression

The interaction between cancer cells and their microenvironment is a paradoxical cycle that exacerbates cancer progression and results in metastasis. Our study investigated the mechanism underlying the synergistic enhancement of release of soluble factors from tumor‐associated dendritic cells and its effect on cancer development. The combination of HB‐EGF (heparin‐binding EGF‐like growth factor) and CXCL5 (CXCL5/epithelial neutrophil‐activating peptide‐78) produced a strong synergistic effect on cancer proliferation, epithelial–mesenchymal transition, migration and invasion. CXCL5 not only potentiated the classical EGFR pathway and the AKT and ERK/RSK1/2 signaling pathways but also increased the phosphorylation of heat shock protein 27 (HSP27), which was slightly increased in A549 cells treated with either HB‐EGF or CXCL5 only. Phosphorylated HSP27 stabilized sustained AKT activity by direct interaction, leading to enhanced tumor spheroid formation. Knockdown of HSP27 by shRNA decreased HB‐EGF plus CXCL5‐mediated tumor spheroid formation in a three‐dimensional culture system, suggesting that AKT/HSP27 was required for HB‐EGF/CXCL5‐mediated cancer progression. Inhibiting RSK also reduces the modulation of c‐Fos phosphorylation, Snail upregulation and cell migration by HB‐EGF plus CXCL5, suggesting a synergistic effect of ERK/RSK and HB‐EGF plus CXCL5 on cell migration. In mice, CXCL5 antibody synergistically enhances the efficiency of the tyrosine kinase inhibitor, gefitinib, without increasing its toxicity. These results provide evidence that elucidates potential cross‐points between extracellular signals affecting lung cancer progression. Targeting CXCL5 may provide therapeutic benefits for lung cancer chemotherapy or immunotherapy.     

Crucial involvement of the CCL3‐CCR5 axis‐mediated fibroblast accumulation in colitis‐associated carcinogenesis in mice

Patients with inflammatory bowel diseases often develop colon carcinoma. Combined treatment of azoxymethane (AOM) and dextran sulfate sodium (DSS) recapitulates colitis‐associated cancer in mice. AOM/DSS‐induced tumor formation was reduced in CCL3‐ or its specific receptor, CCR5‐deficient mice despite the presence of a massive infiltration of inflammatory cells. However, AOM/DSS‐induced type I collagen‐positive fibroblast accumulation in the colon was reduced in CCL3‐ or CCR5‐deficient mice. This was associated with depressed expression of heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF), which is expressed mainly by fibroblasts. Moreover in vitro, CCL3 induced fibroblasts to proliferate and to enhance HB‐EGF expression. Furthermore, CCR5 blockade reduced tumor formation together with reduced fibroblast accumulation and HB‐EGF expression, even when administered after the development of multiple colon tumors. Thus, CCL3‐CCR5‐mediated fibroblast accumulation may be required, in addition to leukocyte infiltration, to induce full‐blown colitis‐associated carcinogenesis. Our studies shed light on a therapeutic potential of CCR5 antagonist for patients with colitis‐associated cancer.     

专业学生乙肝感染状况及乙肝疫苗接种免疫效果观察

目的 :了解医学检验专业学生乙型肝炎病毒 (HBV)感染状况及接种酵母重组基因工程乙肝疫苗 (乙肝疫苗 )的免疫效果。方法 :对 115名医学检验专业学生进行乙肝血清标志物 (HBVM)检测 ,对 2 7名易感者接种乙肝疫苗并追踪免疫效果。结果 :对 HBV有免疫力的有 6 3人 (5 4.78% ) ,感染 19人 (16 .5 2 % ) ;易感者 33人 (2 8.70 % )。对 2 7名易感者全程接种乙肝疫苗后 ,发现乙肝表面抗体 (抗 - HBs)阳转率为 88.89% (2 4/ 2 7) ,2年后抗 - HBs阳性维持率 91.6 7%(2 2 / 2 7)。结论 :医学检验专业学生有乙肝病毒易感者 ,接种乙肝疫苗具有较好的免疫学效果。     

Long term immunogenicity safety and efficacy of a recombinant hepatitis B vaccine in healthy adults

Two hundred healthy adults seronegative for HBV markers received three 10 or 20 mcg injections of a vaccine formulated from HBsAg produced by a recombinant strain of the yeastSaccharomyces cerevisiae. The vaccine was administered intramuscularly at 0, 1, and 6 months in the deltoid region. The seroconversion rates, expressed in GMT/IU/1 were determined at 1, 2, 6, 7, 12, 24, 36 and 48 months following the initial injection. No severe or serious adverse reactions attributable to the HB vaccines were observed in any subject. The seroconversion rates following the 20 mcg dose of recombinant vaccine were always higher than those observed after the 10 mcg dose, but the differences were not statistically significant. Also the GMT values were lower after the 10 mcg dose of vaccine. Females showed a higher anti-HBs response than males; an age-dependent effect was observed in the anti-HBs response as regards both the percentage of responders and the antibody concentrations in the serum. No adverse reactions to the vaccine were observed. The rDNA vaccine did not induce a response to yeast-derived impurities and did not increase anti-yeast IgE antibody titres. The results of this study have shown that the Amgen rDNA vaccine is safe and clinically well tolerated, and that it provides protection against infection and disease. A vaccination dose of 20 mcg appears more advantageous for healthy adult subjects.Corresponding author.     

尿HB检测试剂盒在人群肿瘤筛检中的应用

为了探讨一种新的尿肿瘤标志物ＨＢ检测试剂盒在人群肿瘤筛检及肿瘤辅助诊断中的应用价值，对广州市各种原发性恶性肿瘤病人尿样进行双对照研究。结果表明，该试剂盒对１０多种常见恶性肿瘤检测总阳性率为６９０１％，明显高于良性疾病对照组（１０１４％）和健康人群对照组（４６２％，Ｐ＜０００１），但不同肿瘤类型尿ＨＢ阳性率似乎不同。检测灵敏度和特异度分别为８３０５％和９４９２％，诊断准确度为８８９８％。提示该试剂盒对常见恶性肿瘤的检测有较高的灵敏度和特异性，良性疾病因素对检测结果的干扰较小，并具有广谱、简捷、采样无创伤性等优点，可作为癌症的检测指标，在高危人群或职业人群肿瘤的筛检方面，以及作为恶性肿瘤的辅助诊断方面均有较好的应用价值     

中国10个省乙型肝炎疫苗接种率及其影响因素

本文根据世界银行贷款卫生Ⅶ项目计划免疫接种率基线调查的数据，对１０个项目省的乙型肝炎（乙肝）疫苗接种率及影响接种率的有关主要因素，如经济水平、地理地貌、计划免疫保偿及家长计划免疫知识水平进行了分析。出生于１９９４年７月１日～１９９５年６月３０日的８３８９名儿童，在４个不同层次的经济水平间乙肝疫苗全程接种率分别为城区８２．９％、农村一层４４．３％、农村二层３２．９％、农村三层１８．４％（Ｐ＜０．０００１）；不同地理地貌因素乙肝疫苗接种率分别为山区１８．１％、丘陵地区３６．３％、平原地区６５．５％（Ｐ＜０．０００１）；参加计划免疫保偿乙肝疫苗接种率为６３．６％、未参加者３１．５％（Ｐ＜００００１）；家长计划免疫知识水平的高低与乙肝疫苗接种率水平呈正相关（ｒ＝０．９４，ｐ＝０．００５）。通过多因素分析，发现计划免疫保偿加入与否对乙肝疫苗接种率的影响最大（ＯＲ＝２．８５），其次为地理地貌（ＯＲ＝２．０７）、经济水平（ＯＲ＝１．９８）和家长的一般计划免疫知识水平（ＯＲ＝１．２３）。     

免疫RNA与正常RNA治疗30例慢性乙型肝炎的效果对比观察

HB是一种免疫失调疾病,因此,用特异性和非特异性免疫调节剂治疗是合理的。本文采用双盲法,用免疫RNA和正常RNA对30病HB病人进行了同步性的疗效对比观察。经1-2疗程旨,免疫RNA组自觉症状减轻和肝功能明显改善,细胞免疫功能增强,HBsAg阴转率27％,滴度下降者13.3％,HBeAg阴转40％,并能明显增加外周血白细胞和血小板,治愈率67％,总有效率80％。正常RNA组的HBsAg阴转率27％,HBeAg阴转0％,治愈率20％,总有效率53％。结果显示,特异性HBsAg-iRNA组治疗效果明显优于非特异性正常RNA组。     

拉米夫定合用华蟾素对慢性乙型肝炎伴甲胎蛋白增高者的疗效

慢性活动性乙型肝炎患者中,常有血清甲胎蛋白（AFP）-过性升高或持续性升高,其中有部分AFP呈高水平（AFP〉400μ/L）。笔者应用拉米夫定（贺普丁）联合华蟾素治疗18例AFP〉400μ/L的慢性活动性乙型肝炎患者,结果效果理想,AFP值显著降低。