肿瘤坏死因子及其受体在胆囊癌及结石性胆囊炎中的表达

目的　研究肿瘤坏死因子 (TNF)及其受体 (TNFR)在胆囊粘膜单纯性增生到胆囊癌的发展过程中的表达 ,并探讨其在胆囊癌发生、发展中的意义。方法　采用原位杂交和免疫组织化学SP法染色检测胆囊结石引起的胆囊粘膜单纯性增生、不典型性增生及胆囊癌的TNFmRNA、TNF蛋白及TNFR的表达。结果　①TNFmRNA在胆囊粘膜单纯性增生、不典型性增生和胆囊癌上皮细胞或癌细胞的表达阳性率分别为 0、2 0 %和 90 %(P<0 .0 5 ) ,在高倍视野下计数的阳性细胞数分别为 0个、(3.2 5± 1.89)个和 (12 .2 8± 4 .99)个 (P<0 .0 1) ;②TNFmRNA在胆囊粘膜单纯性增生、不典型性增生及胆囊癌组织中单核细胞 (mononuclearcell,MNC)的表达阳性率分别为 15 %、85 %和 90 % (P<0 .0 5 ) ,其阳性细胞数分别为 (4 .85± 1.5 0 )个、(6 .0 0± 2 .71)个和 (9.33± 3.0 7)个 (P<0 .0 5 ) ;③在胆囊癌组织中 ,癌细胞及MNC表达TNFmRNA随肿瘤进展而增多 ,Ⅰ～Ⅲ期及Ⅳ～Ⅴ期胆囊癌中呈阳性表达的癌细胞数分别为 (9.13± 4 .39)个和 (14 .80± 4 .0 2 )个 (P<0 .0 1) ,MNC数分别为 (7.13± 2 .5 3)个和(11.10± 2 .2 3)个 ,其差异有显著性意义 (P<0 .0 5 ) ;④在胆囊癌组织中 ,癌组织及MNC表达TNFmRNA随肿瘤直径的增大而增高 ,直径 ≥2 .0cm及 <2     

SH3BP2 is a Critical Regulator of Macrophage and Osteoclast Response to M-CSF and RANKL Stimulation

The protein Src homology 3 domain-binding protein 2 (SH3BP2) is a regulator of tumor necrosis factor (TNF)-alpha generation in macrophages and of osteoclast differentiation. SH3BP2 regulates bone marrow monocyte responses to macrophage and osteoclast differentiation signals downstream of the receptors for macrophage colony-stimulating factor and receptor activator of nuclear factor kappaB ligand. SH3BP2 is a potential target for the development of novel anti-TNF-alpha therapeutic interventions as well as a target for suppression of osteoclastogenesis. SH3BP2 is a critical regulator of macrophage and osteoclast response to M-CSF and RANKL stimulation.     

神经生长因子及其受体在胆管结缔组织中的表达及意义

目的 在胆管结扎(BDL)模型中观察神经生长因子(NGF)及其高亲和力受体酪氨酸激酶A(TrkA)在增殖的胆管周围结缔组织中的表达以及梗阻缓解后其表达的变化.方法 46只SD雌性大鼠,随机分为对照组(n=6)和BDL组(n=40),建立大鼠阻塞性黄疸模型,取肝十二指肠韧带,采用免疫组化方法检测NGF和TrkA在胆管结缔组织中的表达和分布.同时左心室采血检测血清总胆红素和谷丙转氨酶水平.结果 BDL组胆总管结扎后,大鼠胆红素水平于早期升高: 3 d时有明显升高,持续到第14 d; 后期下降: 第21 d和28 d时胆红素水平已基本降至正常.BDL组胆管壁直径明显增加,与结缔组织细胞增殖分化相平行.NGF及TrkA受体在胆管结缔组织细胞和炎性浸润细胞胞膜和胞浆中表达,其表达的变化与胆红素水平的变化趋势基本一致.结论 NGF和TrkA受体对胆管周围结缔组织的增殖、分化有调节作用,可能参与了胆管瘢痕的形成过程,淤胆状态的缓解在短期内可能对胆管瘢痕形成无逆转作用.     

The Treatment of Soft Tissue Hemorrhages in a Severe Classical Hemophiliac with an Unusual Antibody to Factor VIII

A known severe classical hemophiliac patient presented with a large hemorrhage into his left shin and complained of paresthesia in his toes. Large doses of factor VIII had failed to halt the expanding shin hematoma. Laboratory investigations revealed an antibody titer of 5 Bethesda units. In vitro and in vivo testing showed swift neutralization of factor VIII to a level of 20% and thereafter degradation of factor VIII in accordance to the half-life expectancy. The patient was successfully treated with a continuous infusion of small doses of cryoprecipitate. The Bethesda method of antibody measurement does not distinguish between low and high affinity antibodies and thus in vitro testing should be carried out before a decision is made on the use of expensive activated prothrombin complex. The initial approach of the physical therapist is to aid in attempting to limit the swelling and enhance hematoma reabsorption. Once the bleeding has been controlled, a long-term physical therapy program is necessary to regain dorsiflexion of the ankle joint.J Orthop Sports Phys Ther 1988;10(4):138-141.     

Antithrombotic pharmacologic prophylaxis use during conservative and surgical management of foot and ankle disorders: a systematic review

The use of antithrombotic pharmacologic prophylaxis during conservative or postoperative management of foot and ankle disorders is controversial. This article presents a systematic review of the incidence of deep venous thrombosis (DVT)/pulmonary embolus (PE) during management of foot and ankle disorders in patients who did or did not receive antithrombotic pharmacologic prophylaxis. Incidence of DVT/PE in both groups was low; however, more than half of the patients in both groups received some form of antithrombotic pharmacologic prophylaxis of varying duration, making it difficult to determine the true protective effect of antithrombotic pharmacologic prophylaxis.     

Allograft Membranous Glomerulonephritis and Renal-vein Thrombosis in a Patient with a Lupus Anticoagulant Factor

A circulating lupus anticoagulant factor was detected in a 38-year-oldman with end-stage renal disease and a ‘lupus-like’syndrome with a diffuse proliferative glomerulonephritis. Whentreated with steroids, the ‘lupus’ complicationswere controlled and the anticoagulant factor disappeared; however,renal function did not recover and the patient commenced regularhaemodialysis. Four months later the patient received a cadaverkidney transplant. At transplantation and during follow-up therewas neither clinical nor laboratory evidence of lupus activity,but 19 months after transplantation, when steroids were taperedto a low dose, the lupus anticoagulant factor was detected,and renal-vein thrombosis complicated by sepsis led to the patient'sdeath. A membranous glomerulonephritis was found on autopsy.This is the first time in which a (probably ‘de novo’)membranous glomerulonephritis has been detected in the allograftof a patient with circulating lupus anticoagulant factor.     

Expression of Vascular Endothelial Growth Factor (VEGF) and Epidermal Growth Factor Receptor (EGFR) is an Independent Prognostic Indicator of Worse Outcome in Gastric Cancer Patients

BACKGROUND: Unlike other human tumors, gastric cancer remains a great therapeutic challenge since no standardized postoperative treatment exists. Knowledge of molecular pathways determining the behavior of individual gastric tumors seems to be crucial for therapeutic decisions, and evaluation of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) expression might be critical for prognosis, assessment, and identification of patients that could be treated with tailored therapies. METHODS: VEGF and EGFR determination was performed in 88 gastric cancer samples as well as 25 normal gastric mucosa specimens from non-cancer patients using a commercially available immunohistochemistry kit. In all samples, the correlation of VEGF and EGFR expression was investigated with each other, and with other prognostic indicators in all samples, and, finally, with survival rates in 69 patients undergoing potentially curative surgery. RESULTS: Forty-eight per cent (42 cases) of gastric cancers expressed VEGF, and 44% (39 cases) stained for EGFR. In curatively treated patients, VEGF and EGFR expression was demonstrated to correlate with worse survival in both univariate and multivariate analyses. Molecular profiling was shown to more accurately estimate the risk of cancer-related death than TNM stage, and, of most interest, to allow sorting out high-risk patients within the same stage. CONCLUSIONS: These findings provide evidence that contemporary evaluation of VEGF and EGFR expression may be crucial to select gastric cancer patients with poor prognosis who may benefit of tailored treatments.     

The Role of the Epidermal Growth Factor Receptor in Breast Cancer

Recent trials of drug therapy targeting the erbB receptor HER2 have met with success in breast cancer. The epidermal growth factor receptor or EGFR is a closely related receptor from this same family that is involved in cellular signal transduction and tumor cell growth and survival. Emerging evidence indicates that EGFR is implicated in the development of hormone-resistant breast cancer, and that its activity is intertwined with estrogen receptor. Here, the role of EGFR in breast cancer is reviewed, and data from selected clinical trials of signal transduction inhibition of this cellular target are summarized.     

表皮生长因子及其受体在睾丸中的分布与功能

睾丸Sertoli细胞和早期生精细胞不仅存在表皮生长因子 (EGF)而且存在EGF受体 (EGFR) ,睾丸Leydig细胞也含有EGFR。EGF通过和EGFR结合 ,发挥特定的生物学效应 ,能刺激睾丸雄激素的合成和生精细胞的成熟。但是高浓度的EGF反而会抑制生精细胞的成熟。     

ROS1 Receptor Tyrosine Kinase, a Druggable Target, is Frequently Overexpressed in Non-Small Cell Lung Carcinomas Via Genetic and Epigenetic Mechanisms

Background

Microarray analyses have revealed significantly elevated expression of the proto-oncogene ROS1 receptor tyrosine kinase in 20–30 % of non-small cell lung carcinomas (NSCLC). Selective and potent ROS1 kinase inhibitors have recently been developed and oncogenic rearrangement of ROS1 in NSCLC identified.

Methods

We performed immunohistochemical evaluation of expression of ROS1 kinase and its downstream molecules in 399 NSCLC cases. ROS1 expression in primary and recurring lesions of 92 recurrent NSCLC cases was additionally analyzed. To elucidate mechanism of expression, two ROS1-nonexpressing NSCLC cell lines (Calu6 and H358) and fresh frozen tissues from 28 consecutive NSCLC patients were examined for ROS1 promoter methylation status and ROS1 expression.

Results

Overall expression rate of ROS1 was 22 % (19 % for adenocarcinomas and 25 % for nonadenocarcinomas) in NSCLC. ROS1 expression was a worse prognostic factor for overall survival in adenocarcinomas of stage I NSCLC. In recurred NSCLC, ROS1 expression was significantly higher in recurring tumors (38 %) than primary tumors (19 %). Two NSCLC cell lines showed increased ROS1 expression after treatment with 5-aza-2′deoxycytidine and/or trichostatin A. Among the 14 adenocarcinomas examined, two (14 %) showed more than twice the level of ROS1 expression in tumor tissue than was observed in matched normal tissue and statistically significant differences in the ROS1 promoter methylation level.

Conclusions

A subset of NSCLC revealed overexpression of ROS1 receptor tyrosine kinase, possibly in relation to epigenetic changes. ROS1 expression was an independent prognostic factor for overall survival in adenocarcinomas of stage I NSCLC. Further studies are needed to validate our results.     

表皮生长因子及其受体对雄性生殖系统的影响

表皮生长因子 (EGF)是首先从小鼠颌下腺分离出来的含 5 3个氨基酸残基的单链多肽 ,通过与其受体(EGFR)相结合发挥多种生物学效应。近年来发现 ,在人类和其他动物的雄性生殖系统有EGF与EGFR表达 ,对雄性生殖器官的发育、维持及变异起着重要的作用 ,同时 ,对雄性激素的分泌和精子发生也有很大的影响。EGFR在睾丸的支持细胞和间质细胞上均有表达 ,可影响睾酮的分泌 ;能维持正常前列腺组织的生长发育 ,刺激前列腺增生组织和前列腺癌组织的生长和分化 ;EGF参与精子发生 ,其作用点主要在减数分裂过程 ;可影响性分化 ,在雄激素诱导下使胚胎向雄性方向发育。     

Clinical Significance of the Epidermal Growth Factor Receptor and HER2 Receptor in Resectable Gastric Cancer

Background: Epidermal growth factor receptor (EGFR or HER1) and its homolog c-erbB-2 (HER2) are membrane receptors. Both EGFR and HER2 genes are overexpressed in a variety of solid human cancers and are related to poor prognosis of the patients. The objective of this work was to evaluate the EGFR and HER2 contents in resectable gastric cancer, their possible relationship with clinicopathologic parameters of tumors, and their prognostic significance.Methods: This was a prospective analysis of 63 patients with resectable gastric carcinomas, with a mean follow-up period of 40.7 months. Membranous EGFR levels were examined by radioligand binding assays, and cytosolic HER2 levels were examined by means of an immunoenzymatic assay.Results: There was a wide variability of EGFR (1–1,239 fmol/mg of protein) and HER2 (7–20,863 NHU/mg of protein) levels in tumors. There was no significant correlation between these levels and patient or tumor characteristics. However, high levels of EGFR and HER2 were significantly associated with a shorter overall survival period (P = .03 and P = .02, respectively).Conclusions: There is a wide variability in membranous EGFR levels and in cytosolic HER2 levels in gastric cancer, which seems to be related to the biological heterogeneity of these tumors. In addition, high tumor EGFR and HER2 levels were associated with an unfavorable outcome in patients with resectable gastric cancer.     

Drug prophylaxis of deep vein thrombosis in traumatology: is there a benefit of a score in outpatients?

Introduction: Guidelines are lacking for the administration of drug prophylaxis of deep vein thrombosis (DVT) in outpatients. This study attempted to develop such a guideline in the form of a score. Patients and methods: In a prospective study of 731 outpatients with injury or surgery of the leg or pelvis a score was assigned based on „simulated physiological conditions“ of the venous flow, including breathing, mobilization (activity of daily live), weight bearing and range of motion of joints of the lower extremities, lesions of the venous endothelium, date of injury, and localization of injury. The decision as to whether to administer drug prophylaxis of DVT was made on the basis of the patient's score. The venous system was investigated by duplex color-coded ultrasound. Results: There were two false-negative findings, meaning that patients without drug prophylaxis showed a thrombotic complication. In neither of these cases had the patient been compliant with medical instructions. In the group with drug prophylaxis there were 4% DVT (n=18). Conclusion: Compared to previous results of 10% DVT in outpatients, our score-assisted drug prophylaxis significantly reduced the incidence of DVT. The score also makes it possible to select patients not requiring drug prophylaxis. Received: 24 November 1997; in revised form: 14 August 1998 / Accepted: 28 August 1998