Histogenesis of subcutaneous malignant tumors resulting from nickel subsulfide implantation

Tumors are described which have been produced by subcutaneous (s.c.) implantation of nickel subsulfide (Ni3S2) in 00 gelatin capsules in the left axillary region of Fischer 344 rats. This is in contradistinction to previous accounts where intramuscular (i.m.) or, in a few cases, subcapsular testicular implantation sites have been used. The advantages of the s.c. route are discussed, including the removal of the difficulties of distinguishing degenerating and regenerating striated muscle cells from tumor cells. The s.c. induced tumors were transplanted as far as the F6 generation, in some cases. Cells from tumor transplanted as far as the F3 generation were grown in tissue culture and then reimplanted s.c. Cytology of the tumors remained remarkably constant in all tumors, even after serial transplants and culture. A characteristic storiform pattern, with two major cell types -myofibroblasts and histiocyte-like cells, was seen. The question of pluripotential cell origin is discussed. The striking similarity of appearance to human malignant fibrous histiocytoma is noted; however, in view of the somewhat controversial origin of the human tumor, the simple designation, "nickel-induced malignant tumor of pluripotential origin", is preferred. The use of this model with its demonstrated ability to reproduce characteristic appearances seems to be valuable for the study of soft tissue sarcomas.     

Chromosomal abnormalities and gene amplification in renal cancers induced in rats by nickel subsulfide

Nickel subsulfide (alpha Ni3S2) was administered to male Fischer-344 rats by unilateral intrarenal (i.r.) injection (20 mg per rat) to establish the time-course of alpha Ni3S2-induced erythrocytosis and to identify chromosomal abnormalities and molecular genetic aberrations in ensuing renal cancers. Blood hematocrit values were increased in alpha Ni3S2-treated rats during two to 36 weeks post-injection, attained a maximum of 77 percent (SD +/- 5) at 16 weeks (vs 51 +/- 3 percent in vehicle controls), and returned to baseline at 40 weeks. Within 21 months, malignant neoplasms (five sarcomas, one carcinoma) occurred in the injected kidneys of 6/28 alpha Ni3S2-treated rats (vs 0/13 controls). Cytogenetic analyses of direct preparations or primary cell cultures showed prominent chromosomal aberrations in three neoplasms, with rearranged marker chromosomes, polyploidy, and in one case an homogeneously staining region (HSR). Assays for gene amplification were performed with probes for murine erythropoietin (EPO) gene and H-ras, c-fos, c-myc, and N-myc oncogenes, using deoxyribonucleic acid (DNA) samples isolated from injected kidneys and renal neoplasms, as well as from the contralateral, non-injected kidneys. No consistent pattern was found; in one sarcoma, N-myc was amplified six-fold and c-fos was amplified two-fold; in another sarcoma, H-ras, c-fos, and EPO were amplified two-fold. This study shows that (a) karyotypes of 3/6 renal neoplasms of alpha Ni3S2-treated rats contained prominent marker chromosomes, (b) oncogene amplification was noted in 2/6 renal neoplasms, and (c) the EPO gene was not consistently amplified in DNA from the injected kidneys of alpha Ni3S2-treated rats during the initiation of erythrocytosis, or in subsequent renal neoplasms.     

Effects of unilateral nephrectomy on erythrocytosis and arteriosclerosis induced in rats by intrarenal injection of nickel subsulfide

Summary Administration of Ni₃S₂ to rats by unilateral inrarenal (ir) injection (5 mg/rat) caused erythrocytosis, arteriosclerosis, and abnormal plasma concentrations of asparagine, glycine, histidine, and lysine. Resection of the ipsilateral (Ni₃S₂-treated) kidney on the fourth day after the ir injection prevented erythrocytosis, amino acid disturbances, and severe arteriosclerotic lesions (fibrous intimal plaques and focal medial necrosis), but did not prevent early arteriosclerotic lesions (subintimal oedema with splitting of elastica). The early arteriosclerotic lesions appear to be initiated by vascular dissemination of Ni₃S₂ particles immediately post-injection, whereas the erythrocytosis, amino acid disturbances, and advanced arteriosclerotic lesions depend upon continued presence of the Ni₃S₂-injected kidney. Resection of the contralateral (non-injected) kidney has no effect upon Ni₃S₂-induced erythrocytosis, arteriosclerosis, or amino acid disturbances. Glomerulomegaly and mesangial hyperplasia developed in control rats following unilateral nephrectomy, owing to compensatory renal hypertrophy. Glomerulomegaly was more pronounced in Ni₃S₂-treated rats following contralateral nephrectomy than following ipsilateral nephrectomy, suggesting that erythrocytosis and compensatory renal hypertrophy act synergistically to enhance glomerulomegaly.Supported by grants from the U.S. Department of Energy (EV-03140) and the National Institute of Environmental Health Sciences (ES-01337)     

Erythrocytosis,glomerulomegaly, mesangial hyperplasia,sialyl hyperplasia,and arterioscleriosis induced in rats by nickel subsulfide

Summary Histopathological examinations were performed upon groups of male Fischer rats killed at intervals from 1 h to 18 weeks after unilateral intrarenal (ir) injection of nickel subsulfide (2.5 or 5 mg of Ni₃S₂/rat). Consistent with previous findings, erythroid hyperplasia of bone marrow and spleen occurred from 2 to 18 weeks after Ni₃S₂-treatment, resulting in pronounced erythrocytosis. Hitherto unreported effects of Ni₃S₂-treatment include: (a) marked glomerulomegaly and hyperplasia of mesangial cells in both kidneys; (b) hyperplasia of submandibular salivary glands, and (c) widespread arteriosclerotic lesions. The present study suggests that mesangial cells of renal glomeruli produce erythropoietin. Discovery that ir injection of Ni₃S₂ induces arteriosclerotic lesions in rats furnishes a new experimental model to investigate the pathogenesis of arteriosclerosis.Supported by grants from the U.S. Department of Energy (EV-03140) and National Institute of Environmental Health Sicences (ES-01337)     

Local induction of tumor necrosis factor as a molecular mechanism of mucosal damage by gonococci.

Tumor necrosis factor (TNF) is an endogenously produced cytokine that plays a critical role in mediating septic shock and multi-organ failure, but previous studies of the role TNF in disease have not examined its role in mucosal disease processes. In an experimental model of acute gonococcal salpingitis, gonococcal infection of human fallopian tube mucosa resulted in increased mucosal production of TNF. Recombinant human TNF-alpha damaged fallopian tube mucosa in a dose-response manner and produced epithelial damage with the same ultrastructural features as those observed in gonococcal infection. Blocking production of TNF during gonococcal infection diminished the extent of damage to fallopian tube mucosa. In addition to mediating systemic disease, such as septic shock, TNF is also produced locally, and can play a critical role in mediating mucosal disease processes, such as acute gonococcal salpingitis.     

DC-CIK细胞免疫治疗恶性肿瘤的临床研究

目的 探讨树突状细胞(DC)-细胞因子诱导的杀伤细胞(CIK)细胞免疫治疗恶性肿瘤的疗效及机制.方法 采集13例恶性肿瘤患者外周血单个核细胞,贴壁细胞经IL-4、GM-CSF、TNF-a诱导,并经流式细胞仪检测证实为DC,悬浮细胞经CD3单抗、у-干扰素、IL-2诱导,并经流式细胞仪检测证实为CIK细胞.DC分次淋巴引流区皮下注射,CIK细胞静脉输注.结果 除1例肝癌骨转移患者经治疗无效死亡外,其余患者的临床症状、影像学均提示病变较前好转.结论 DC-CIK细胞免疫治疗恶性肿瘤有确切疗效,延长患者生存期,提高生活质量.     

Abnormal cytodifferentiation in leiomyosarcomas induced with injection of nickel subsulfide into skeletal muscles of rats. Light and electron microscopic observations

Seven leiomyosarcomas, induced individually with a single injection of nickel subsulfide (0.4 mg) into skeletal muscles of Fisher 344 male rats were studied with the light and with the electron microscope. The tumors consisted of fibroblast-like cells lacking the cytoplasmic filaments found in normal maturing and mature smooth muscle, and of cells in which the appearance of these filaments occurred in the following sequence: first, actin filaments in concomitance with intermediate filaments; second, myosin filaments. According to work from several laboratories, normal embryonic smooth muscle was derived from fibroblast-like cells and a characteristic of their early differentiation was the appearance of filaments in a sequence similar to that in the present tumors. Similarities between normal and neoplastic muscle were also observed in the orientation of the filamentous components and in the changes in quantity occurring in them during the course of differentiation. However, in the neoplastic cells, nonfilamentous structures, such as gap junctions which normally increase in number with advancing cell maturation, were rarely detected. In addition, the sarcoplasmic reticulum was constantly far less developed than in the normal mature prototypes. The present observations suggest that the differentiation of the neoplastic cells in the early stages is similar to that under normal conditions of smooth muscle development, but it becomes abnormal in the advanced stages.     

肿瘤的免疫逃逸机制研究进展

大量研究证实,肿瘤病人体内存在广泛的免疫逃避现象。目前所知的肿瘤逃逸机制很多,比如产生免疫抑制因子,改变表面抗原,通过Fas/Fasl反击机体的免疫系统而逃避机体的免疫监视,从而发生免疫逃逸。本文就肿瘤发生免疫逃逸机制的研究现状作一综述。     

中药诱导肿瘤细胞自噬及其分子机制

自噬是细胞膜结构吞噬自身的细胞质形成自噬体,并与溶酶体结合对细胞内蛋白质和细胞器降解的过程。自噬参与细胞诸多生理和病理过程,其与肿瘤发生密切相关。近年来对细胞自噬在肿瘤中的作用及其作为抗肿瘤药物的作用机制的研究有了较大进展,特别是某些中药及有效成分如姜黄素、苦参碱、雷公藤内酯等能诱导肿瘤细胞自噬,自噬将成为肿瘤研究的一个新热点。现将自噬的分子机制、自噬与肿瘤、中药诱导肿瘤细胞自噬及其分子机制的研究进展做一综述。     

应用剂量体积直方图分析放疗对心脏毒性影响

目的:本文回顾性研究一组连续收治行放射治疗的恶性胸腺肿瘤病例,应用剂量体积直方图分析心脏受照情况,同时结合临床随访放射性心脏损伤的结果,探讨了影响心脏损伤的因素和避免或减少心脏损伤的有效方法。方法:1983年3月至2001年9月,50例胸腺肿瘤患者在北京大学临床肿瘤学院放射治疗科接受放射治疗。Masaoka分期Ⅱ期14例,Ⅲ期22例和Ⅳ期14例。47例患者接受普通二维技术放射治疗,三例患者接受三维适形放射治疗。治疗的剂量范围为10Gy～84.5Gy穴中位剂量为55Gy雪。根治性放疗20例,术后放疗14例,术前放疗2例和姑息性放疗14例。对所有病例均在三维治疗计划系统上模拟进行CT图象的三维重建和剂量分布的计算,由心脏的剂量体积直方图,借助于正常组织和器官并发症概率模型,计算心脏1/3等效体积的等效剂量,进而导出放射相关心脏疾患发生的概率,并与临床观测结果进行比较。结果:普通照射技术治疗组的心脏等效1/3体积中位剂量为57.9Gy穴21.6Gy～83.3Gy雪;三维适形放射治疗的心脏等效1/3体积中位剂量为26.3Gy穴22.7Gy～52.0Gy雪。全组病例中位随访期为13个月(0.6～111.3个月)。在45例有心脏状况记录的病例中发现7例有放射相关的心脏疾患,SOMA分级1～3级。结论:该研究结果表明,心脏损伤随着心脏等效体积剂量增大而明     

Extraovarian malignant Brenner tumor

Extraovarian malignant Brenner tumour in a female of 35. Rapid infiltrating growth with the destruction of tumour. All extraovarian tumours described so far were benign, located in the mesosalpinx, uterus or vagina. In this case the starting point of the tumour was in the vagina wall or in the recto-vaginal septum. Histological picture produced difficulties in establishing histogenesis of malignancy. The true nature of the tumour was established only immunohistochemically.     

五例恶性Brenner氏瘤的超微结构观察

Electron microscopic study of five malignant Brenner tumors showed that the histologic features resembled nonkeratinized squamous carcinoma of uterine cervix. Intracytoplasmic glands and cysts, abundant glycogen, numerous desmosome, cilia and desmosome-tonofilament complex were the ultrastructural features of malignant Brenner tumor. Among them, cilium is characteristic for ovarian surface epithelium and Mullerian epithelium, rather than for uro-epithelium. The desmosome-tonofilament complex is the specific structure for squamous cell, also not for uro-epithelium. So the appearance of cilium in malignant Brenner tumor indicates that the tumor is derived from Mullerian epithelium, and the presence of desmosome-tonofilament complex evidences that the tumor cells possess the characteristics of squamous cells. This study further proves that malignant Brenner tumor arises from Mullerian epithelium.