Role of mesenchymal-epithelial interactions in mammary gland development

The mammary gland is a hormone-target organ derived from epidermis and develops as a result of reciprocal mesenchymal-epithelial interactions. The induction of mammary differentiation from indifferent epidermal cells by mammary mesenchyme implies induction of the complement of hormone receptors characteristic of normal mammary epithelium in cells of the epidermis. Considering the facts that mammary epithelial differentiation is induced by mammary mesenchyme and that certain aspects of hormone response (androgen-induced mammary regression) are inextricably linked to mesenchymal-epithelial interactions, it is evident that the biology of the mammary gland arises from and is maintained via cell-cell interactions. As a corollary, perturbation of stromal-epithelial interactions in adulthood may play a role in mammary carcinogenesis and in turn may provide opportunities for differentiation therapy.     

Role of endogenous interferon gamma in murine tumor growth and tumor necrosis factor alpha antitumor efficacy

Background: The anticancer role of tumor necrosis factor-alpha (TNF-) has been limited by toxicity. These experiments evaluate blocking endogenous interferon-gamma (IFN-) activity to abrogate TNF- toxicity. Methods: C57Bl/6 mice bearing MCA 105 tumor were treated with TNF- and anti-IFN- antibody (Ab) to evaluate the effect on the acute lethality of TNF- and their efficacy as evaluated by tumor growth rate, tumor histology, and survival. Results: Anti-IFN- Ab decreased TNF- lethality. Anti-IFN- Ab alone increased tumor growth significantly more than did nonimmune IgG (p₂<0.0001). Tumor-bearing mice that received nonimmune IgG and TNF- had slower tumor growth (p₂<0.02) and a trend toward improved survival (p=0.07) compared with saline-treated controls. Anti-IFN- Ab abrogated the antitumor effect of TNF-, prevented acute tumor necrosis histologically, and resulted in tumor growth rate and host survival similar to that of controls. The findings in mice that received anti-IFN- Ab and high-dose TNF- were comparable with those in mice that received a lower, equitoxic dose of TNF- alone. Conclusions: Blocking endogenous IFN- accelerates tumor growth in this model and partially abrogates the toxic and antitumor activity of exogenous TNF- equally. This suggests that blocking endogenous IFN- activity is not a useful strategy for limiting TNF- treatment toxicity.Presented in part at the 45th Annual Cancer Symposium of The Society of Surgical Oncology, New York, New York, March 15–18, 1992.     

山蒟醇提取物的抗血小板聚集作用?

以山蒟醇提取物在兔的体内和体外-体内进行抗血小板聚集实验。结果表明山蒟醇提取物可抑制由血小板活化因子和花生四烯酸所致的血小板聚集,对2者所致的血小板聚集（体外试验）的IC_（50）。分别为40． 34、345． 46 mg／L。静脉注射山蒟醇提取物30 mg／kg,15 min后产生的抗血小板聚集作用最明显,其对血小板活化因子和花生四烯酸所致的血小板聚集（体内-体外试验）的抑制率分别为82．75％和33．34％;血小板聚集的持续时间分别为60、30 min。这表明山蒟醇提取物对血小板活化因子作用有一定的选择性。     

重组人表皮生长因子防治乳腺癌放射性皮肤反应的临床研究

目的 观察重组人表皮生长因子(rhEGF)局部外用对乳腺癌放疗皮肤反应的防治作用。方法 将30例乳腺癌根治术后放疗的患者,随机分为2组,每组15人,以胸壁出现的放疗反应及用药后的变化作为观察指标。结果 A组:使用rhEGF治疗Ⅱ°湿性皮肤反应的平均愈合时间为5.2±1.1天,使用常规治疗方法(氢地油)平均愈合时间为12.4±2.2天(P<0.01)。B组:胸壁上1/2使用rhEGF的患者仅1例出现Ⅱ°湿性放射性皮肤反应,而下1/2不用药者有6例出现Ⅱ°湿性反应(P<0.05)。结论 使用rhEGF可使乳腺癌放疗中出现的Ⅱ°湿性皮肤反应的愈合时间明显缩短,在乳腺癌术后放疗期间尽早使用rhEGF能有效防止放射性皮肤反应的发生。     

Cytokines predict coronary aneurysm formation in Kawasaki disease patients

In this study, we measured serially the serum levels of cytokines including interleukin-6 (IL-6), IL-8, soluble IL-2 receptor (sIL-2R) and tumour necrosis factor (TNF-) in 60 patients with Kawasaki disease (KD) and evaluated the clinical significance of these cytokines in predicting coronary aneurysm formation. Of the 60 patients, 12 were complicated with coronary aneurysm. Blood samples were collected within the 1st week after onset of fever, then once a week for the 1st month, and once a month for another 5 months. The serum levels of IL-6, IL-8, sIL-2R and TNF were measured using an ELISA or RIA method. Our results show that the changes in serum IL-6 and IL-8 were faster than those of sIL-2R and TNF. Within the 1st week, the serum levels of IL-6 and IL-8 were significantly higher in the patients with than in those without coronary aneurysm (P<0.001). In addition, the serum levels of IL-6 and IL-8 obtained in the 1st week were highly correlated (P<0.001) with those of C-reactive protein and erythrocyte sedimentation rate, and the serum levels of sIL-2R and TNF were also increased at the 1st week reaching the highest level in the 2nd week. In the 2nd week, the serum levels of sIL-2R and TNF were significantly higher in the patients with than in those without coronary aneurysm (P<0.05). These findings suggest that the serum levels of IL-6 and IL-8 obtained in the 1st week may serve as useful parameters in predicting coronary aneurysm formation in KD patients.     

Spike conduction properties of T-shaped C neurons in the rabbit nodose ganglion

Noradrenaline (NA) and angiotensin II (A II) were infused intravenously in conscious dogs without (series I) and with (series II) additional infusions of sodium nitroprusside at doses re-establishing normal levels of mean arterial pressure (MAP). In series I, NA infusion (1.6 g/min per kg for 30 min) initially elevated MAP by some 25 mm Hg and lowered heart rate by some 30 beats/min. Plasma concentrations of arginine vasopressin (AVP) remained constant, while those of A II and atrial natriuretic factor were slightly, but significantly, increased. Infusion of A II (10 or 20 ng/min per kg for 30 min) induced similar rises in MAP and slight reductions of heart rate and increased plasma AVP by 70% and atrial natriuretic factor by 60%. In series II, sodium nitroprusside (1–4 g/min per kg) was added for 30 min to infusions of NE (1.6 g/min per kg) and A II (20 ng/min per kg) in order to maintain MAP at its control level. This resulted in an 11-fold increase in plasma AVP during NA infusion and a 19-fold increase during A II infusion. Infusing sodium nitroprusside (4 g/min per kg) alone lowered MAP to clearly hypotensive levels, but the resulting rises in plasma AVP were less than, rather than equal to, those seen at normotensive MAP levels during the combined infusions of sodium nitroprusside with A II or NA, respectively. It is concluded that both NA and A II exert strong stimulatory actions on AVP release which are, however, counteracted by inhibitory influences arising from the hypertensive effects of NA and A II.     

Tumour necrosis factor alpha and interleukin 2 in normal and infected human seminal fluid

The presence of cytokines such as the tumour necrosis factoralpha (TNF) and interleukin 2 (IL2) in human spermatozoa isstill to be defined. The aim of this study was to measure theconcentration of both soluble factors in seminal fluid. Datafrom normal semen samples (n = 24) confirmed the presence ofIL2 (258 ± 84 fmol/ml corresponding to 953 ± 369fmol/total volume of ejaculate) and TNFa (62.2 ± 16.4fmol/ml corresponding to 231.3 ± 86 fmol/total volumeof ejaculate). A significant positive correlation (r = 0.59;P < 0.01) was observed between the TNFa and the IL2 concentrations.The concentrations of these cytokines were not related to spermparameters. In contrast, IL2 concentrations (196.9 ±60.4 fmol/ml; 686.2 ± 236.7 fmol/total volume of ejaculate)evaluated in 16 seminal fluids with identified bacterial agentswere lower than in the control group, whereas TNF concentrations(68.6 ± 12.3 fmol/ml; 241.3 ± 78.9 fmol/totalvolume of ejaculate) were not significantly different from thecontrols. Further studies are needed to determine the potentialrole of these cytokines in the physiology of semen and theirusefulness as indicators of reproductive pathology.     

Fibroblast growth factor induces primitive streak formation in rabbit pre-implantation embryos in vitro

Culturing of rabbit pre-implantation embryos was performed in Ham's F10 medium supplemented with polyvinylpyrrolidone. Under these culture conditions, day 6 post coitum blastocysts increased their diameter within 24 h to 80% of that of day 7 blastocysts grown in vivo. Despite this substained growth, the embryonic disc remained undifferentiated with clear signs of degeneration after 24 h of culture. Basic fibroblast growth factor (bFGF) was able to overcome this developmental block. After 12 h of culture, day 6 blastocysts showed pear-shaped embryonic discs, and after 24 h, the primitive streak with Hensen's node was visible. The bFGF had no comparable effects on day 5 and day 7 blastocysts. The embryonic discs of day 5 blastocysts degenerated, even in the presence of bFGF, whereas day 7 blastocysts were able to form their primitive streak, also in the absence of bFGF. TGF ₁ did not promote embryonic development in vitro. The data indicate that the onset of mesoderm formation in the rabbit is controlled by a growth factor of the FGF-family.     

Divergent regulation of cell surface protease expression in HL-60 cells differentiated into macrophages with granulocyte macrophage colony stimulating factor or neutrophils with retinoic acid

Taking advantage of the recently demonstrated presence of N-aminopeptidasesand the serine protease dipeptidyi aminopeptidase IV (DPP IV)at the surface of human myeloblastic HL-60 cells, the regulationof these protease activities in HL-60 cell differentiation hasbeen assessed using combined spectrophotometric and flow cytometricassays. Addition of human recombinant granulocyte macrophagecolony stimulating factor (rHu-GM-CSF) to HL-60 cells to inducedifferentiation into macrophages led to a time and dose-dependentincrease in both cell surface N-aminopeptidase and DPP IV activities.Protease up-regulation was due to an enhancement in cell surfaceprotease number, associated with a slight rise in apparent affinitiesof the enzymes for their substrates. In contrast, in HL-60 cellsinduced to differentiate into neutrophils in the presenceofretinoic acid, expression of cell surface N-amlnopeptidaseswas almost completely abolished in a time-and dose-dependentfashion, and this down-regulation was accompanied by a weakbut significant decrease in affinity. However, no noticeabledifference was seen in serine DPP IV expression between retinoicacid-treated and untreated HL-60 cells. Retinoic acid treatmentalso reduced soluble protease activity in vitro indicating thatdown-regulation of membrane aminopeptldases was not due to theirproteolytic clip. No modulation in the activity of any of theenzymes tested was seen with human recombinant tumor necrosisfactor- or retinol which do not induce HL-60 cell differentiation.The up-regulation of cell surface protease expression in HL-60cells differentiated into macrophages was similar to that observedin monocytes isolated from peripheral blood: both DPP IV andN-aminopeptidase activities strictly increased on cells thatundergo macrophage maturation (up to 5-fold) and independentlyof the nature of the differentiation inducer. Thus, the distinctivepatterns of N-aminopeptidase and DPP IV expression that areseen in differentiating neutrophils and macrophages appear tobe relatedto differences in stage of myeloid maturation. Becausecell surface proteases are crucially involved in leukocyte functions,the data presented suggest that alterations in cell surfaceprotease expression are associated with events controlling thedifferentiation of immature cells.     

A model mechanism for the chemotactic response of endothelial cells to tumour angiogenesis factor

Present address: Program in Scientific Computing and Computational Mathematics, Division of Applied Mechanics, Durand 252, Stanford University, California 94305, USA. In order to accomplish the transition from avascular to vasculargrowth, solid tumours secrete a diffusible substance known astumour angiogenesis factor (TAF) into the surrounding tissue.Endothelial cells which form the lining of neighbouring bloodvessels respond to this chemotactic stimulus in a well-orderedsequence of events consisting, at minimum, of a degradationof their basement membrane, migration, and proliferation. Amodel mechanism is presented which includes the diffusion ofthe TAF into the surrounding host tissue and the response ofthe endothelial cells to the chemotactic stimulus. The modelaccounts for the main observed events associated with the endothelialcells during the process of angiogenesis (i.e. cell migrationand proliferation); the numerical results compare very wellwith experimental observations. The situation where the tumour(i.e. the source of TAF) is removed and the vessels recede isalso considered.