Interleukin-6 cDNA transfected Lewis lung carcinoma cells show unaltered net tumour growth rate but cause weight loss and shortened survival in syngeneic mice

HuIL-6 cDNA, cloned into a neomycin resistant conferring expression vector, BMGNeo, was transfected into Lewis Lung Carcinoma (LLC) cells. LLC cells (5 x 10(6) ml-1) transfected with IL-6 cDNA (LLC-IL6) secreted IL-6 into the culture supernatant at a concentration of 9.9 ng ml-1 within 48 h. When 1,000,000 of untransfected LLC, BMGNeo vector transfected LLC (LLC-Neo) or LLC-IL6 cells were transplanted into C57BL/6 mice subcutaneously, the mean +/- s.d. of survival times of these mice were 33.3 +/- 9.7, 34.3 +/- 7.1 and 17.0 +/- 3.1 days, respectively. The survival time of LLC-IL6 cells transplanted mice was significantly shorter than that of LLC (P < 0.01) or LLC-Neo (P < 0.01) cells transplanted mice without a measurable difference of tumour size. Plasma concentration of IL-6 steadily increased in LLC-IL6 transplanted mice. Body weight and serum albumin were significantly lower in LLC-IL6 transplanted mice than in LLC transplanted mice. Mouse IL-1 alpha and mouse TNF-alpha were not detected in the plasma of LLC-IL6 transplanted mice. These data suggested that secretion of IL-6 from LLC cells was unable to alter net tumour growth rate but rather caused a state similar to cachexia without detectable increase of IL-1 alpha and TNF-alpha in the plasma. This state may be responsible for the shortened survival of LLC-IL6 tumour-bearing mice.     

Boundary element analysis of thin plates internally bounded by rigid patches

Procedures are described for modelling a structural system consisting of thin Kirchhoff plates with internal patch areas capable of displacing as rigid flat surfaces. The physical prototype for these patches could be interconnection points for one-dimensional frame type elements of various shapes and layout, rigidly connected at these finite size 'joints' in the plate. The numerical procedure for modelling the thin plate is the Direct Boundary Element Method (DBEM) and a simple overview of this procedure is provided. Potential trouble spots, of which the user should be aware, are described. The paper will be of interest to structural engineers for analysis of frames having both plate and simple frame elements, for example, building frames; and also to researchers seeking the greater detail that this refined procedure can provide. As a practical tool, the methods described are computationally competitive with existing procedures, including the more rugged approaches used by building structural engineers for dynamic and torsional analysis.     

Localization of Function Within the Dorsal Hippocampus: The Role of the CA3 Subregion in Paired-Associate Learning.

Computational models and electrophysiological data suggest that the CA3 subregion of the hippocampus supports the formation of arbitrary associations; however, no behavioral studies have been conducted to test this hypothesis. Rats with neurotoxin-induced lesions of dorsal dentate gyrus (DG), CA3, or CA1 were tested on object-place and odor-place paired-associate tasks to test whether the mechanism that supports paired-associate learning is localized to the CA3 subregion of the dorsal hippocampus or whether all hippocampal subregions contribute to paired-associate learning. The data indicate that rats with DG or CA1 lesions learned the tasks as well as controls; however, CA3-lesioned rats were impaired in learning the tasks. Thus, the CA3 subregion of the dorsal hippocampus contains a mechanism to support paired-associate learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

In vivo effects of activated H-ras oncogene expressed in the liver and in urogenital tissues

PURPOSE: The clinical significance of isolated calf vein thrombosis (CVT), particularly with respect to development of the postthrombotic syndrome, remains controversial. The purpose of this study was to define the early natural history of CVT in relation to persistent lower extremity symptoms, propagation, recanalization, and the development of valvular incompetence. METHODS: Over a 116-month period, 499 patients with acute deep venous thrombosis (DVT) were referred to our research laboratory, of whom 58 (12%) had thrombosis confined to the calf veins of at least one extremity. The lower extremities of 268 patients (29 with isolated CVT) were followed-up clinically and with duplex ultrasonography at intervals of 1 day, 7 days, 1 month, every 3 months for the first year, and yearly thereafter. RESULTS: Seventy percent of extremities with CVT were symptomatic at presentation. Although the prevalence of clinical signs and symptoms decreased to 29% by 1 month, 23% of patients had persistent pain, edema, or both at 12 months. In contrast, 9% of uninvolved extremities contralateral to a CVT and 54% of extremities with proximal DVT remained symptomatic at 1 year (p = 0.004). Recanalization proceeded rapidly such that the mean thrombus load was reduced by 50% at 1 month and to zero at 1 year. The prevalence of valvular incompetence progressively increased such that reflux was present in 24% of extremities at 1 year. Although its investigation was not a primary goal of this study, pulmonary embolism was diagnosed at presentation and during follow-up in 11% and 3% of patients, respectively. CONCLUSIONS: The natural history of CVT is complicated by persistent symptoms and the development of valvular incompetence in approximately one-quarter of patients. This potential for persistent lower extremity symptoms should be considered in evaluating the clinical relevance of isolated calf vein DVT.     

Selective interference with class I major histocompatibility complex presentation of the major immediate-early protein following infection with human cytomegalovirus

Responses of cytotoxic T-cells (Tc) to human cytomegalovirus (CMV) represent the predominant mechanism by which hosts resist CMV infection. The CMV major immediate-early protein (IE) is present throughout the virus replicative cycle. Studies were performed to determine whether Tc specific for IE effectively lyse CMV-infected targets and are thus capable of providing protective immunity against infection. After in vitro stimulation of peripheral blood mononuclear cells with CMV-infected autologous fibroblasts, Tc specific for IE were not readily detectable in CMV-reactive polyclonal Tc lines. However, after stimulation of peripheral blood mononuclear cells with cells selectively expressing IE, weak but detectable IE-specific Tc responses were observed. The frequency of IE-specific Tc clones derived from cultures stimulated with IE-expressing cells was 50 to 100 times lower than the frequency of Tc clones specific for other CMV proteins isolated from cultures stimulated with CMV-infected cells. All of the IE-specific Tc clones, which efficiently lysed targets selectively expressing IE, demonstrated minimal lysis of CMV-infected fibroblasts, despite abundant IE expression in these target cells. In contrast to these results with IE, other viral proteins were efficiently presented during all phases of CMV infection. These data suggest that CMV has evolved a unique mechanism for selectively limiting the presentation of the potentially immunogenic IE protein, which may preclude IE-specific Tc from providing protective immunity to CMV infection.     

Elucidation of mitochondrial effects by tetrahydroaminoacridine (tacrine) in rat, dog, monkey and human hepatic parenchymal cells

Tetrahydroaminoacridine (tacrine) causes morphological and functional changes in the endoplasmic reticulum, ribosomes, and mitochondria in the liver of humans and animals. In order to investigate species differences as well as to understand the morphological changes, we examined the effects of tacrine on respiration and electron transport in mitochondria isolated from rat, dog, monkey, and human liver. Tacrine produced significantly decreased respiratory control ratios (RCR) in all species at concentrations ranging from 5 to 25 microg/ml. Human mitochondria were more sensitive to tacrine effects with RCR decreased 24% at 5 microg/ml while other species were unaffected at this concentration. The tacrine effects were characterized by increased hepatic mitochondrial State 4 respiration in rats and decreased State 3 respiration in humans. Mitochondria from aged rats were more sensitive to the effects of tacrine than mitochondria from young animals, with significantly decreased RCR at 10 microg/ml in aged rats while mitochondria from young rats were unaffected at this concentration. Concomitant with the respiratory changes, mitochondrial DNA synthesis was impaired. Since tacrine undergoes extensive biotransformation, we also explored the possibility that metabolites could exert detrimental effects. The ranking order of potency for decreasing RCR caused by monohydroxylated metabolites was: tacrine > 4-OH and 7-OH > 2-OH, 1-OH, and velnacrine with the latter group of metabolites having no effect on mitochondrial respiration at concentrations up to 50 microg/ml. In vivo administration of 20 mg/kg tacrine to rats for up to 20 days caused a paradoxical increase in RCR and P/O on Day 1 and decreased RCR on Days 9 and 20, the later findings being consistent with in vitro data. From these data we propose that tacrine does not necessarily have to be metabolized to exert effects on mitochondria at different sites in the electron transport chain that differ among species. These effects are exacerbated in mitochondria from older animals and humans appear to be more sensitive than the laboratory animals studied.     

Relative involvement of protein kinase C and of the estrogen receptor in the cytotoxic action of a population of triphenylethylenes on MCF7 cells as revealed by correspondence factorial (CF) analysis

A multivariate statistical method, correspondence factorial (CF) analysis, was used to examine the correlations among the protein binding and cell proliferation effects of a series of 36 di- and triphenylethylenes (DPEs and TPEs). The analysis was applied to a study which measured their competition for estradiol binding to cytosol estrogen receptor (ER), their influence on protein kinase C (PKC) activity under different conditions of enzyme activation, their ability to promote the growth of a breast cancer cell line and to inhibit growth at high concentrations (cytotoxicity). The CF analysis revealed several levels of correlation. First, it distinguished those molecules within the population that stimulated rather than inhibited PKC activity. Second, it made apparent a strong correlation between cytotoxicity and inhibition of Ca++ and phosphatidylserine-dependent PKC activity, which was most marked when the enzyme had been activated by diacylglycerol indicating that PKC inhibition under physiological conditions might contribute to the overall cytotoxicity of these compounds. Third, a lower level of correlation was established between competition for ER binding and cytotoxicity. Taken together, the results suggest that MCF7 cells might be most sensitive to a cytotoxic effect of TPEs (via PKC and other targets) when they at the same time decrease estrogen-stimulated proliferation via an ER-mediated antiestrogenic effect.     

Cancer prevention--behavior changes: the short and the long of it

BACKGROUND: Behavioral factors play an important role in the adoption and maintenance of nutritional modifications, delivered either through chemopreventive regimens or through dietary adaptation. A body of research supports a protective role of fruits and vegetables, dietary fiber, and eating a low-fat diet in reducing cancer risk. There is only limited knowledge, however, about the cancer-preventing properties of specific micronutrients, apart from beta-carotene; about optimal levels of intake of differing micronutrients; and about patterns of food intake associated with reduced cancer risk. Thus, it would seem preferable, overall, to be able to recommend cancer prevention through dietary modification rather than through the administration of individual agents. METHODS: Studies of dietary adherence in cancer prevention have yielded varying success rates, but are generally quite promising. We have developed a model that encompasses the range of behavioral, psychological, social, and systemic variables thought to influence adherence to nutritional regimens. RESULTS: The model is being utilized to influence the form and content of nutritional regimens and to promote short-term change which can then be sustained as long-term lifestyle modification. The model can also be applied to evaluate adherence to nutritional or other behavioral modifications and to determine the factors predictive of success.