The treatment of patients with pancreatic cancer requires the expertise of medical oncologists, radiation oncologists, radiologists, and surgical oncologists. The surgeon's role in the management of patients with pancreatic cancer extends beyond the performance of surgical resection and bypass procedures to include diagnosis, staging (including determination of resectability), and therapy (both curative and palliative). If a lesion is deemed resectable, the surgeon's goal is to achieve clear pathologic margins in order to optimize the patient's chances for cure. The surgeon also plays a key role in the palliation of disease in patients with unresectable lesions. Biliary and duodenal bypass, endoscopic stenting, laparoscopy, and celiac ganglion injection may be needed to maximize a patient's remaining quality of life. In addition, the surgical oncologist should be involved in clinical trials testing neoadjuvant or adjuvant chemoradiotherapies that may lead to the development of more effective therapies for pancreatic cancer.

Biopsy, Needle↗

PubMed1995

A novel promoter for vascular endothelial growth factor receptor (flt-1) that confers endothelial-specific gene expression.

The human transmembrane fms-like receptor tyrosine kinase Flt-1 is one of the receptors for vascular endothelial growth factor, a growth factor which induces endothelial proliferation and vascular permeability. Flt-1 is expressed specifically in endothelium and is likely to play a role in tumor angiogenesis and embryonic vascularization. To elucidate the molecular basis for the endothelial specific expression of Flt-1, the promoter region has been isolated and functionally characterized. The promoter region contains a TATA box, a GC-rich region, and putative transcription factor binding elements such as cAMP response element binding protein/activating transcription factor (CREB/ATF) and ets. Adenovirus-mediated transient expression of the flt-1 promoter/luciferase fusion gene in endothelial cells and other cell types demonstrated that a 1-kilobase fragment of the 5'-flanking region of flt-1 is involved in the endothelial-specific expression. A CREB/ATF element was found to be essential for basal transcription of the flt-1 expression. In addition, we also showed that the first intron negatively regulates flt-1 promoter activity. The flt-1 promoter will be useful in functional studies on the regulation of endothelial-specific gene expression and also as a tool in targeting the expression of exogenously introduced genes to the endothelium.

Adrenal Glands↗

PubMed1995

Inhibition of tumor cell proliferation in vitro and in vivo by exogenous p110RB, the retinoblastoma tumor suppressor protein.

Reconstitution of retinoblastoma gene (RB) deficient tumor cells with RB generally leads to growth suppression in vitro and/or reduced tumorigenicity in nude mice. An alternate approach to gene replacement is the delivery of the RB gene product (p110RB) into cells lacking its expression. In this report we demonstrate that exogenously added p110RB is taken up by and localized to the nucleus of cultured cells and has growth suppression properties similar to endogenous RB. RB-negative (RBneg) tumor cells are preferentially growth inhibited while most RB-positive (RBpos) tumor cells and normal cells are much less sensitive. We have extended these studies to relevant nude mouse xenograft models for human lung cancer. Local or systemic administration of p110RB inhibits tumor growth in treated animals. These results represent the first use of a tumor suppressor protein as a potential cancer therapeutic.

Animals↗

PubMed1995

Modulation of nitric oxide-dependent relaxation of pig tracheal smooth muscle by inhibitors of guanylyl cyclase and calcium activated potassium channels.

Nitric oxide is released from intrinsic nonadrenergic, noncholinergic (NANC) nerves of pig tracheal smooth muscle (TSM) in response to electrical field stimulation (EFS). In this study, we investigated the role of guanylyl cyclase in the NANC relaxation by using guanylyl cyclase inhibitors, LY83583 and methylene blue (MB). The role of large conductance calcium-activated potassium (KCa) channels in mediating NANC relaxation was studied by using inhibitors of this channel, charybdotoxin and iberiotoxin. In carbachol-contracted TSM strips, LY83583 (10-20 microM) and MB (10-100 microM) resulted in inhibition of EFS-induced relaxations at all frequencies studied. Relaxations induced by exogenous 8-Bromo-cyclic 3',5'-guanosine monophosphate (8-Br-cGMP) were unaffected by LY83583. The concentration-relaxation curves to isoproterenol, which acts by elevating adenosine-3',5'-cyclic monophosphate (cAMP), and the nitric oxide donors sodium nitroprusside (SNP) or S-nitroso-n-acetylpenicillamine (SNAP) were unaffected by LY83583. Both charybdotoxin (240 nM) and iberiotoxin (180 nM) attenuated relaxations induced by EFS and SNAP. The role of guanylyl cyclase activation in the relaxation to EFS of pig TSM is suggested by the sensitivity of the responses to MB. The selective inhibitory effects of LY83583 on relaxation to neurally released, but not to the nitric oxide donors, suggests that it acts by inhibiting nitric oxide release. The lack of any effect of LY83583 on isoproterenol- or guanosine, 3'5'-cyclic monophosphate (cGMP)-mediated relaxation suggests a mechanism that does not involve elevation of cAMP but lies proximal to the generation of cGMP. The susceptibility of the relaxations to EFS and SNAP to charybdotoxin and iberiotoxin suggests a mechanism that involves the selective activation of KCa channels in airway smooth muscle cells.

Aminoquinolines↗

PubMed1995

The growth inhibitory properties of a dopamine agonist (SKF 38393) on MCF-7 cells.

Dopamine agonists have been indicated as treatment for disorders such as Parkinson's disease, cardiogenic shock and dopamine insufficiency. A unique relationship exists between dopamine and carcinogenicity. Chronic prolactin stimulation has been identified as a promoter of carcinogenicity. Prolactin secretion is regulated through dopamine receptor activation. Dopaminergic agonists inhibit prolactin release and antagonists increase release. High levels of prolactin have been shown to suppress production of estrogen and progesterone. As a result of these findings, a series of experiments were designed to examine the effects of a specific dopamine agonist, SKF 38393, against MCF-7 cells. MDA-MB231 and MCF-10 cells were used as negative controls. The breast cancer in vitro screening procedure involved the plating of MCF-7, MDA-MB231 and MCF-10 cells in a 96-well plate assay. After 1 day, the cells were exposed to SKF 38393 for 2 days and cell growth was determined by the Alamar blue dye reagent method. The optical density data was analyzed and IC50 values determined. The results indicated that SKF 38393 caused a significant decrease in proliferation of MCF-7 cells. The IC50 value was 0.1 +/- 0.03 microM. The results also indicated no significant effect on MDA-MB231 and MCF-10 cells.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1995

Technical note: assessing the consistency of measurement procedures in animal energetics and nutrition.

Our objective was to assess the consistency of representative digestion and energetics determinations used in animal nutrition. We used distribution theory of quadratic forms that allow for the attainment of width of confidence intervals (WI) for intraclass correlations. Three models commonly used in animal nutrition were analyzed, and their respective programs were coded to obtain the required confidence limits. Data sets were obtained from previous research published by our laboratory. Urinary, CH4, and ME were analyzed assuming a two-factor nested balanced variance component model. Rate of ruminal NDF disappearance (kd) and DM digestibility by an 8-d conventional collection trial were fitted to a two-factor crossed variance component model without interaction with a single observation per cell. Empty BW (EBW), carcass energy, and EBW energy were fitted to a two-factor crossed variance component model with interaction. Widths of confidence intervals varied with the example data set and variable tested. The narrowest WI was that of DM digestibility, less than .07 at a 95% confidence level for all the intraclass correlations, which shows the high consistency of the DM digestibility measurement in the specific study. Medium to large WI were found for kd and EBW; WI estimates were less than .70 at a 95% confidence level. Large WI, from .8 to 1.0 at a 95% confidence level, were found for the remaining variables, indicating the greater variability of these measurements. This methodology allows the assessment of the consistency of a measurement process and provides a method to monitor it each time a determination is made.

Analysis of Variance↗

PubMed1995

Methane emissions from cattle.

Increasing atmospheric concentrations of methane have led scientists to examine its sources of origin. Ruminant livestock can produce 250 to 500 L of methane per day. This level of production results in estimates of the contribution by cattle to global warming that may occur in the next 50 to 100 yr to be a little less than 2%. Many factors influence methane emissions from cattle and include the following: level of feed intake, type of carbohydrate in the diet, feed processing, addition of lipids or ionophores to the diet, and alterations in the ruminal microflora. Manipulation of these factors can reduce methane emissions from cattle. Many techniques exist to quantify methane emissions from individual or groups of animals. Enclosure techniques are precise but require trained animals and may limit animal movement. Isotopic and nonisotopic tracer techniques may also be used effectively. Prediction equations based on fermentation balance or feed characteristics have been used to estimate methane production. These equations are useful, but the assumptions and conditions that must be met for each equation limit their ability to accurately predict methane production. Methane production from groups of animals can be measured by mass balance, micrometeorological, or tracer methods. These techniques can measure methane emissions from animals in either indoor or outdoor enclosures. Use of these techniques and knowledge of the factors that impact methane production can result in the development of mitigation strategies to reduce methane losses by cattle. Implementation of these strategies should result in enhanced animal productivity and decreased contributions by cattle to the atmospheric methane budget.

Animal Feed↗

PubMed1995