QUEEN'S UNIV KINGSTON (Ont.)
Most widely held works by QUEEN'S UNIV KINGSTON (Ont.)
Role of Hepatocyte Growth Factor Autocrine Loop in Growth and Metastasis of Breast Cancer ( Book )
3 editions published between 1997 and 2000 in English and held by 2 libraries worldwide
Recent evidence has shown that hepatocyte growth factor (HGF) is upregulated in human breast cancer, and that this high level of expression is a reliable indicator of recurrence and of poor overall survival of breast cancer patients. We have recently demonstrated co-expression of HGF and HGF receptor (Met) mRNA in invasive human breast carcinomas, as well as in regions of benign hyperplasia. In contrast, most nonmalignant epithelia express Met, but not HGF. These observations suggest that aberrant expression of HGF and subsequent establishment of an autocrine HGF loop could lead to abnormal growth, tumorigenesis and metastasis. The objectives of this grant are: (a) to assess expression of HGF and Met in nonmalignant and malignant breast epithelia, (b) to examine the transcriptional and post-transcriptional mechanisms of regulation of HGF mRNA and protein, and (c) to determine if upregulating, or downregulating HGF or Met expression affects the transformed and tumorigenic phenotypes of mammary carcinoma cells in vitro and in vivo.
Effects of Human Pregnancy on Responses to Exercise Above and Below the Ventilatory Anaerobic Threshold ( Book )
2 editions published in 1997 in English and held by 2 libraries worldwide
The purpose of this contract is to study the effects of healthy human pregnancy on cardiac autonomic function (Study #1), oxygen uptake kinetics (Study #2), and acid-base regulation (Study #3) at rest and during upright cycling at intensities above and below the ventilatory anaerobic threshold (T(vent)). Study #1 is currently in progress and results to date support our hypotheses that cardiac parasympathetic nervous system activity is blunted in the resting state and that sympathetic activity is reduced during strenuous exercise above T(vent) in late gestation. Technical aspects of the study and the testing protocol have been finalized for Study #2 and data collection will begin in January 1998. Study #3 is essentially complete and supports the concept that arterialized plasma H+ is lower in the pregnant vs. nonpregnant state. However, changes in H+ induced by standardized strenuous exercise are comparable in the pregnant vs. nonpregnant state. Nonpregnant subjects may have greater reductions in the strong ion difference (SID) in response to exercise above (T(vent)), but this is compensated by a greater respiratory response and a reduced arterial plasma carbon dioxide tension. Our results to date support the hypothesis that healthy physically active women can safely adapt to short bouts of strenuous exercise in late gestation.
Signal Transduction in Regulation of Autocrin HGF Expression in Breast Cancer Metastasis ( Book )
4 editions published between 1999 and 2003 in English and held by 1 library worldwide
In the normal breast, hepatocyte growth factor (HGF), also known as scatter factor, is expressed primarily by stromal cells, while epithelial cells express the HGF receptor, Met. Thus, epithelial cells exhibit a tight paracrine loop regulating HGF-dependent responsiveness. In invasive human breast carcinomas, HGF and Met are frequently over-expressed, thereby establishing an autocrine HCF/Met signaling pathway and promoting tumor cell invasion. However, the mechanisms leading to aberrant expression of HGF in carcinoma cells are not known. We previously demonstrated a co-operative effect of c-Src tyrosine kinase and Stat3 in the activation of HGF transcription in mammary carcinoma cells. In the present report, we have shown that non-malignant breast epithelial cells over-expression activated c-Src and Stat3 exhibit increased activation of Stat3, HGF transcription, and cell scattering. Mutational analysis of the HGF promoter revealed a novel Stat3 binding site at nt -95, which is required for the c-Src/Stat3 co-operative effect. Our results delineate a novel c-Src/Stat3-dependent mechanism that regulates HGF transcription in breast carcinomas. This study could lead to novel strategies inhibition of HGF gene expression in tumor cells with minimal effects on normal HGF/Met function.
Identification of Hepatocyte Growth Factor Autocrine Loops in Breast Carcinomas: Possible Target for Therapeutic Intervention ( Book )
3 editions published between 2001 and 2003 in English and held by 1 library worldwide
Hepatocyte growth factor (HGF) binding to its transmembrane receptor, Met, results in an increase in breast epithelial cell motility, morphogenesis and metastasis. HGF-like forms have been detected as secretion products of the human breast epithelial carcinoma cell line, MCF10A1T3B. The two major products are ^56 and ^32 kDa. Recombinant HGF treatment with elastase produced the ^56 kDa HGF antagonistic product, an NK4-like form. Anion exchange chromatography of conditioned medium indicated that MCF10A1T3B secretion products have decreased affinity compared to endogenous full-length HGF.
Analysis of HRAD1, a Human G2 Checkpoint Control Gene ( Book )
3 editions published between 1999 and 2002 in English and held by 1 library worldwide
Genomic instability has long been thought to contribute in tumorigenesis. Cell cycle checkpoints are a key regulatory mechanism, which maintains the integrity of the genome. The S-Phase and G2/M checkpoints have been shown to halt cell cycle progression in response to aberrant DNA structures during replication as well as in response to DNA damaging agents. The G2/M checkpoint gene hRadl has been demonstrated to be essential for checkpoint activity in humans. HRadl has been demonstrated by our lab to exist in a ternary complex with two other checkpoint proteins, hRad9 and hHusl. Since taking over the project in November of 1999, I have been pursuing other interacting partners with the hRadl, hRad9, hHusl complex by various methodologies, including: Yeast-2-Hybrid, Gel Filtration chromatography, and metabolic labeling.
Regulation of Anchorage-Independent Growth in Breast Cancer: Role of Signalling by Extracellular Matrix and Growth Factors ( Book )
3 editions published between 1995 and 1997 in English and held by 1 library worldwide
In this report we investigate the role of ECM proteins and growth factors in anchorage-independent survival and growth of a murine mammary carcinoma-derived cell line, designated SP1. We demonstrate that SP1 cells adhere well to FN and VN and express a number of integrins, including a5beta1, alpha v beta 3, alpha 6 beta 1, alpha 3 beta 1 and alpha 2 beta 1, the latter being upregulated under anchorage- independent conditions. We also demonstrated by partially removing FN from 7% FBS or adding FN to 1% FBS that FN is required for SP1 cell colony growth.
The Role of Fps in Tumor-Associated Angiogenesis ( Book )
3 editions published between 2002 and 2004 in English and held by 1 library worldwide
The tyrosine kinase Fps has been implicated in angiogenesis. Expression of activated Fps - (MFps) causes hyper-vascularity in mice (fpsMF mice) suggesting that Fps may regulate angiogenesis. Studies have shown that the magnitude of vascularity is elevated l.7-fold and is highly-disorganized and tortuous in nature. Stimulation of endothelial cells (EC) isolated from these mice has shown that MFps, but not Eps is activated in response to PDGF and VEGF. This suggests that MFps mediates hyper-sensitization of EC to these growth factors, an abnormality which may underlie the proangiogenic phenotype in these mice. In other studies we have shown early tumor onset in the context of loss-of-function Eps genetic backgrounds suggesting that Fps may behave as a tumor suppressor. Thus, Eps may be a suitable target for the development of anti-tumorigenic and anti-angiogenic therapeutics. Lastly, fpsMT mice may have a DIC-like phenotype. This was suggested by hemostatic defects and by an array of phenotypic features characteristic of disorders associated with vascular hyperplasia. This is an important finding, since DIC occurs as a lethal complication in advanced cancers, including those of the breast.
Studies on Platelet-Derived Growth Factor Beta-Receptor and Hepatocyte Growth Factor Receptor c-met in Paracrine Interactions in Human Breast Cancer ( Book )
2 editions published between 1995 and 1996 in English and held by 1 library worldwide
Platelet-derived growth factor (pDGF) and hepatocyte growth factor (HGF) are key regulators of breast stromal- epithelial interactions. We examined the expression of PDGF 13-receptor, HGF receptor/Met and the corresponding ligands in primary human breast cancer using in situ hybridization and imunohistochemical techniques. The results showed that PDGF 13-receptor was localized in smooth musclie-actin-positive cells and vascular endothelial cells in the periepithelial stroma, but not in the epithelial component of ductal carcinoma in situ. These findings support the notion that PDGF BB, which is produced by breast carcinoma cells, functions in the paracrine stimulation of the stroma by adjacent carcinoma cells. In contrast, HGF receptor/Met was exclusively expressed on nonmalignant and malignant epithelial cells. However, HGF mRNA was expressed in both stromal cells and in carcinoma cells in regions of invasive cancer; these results. suggest that both paracrine and autocrine stimulation by HGF of mammary carcinoma cells can occur. Our hypothesis is that co-expression of HGF and HGF receptor/Met results in the establishment of an HGF autocrine loop which provides a selective advantage for autonomous growth and metastasis of mammary carcinoma cells. To further investigate the possible role of an HGF autocrine loop in the progression of breast cancer, we are currently examining expression and function of HGF in human and murine primary breast carcinomas and carcinoma cell lines.
Determining the Function of the Fps/Fes Proto-Oncogene in Breast Development and Malignancy ( Book )
2 editions published between 2004 and 2005 in English and held by 1 library worldwide
The fps/fes proto-oncogene encodes a 92 kDa protein tyrosine kinase. To understand the physiological function of Fps we have generated a knockout mouse line that lacks Fps expression. Fps-knockout female mice produce litters that gain weight more slowly than wildtype mice, and develop breast tumors more quickly than wildtype mice. These data suggest that Fps participates in regulating mammary gland development and tumorigenesis. To address these hypotheses we are examining the biological and biochemical function(Fps) of Fps in the mammary gland. To date, we have shown that Fps is expressed specifically in epithelial cells. Examination of Fps during different mammary stages has shown that expression begins to increase during pregnancy and reaches maximal levels during lactation. An upregulation of Fps tyrosine kinase activity displays a similar profile. This would suggest that Fps might regulate epithelial cell differentiation. However, morphological and histological analyses could not detect any obvious differences in the pattern or quantity of alveolar structures between wildtype and knockout mice. Examination of ducts during lactation indicates that knockout cells may have a distorted shape with respect to their apical surface being more extended into the lumen of the duct. The exact nature of this potential phenotype has not yet been fully characterized but it suggests that Fps may regulate an aspect of lactation.
Clothe the Soldier Prototype Modular Load Carriage System Design Assessment using the APLCS Load Carriage Simulator ( Book )
1 edition published in 2006 in English and held by 1 library worldwide
The objective of this study was to conduct a standardized assessment of the CTS prototype modular (M1) pack on a computerized Load Carriage (LC) Simulator. Specifically, the LC Simulator measured variables which assess load control and load transfer capability of the M1 pack. These aspects of pack design were comprised of several displacement, force, moment and pressure variables that had been validated on previously tested systems where LC Simulator outputs were compared to assessments by experienced users during human trials.
Asymptotic Efficiency of the Maximum Likelihood Estimator of a Parameter for the M/G/1 Queueing System ( Book )
1 edition published in 1992 in English and held by 1 library worldwide
This paper discusses asymptotic efficiency of the maximum likelihood estimator of the parameters of the M/G/1 queueing system for full likelihood and reduced likelihood functions. The efficiency of the maximum likelihood estimator of the reduced likelihood function relative to full likelihood function is derived.
Training the Absolute Identification of Pitch ( Book )
1 edition published in 1969 in English and held by 1 library worldwide
Two methods for training the absolute judgment of pitch, reference training and series training, were studied. Reference training concentrated during training on the identification of three reference tones in a set of nine pure tones, while series training gave equal weight during training to the identification of all nine tones. Results of pre- and posttraining tests, scored for the number of correct judgments, showed that reference training was more effective than series training for listeners with musical experience. In addition, discriminability (d) scaling of pre- and posttest performance indicated that reference training was particularly effective for training listeners with musical experience when the nine tones of a set were grouped into three pitch classes-high, medium, and low pitch. Listeners without musical experience benefited from both training methods, but their overall improvement was less than that for musical listeners. (Author).
Recognition Memory for Pitch of Fixed and Roving Stimulus Tones ( Book )
1 edition published in 1970 in English and held by 1 library worldwide
The method of delayed comparison was used to measure pitch memory under two conditions of presentation, either the same standard tone on every trial (fixed S) or one of four equally likely standard tones (roving S), six durations of interference interval ranging from 0.0 to 4.0 sec, and two types of interference interval, either blank or filled with a pure tone. Listeners were instructed not to rehearse the S tone during the interference interval. For both fixed-S and roving-S conditions, accuracy of performance, as measured by area under the ROC curve, declined as interval duration increased and declined more rapidly following an interference-filled than following a blank interval. In general, forgetting proceeded at a slower rate under fixed-S conditions than under roving-S conditions. A second experiment showed that very little forgetting is obtained over 4 sec for roving-S conditions if instructions permit rehersal of the S tone and suggests that the conclusions from the first experiment be restricted to nonrehersal instructional conditions. (Author).
Reaction of chromyl chloride with some olefins. ii. the oxidation of tetraarylethylenes ( Book )
1 edition published in 1968 in English and held by 1 library worldwide
Chromyl chloride oxidation of tetraphenylethylene results in a novel cyclization reaction giving 9,10-diphenylphenanthrene in high yield. Some cyclization between geminal phenyl groups and cleavage of the olefinic bond occurs as evidenced by the presence of fluorenone and benzophenone as minor products. Polynuclear hydrocarbons such as 1,1'-binaphthyl and o-terphenyl which can be cyclized by Lewis acids are unreactive towards chromyl chloride. The observation of rotation about the central bond of a substituted tetraphenylethylene and of retardation of cyclization by substituent chlorine suggest that the oxidative cyclization proceeds by initial electrophilic attack at the olefinic bond to give a carbonium ion. (Author).
A Relationship between Chip Type and Shear Strain ( Book )
1 edition published in 1971 in English and held by 1 library worldwide
Results of experiments are presented in which SAE 1040 steel and 26S aluminum were cut orthogonally using limited-face tools of several face lengths and full face tools with a variety of rake angles. These indicate that the change in chip type from ribbon-like to segmented occurs when the nominal shearing strain reaches a critical value which depends upon the normal stress on the 'shear' plane and is a property of the workpiece material.
Performance Characteristics of Leaky Coaxial Cables ( Book )
1 edition published in 1980 in English and held by 1 library worldwide
This work deals with guided radar and reports on the experiments and analysis that were performed to obtain information on the function of leaky coaxial cables used as radio frequency intrusion sensors. Four subjects were investigated: (1) environmental effects on the leaky coaxial cable and the guided radar system, (2) use of doppler shift caused by an intruder to determine the velocity and direction of the intruder, (3) target identification, classification and signature, and (4) a single leaky coaxial cable intrusion detection system. The most important environmental factor was moisture, either rain or snow. Results have demonstrated that the velocity of a target moving longitudinally between the leaky cable sensors can be measured, based on the doppler shift in the return signal. Rudimentary target classification has been demonstrated based on a defined target signature--the log-magnitude of the Fourier transform of the target vector. A single cable intrusion detection system was investigated which incorporated a modulation technique which allowed the intruder to be located. (Author).
Photoelastic determination of cutting tool stresses ( Book )
1 edition published in 1960 in English and held by 1 library worldwide
The determination of pressure distribution on the tool surfaces in an important step in the study of the mechanism of chip formation. This paper describes the method of determining the instantaneous stress distribution in a photoelastic tool while it was being used to cut lead. The method used to compute the stresses is also described. A periodic variation in the stress pattern confirmed the periodic nature of the cutting process recently suggested (3), and necessitated the determination of the instantaneous pressure distribution at the tool-chip interface. (Author).
RESPONSE TO COLD OF ESKIMOS OF THE EASTERN CANADIAN ARCTIC ( Book )
1 edition published in 1962 in English and held by 1 library worldwide
Role of Nitric Oxide as a Chemosensitizer in Prostate Cancer ( Book )
1 edition published in 2004 in English and held by 1 library worldwide
Most patients who die of prostate cancer do so because of therapy failure. Regional hypoxia is a prevalent feature of prostate carcinomas and hypoxia contributes to chemoresistance in various types of cancer. Thanks to the funding provided by the US Army Medical Research and Material Command (Award no. DAMDl7-03-l-OO7O), we have shown that hypoxia increases resistance to more than one class of chemotherapeutic agents in human and rodent prostate cancer cells. Specifically, our studies reveal that incubation of human (PC-3 and DU-l45) as well as mouse (TRAMP-C2) prostatic adenocarcinoma cells under hypoxia (O.5%02) significantly increases their resistance to chemotherapeutic drugs that exert their cytotoxic effects via different mechanisms, i.e. doxorubicin and paclitaxel. Moreover, we have also demonstrated that the effect of hypoxia on chemoresistance of prostate cancer cells can be prevented by very low concentrations of nitric oxide mimetic agents (Task 1). As initially proposed in the Statement of Work, we were able to accomplish these objectives within the first 12 months of funding. These findings suggest that it may be feasible to use NO mimetics as adjuvants to chemotherapy in prostate cancer patients.
Signaling Transduction in Regulation of Autocrin HGF Expression in Breast Cancer Metastasis ( Book )
1 edition published in 2002 in English and held by 1 library worldwide
This fellowship was initially awarded to Dr. Wesley Hung who was a postdoctoral fellow in Dr. Bruce Elliott's laboratory (1998-2000). After Dr. Hung's departure, a new trainee, Dr. Ewa Joanna Wojcik, was recruited to the group as an MSc graduate student in Pathology Approval to transfer the remaining funds of the award to support Dr. Wojcik from July 1, 2002 to June 30, 2003 was granted by the USAMRMC (see attached letter). Dr. Elliott continues his supervisory role of this project. In addition, Dr. Christopher Mueller, who has extensive expertise in regulation of gene transcription and promoter analysis, functions as co-supervisor. This report provides a brief update of the current aims and preliminary results of the revised program. A more detailed report will be provided at the end of the award period.