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Sabbatical leaves are viewed as being essential to the ongoing nature of a self-renewing community of scholars. This study was undertaken to provide data on current use of sabbatical leave plans in universities in several countries - Canada; the United States; England, Northern Ireland, Scotland, Wales; Australia, and New Zealand - to provide useful information for possible revision of leave plans. Sixty-six universities were surveyed by means of a questionnaire and the results revealed similarities among the four groups of countries regarding the length of service prior to leave (generally 6 years); differences among the four groups, including the use of retraining leaves as a form of sabbatical; salary paid during regular sabbatical leave; and travel expenses. The conclusions drawn from the data are that Canadian leave plans are not nearly as uniform as those in United States universities; Canadian plans have become more formalized and better documented since 1969; salary paid for full-year leaves in Canadian universities has improved since 1969 and is now substantially better than in the United States, but not as good as in Australia and New Zealand; and participation rates in all countries appear to be higher than those reported prior to 1965 by Ingraham. (JMF)

Currently amputation, arthrodesis (joint fusion), or joint replacement are used to treat a joint with an intra-articular fracture or destroyed by a combat injury. Generation of personalized, anatomically shaped biological implants formed using techniques of regenerative medicine in conjunction with biodegradable biomaterial structures to restore a damaged articular joint surface to normal tissue structure, form and function is one way to overcome the limitations associated with current treatment methods. The aims of this study are to: 1) identify the parameters that generate anatomically shaped bone substitutes of optimal composition and structure with an articulating profile. 2) to develop a source of human chondrocytes that can generate sufficient amounts of a cartilage layer to cover the bone substitute; and 3) to evaluate the structures formed in a preclinical model. The ongoing studies will further our understanding of the regulation of cell differentiation to chondrocytes and the bone substitute properties required to form a biological joint replacement., See also ADA573823.

The Defense Acquisition University (DAU) is an integral component in the career of every Defense Acquisition Workforce member, from the time they enroll in their first DAU course until they retire. One of the many keys to DAU's success is its ability to measure the effectiveness of its training programs, monitor performance, and improve its curriculum. To this end, the authors conducted a data mining exercise within the training evaluation data to determine the key drivers of its success. This article explains the methodological approach used (structural equation modeling) as well as the results, recommended actions, and outcomes. Within the DAU learning enterprise, more than 326,000 training events were evaluated during 19 months between January 1, 2008, and July 30, 2009. Results indicate that DAU's learning enterprise positively influences job impact and business results., Published in the Defense Acquisition Research Journal, v18 n4 p348-367, October 2011.

Soldiers in the field work in an acoustically complex environment. Spoken words of particular interest may be embedded in other less important speech or environmental noise. Loud engine noise and impulsive sounds may also threaten not only the soldier?s awareness of their surroundings, but their hearing as well. Just as importantly, some sounds (including impulsive events), are critical for situational awareness, which the soldier must hear or be made aware of. To address these competing problems, we have introduced the Smart Helmet system which combines hearing protection, speech enhancement and source localization. This report outlines the overall system design, presents lab−testable prototypes, and describes more integrated software models that may be used for further investigation. Areas needing further research are also described.

To develop a novel high content screen to identify inhibitors that block Myc:TRRAP interaction, in the first year of this project we constructed several fluorescent fusion protein constructs of Myc and TRRAP, and evaluated their ability to bind and engage in fluorescence energy transfer (FRET) in vivo. All year-one tasks were completed in the first year of the grant. During the second year we discovered that expression of Myc-CFP was toxic to some cells and in other cells the Myc-CFP did not show the expected blue fluorescence. Due to the short half-life of Myc most of the CFP-Myc proteins were turning over before the CFP matured and became fluorescent. To overcome this unexpected issue, we introduced a mutation (T58A) to increase the stability of the CFP-Myc fusion protein and we evaluated additional cell lines, as well as new expression constructs. Conditions were identified in which sufficient CFP-Myc folded correctly and became fluorescent. To define Myc:TRRAP co-regulated target genes we established a Myc-dependent transformation system in the MCF10A cells and conducted Myc-specific ChIP-on-chip in these cells with and without ectopic Myc expression. Expression profiling of these cells was also conducted and data analysis revealed the subset of genes whose promoter was bound and regulated by Myc. During validation of the compound screen we discovered an engineering problem with the FRET-FLIM screening device that prevented the analysis of large numbers of samples. To rectify this we designed and built a pulse stretcher for the FLIM-Opera screening instrument., The original document contains color images.

Women with breast cancer desire more information about their disease, in part, to be involved in making treatment decisions (TDs). Patient involvement responds to patients desires for autonomy and addresses ethical concerns about rights to make TDs. However, several researchers have reported that patients actual experiences in TDM did not match their preferences. The study objectives are to 1) understand the meaning of involvement in TDM from the perspectives of women with early stage breast cancer (ESBC); 2) identify stages/ steps of TDM used by women and their physicians during the treatment consultation(s); and 3) identify the behaviors of women and physicians that facilitate or impede womens involvement in TDM. Methods: A qualitative approach with interviews and video-stimulated recall was used. In Phase 1, interviews with 19 women with ESBC were held to understand the concept of involvement in TDM. In Phase 2, surgical (n=6) or medical oncology (MO) consultations (n=15) with new ESBC patients were videotaped. Subsequently, women and medical oncologists or surgeons separately viewed their consultation. Interviews were taped, transcribed, and analyzed. Findings: Phase 1: Most women wanted high quality information soon after diagnosis but many felt isolated and uninformed until the surgical or the MO visit. In Phase2, most women described an iterative TDM process where they made a preliminary treatment decision prior to the consultation, often based upon experiences of family or friends. Clinicians described many behaviours used to facilitate the patients involvement in TDM. While women reported some of these behaviours, they also reported fewer or different behaviours than clinicians. Significance: The information from this study will be useful to patients and physicians for promoting patient involvement. It can be used to develop and evaluate training programs for both physicians and patients to involve patients with cancer in decisions about their care.

There is an urgent need for novel anti-breast cancer therapeutics. Our hypothesis is that by identifying small molecules that target the Myc oncogene, we will develop an effective therapeutic that will improve breast cancer patient care and contribute to the eradication of disease. Our OBJECTIVE is to identify compounds that can be used to selectively inhibit the oncogenic activity of Myc by inhibiting its interaction with one of its key binding partners TRRAP. To this end, we aim to 1) develop a novel high content screen to identify inhibitors that block Myc:TRRAP interaction; 2) determine the transcriptional signatures of Myc:TRRAP target genes; 3) screen drug and chemical libraries to identify compounds that disrupt Myc:TRRAP interaction; and, 4) validate lead compounds that disrupt Myc:TRRAP interaction and block the transformation potential of breast cancer cells. In the first year of this grant we have constructed several fluorescent fusion protein constructs of Myc and TRRAP, and evaluated their ability to bind and engage in fluorescence resonance energy transfer (FRET) in vivo. We have identified FRET pairs that are functional and established methodology using novel instrumentation that will enable the high throughput screening of chemical libraries. In the course of our work, we have shown that the cell systems we were aiming to use are unfortunately sensitive to expression of the fusion proteins. To overcome this unexpected issue, we are evaluating additional cell systems, as well as new expression constructs that will enable stable cell lines to be developed that constitutively and conditionally express the Myc and TRRAP fusion proteins, respectively. We have completed all tasks that we aimed to achieve in the first year of the grant and we are well positioned to fulfill the objectives of our proposal by the end of the second year of this grant., The original document contains color images.

Kaiso is a member of the POZ-ZF family of transcription factors, first identified as a binding partner for the p120ctn cell adhesion co-factor. Previous work in our laboratory showed that Kaiso was misexpressed in ~40% of human breast tumors and we also identified cyclin D1 as a putative Kaiso target gene. This project elucidated the mechanism by which Kaiso regulates cyclin D1 expression and the effects of this on breast cell tumorigenesis. Using minimal promoter assays, electrophoretic mobility shift assays and immunoblotting we showed how Kaiso regulates cyclin D1 expression. Our work to date demonstrates that Kaiso regulates cyclin D1 transcription through its binding properties (by binding to both sequence specific TCCTGCNA and methylated CpG sites within the promoter). We also demonstrated that Kaiso and p120ctn can modulate canonical Wnt signaling and activation of cyclin D1., The original document contains color images.

We planned to employ phage-display methodology to unveil novel breast cancer epitopes for the development of multivalent breast cancer vaccines. Some of the patients on our study were receiving Herceptin, a monoclonal antibody, that could complicate our analysis. We demonstrated that, in fact, our screening strategy would identify Herceptin. So, it was necessary to remove Herceptin from the sera before screening. We developed high affinity Herceptin mimotopes that could be employed to remove Herceptin from the serum samples, however we failed to successfully employ the Herceptin mimotope in a manner that would remove Herceptin from our test serum. Future studies will require samples from patients who were not receiving monoclonal antibody therapy. Over the same period, we successfully refined our algorithms to enable epitope definition based on results from polyclonal antiserum by using a collection of 5 monoclonal antibodies with defined specificity as a test case., The original document contains color images.

Women with breast cancer desire more information about their disease, in part, to be involved in making treatment decisions (TDs). Patient involvement responds to patients' desires for autonomy and addresses ethical concerns about rights to make TOs. However, several researchers have reported that patients' actual experiences in TDM did not match their preferences. The study objectives are to 1) understand the meaning of involvement in TOM from the perspectives of women with early stage breast cancer (ESBC); 2) identify stages/steps of TDM used by women and their physicians during the treatment consultation(s); and 3) identify the behaviors of women and physicians that facilitate or impede women's involvement in TDM. A qualitative approach with interviews and video-stimulated recall is being used. In Phase 1, interviews with 19 women with ESBC were held to understand the concept of involvement in TOM. In Phase 2, surgical (n=6) or medical oncology (MO) consultations (n=15) with new ESBC patients were videotaped. Subsequently, women and medical oncologists or surgeons separately viewed their consultation. Interviews were taped, transcribed, and analyzed. Phase 1: Most women wanted high quality information soon after diagnosis but many felt isolated and uninformed until the surgical or the medical oncology visit. In Phase 2, most women described an iterative TOM process where they made a preliminary treatment decision prior to the consultation, often based upon experiences of family or friends. Clinicians described many behaviors used to facilitate the patient's involvement in TOM. While women reported some of these behaviors, they also reported fewer or different behaviors than clinicians. Significance: The information from this study will be useful to patients and physicians for promoting patient involvement. It can be used to develop and evaluate training programs for both physicians and patients to involve patients with cancer in decisions about their care.

Kaiso is a novel member of the POZ-ZF family of transcription factors, first identified as a binding partner to the p120ctn cell adhesion co-factor. Preliminary work in our laboratory indicated that Kaiso was misexpressed in ~40% of human breast tumors and identified cyclin D1 as a putative Kaiso target gene. The objective of this project is to determine the mechanism by which Kaiso regulates cyclin D1 expression and how this affects breast cell proliferation and tumorigenesis. Using techniques such as artificial promoter assays, electrophoretic mobility shift assays and semi-quantitative PCR we sought to determine how Kaiso regulates cyclin D1 promoter binding and expression. Our work to date demonstrates that Kaiso transcriptionally represses the cyclin D1 promoter through it's bimodal binding properties (binding to both sequence specific sites and methylated CpG sites within the promoter). We have also demonstrated that Kaiso and p120ctn activity may be modulating canonical Wnt signaling and activation of cyclin D1.

The main objective of this study is to further enhance information transfer between the doctor and the patient, giving women with early stage breast cancer an opportunity to more fully participate in treatment decision making. To accomplish this, the authors developed a decision aid, called the Decision Board (DB), for women regarding choices in breast cancer with respect to surgical treatment and adjuvant chemotherapy. The study compares three versions of the decision board (DB), all containing the same information but using different forms of media: (1) the standard DB, which is a foam core, poster-sized version with pull-out panels; (2) the computer DB, which uses a Windows-based program that resembles the standard DB and is available on a laptop computer; and (3) the paper DB, which is a small 8.5 x 11-inch paper version of the standard DB that also serves as the take-home brochure for the standard DB. The different versions of the DB were developed to improve the instrument's usefulness and to allow for information to be updated more readily. A total of 310 patients were accrued to the study and were randomly assigned to one of the three versions. The DB presents one of two treatment choices: (1) an adjuvant chemotherapy decision for women with stage I or II moderate risk breast cancer (no chemotherapy vs. CMF [Cyclophosphamide, Methotrexate, and Fluorouracil] vs. AC [Adriamycin and Cyclophosphamide] vs. ACT [Adriamycin, Cyclophosphamide, and Taxol]); and (2) a surgical decision (mastectomy vs. lumpectomy plus radiation). Preliminary analyses show that the three versions of the DB indicate similar levels of patient knowledge, decisional conflict, and satisfaction with decision making among the patients who used them. The three instruments also showed a similar level of usefulness to patients and physicians. The study supports the use of computer-based and paper-based versions of the DB in treatment decision-making.

In many breast cancer cells, expression of the programmed cell death (apoptosis) promoting protein Bax is higher than in normal cells, yet surprisingly the cells do not die. This observation suggests that one of the ways that breast cancers avoid undergoing apoptosis that would normally clear the tumor from the body at an early stage is by preventing Bax activation. Thus, we hypothesized that agents that specifically but inefficiently activate Bax would selectively eradicate breast cancer cells. To test the hypothesis that activation of Bax would selectively induce apoptosis in breast cancer cells requires an agent that will act directly upon the Bax protein to activate it. To provide a reagent that would demonstrate proof-of-principle as well as provide a lead compound for drug discovery programs, aptamers (small peptides or nucleic acids with high affinity and selectivity) were selected for different conformers of Bax by Covalent Display and SELEX. Covalent Display libraries of aptamers lacked sufficient diversity for the selection of high affinity aptamers. This was due to inefficient binding of P2A to DNA. Two other approaches to selecting aptamers were implemented and yielded promising preliminary results.

The objectives of this award are to establish a viable -program of research focusing on weight and body composition management in breast cancer, and to lay the groundwork for a feasibility study of a home-based exercise intervention for weight and body composition management. The specific aims of the award are: 1) to develop a systematic literature review of studies on exercise and breast cancer that include the outcomes of weight and/or body composition, 2) to examine the relationships between physical activity and body composition changes during adjuvant chemotherapy, and the changes in proportions of body water and lean tissue underlying changes in body composition that were suggested in the Pi's dissertation research, 3) to acquire skills in designing and applying tailored exercise programs, measuring fitness and weight-related outcomes, managing clinical trials research, and designing exercise intervention trials, and 5) to develop multidisciplinary teambuilding and grantsmanship capabilities. All tasks outlined in the Statement of Work have been addressed and all are completed or nearing completion. One manuscript has been accepted for publication thus far, and a systematic literature review has been carried out. The major differences for the original submission are in-the timeline first proposed.

Women with breast cancer have indicated their desire to be involved in decisions about their care. We have developed a decision aid, called the Decision Board, for women regarding choices in breast cancer with respect to surgical treatment and adjuvant chemotherapy. Randomized trials have demonstrated that the Decision Board not only increases patient knowledge, but improves patient satisfaction, decreases decisional conflict, and facilitates shared decision-making between the physician and the patient. This present study builds on previous work and involves the development of versions of the Decision Board using different types of media in order to improve the effectiveness of these instruments. Two new versions have been produced: a computer-based version, which is presented on a laptop computer, and an easy-to-use paper based version which are being compared with a standard poster size foam-core version in a randomized trial. Important outcomes will include patient comprehension and acceptability. Currently 212 patients are entered into the study, with a target of 300 by October 2005. Newer versions of the Decision Board that are easier to use and present will lead to wider use in the community resulting in more knowledgeable and satisfied breast cancer patients.

Women with breast cancer have indicated their desire to be involved in decisions about their care. We have developed a decision aid, called the Decision Board for women regarding choices in breast cancer with respect to surgical treatment and the use of adjuvant chemotherapy. Randomized trials have demonstrated that the Decision Board not only increases patient knowledge, but improves patient satisfaction, decreases decisional conflict, and facilitates a shared decision-making between the oncologist and the patient. This present study builds on previous work and involves the development of different versions of the Decision Board using different types of media in order to improve the effectiveness of these instruments and to facilitate their wider use in the community. Two new versions have been produced: a computer-based version, which is presented on a laptop computer, and an easy-to-use paper-based version. These versions are currently being compared with a standard poster size foam-core version in a randomized trial. Important outcomes will include patient comprehension and acceptability. Newer versions of the Decision Board that are easier to use and present will lead to wider use in the community resulting in more knowledgeable and satisfied breast cancer patients.

The ErbB2 receptor tyronsine kinase plays important roles in development and disease. To investigate the developmental roles of ErbB2 mediated signaling in vivo, we have generated a series of erbB2 cDNA knock-in animals expressing different ErbB2 mutants under the transcriptional control of the endogenous promoter. Firstly, we showed that the kinase activity of ErbB2 is essential for embryonic development since this mutant is a phenocopy of the erbB2 null mutants, which die at midgestation with cardiac and peripheral nervous system defects. In our studies, we also established a minimal threshold level of ErbB2 that was required for embryonic development and survival. The tyrosone autophosphorylation site YlO28 mediated a negative regulatory signal that affected the level of ErbB2 proteins expressed. This tyronsine appears to play a role in normal signaling and development. The mechanism of action is known at this point, however, the downregulatory effect is independent of Cbl binding and ubiquitylation of the receptor. In fact, we have also identified the phosphorylation sites in ErbB2 that is required for it's interaction with Cbl, although ErbB2 appears to be refractory to the downregulatory effect of Cbl. The results of my studies will provide important insight into the regulatory mechanisms controlling ErbB2 signaling and may lead to improved therapeutics., The original document contains color images. All DTIC reproductions will be in black and white.

The human ETS gene family comprises 27 individual members and encodes sequence specific DNA binding proteins that regulate transcription. PEA3 is the founding member of a subfamily of ETS genes, which also include ER81 and ERM. PEA3 is overexpressed in 76% of all human breast tumors and in 93% of the HER2-positive subclass of such tumors. PEA3 is also overexpressed in most human breast tumor cell lines by comparison to non-transformed immortalized human mammary epithelial cells. Furthermore, PEA3 transcripts are elevated in the mammary tumors of three different breast cancer prone transgenic mouse strains and inhibition of the function of PEA3 (and ER81 and ERM) in mammary epithelial cells abrogates mammary oncogenesis induced by Her2. These findings imply that PEA3 and its subfamily members are required for mammary oncogenesis by regulating the expression of genes whose products play cardinal roles in breast cancer. Our objective is to identify PEA3 regulated genes in human mammary tumor cells; such genes may encode diagnostic and prognostic markers and molecular targets for drug discovery. To this end we constructed and characterized recombinant human adenoviruses encoding PEA3 or dominant-negative PEA3 and assessed their capacity to infect and regulated expression of cellular genes in untransformed and transformed human mammary epithelial cells., The original document contains color images. All DTIC reproductions will be in black and white.

Breast cancer is a prevalent, yet poorly understood disease. Of the women afflicted with breast cancer, 20-30 % of cases contain amplified and overexpressed ErbB2 (Neu, HER2). In order to examine the role of ErbB2 in mammary gland development and tumorigenesis, I have sought to both create mice containing a mammary specific knockout of ErbB2 and a mammary specific activation of the oncogenic form of ErbB2. To achieve these goals, a line of transgenic mice expressing Cre Recombinase in the mammary epithelium was created. These mice have been interbred with mice containing a loxP flanked erbB2 cDNA in place of exon one at the genomic erbB2 locus. This resulted in a delay in ductal outgrowth in the early stages of mammary gland development. However, by 6 weeks of development, the mammary glands lacking ErbB2 are indistinguishable from wild type glands and appear to lactate normally.

Women with breast cancer have increasingly indicated a desire for more information about their disease and the need to be involved in making decisions about their care. We have developed two decision aids called Decision Boards (DB) to help clinicians inform patients about their treatment options. One DB involves the surgical decision between mastectomy and lumpectomy plus radiation (DECIDE-S); the other involves the decision between chemotherapy options for the treatment of node-negative and early node-positive breast cancer (DECIDE-C). The objectives of this study are to; i) develop computer based versions of both the DB for the surgical treatment of breast cancer and the DB for chemotherapy for node-negative and early node-positive breast cancer; and ii) to compare the relative effectiveness of the computer- based versions and paper versions with the standard versions of the DB for women with early breast cancer. In the fourth year, there were a number of key accomplishments. We extended the eligibility criteria to include node-positive patients in - the DECIDE-C trial; revised the DECIDE-C and DECIDE-S take-home versions; conducted an extensive revision of the DECIDE-C computer-based version; and revised the DECIDE-S computer-based version. We have accrued 25 patients to the DECIDE-C study and expect to start the DECIDE-S study on November 15, 2002., The original document contains color images. All DTIC reproductions will be in black and white.

The ErbB-2/Neu receptor tyrosine kinase plays important roles in development and disease. To genetically dissect the ErbB-2 mediated signaling pathway in vivo, we have generated neu cDNA knock-in mutants harboring subtle mutations and expressed under the transcriptional control of the endogenous promoter. We have shown that the kinase activity of ErbB-2 is essential for embryonic development since this mutant is a phenocopy of the erbB-2 null mutants. We also demonstrate that the loss of tyrosine 1028 results in a hypermorphic phenotype in animals, strongly suggesting that Y1028 does indeed convey a negative regulatory signal on ErbB-2. The mechanism for this action is under investigation. However, we investigated the possibility that c-Cbl was mediating this downregulatory action by interacting with YlO2B and targeting ErbB-2 for ubiquitylation and degradation. Although we did not observe c-Cbl association with Y1028, we did identify c-Cbl association with two other tyrosine phosphorylation sites, Y1144 and Yl227. The nature and significance of this interaction is currently under investigation. The identity of signaling events that may lead to the downregulation of ErbB-2 would have important therapeutic and clinical implications., The original document contains color images. All DTIC reproductions will be in black and white.

The molecular basis for progression of breast cancer from hormone dependence to hormone independence remains one of the critical issues in this prevalent but poorly understood disease. The principle objective of this proposal is to test the hypothesis that elevated stimulation of the c-Src kinase signaling pathway plays a critical role in modulating estrogen receptor function. The first specific aim of this proposal will assess whether the ductal outgrowth is due to the intrinsic inability of the mammary epithelial cell to respond to estrogen stimulation. To test this hypothesis we plan to assess whether introduction of exogenous estrogens can induce the c-Src deficient mammary epithelial cells to activate the MAP kinase pathway., The original document contains color images. All DTIC reproductions will be in black and white.

The major objective of our DOD sponsored research program is to assess the role od the integrin linked kinase in mammary tumorigenesis and metastasis. Based on previous observation that ILK is overexpressed in human breast cancers, we have derived several independent transgenic strains that express ILK in the mammary epithelium. Genetic and biochemical analysis of these strains revealed that female transgenic strains developed focal mammary tumors after a long latency period. Interestingly mammary tumors derived from these strains have undergone epithelial-mesemcyhmal transition (EMT) . The results of these studies provide direct evidence that overexpression of ILK may be an important step in mammary tumor progression., Original contains color plates: All DTIC reproductions will be in black and white.

The objective of this research is to elucidate the roles of the phosphatidylinositol 3'-OH kinase (PI3K) and its downstream target Akt kinase in the induction of mammary tumors. To assess the role of Akt in mammary development and tumorigenesis, we generated transgenic mice that express an activated Akt (Akt-DD) in the mammary epithelium. Although expression of Akt-DD interferes with apoptosis during normal mammary gland involution, mammary tumors are not observed in these strains. To explore the role of Akt in mammary tumorigenesis, mice co-expressing Akt-DD and activated ErbB-2 or a mutant form of Polyomavirus middle T (PyV mT) antigen de-coupled from PI3K/Akt signaling were generated. Co-expression of Akt-DD with mutant PyV mT resulted in dramatic acceleration of mammary tumorigenesis. This acceleration was further correlated with reduced apoptotic cell death, phosphorylation of FKHR and overexpression of cyclin Dl. However, activation of Akt does not to affect metastatic progression. Akt activation also contributes to ErbB- 2 mediated mammary tumori genes is as bi-transgenics co-expressing Akt-DD and activated ErbB-2 transgenes show higher rates of tumorigenesis correlated with increased proliferation and overexpression of cyclin Dl. These observations indicate that Akt activation can impede mammary gland regression and contribute to tumor progression by providing survival and proliferation signals., Original contains color plates: All DTIC reproductions will be in black and white.

The research objective outlined in the original proposal was to determine the role of the integrin-linked kinase (ILK) in the induction and progression of mammary tumors. This work was initially based on the observation that overexpression of ILK in cultured epithelial cells results in changes characteristic of oncogenic transformation (Hannigan et al., 1996). In order to evaluate the oncogenic potential of ILK in the mammary gland, we derived transgenic mice expressing ILK under the transcriptional control of the MMTV promoter. The appearance of mammary tumors in these MMTV/ILK mice confirmed that mammary-specific overexpression of ILK can facilitate malignant transformation in vivo. This result provides the first direct demonstration of an oncogenic role for ILK, which may have significance to the clinical management of breast cancer, given that ILK protein levels are elevated in human tumors and tumor cell lines (Chung et al., 1998; Janji et al., 1999). The results of the experiment were published in the journal Oncogene. In addition to this main research objective, we have also shown that mammary-specific expression of a kinase-dead allele of ILK does not inhibit erbB-2-mediated tumorigenesis, suggesting the importance of ILK protein adaptor functions, retained in the kinase-dead allele., Original contains color plates: All DTIC reproductions will be in black and white.

Magnetic nerve stimulation is a non-invasive method of exciting neural tissue. The major limitation of using magnetic stimulation is the lack of a focused field. At sufficiently high magnetic pulses the diffused field not only stimulates the target population of neurons, but also stimulates adjacent structures as well. Further, for deeply penetrating fields, as is the case in transcranial stimulation, excessively high amplitude current pulses are required in the coils because a significant fraction of the field energy is spread throughout the tissue under the coil. In this paper we propose two new coil designs that can be used for magnetic stimulation of the peripheral or central nervous system. The purpose of the design was to increase field focality and depth of penetration. The magnetic fields produced by these coils, when driven by biphasic pulses, were simulated using a finite element technique coupled with a transient solver. The resultant field densities and gradients were compared with those obtained from the commonly used Figure-8 coil. Both the air core and the ferromagnetic core designs have superior results when compared to the Figure-8 coil., Proceedings from the Annual Int'l Conf. (23rd) of the IEEE Engineering in Medicine and Biology Society, held in Istanbul, Turkey on 25-28 Oct 2001. See also ADM001351 for entire conference on CD-ROM.

20 TO 30% OF HUMAN BREAST CANCERS AMPLIFY AND OVEREXPRESS ErbE2 (HER2, Neu). To examine the role of this receptor tyrosine kinase in both normally mammary gland development and in mammary tumorigenesis, I have created several mouse models. To examine the role of ErbB2 in mouse mammary development I have utilized Cre/loxP technology to create a mammary specific knockout of ErbB2. Although the loxP flanked construct was shown to be functional, as were the transgenic mice expressing Cre in the mammary epithelium, we have not yet observed mammary specific inactivation of ErbB2. This is likely due to background specific methylation of the transgene and we have completely introgressed the mice onto an FVB background. To examine the role of ErbB2 in mammary tumorigenesis, I have created a mouse model that expresses activated ErbB2 specifically in the mammary gland. This resulted in mammary adenocarcinomas that amplified and overexpressed ErbB2, closely mimicking the human condition. Further, the mammary epithelium escapes from the normal confines of the stroma in these mice. Additional experiments have revealed double minute chromosomes, overexpression of various genes and I have now isolated three cell lines from the tumors in order to examine these tumors more fully., Original contains color plates: All DTIC reproductions will be in black and white.

Magnetic nerve stimulation has proven to be an effective non-invasive technique that can be used to excite peripheral and central nervous systems. In this technique, the excitement of the neural tissue depends on exposing the body to a transient magnetic field. This field can be generated by passing a high pulse of current through a coil over a short period of time. This paper presents general guidelines for designing and constructing a magnetic stimulator. These guidelines cover theoretical concepts, hardware aspects and components required to build these systems. The critical points discussed in this paper are based on key findings and difficulties encountered during the process of building the system used for this study. Furthermore, some suggestions were addressed to improve future designs., Proceedings from Annual Int'l Conf. (23rd) of the IEEE Engineering in Medicine and Biology Society, held in Istanbul, Turkey on 25-28 Oct 2001. Prepared in cooperation with the Natural Sciences and Engineering Council of Canada. See also ADM001351 for entire conference on CD-ROM.

The International Hypoxia Symposia (IHS) meet every other year to bring together international experts from many fields to focus on and discuss the state of the art in normal and pathophysiological responses to hypoxia. Representatives from six continents and 32 countries joined together in March 2001 for four days of intense scientific discourse in the dramatic mountain setting of Jasper Park Lodge. In 2001 we also had the privilege of honoring John T. Reeves as a friend, colleague, mentor and inspiration to many in the field. Robert Grover's personal tribute to John "Jack" Reeves is the first chapter in this volume. As organizers of the IHS, we strive to maintain a near quarter century tradition of presenting a stimulating blend of clinical and basic science talks.

Women with breast cancer have increasingly indicated a desire for more information about their disease and the need to be involved in making decisions about their care. We have developed two decision aids called Decision Boards (DB) to help clinicians inform patients about their treatment options. One DB involves the surgical decision between mastectomy and lumpectomy plus radiation; the other involves the decision between chemotherapy options for the treatment of node-negative breast cancer. The objectives of this study are to; (1) develop computer based versions of both the DB for the surgical treatment of breast cancer and the DB for chemotherapy for node-negative breast cancer; and (2) to compare the relative effectiveness of the computer-based versions with standard versions for women with early breast cancer. In the third year, we have revised the standard and computer versions of the node-negative chemotherapy decision board. Both computer-based versions (for surgery and chemotherapy) have now been developed, revised and field-tested. Both instruments have been shown to be easy to use and understand, and acceptable to patients and physicians. We are now in a position to begin the randomized trial comparing the computer-based versions to the standard versions., Original contains color plates: All DTIC reproductions will be in black and white.

The Akt/PKB serine/threonine kinase plays roles in coupling growth factor receptors to cell survival pathways. Although evidence suggests roles for phosphatidylinositol 3'-OH Kinase (PI3K) and Akt in normal mammary development 1 and tumorigenesis, the role of these signaling molecules in these processes remains to be elucidated. To directly assess the role of Akt in mammary epithelial development and tumorigenesis, we have generated transgenic mice that express a constitutively active Akt (Akt-DD) in the mammary epithelium. Although expression of Akt-DD interferes with normal mammary gland involution, mammary tumors were not observed in these strains. To explore the potential role of Akt in mammary tumor progression, mice co-expressing Akt-DD and a mutant form of Polyomavirus middle T (PyV mT) antigen de-coupled from PI3K/Akt signaling pathways were generated. Co-expression of Akt-DD with mutant PyV mT resulted in dramatic acceleration of mammary tumorigenesis. This acceleration was further correlated with reduced apoptotic cell death in mammary epithelium expressing the mutant form of PyV mT. Taken together these observations indicate that activation of Akt can contribute to tumor progression by providing an important cell survival signal., Original contains color plates: All DTIC reproductions will be in black and white.

The ErbB-2 receptor tyrosine kinase is an important member for the Epidermal Growth Factor Receptor family. It has both a potent tyrosine kinase domain that can transphosphorylatate its dimerization partner or other substrates and it has a carboxy- terminal domain containing several tyrosine autophosphorylations sites. We are interested in studying the role and significance of these two domains using a physiologically relevant in vivo system. We have used a targeted knock-in strategy to generate mice expressing these mutant ErbB-2 receptors under the control of the endogenous erbB-2 promoter. The ErbB-2 kinase domain is absolutely essential for the receptors function since impairment of its activity resulted in a null phenotype. We have also generated mice expressing the ErbB-2 receptor where the five tyrosine phosphorylation sites have been mutated to phenylalanine residues (Neu-NYPD) . Characterization of these mice will begin as we expand the colony., Original contains color plates: All DTIC reproductions will be in black and white.

The objective of this research is to elucidate the roles of the phosphatidylinositol 3'-OH kinase (PI3K) and its downstream targets such as the Akt kinase in the induction of mammary tumors. To assess the role of Akt in mammary development and tumorigenesis, we have generated transgenic mice that express an activated Akt (Akt-DD) in the mammary epithelium. Although expression of Akt-DD interferes with apoptosis during normal mammary gland involution, mammary tumors are not observed in these strains. To explore the role of Akt in mammary tumorigenesis, mice co-expressing Akt-DD and a mutant form of Polyomavirus middle T (PyV mT) antigen de-coupled from PI3K/Akt signaling were generated. Co-expression of Akt-DD with mutant PyV mT resulted in dramatic acceleration of mammary tumorigenesis. This acceleration was further correlated with reduced apoptotic cell death, phosphorylation of FKHR and overexpression of cyclin D1. However, activation of Akt does not to affect metastatic progression. Aid activation may also be able to contribute to ErbB-2 mediated mammary tumorigenesis as bi-transgenics co-expressing Akt-DD and activated ErbB-2 transgenes show higher rates of tumorigenesis. Taken together these observations indicate that Aid activation can impede mammary gland regression and contribute to tumor progression by providing an important cell survival signal., Original contains color plates: All DTIC reproductions will be in black and white.

The primary objective of this proposal is to elucidate the role of the integrin linked kinase in the induction of mammary tumors. To accomplish this, we have generated transgenic mice that express a cDNA encoding ILK under the transcriptional control of the mouse mammary tumor virus (MMTV) promoter enhancer. Although mammary epithelial expression of ILK was capable of inducing mammary tumors in female transgenic mice, these tumors were focal in nature and arose with a long latency period. Tumor progression in these strains involved a dramatic upregulation in both the levels of ILK and cyclin D1 protein. In addition, constitutive phosphorylation of AKt on serine 473 was also observed in both normal and tumor material. These observations suggest that ILK is capable of inducing tumors through the concerted activation of multiple distinct signaling pathways. We have also recently derived transgenic mice that express a kinase defective ILK under the MMTV promoter. Future crosses with both types of ILK strains with other oncogene bearing transgenic strains will provide important insight into the role of ILK in mammary tumorigenesis and metastasis., Original contains color plates: All DTIC reproductions will be in black and white.

The research objective outlined in the original proposal was to determine the role of the integrin-linked kinase (ILK) in the induction and progression of mammary tumors. This work was initially based on the observation that overexpression of ILK in cultured epithelial cells results in changes characteristic of oncogenic transformation (Hannigan et al., 1996). In order to evaluate the oncogenic potential of ILK in the mammary gland, we derived transgenic mice expressing ILK under the transcriptional control of the MMTV promoter. The appearance of mammary tumors in these MMTV/ILK mice confirmed that mammary-specific overexpression of ILK can facilitate malignant transformation in vivo. This result provides the first direct demonstration of an oncogenic role for ILK, which may have significance to the clinical management of breast cancer, given that ILK protein levels are elevated in human tumors and tumor cell lines (Chung et al., 1998; Janji et al., 1999). The results of the experiment were submitted as a manuscript to the journal Oncogene. In addition to this main research objective, we have also shown that mammary-specific expression of a kinase-dead allele of ILK does not inhibit erbB-2-mediated tumorigenesis, suggesting the importance of ILK protein adaptor functions, retained in the kinase-dead allele., Original contains color plates: All DTIC reproductions will be in black and white.

Plasma chemistry and technology represents a significant advance and improvement for green manufacturing, pollution control, and various processing applications. The US Army as well as the DoD have a very large number of operational and military needs that can be addressed by state-of-the-art plasma technologies. These include clean-up/restoration of a wide range of contaminated sites (soils and groundwater), control of release of toxic vapors during peacetime operations at military bases and depots, as well as combat applications such as decontamination of personnel clothing and materiel contaminated by CBW agents. The Pacific Basin Chemical Societies jointly organize a major Congress every five years. The Pacifichem 2000 was held from December 14-19, 2000 in Honolulu, HI. This Congress consists of over 120 symposia. amongst them the Symposium on Plasma Chemistry and Technology for Green Manufacturing, Pollution Control, and Processing Applications. This symposium was aimed at highlighting many of the new and exciting developments in the plasma chemistry many field beyond the more traditional and mature fields of semiconductor and materials processing. This symposium was focus on three areas: Pollution Control with Standard and Hybrid Non-Thermal Plasmas; Green Chemical Synthesis, Conversion, and Materials Modification; and Plasmas in Food and Agricultural applications.

In human breast cancer, 20 to 30% of human breast cancers amplify and overexpress the Neu proto-oncogene. To fully elucidate the role of this gene in normal development and breast cancer, we have designed and implemented experiments to test the gain and loss of function of Neu in the mouse mammary epithelium. Since the knockout of Neu results in embryonic lethality, the null mutation is not easily examined. To examine mammary development in the absence of Neu, we have knocked Neu out specifically in the mammary epithelium through the use of Cre Recombinase. The preliminary analysis has not revealed a phenotype, however we have not yet examined lactation and regression. To address the role of Neu in mammary tumorigenesis, I have conditionally placed NeuNT under the control of the endogenous promoter specifically in the mammary gland. These mice express NeuNT during mammary gland development, resulting in abnormal mammary gland development, characterized by numerous side branches and lobuloalveolar side buds. Tumorigenesis in this strain occurs in 50% of the afflicted female by 13.52 months and is associated with both membrane and cytoplasmic immunoreactivity for NeuNT. Interestingly, there is both amplification and overexpression of the NeuNT allele in this tumor model., Original contains color plates: All DTIC reproductions will be in black and white.

The major focus of DOD sponsored research program is to assess the role of the phosphadityl inositol 3f (PI-3f) and Akt-1 kinases in mammary tumorigenesis and metastasis. Although evidence suggests roles for phosphatidylinositol 3f-OH kinase (PI3K) and Akt in normal mammary development and tumorigenesis (Farrelly et al., 1999; Stambolic et al., 1998; Webster et al., 1998),the role of these signaling molecules in these processes remains to be elucidated. To directly assess the role of Akt and PI-3f kinase in mammary epithelial development and tumorigenesis, we have generated transgenic mice that express a constitutively active Akt (Akt-DD) or PI-3f kinase in the mammary epithelium. To accomplish this goal we have generated transgenic mice that carry constyitutively activated forms of the Akt and PI-3f kinase under the transcriptional control of the mouse mammary tumor vims (MMTV) promoter/enhancer. To this end we thus far derived 11 independent transgenic lines carrying the MMTV/activated Akt strains and 4 independent lines expressing the MMTV/activated PI-3f kinase. Expression amalyses of these strainshas revealed that 3 of 11 MMTV/activated Akt mice express the activated Akt transgene in the mammary epithelium whereas we have not yet detected transgene expression in any of the MMTV/PI-3f kinase strains. Although expression of Akt-DD interferes with normal mammary gland involution, mammary tumors were not observed in these strains. To explore the potential role of Akt in mammary tumor progression, mice co-expressing AktnDD and a mutant form of Polyomavirus middle T (PyV mT) antigen de-coupled from PI3KIAkt signaling pathways were generated. Co- expression of Akt-DD with mutant PyV mT resulted in dramatic acceleration of mammary tumorigenesis. This acceleration was further correlated with reduced apoptotic cell death in mammary epithelium expressing the mutant form of PyV mT. Taken together these observations indicate that activation of Akt can contribute to tumoc, Original contains color plates: All DTIC reproductions will be in black and white.

The objectives of this study are to develop i) computer-based versions of the Decision Boards for (a) surgical treatment of breast cancer; (b)chemotherapy for node-negative breast cancer, and (c) chemotherapy for premenopausal node-positive breast cancer; and ii) to compare the relative effectiveness of the computer-based versions with standard Decision Boards for women with early breast cancer. In our second year, after extensive revisions, field testing was conducted on the revised standard node positive chemotherapy Decision Board. Prototypes of the computer-based chemotherapy boards were developed and are being field tested. Field testing of the computer-based version of the surgery Decision Board has demonstrated that the instrument is easy for the patient to understand, easy for the surgeon to use and acceptable to both. The randomized controlled trial of the instruments will begin early in the new year., Original contains color plates: All DTIC reproductions will be in black and white.

The research objective outlined in the original proposal was to determine the role of the integrin-linked kinase (ILK) in the induction and progression of metastatic mammary tumors. This work was initially based on the observation that overexpression of ILK in cultured epithelial cells results in changes characteristic of oncogenic transformation (Hannigan et al, 1996; Novak et al., 1998; Radeva et al., 1997; Wu et al., 1998). In order to evaluate the oncogenic potential of ILK in the mammary gland, we derived transgenic mice that express ILK under the transcriptional control of the MMTV promoter. The appearance of focal mammary tumors in these MMTV/ILK mice confirms that mammary-specific expression of ILK can facilitate malignant transformation in vivo. A second major objective was to determine the role of ILK in tumor progression by ablating its function. For this purpose, we established transgenic mice expressing a kinase-dead allele of ILK in the mammary epithelium. We are currently breeding these mice with our MMTV/erbB-2 strains to assess the importance of ILK in erbB-2-mediated mammary tumorigenesis and metastasis. This last experiment is particularly relevant to the understanding and treatment of human breast cancer, given the known importance of erbB-2 in the progression of this disease.

Hypoxia is a constant threat throughout life. The International Hypoxia Symposia brings together international experts from many different fields, with clinicians, clinical researchers and basic scientists present to discuss the state-of-the-art regarding normal and abnormal (pathophysiological) responses to hypoxia. Representatives from 27 countries joined together for four days of intense presentations, interspersed with superb skiing on nearby Marmot Mountain. At the end of the millennium, many of the papers contained herein mentioned the frontiers yet to be explored in human and animal responses to hypoxia., Proceedings