A study of factors regulating the autonomous proliferation of the steroid hormone-induced LJ6195 murine reproductive tract tumor

Neonatal estrogen treatment of BALB/c mice results in the unregulated proliferation of the cervicovaginal epithelium and eventually tumorigenesis. The conversion of the normally estrogen responsive cyclic proliferation of the vaginal epithelium to a continuous estrogen-independent pattern of growth is a complex phenomenon. The aim of this study was to gain an understanding of the mechanism(s) by which steroid hormone administration during a critical period of development alters the cyclic proliferation of vaginal epithelium, ultimately leading to carcinogenesis in the adult animal.^ The LJ6195 murine cervicovaginal tumor was induced by treating newborn female BALB/c mice with 20 $\mu$g 17$\beta$-estradiol plus 100 $\mu$g progesterone for the first 5 days after birth. In contrast to proliferation of the normal vaginal epithelium, proliferation of LJ6195 is not regulated by estradiol. Northern blot analysis of RNA from vaginal tracts of normal mice, neonatal-estrogen treated mice, and LJ6195 indicate that there is an alteration in the expression of several genes such as the estrogen receptor, c-fos, and HER2/neu. In response to neonatal estrogen treatment, the estrogen receptor is down regulated in the murine vaginal tract. Therefore, the estrogen-independent nature of this tissue is established as early as 3 months after treatment. There is strong evidence that the proliferation of LJ6195 is regulated through an autocrine growth pathway. The LJ6195 tumor expresses mRNA for the epidermal growth factor receptor. In addition, conditioned medium from the LJ6195 tumor cell line contains a growth factor(s) with epidermal growth factor-like activity. Conditioned medium from the LJ6195 cell line stimulated the proliferation of the EGF-dependent COMMA D mouse mammary gland cell line in a dose-dependent manner. The addition of an anti-mEGF-antibody to LJ6195 cell cultures significantly decreased growth. These results suggest that the EGF-receptor mediated growth pathway may play a role in regulating the estrogen-independent proliferation of the LJ6195 tumor. ^

Breast cancer risk with aromatase inhibition and phytoestrogen-free diet

In this thesis a mouse model was used to examine the effect of pubertal estrogen inhibition and a phytoestrogen-free diet on the development of mammary glands. The study question was does treatment with aromatase inhibitor during puberty increase susceptibility to breast cancer among cohorts that consumed a diet free of phytoestrogens. The study design consisted of a cohort of mice treated with aromatase inhibitor, letrozole, during puberty and a vehicular group that was used as a control. Both groups were fed a diet free of phytoestrogens from the time of weaning until sacrifice during adulthood. The study aimed to assess mammary gland development in terms of breast cancer risk. The methods employed in this research included morphological and histological analysis of mammary glands, as well as estradiol, RNA and protein analysis. The main finding of the study was that mice exposed to aromatase inhibitor during puberty developed mammary glands with specific characteristics suggestive of vulnerability to oncogenesis such as increased lateral branching, increased number of glands, increase ductal hyperplasia, and diminished expression of TGFβ and p27 protein levels. The conclusions suggest that puberty is a critical period in which the mammary gland is susceptible to environmental threats that may result in deleterious epigenetic effects leading to an increased breast cancer risk in adulthood. This study has several public health implications; the most significant is that environmental threats during puberty may result in adverse mammary gland development and that phytoestrogen sources in the diet are necessary for normal maturation of the mammary glands.^

Calcium-dependent mechanisms and long-term potentiation: Role of NMDA receptors, voltage -dependent calcium channels and persistent protein kinase activity

Long-term potentiation (LTP) is a rapidly induced and long lasting increase in synaptic strength and is the leading cellular model for learning and memory in the mammalian brain. LTP was first identified in the hippocampus, a structure implicated in memory formation. LTP induction is dependent on postsynaptic Ca2+ increases mediated by N-methyl-D-aspartate (NMDA) receptors. Activation of other postsynaptic routes of Ca2+ entry, such as voltage-dependent Ca2+ channels (VDCCs) have subsequently been shown to induce a long-lasting increase in synaptic strength. However, it is unknown if VDCC-induced LTP utilized similar cellular mechanisms as the classical NMDA receptor-dependent LTP and if these two forms of LTP display similar properties. This dissertation determines the similarities and differences in VDCC and NMDA receptor-dependent LTP in area CA1 of hippocampal slices and demonstrates that VDCCs and NMDA receptors activate similar cellular mechanisms, such as protein kinases, to induce LTP. However, VDCC and NMDA receptor activated LTP induction mechanisms are compartmentalized in the postsynaptic neuron, such that they do not interact. Consistent with activation properties of NMDA receptors and VDCCs, NMDA receptor and VDCC-dependent LTP have different induction properties. In contrast to NMDA-dependent LTP, VDCC-induced potentiation does not require evoked presynaptic stimulation or display input specificity. These results indicate that there are two different routes of postsynaptic Ca2+ which can induce LTP and the compartmentation of VDCCs and NMDA receptors and/or their resulting Ca2+ increases may account for the distinction between these LTP induction mechanisms.^ One of the molecular targets for postsynaptic Ca2+ that is required for the induction of LTP is protein kinases. Evidence for the role of protein kinase activity in LTP expression is either correlational or controversial. We have utilized a broad range and potent inhibitors of protein kinases to systematically examine the temporal requirement for protein kinases in the induction and expression of LTP. Our results indicate that there is a critical period of persistent protein kinase activity required for LTP induction activated by tetanic stimulation and extending until 20 min after HFS. In addition, our results suggest that protein kinase activity during and immediately after HFS is not sufficient for LTP induction. These results provide evidence for persistent and/or Ca2+ independent protein kinase activity involvement in LTP induction. ^

Critical indicators associated with negative performance in a selectively manned unit

Introduction. Selectively manned units have a long, international history, both military and civilian. Some examples include SWAT teams, firefighters, the FBI, the DEA, the CIA, and military Special Operations. These special duty operators are individuals who perform a highly skilled and dangerous job in a unique environment. A significant amount of money is spent by the Department of Defense (DoD) and other federal agencies to recruit, select, train, equip and support these operators. When a critical incident or significant life event occurs, that jeopardizes an operator's performance; there can be heavy losses in terms of training, time, money, and potentially, lives. In order to limit the number of critical incidents, selection processes have been developed over time to “select out” those individuals most likely to perform below desired performance standards under pressure or stress and to "select in" those with the "right stuff". This study is part of a larger program evaluation to assess markers that identify whether a person will fail under the stresses in a selectively manned unit. The primary question of the study is whether there are indicators in the selection process that signify potential negative performance at a later date. ^ Methods. The population being studied included applicants to a selectively manned DoD organization between 1993 and 2001 as part of a unit assessment and selection process (A&S). Approximately 1900 A&S records were included in the analysis. Over this nine year period, seventy-two individuals were determined to have had a critical incident. A critical incident can come in the form of problems with the law, personal, behavioral or family problems, integrity issues, and skills deficit. Of the seventy-two individuals, fifty-four of these had full assessment data and subsequent supervisor performance ratings which assessed how an individual performed while on the job. This group was compared across a variety of variables including demographics and psychometric testing with a group of 178 individuals who did not have a critical incident and had been determined to be good performers with positive ratings by their supervisors.^ Results. In approximately 2004, an online pre-screen survey was developed in the hopes of preselecting out those individuals with items that would potentially make them ineligible for selection to this organization. This survey has aided the organization to increase its selection rates and save resources in the process. (Patterson, Howard Smith, & Fisher, Unit Assessment and Selection Project, 2008) When the same prescreen was used on the critical incident individuals, it was found that over 60% of the individuals would have been flagged as unacceptable. This would have saved the organization valuable resources and heartache.^ There were some subtle demographic differences between the two groups (i.e. those with critical incidents were almost twice as likely to be divorced compared with the positive performers). Upon comparison of Psychometric testing several items were noted to be different. The two groups were similar when their IQ levels were compared using the Multidimensional Aptitude Battery (MAB). When looking at the Minnesota Multiphasic Personality Inventory (MMPI), there appeared to be a difference on the MMPI Social Introversion; the Critical Incidence group scored somewhat higher. When analysis was done, the number of MMPI Critical Items between the two groups was similar as well. When scores on the NEO Personality Inventory (NEO) were compared, the critical incident individuals tended to score higher on Openness and on its subscales (Ideas, Actions, and Feelings). There was a positive correlation between Total Neuroticism T Score and number of MMPI critical items.^ Conclusions. This study shows that the current pre-screening process is working and would have saved the organization significant resources. ^ If one was to develop a profile of a candidate who potentially could suffer a critical incident and subsequently jeopardize the unit, mission and the safety of the public they would look like the following: either divorced or never married, score high on the MMPI in Social Introversion, score low on MMPI with an "excessive" amount of MMPI critical items; and finally scores high on the NEO Openness and subscales Ideas, Feelings, and Actions.^ Based on the results gleaned from the analysis in this study there seems to be several factors, within psychometric testing, that when taken together, will aid the evaluators in selecting only the highest quality operators in order to save resources and to help protect the public from unfortunate critical incidents which may adversely affect our health and safety.^

Democracy in the healthcare workplace: A critical perspective

A review of existing literature revealed at least two distinct theoretical perspectives or schools of thought which are troubled by problems of the lack of participation in the workplace: Jurgen Habermas' ideal of communicative rationality (1984; 1987); and the field of workplace democracy. Whereas Habermas' ideal of communicative rationality establishes communication as necessary to attain a democratic workplace, the ideal of workplace democracy focuses on a participatory ideal in which conditions of open participation must be fulfilled in order to attain a democratic workplace. This study compared the strengths and weaknesses of the conditions proposed by Habermas with the strengths and weaknesses of the conditions selected to represent the workplace democracy ideal. Two incidents were selected for analysis which occurred within a period of one year within one large healthcare organization. The author was present as a participant-observer to assess these incidents. Each of the conditions for the ideal of communicative rationality and for the workplace democracy ideal was systematically applied to both incidents selected for analysis. The results of the analysis suggested that application of Habermas' theory provided more insight into potential distortions in communication than did the conditions selected to represent workplace democracy. Although the conditions of both models were frequently complementary and even overlapping at times, application of each theory to the same incident produced distinctly different results. ^