Encumbered and Traditional Anthropometry of Law Enforcement Officers for Vehicle Workspace and Protective Equipment Design.

OBJECTIVES: This study investigated anthropometric changes of national law enforcement officers (LEOs) in 46 years, compared the differences between LEO data and civilian anthropometry, and identified the magnitude of differences in dimensions measured with gear versus semi-nude measurements. BACKGROUND: The best available 46-year-old anthropometric dataset of LEOs has largely become outdated due to demographic changes. Additionally, anthropometric data of female LEOs and LEO measurements with gear are lacking. METHOD: Thirty-four traditional body dimensions and 15 with gear measurements of 756 male and 218 female LEOs were collected through a stratified national survey using a data collection trailer that traveled across the U.S. and the data were compared to the LEO anthropometric data from 1975 and existing civilian anthropometric databases. RESULTS: LEO body size and shape have evolved over the past 46 years - an increase of 12.2 kg in body weight, 90 mm in chest circumference, and 120 mm in waist circumference for men. No previous data was available for comparison for females. Compared to civilians, both male and female LEOs have a larger upper body build. LEO gear added 91 mm in waist breadth for men and 120 mm for women, and 11 kg in weight for men and 9 kg for women. CONCLUSION: The study reveals that equipment design based on the existing civilian datasets or 46-year-old LEO dataset would not accommodate the current LEO population. The new data fill this gap. Application: The differences reported above are important for LEO body gear, vehicle console, and vehicle ingress/egress design.

The human papillomavirus E6 oncogene dysregulates the cell cycle and contributes to cervical carcinogenesis through two independent activities.

Cervical cancer is a leading cause of death due to cancer among women worldwide. Using transgenic mice to dissect the contributions of the human papillomavirus (HPV) 16 E6 and E7 oncogenes in cervical cancer, E7 was identified previously to be the dominant oncogene. Specifically, when treated with exogenous estrogen for 6 months, E7 transgenic mice developed cancer throughout the reproductive tract, but E6 transgenic mice did not. E6 contributed to carcinogenesis of the reproductive tract, as E6/E7 double transgenic mice treated for 6 months with estrogen developed larger cancers than E7 transgenic mice. In the current study, we investigated whether the E6 oncogene alone could cooperate with estrogen to induce cervical cancer after an extended estrogen treatment period of 9 months. We found that the E6 oncogene synergizes with estrogen to induce cervical cancer after 9 months, indicating that E6 has a weaker but detectable oncogenic potential in the reproductive tract compared with the E7 oncogene. Using transgenic mice that express mutant forms of HPV16 E6, we determined that the interactions of E6 with cellular alpha-helix and PDZ partners correlate with its ability to induce cervical carcinogenesis. In analyzing the tumors arising in E6 transgenic mice, we learned that E6 induces expression of the E2F-responsive genes, Mcm7 and cyclin E, in the absence of the E7 oncogene. E6 also prevented the expression of p16 in tumors of the reproductive tract through a mechanism mediated by the interaction of E6 with alpha-helix partners.

Comparative analysis of cervical cancer in women and in a human papillomavirus-transgenic mouse model: identification of minichromosome maintenance protein 7 as an informative biomarker for human cervical cancer.

Human papillomaviruses (HPVs), such as HPV-16, are associated with >99% of cervical cancers in women. Two viral oncogenes, E6 and E7, are selectively expressed in these cancers. K14E6 and K14E7 transgenic mouse strains, which express the HPV16 E6 or E7 gene in stratified squamous epithelia, display many acute and long-term phenotypes indicative of the oncogenic potential of E6 and E7 including epithelial hyperplasia, abrogation of normal DNA damage responses, and spontaneous skin tumors. When treated with estrogen, these HPV-16 transgenic mice develop a progressive disease leading to cervical cancer that shows many histopathological parallels to cervical cancer in women. In this study, we evaluated the cervical lesions that arise in these transgenic mice for the expression of biomarkers induced in human cervical cancer. These analyses, which showed close parallels in the timing and pattern of expression of cyclin E and Ki-67 in the mouse cervical disease compared with that in humans, provided further validation of this HPV-16 transgenic mouse model for human cervical cancer. We then used our mouse model to identify minichromosome maintenance protein 7 (MCM7), an E2F-induced cellular DNA replication factor, as a novel biomarker for cervical cancer. In both the mouse and human disease, strong, full thickness staining for MCM7 was seen selectively in the epithelium of high-grade intraepithelial lesions and in frank cancer. The uniform staining pattern and strong signal for MCM7 suggest that MCM7 may be a highly informative biomarker for cervical cancer.

Dissection of human papillomavirus E6 and E7 function in transgenic mouse models of cervical carcinogenesis.

Human cervix cancer is caused by high-risk human papillomaviruses encoding E6 and E7 oncoproteins, each of which alter function of distinct targets regulating the cell cycle, apoptosis, and differentiation. Here we determined the molecular contribution of E6 or E7 to neoplastic progression and malignant growth in a transgenic mouse model of cervical carcinogenesis. E7 increased proliferation and centrosome copy number, and produced progression to multifocal microinvasive cervical cancers. E6 elevated centrosome copy number and eliminated detectable p53 protein, but did not produce neoplasia or cancer. E6 plus E7 additionally elevated centrosome copy number and created large, extensively invasive cancers. Centrosome copy number increases and p53 loss likely contributed to malignant growth; however, dysregulated proliferation and differentiation were required for carcinogenic progression.

Vulnerable elderly patients and overactive bladder syndrome.

Overactive bladder (OAB) prevalence increases with age, and the elderly population is rapidly increasing worldwide, particularly those aged >or=75 years. OAB symptoms may be associated with co-morbid conditions, particularly bowel symptoms and falls related to nighttime lavatory trips, as well as with higher rates of mortality in elderly persons. Physical changes associated with age that result in altered bladder function and altered drug solubility, metabolism and clearance, as well as increased polypharmacy, may impact disease management in elderly patients. Clinical trial data indicate that current treatments for OAB are generally effective and well tolerated in elderly patients. However, clinical trial participants have generally been relatively healthy persons aged >or=65 years, which may not reflect the true elderly population. Limited data exist that are specific to the vulnerable elderly, who have been defined as patients aged >or=65 years who are at increased risk of functional decline or death over a 2-year period. Identification and treatment of vulnerable elderly patients with OAB is important, because intervention may limit functional deterioration. Antimuscarinics are associated with improvement in OAB symptoms and health-related quality of life in older patients, although adverse effects such as constipation may be of particular concern in vulnerable elderly patients. Additional research is needed on the potential impact of antimuscarinics on cognition in vulnerable elderly persons. Behavioural interventions, including biofeedback, prompted voiding and pelvic floor muscle exercises, may be effective in some elderly patients without risk of adverse events, and they may enhance the efficacy of antimuscarinic treatment. The International Consultation on Incontinence has recommended behavioural interventions with the cautious addition and trial of antimuscarinic drugs for the treatment of urinary incontinence in frail elderly individuals or those already in a state of decline; these recommendations may also be useful for vulnerable individuals. Greater representation of vulnerable elderly individuals in clinical trials, the development and inclusion of outcomes relevant to this population, and the creation and testing of validated, evidence-based models to guide treatment decisions in vulnerable elderly individuals are needed.

Human papillomavirus E7 oncoprotein overrides the tumor suppressor activity of p21Cip1 in cervical carcinogenesis.

The E7 oncoprotein of the high-risk human papillomaviruses (HPV) is thought to contribute to cervical carcinogenesis at least in part by abrogating cell cycle regulation. E7 can dysregulate the cell cycle through its interaction with several cellular proteins including the retinoblastoma suppressor protein pRb, as well as the cyclin-dependent kinase inhibitor p21(Cip1). Inactivation of pRb in cervical epithelia is not sufficient to explain the ability of E7 to cause cervical cancers in transgenic mice. In the current study, we focused on the role of p21(Cip1) in cervical cancer. Cervical disease was significantly increased in p21(-/-) mice compared with p21(+/+) mice, showing that p21(Cip1) can function as a tumor suppressor in this tissue. Importantly, the ability of E7 to induce cervical cancers was not significantly enhanced on the p21-null background, consistent with the hypothesis that the ability of E7 to inhibit p21(Cip1) contributes to its carcinogenic properties. Further supportive of this hypothesis, cervical carcinogenesis in mice expressing a mutant form of HPV-16 E7, E7(CVQ), which fails to inactivate p21(Cip1), was significantly reduced compared with that in K14E7(WT) mice expressing wild-type HPV-16 E7. However, K14E7(CVQ) mice still displayed heightened levels of cervical carcinogenesis compared with that in nontransgenic mice, indicating that activities of E7 besides its capacity to inactivate p21(Cip1) also contribute to cervical carcinogenesis. Taken together, we conclude that p21(Cip1) functions as a tumor suppressor in cervical carcinogenesis and that p21(Cip1) inactivation by HPV-16 E7 partially contributes to the contribution of E7 to cervical carcinogenesis.

Induction of ovarian leiomyosarcomas in mice by conditional inactivation of Brca1 and p53.

BACKGROUND: Approximately one out of every ten cases of epithelial ovarian cancer (EOC) is inherited. The majority of inherited cases of EOC result from mutations in the breast cancer associated gene 1 (BRCA1). In addition to mutation of BRCA1, mutation of the p53 gene is often found in patients with inherited breast and ovarian cancer syndrome. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the role of loss of function of BRCA1 and p53 in ovarian cancer development using mouse models with conditionally expressed alleles of Brca1 and/or p53. Our results show that ovary-specific Cre-recombinase-mediated conditional inactivation of both Brca1(LoxP/LoxP) and p53(LoxP/LoxP) resulted in ovarian or reproductive tract tumor formation in 54% of mice, whereas conditional inactivation of either allele alone infrequently resulted in tumors (< or =5% of mice). In mice with conditionally inactivated Brca1(LoxP/LoxP) and p53(LoxP/LoxP), ovarian tumors arose after long latency with the majority exhibiting histological features consistent with high grade leiomyosarcomas lacking expression of epithelial, follicular or lymphocyte markers. In addition, tumors with conditional inactivation of both Brca1(LoxP/LoxP) and p53(LoxP/LoxP) exhibited greater genomic instability compared to an ovarian tumor with inactivation of only p53(LoxP/LoxP). CONCLUSIONS/SIGNIFICANCE: Although conditional inactivation of both Brca1 and p53 results in ovarian tumorigenesis, our results suggest that additional genetic alterations or alternative methods for targeting epithelial cells of the ovary or fallopian tube for conditional inactivation of Brca1 and p53 are required for the development of a mouse model of Brca1-associated inherited EOC.

Cyclin G2 is a centrosome-associated nucleocytoplasmic shuttling protein that influences microtubule stability and induces a p53-dependent cell cycle arrest.

Cyclin G2 is an atypical cyclin that associates with active protein phosphatase 2A. Cyclin G2 gene expression correlates with cell cycle inhibition; it is significantly upregulated in response to DNA damage and diverse growth inhibitory stimuli, but repressed by mitogenic signals. Ectopic expression of cyclin G2 promotes cell cycle arrest, cyclin dependent kinase 2 inhibition and the formation of aberrant nuclei [Bennin, D. A., Don, A. S., Brake, T., McKenzie, J. L., Rosenbaum, H., Ortiz, L., DePaoli-Roach, A. A., and Horne, M. C. (2002). Cyclin G2 associates with protein phosphatase 2A catalytic and regulatory B' subunits in active complexes and induces nuclear aberrations and a G(1)/S-phase cell cycle arrest. J Biol Chem 277, 27449-67]. Here we report that endogenous cyclin G2 copurifies with centrosomes and microtubules (MT) and that ectopic G2 expression alters microtubule stability. We find exogenous and endogenous cyclin G2 present at microtubule organizing centers (MTOCs) where it colocalizes with centrosomal markers in a variety of cell lines. We previously reported that cyclin G2 forms complexes with active protein phosphatase 2A (PP2A) and colocalizes with PP2A in a detergent-resistant compartment. We now show that cyclin G2 and PP2A colocalize at MTOCs in transfected cells and that the endogenous proteins copurify with isolated centrosomes. Displacement of the endogenous centrosomal scaffolding protein AKAP450 that anchors PP2A at the centrosome resulted in the depletion of centrosomal cyclin G2. We find that ectopic expression of cyclin G2 induces microtubule bundling and resistance to depolymerization, inhibition of polymer regrowth from MTOCs and a p53-dependent cell cycle arrest. Furthermore, we determined that a 100 amino acid carboxy-terminal region of cyclin G2 is sufficient to both direct GFP localization to centrosomes and induce cell cycle inhibition. Colocalization of endogenous cyclin G2 with only one of two GFP-centrin-tagged centrioles, the mature centriole present at microtubule foci, indicates that cyclin G2 resides primarily on the mother centriole. Copurification of cyclin G2 and PP2A subunits with microtubules and centrosomes, together with the effects of ectopic cyclin G2 on cell cycle progression, nuclear morphology and microtubule growth and stability, suggests that cyclin G2 may modulate the cell cycle and cellular division processes through modulation of PP2A and centrosomal associated activities.

Estrogen contributes to the onset, persistence, and malignant progression of cervical cancer in a human papillomavirus-transgenic mouse model.

Cervical cancer is a leading cause of death by cancer among women worldwide. High-risk human papillomaviruses (HPVs) are the major etiological agents for cervical cancer, but other factors likely contribute to cervical cancer, because these cancers commonly arise decades after initial exposure to HPV. Estrogen is thought to be one such cofactor; however, its temporal requirements in human cervical cancer are not known. Here we evaluate the temporal requirements of estrogen in cervical carcinogenesis in a mouse model for HPV-associated cervical cancer. Tumors arising in HPV16 transgenic mice treated with estrogen for 9 months were greatly increased in their size compared with tumors developing after 6 months of estrogen treatment. HPV16 transgenic mice treated 6 months with estrogen followed by 3 months without exogenous estrogen had significantly fewer tumors and the tumors were smaller and less aggressive than those arising in mice treated the full 9 months. Importantly, cervical cancers that arose in the mice treated the first 6 of 9 months with estrogen must have regressed, based upon the reduced incidence of cancers in these mice compared with those treated for 6 months with estrogen, then immediately analyzed. We conclude that estrogen plays a critical role not only in the genesis of cervical cancer but also in its persistence and continued development in this mouse model. These findings raise the clinically relevant possibility that, if human cervical cancer has a similar dependence on estrogen for continued tumor growth, then antiestrogen therapy may be effective in the treatment of cervical cancer.

Cyclin G2 associates with protein phosphatase 2A catalytic and regulatory B' subunits in active complexes and induces nuclear aberrations and a G1/S phase cell cycle arrest.

Cyclin G2, together with cyclin G1 and cyclin I, defines a novel cyclin family expressed in terminally differentiated tissues including brain and muscle. Cyclin G2 expression is up-regulated as cells undergo cell cycle arrest or apoptosis in response to inhibitory stimuli independent of p53 (Horne, M., Donaldson, K., Goolsby, G., Tran, D., Mulheisen, M., Hell, J. and Wahl, A. (1997) J. Biol. Chem. 272, 12650-12661). We tested the hypothesis that cyclin G2 may be a negative regulator of cell cycle progression and found that ectopic expression of cyclin G2 induces the formation of aberrant nuclei and cell cycle arrest in HEK293 and Chinese hamster ovary cells. Cyclin G2 is primarily partitioned to a detergent-resistant compartment, suggesting an association with cytoskeletal elements. We determined that cyclin G2 and its homolog cyclin G1 directly interact with the catalytic subunit of protein phosphatase 2A (PP2A). An okadaic acid-sensitive (<2 nm) phosphatase activity coprecipitates with endogenous and ectopic cyclin G2. We found that cyclin G2 also associates with various PP2A B' regulatory subunits, as previously shown for cyclin G1. The PP2A/A subunit is not detectable in cyclin G2-PP2A-B'-C complexes. Notably, cyclin G2 colocalizes with both PP2A/C and B' subunits in detergent-resistant cellular compartments, suggesting that these complexes form in living cells. The ability of cyclin G2 to inhibit cell cycle progression correlates with its ability to bind PP2A/B' and C subunits. Together, our findings suggest that cyclin G2-PP2A complexes inhibit cell cycle progression.