Search

Neck pain is pervasive problems in military population, especially in those working in vibrating environments. Previous studies show neck pain is strongly associated with degeneration of Intervertebral Disc (IVD), which is commonly caused by repetitive loading and aging. To reduce the risk of cervical spine disease, there is a need to measure the effect by helmet, equipment and seating. However, in-vivo displacement and loading condition of cervical spine are difficult to measure during operation. Clinical ultrasound (US) is being explored as a valuable tool to image motion of the cervical spine, specifically vertebral motion and intervertebral disc deformation. A dual US imaging system is being developed to measure 3D motion of contiguous cervical vertebrae and IVD strain ( height of IVD/original IVD height) of intervening functional spine units (FSU). This system was validated ex-vivo using cadaveric C-spines mounted in a servo-hydraulic material testing machine by comparing dynamic US measurement to direct measurements using a linear variable differential transformer (LVDT) system in our previous 2013-2014 annual progress report. In year 2014-2015, we further developed the performance of hardware/software of dual ultrasound system. The capability of dual US to measure C-spine properties in-vivo in simulation environment is currently being tested. Biomechanics finite element(FE) models were developed to examine how dynamic forces applied to the occipital-atlantal junction (i.e. C1) are transferred to the subaxial C-spine., The original document contains color images. Prepared in collaboration with the Medical College of Wisconsin, Milwaukee, WI.

During the Year-1 we characterized the role of RCP in ErbB2-driven breast cancer model. To directly evaluate the RCP in ErbB2 mammary tumorigenesis, we have derived transgenic mice that inducibly express RCP in the mammary epithelium and interbreed these mice with separate strain expressing an MMTV activated ErbB2 transgene. Induction of RCP expression in the ErbB2-driven model results in a tumor onset delay in addition to a drastic defect in metastasis formation. Furthermore, elevated RCP expression promotes a significant decrease in cell proliferation that is associated with a Senescence Associated to Heterochromatin Foci cellular senescence phenotype. In addition, using in vitro 3D-cell culture model of ErbB2 positive breast cancer, we showed that RCP is essential to the maintenance of adherens junctions by regulating E-cadherin endocytosis. Conversely depletion of RCP in ErbB2 positive cell lines leads to a significant increase in the number of lung metastases. Consistent with the importance of RCP as negative regulator of ErbB2 positive breast cancer progression, gene expression profile analysis of tumor banks of human breast tumors showed that the expression of RCP is inversely correlated with ErbB2 levels. Overall, ether, these observations argue that RCP acts as a tumor suppressor in ErbB2-driven breast cancer progression., The original document contains color images.

Advances in nutrition during the past century have helped untold numbers of people around the world enjoy healthier and longer lives and be more productive members of society. These advances include the identification of numerous essential nutrients, the identification of common disease states that can arise as a consequence of deficiencies of these essential nutrients, the use of food fortification to correct common deficiencies in the diet, and improvements in agricultural practices and food processing that have resulted in marked advances in food safety and quality. However, many challenges still remain. To a significant extent, these challenges reflect expectations of what constitutes a good diet and what the result of following food guidelines will produce. Moving forward in time in an era of limited economic resources and expanding populations, a critical focus is required to direct attention to the most pressing challenges with the greatest need and opportunity for return on investment. Balancing the desire for quick and effective solutions with the slow, steady, and incremental nature of nutrition research is a struggle confronting academia, industry, and government. To address these challenges, a group of distinguished nutrition scientists gathered for a panel symposium in celebration of the 10th anniversary of the Kosuna Distinguished Lecture in Nutrition at the University of California, Davis. Eight of the panelists were previous Kosuna Distinguished Lecturers. The symposium discussion revolved around 2 questions that were posed to the panel members prior to the meeting: (1) What will be the hottest areas of nutrition research in 2020 and (2) If one were just starting a career in nutrition, what would be a reasonable focus for one s work? A distillation of the discussion follows, organized from the most global to the most individual topics, with some concluding thoughts on the nature of nutrition research., Published in the Journal of the American College of Nutrition, 2014.

Falls and debilitating bone fractures are a major problem for veterans, and more than 40,000 veterans suffered hip fractures from 2000-2002. Falls are the main etiological factor in more than 90% of fractures, and so treatments that can improve muscle strength while at the same time increasing bone mass will significantly reduce fracture-related morbidity and mortality. Myostatin is a factor that induces muscle wasting and suppresses bone formation. Our data collected thus far demonstrate i) myostatin suppresses proliferation of aged, but not young, myoblasts, ii) myostatin is elevated with age in muscles composed primarily of slow-twitch fibers (e.g. soleus), and iii) myostatin increases muscle mass and muscle fiber size in aged mice. These findings suggest that myostatin inhibitors may have potential for suppressing muscle wasting and improving muscle repair in older individuals, but their effect on bone may be less significant., The original document contains color images.

Addressing specific objectives of the project we developed, constructed and implemented a cranium only blast injury apparatus (COBIA) for production of standardized and reliable rat model of dose dependent blast-TBI (bTBI) to study the direct transcranial effects of blast on the brain, independent of indirect transthoracic effects Detailed anatomical evaluation revealed that cranium only blast impacts brain-blood barrier transiently, immediately after the blast. Long term impact of the blast is manifested predominantly in the brain tissues at the density boundaries, with elevated markers of the neuroinflammation, neurodegeneration and neuronal cell death. COBIA bTBI resulted in the transient vestibulomotor abnormalities and long term spatial memory deficits. After COBIA bTBI Sur1 and TRPM4 RNA and protein up-regulation was detected as early 4 hours after the blast consistent with de-novo expression of the SUR1 regulated NCCa-ATP channel Studies (including GLP-compliant protocol) with chronic administration of the SUR1 antagonist showed that post-bTBI Glyburide does not alter blast-induced long term cognitive deficits but improves anxiety-like behavior. In contrast prophylactic treatment with Glyburide improved performance in spatial memory task related to the hippocampal function. Study on the human volunteers showed that Glyburide is safe drug to be used for potential prophylaxis against blast TBI., The original document contains color images.

The Breast Cancer Epidemiology in Puerto Rico project had two major goals: training researchers from a minority academic institution and developing the infrastructure to design and conduct a population based pilot study of breast cancer in Puerto Rico. All investigators from the University of Puerto Rico have acquired new expertise or have strengthened their skills thru weekly conference calls, formal academic training and direct involvement in study design, instruments, quality control processes, data analysis, presentations and manuscripts preparation. A population based case control study was designed to evaluate risk factors for breast cancer among Hispanic women living in the San Juan Metropolitan of Puerto Rico. Breast cancer cases were identified from the Puerto Rico Central Cancer Registry and patient lists from hospitals and physician offices in the Metropolitan San Juan Area. Of 1809 referrals of breast cancer cases, 442 met the eligibility criteria and 317 (72%) agreed to participate and complete the interview and clinical evaluation. Controls were selected from a probabilistic sample of women in the same age groups that lived in the same municipalities as the cases. During the recruitment 1,136 households were visited, 538 women were eligible and 348(65%) agreed to participate., The original document contains color images.

This thesis analyzes the effects of different enlistment age on the first-term attrition for U.S. Army, Navy, Air Force, and Marine Corps enlisted personnel with non-prior service and prior service that attrited between fiscal years of 1995 and 2013. Two separate probit models were used to analyze attrition behavior. The first model was formed to analyze the effect of age at entry on the first-term attrition for four forces. The second model focuses on the attrition based on the character disorder and analyzes the effect of different enlistment ages on this attrition. Both attrition models are conditional and analyzing attrition behavior for four terms at six months, between 6 and 12 months, between 12 and 24 months, and between 24 and 45 months. The independent variables for the two models types included demographic variables, such as Black, White, Hispanic, other race, and unknown; education level; different enlistment age dummies between 18 and 42; female or male; and AFQT Cat. Unemployment rates by states were included in the regressions. The study concluded that enlistment ages do significantly affect the attrition of enlisted personnel. This effect varies across different time periods the first six months, the second six months, the second year, and 45-months and different forces.

A cohort consisting of 127 American repatriated prisoners of war (RPWs) was studied in order to ascertain whether there were statistically significant correlations between Leukocyte Telomere Length (LTL) obtained from a commercially available LTL test and 47 clinical indicators of health, environmental stress and aging. Methods: Data was obtained from an annual examination of the RPW cohort. LTLs were determined by a commercial laboratory and compared to the results from common blood and urine tests, historical data related to incarceration length and solitary confinement, and qualitative health assessment tools. Analysis of descriptive statistical data, the construction of stepwise linear and logistic regression models and Fisher exact calculations were performed. Results: There is no apparent difference between the demographically homogenous RPW cohort s mean LTL (6.48 1.18 Kb) and the commercial laboratory s mean LTL [6.49 Kb (no SD available)] for its sample population of undisclosed demographics. Statistical analysis did not yield any significant correlations between LTL and the clinical data studied. Discussion: The negative statistical results of this study, coupled with the questionable quality of the commercial LTL data utilized, does not support our program s use of the publicly available LTL test studied in this work for monitoring repatriate health., Prepared in collaboration with the United States Army Aeromedical Research Laboratory, Ft. Rucker, AL.

The overall goal of the study was to develop a cell culture system from patient-derived induced pluripotent stem cells that expresses genes that can accelerate the aging process to facilitate modeling of neurodegenerative diseases such as Parkinson s disease. The objective of this study was to introduce the truncated lamin A gene, progerin, into patient-derived induced pluripotent stem cells using a doxycycline (Dox)-inducible expression system and differentiate them into dopaminergic neurons with the goal to accelerate the aging process of these cells and to promote a PD-related phenotype thus establishing a disease-in-a-dish model for PD. During our study, a publication from Lorenz Studer showed a very similar approach with lentiviral constructs of truncated lamin A in iPSC-differentiated neurons (Miller et al. 2013). It shows that our hypothesis is correct and that the introduction of mutant forms of lamin A that can cause Hutchinson Gilford Progeria syndrome is accelerating the neurodegenerative phenotype in vitro., The original document contains color images.

Studies to evaluate the interaction of the synthetic cannabinoid WIN55,212-2 (WIN2) and ionizing radiation have led to preliminary results implicating a novel site of action of WIN2 in the MCF-7 breast cancer model. In previous reports, WIN2 was found to stereoselectively inhibit the growth of breast cancer cells in a dose-dependent but cannabinoid receptor-independent mechanism. Experiments described in this report evaluated antiproliferative mechanisms of WIN2 treatment both alone and in combination with ionizing radiation (IR). Evaluation of autophagy, apoptosis and necrotic mechanism failed to indicate that WIN2 promoted death of the tumor cells. Autophagy was induced both for radiation alone, WIN2 alone and WIN2 + radiation, but did not appear to be involved in the antiproliferative mechanisms of either treatment. Senescence, quantified by β-galactosidase staining, and DNA damage, quantified by γH2AX formation, confirmed that radiation treatment induced senescent growth arrest both alone and in combination with WIN2; however, WIN2 was unable to alter the magnitude of senescent growth arrest induced by IR. Comparison of γH2AX levels at 1 and 24 h also showed that WIN2 did not alter the rate of DNA repair after radiation treatment. These data assessing cell death and senescence combined with additional temporal cell count studies indicated that WIN2 induces growth arrest but not cell death. It was further concluded that augmentation of IR induced antiproliferative effects by WIN2 occur from the parallel induction of both senescent and classical growth arrest responses in the breast tumor cells.

Summary: BDNF is a neurotrophin that enhances neural health and is increased by exercise. PURPOSE: To compare moderate continuous (MCE) and high-intensity interval exercise (HIE) effects on serum BDNF levels, and examine the relationship between BDNF and lactate. METHODS: Seven males completed a VO2peak test and two protocols on separate days, (MCE) 28 min at 60% Workrate max (WRmax) and (HIE) 28 min of intervals at 90%WRmax (10- 1 min intervals separated by 2 min of rest). Serum BDNF and lactate were determined prior, during, and following both protocols. RESULTS: BDNF levels (pg/mL) increased from baseline during HIE and MCE (p<.05). The BDNF response to HIE correlated with lactate for area under the curve (AUC) (r=0.901; P<0.05). CONCLUSION: HIE is an effective alternative to MCE at increasing BDNF. Additionally, lactate may act as a measure of intensity or a mediator of the BDNF response to exercise., 2014, Includes bibliography., Degree granted: Thesis (M.S.)--Florida Atlantic University, 2014., Collection: FAU Electronic Theses and Dissertations Collection

Anaemia is a problem that affects almost 10 % over 65 years and 20 % over 85 years. There is no physiological anaemia in the elderly. Any anaemia expresses the existence of a pathological process, regardless of its severity. Anaemia in the elderly is always associated with a poor prognosis that is in terms of mortality, morbidity and risk of fragility. The diagnostic approach to anemia in the elderly is the same as in younger individual. There are many causes of anaemia ;anaemia balance is a complex diagnostic process. Most anaemias are due to a deficiency, chronic inflammation or comorbidity. However, in the elderly, the etiology of anaemia is often multifactorial. In a number of cases remain unexplained anaemia. In a number of cases, anemia remain unexplained. Treatment of anaemia is the treatment of the cause, but specific therapeutic aspects to the elderly should be considered, as among other martial substitution or use of erythropoietin (EPO)., SCOPUS: ar.j, info:eu-repo/semantics/published

Modulation of the mu-alpha and mu-beta spontaneous rhythms reflects plastic neural changes within the primary sensorimotor cortex (SM1). Using magnetoencephalography (MEG), we investigated how aging modifies experience-induced plasticity after learning a motor sequence, looking at post- vs. pre-learning changes in the modulation of mu rhythms during the execution of simple hand movements. Fifteen young (18-30 years) and fourteen older (65-75 years) right-handed healthy participants performed auditory-cued key presses using all four left fingers simultaneously (Simple Movement task - SMT) during two separate sessions. Following both SMT sessions, they repeatedly practiced a 5-elements sequential finger-tapping task (FTT). Mu power calculated during SMT was averaged across 18 gradiometers covering the right sensorimotor region and compared before vs. after sequence learning in the alpha (9/10/11Hz) and the beta (18/20/22Hz) bands separately. Source power maps in the mu-alpha and mu-beta bands were localized using Dynamic Statistical Parametric Mapping (dSPM). The FTT sequence was performed faster at retest than at the end of the learning session, indicating an offline boost in performance. Analyses conducted on SMT sessions revealed enhanced rebound after learning in the right SM1, 3000-3500ms after the initiation of movement, in young as compared to older participants. Source reconstruction indicated that mu-beta is located in the precentral gyrus (motor processes) and mu-alpha is located in the postcentral gyrus (somatosensory processes) in both groups. The enhanced post-movement rebound in young subjects potentially reflects post-training plastic changes in SM1. Age-related decreases in post-training modulatory effects suggest reduced experience-dependent plasticity in the aging brain., JOURNAL ARTICLE, SCOPUS: ar.j, SCOPUS: ar.j, SCOPUS: ar.j, info:eu-repo/semantics/published

Prior work documented that surgical removal of approximately 70% of the bladder (subtotal cystectomy) in 12-week-old female rats induced complete functional regeneration of the bladder within 8 weeks. To determine whether animal age affects bladder regeneration, female F344 rats aged 12 weeks (young) and 12 months (old) underwent subtotal cystectomy, and then when evaluated from 1 to 26 weeks after subtotal cystectomy. Af 26 weeks after subtotal cystectomy, bladder capacity in young animals was indistinguishable from that in age-matched controls, but bladder capacity in old animals was approximately 56% of that in age-matched controls. There was no detectable difference in residual volume among treatment groups, but the diminished regeneration in old animals was associated with a corresponding increase in the ratio of residual volume to micturition volume. The majority of old animals exhibited evidence of chronic kidney damage after subtotal cystectomy. Maximal contraction of bladder strips to electric field stimulation, as well as activation with carbachol, phenylephrine, and KCI, were lower in old than in young animals at 26 weeks after subtotal cystectomy. Immunostaining with proliferating cell nuclear antigen and Von Willebrand factor revealed delayed and/or diminished proliferative and angiogenic responses, respectively, in old animals. These results confirm prior work and suggest that multiple mechanisms may contribute to an age-related decline in regenerative capacity of the bladder., Published in the American Journal of Pathology, v183 n5 p1585-1595, November 2013.

Background: iPS reprogramming to model 'disease-in-a-dish has become an attractive approach to study disease mechanisms. However, a frank pathophysiological phenotype in iPSC-derived PD neurons remains to be shown. Objective/Hypothesis: The objective of this proposal is to accelerate the aging process of iPS-derived dopaminergic neurons with the goal of reproducing a Parkinson s disease (PD) specific phenotype in vitro. Specific Aim 1. To generate vector constructs and to establish Dox-inducible iPSC lines that express the Hutchinson-Gilford progeria (HGPS) gene (mutant lamin A with an in-frame loss of 150 nucleotides) and differentiate them into dopaminergic neurons. Deliverable of this aim is the introduction of mutant lamin A in iPSC lines and optimization of inducible expression of mutant lamin A in iPSCs and during the differentiation into dopaminergic neurons. Specific Aim 2. To test whether iPSC-derived dopaminergic neurons transduced with mutant lamin A show changes in age-regulated genes at the mRNA and protein levels at different time-points during differentiation, thus exhibiting an accelerated aging. Deliverable of this aim is the assessment of specific age-related aging pattern of gene and protein expression in induced mutant lamin A modified iPSC-derived neurons. Specific Aim 3. To test whether induced mutant lamin A cell lines differentiated into dopaminergic neurons exhibit hallmark pathology of PD, such as protein aggregation of alpha-synuclein, posttranslational modification, and signs of mitochondrial pathology. Deliverable of this aim is the assessment of the pathological PD-related phenotype in induced mutant lamin A modified iPSC-derived neurons., The original document contains color images.

Using an adult rat model of blast wave exposure, we rigorously characterized the cellular and functional damage to the eyes (retinas) and brain visual processing centers, by electroretinography (ERG), visual discrimination behavioral testing, and histopathology. Blast wave injury was carried out by placing the rats in a compressed air driven shock tube and exposing them, in a right side on orientation, once to a 20 psi (260 Hz) blast over pressure wave. Rats were assessed at baseline and then 1, 7, and 14 days post-exposure. By 7 to 14 days out, blasted rats versus shams showed significantly decreased ERG waveform amplitudes for the right side eyes ( 30% less; n = 15 vs.14), a trend for impaired ability to visually discern a cue light to earn food rewards ( 30% less; n = 10 vs. 11), and significant neuronal cell degeneration within the right side retinas and both brain optic tracts (2 and 3-fold more, respectively; n = 11 vs. 11). ERG and histopathology results significantly correlated with each other (r = - 0.7). There also was a strong relationship between the retina and brain optic tract cell damage (r = 0.8). Overall, our findings demonstrate that blast wave exposure leads to loss of vision in rats, likely through retinal cell death followed by anterograde degeneration of brain visual processing centers from lack of signaling input., The original document contains color images.

Prostate tumor-initiating cells (TICs) have intrinsic resistance to current therapies. BMI-1 (B-cell-specific MMLV insertion site-1) regulates stem cell self-renewal, and is over-expressed in TICs. We developed a combined immunophenotypic and time-ofadherence assay to identify human prostate TICs with increased BMI-1 expression. Tumor initiation and dissemination were consistently observed in the immune-permissive zebrafish microenvironment from collagen-adherent 2 1hi/CD44hi cells. Utilizing the zebrafish xenograft model, we identified the first known translational inhibitors of BMI-1 that target prostate TICs. BMI-1 inhibitors induced prostate cancer cell senescence, and G1 cell cycle arrest. Targeting of BMI-1 significantly reduced clonogenic, migration, and invasion abilities of TICs, and increased cellular senescence. Treatment of zebrafish and mouse xenografts with BMI-1 inhibitor reduced the metastatic potential of zebrafish TIC-derived xenografts, and inhibited tumor growth in mouse xenografts, respectively. Therefore, we have accomplished our first year s goal to demonstrate the beneficial effects of targeting prostate TICs with BMI-1 inhibitors. The next phase of studies will examine BMI-1 targeted therapy in combination with Taxotere and other recently approved therapies. These studies will allow us to accomplish the goals of this synergistic award between three laboratories (Sabaawy, Bertino, and Kim) to develop a therapeutic strategy for BMI-1 inhibitors in prostate cancer., The original document contains color images.

Current osteoporosis therapies are able to treat the symptoms of osteoporosis, however little progress has been made toward understanding and addressing the underlying mechanisms contributing to age-related bone loss, or the ability to adapt to mechanical loading (exercise). Degeneration in peripheral nerve function with age may be one of these mechanisms, as neuropeptides affect the function of osteoblasts and osteoclasts in vitro, and nerve deactivation causes bone loss in vivo. This research investigates mechanisms by which peripheral sensory nerves influence bone maintenance and mechanotransduction using capsaicin-injected mice as a model of decreased peripheral sensory nerve function. We hypothesize that decreased sensory nerve function will result in increased functional adaptation of bone. In Aim 1 we investigated the relationship between peripheral sensory nerve function and bone structure. We found that capsaicin treatment resulted in a small but statistically significant decrease in trabecular and cortical bone structure. In Aim 2 we will determine the bone adaptation response of capsaicin- and vehicle-treated mice to increased mechanical loading. We hypothesize that capsaicin-treated mice will have an increased bone adaptation response to mechanical loading. The proposed research will establish the role of peripheral sensory nerves in age-related decreases in bone s ability to adapt to exercise. These studies may lead to novel therapies aimed at preserving healthy bone turnover with age. This research will be the basis for future studies investigating the interaction of peripheral nerves and bone, and peripheral nerve function as a potential mechanism of age-related bone loss., The original document contains color images.

Prostate tumor-initiating cells (TICs) have intrinsic resistance to current therapies. BMI-1 (B-cell-specific MMLV insertion site-1) regulates stem cell self-renewal, and is over-expressed in TICs. We developed a combined immunophenotypic and time-ofadherence assay to identify human prostate TICs with increased BMI-1 expression. Tumor initiation and dissemination were consistently observed in the immune-permissive zebrafish microenvironment from collagen-adherent 2 1hi/CD44hi cells. Utilizing the zebrafish xenograft model, we identified the first known translational inhibitors of BMI-1 that target prostate TICs. BMI-1 inhibitors induced prostate cancer cell senescence, and G1 cell cycle arrest. Targeting of BMI-1 significantly reduced clonogenic, migration, and invasion abilities of TICs, and increased cellular senescence. Treatment of zebrafish and mouse xenografts with BMI-1 inhibitor reduced the metastatic potential of zebrafish TIC-derived xenografts, and inhibited tumor growth in mouse xenografts, respectively. Therefore, we have accomplished our first year s goal to demonstrate the beneficial effects of targeting prostate TICs with BMI-1 inhibitors. The next phase of studies will examine BMI-1 targeted therapy in combination with Taxotere and other recently approved therapies. These studies will allow us to accomplish the goals of this synergistic award between three laboratories (Sabaawy, Bertino, and Kim) to develop a therapeutic strategy for BMI-1 inhibitors in prostate cancer., The original document contains color images.

Bone is the most common metastatic site for prostate cancer which affects approximately 70% of patients with advanced disease. Despite this clinical importance, the exact molecular mechanism of the bone-specific metastasis has not been clearly defined. The growth of the tumor cells in the bone is generally slow and they often become dormant until an appropriate microenviroment is established for their re-growth. According to the recent cancer stem cell theory, which still remains a hypotheses, recurrent tumor must arise from a dormant tumor stem cell. However, the precise mechanism of dormancy is virtually unknown, and identifying the responsible factors and understanding the underlining mechanism are crucial for developing a novel therapeutic approach. Our recent preliminary data suggest that BMP7 (bone morphogenetic protein 7) which is secreted from bone stromal cells is able to induce senescence to prostate tumor cells and that this induction is mediated by activation of the tumor metastasis suppressor gene, NDRG1 (N-myc downstream regulated gene 1). Therefore, we hypothesize that a prostatic tumor stem cell becomes dormant in the bone through the BMP7-mediated activation of p38 and NDRG1., The original document contains color images.

Individuals exposed to traumatic brain injury (TBI) are at a greatly increased risk for developing a number of neurodegenerative diseases including Alzheimer s disease (AD). TBI promotes the development of the pathological hallmarks of AD including production and extracellular deposition of the beta -amyloid peptide in senile plaques and intracellular aggregation of hyperphosphorylated, microtubule-associated protein tau (MAPT) in neurofibrillary tangles (NFTs). Several lines of evidence suggest that altered monocyte infiltration and microglial activation may be directly involved in the pathogenesis of both beta-amyloid and MAPT pathologies. The primary hypothesis to be tested in the current studies is that TBI induces infiltration of peripheral monocytes as well as acute and local activation of brain microglia within the injured brain and that these two cell types play roles distinct from each other in inducing both beta-amyloid pathologies and MAPT phosphorylation and aggregation leading to chronic pathological conditions that pre-dispose individuals exposed to TBI to develop AD later in life. Here we report that TBI results in brain cavitation and a widespread neuroinflammatory response including microglial activation and monocyte infiltration. Interestingly, the acute macrophage response to TBI is reduced in a mouse model of amyloid pathology (R1.40) compared to control mice; however, long-term behavioral outcome and neurodegeneration are worse at chronic postinjury time points. By contrast, pilot data examining TBI in hTau mice revealed increased phosphorylation of tau within neurons as well as enhanced microglial activation including swollen cell bodies and thickened processes when compared to brain injured controls. Recent data suggests that the macrophage response is also enhanced in brain injured hTau mice at acute postinjury time points., The original document contains color images.

Anxiety is a normal reaction to stress; however, in individuals with anxiety disorder, the anxiety becomes chronic and exaggerated, and affects the physical and psychological health of the individual. Th e main types of anxiety disorders are generalized anxiety disorder, panic disorder, post-traumatic stress disorder (PTSD), phobias, and obsessive-compulsive disorder (OCD). Incident diagnoses of anxiety disorders among active component service members steadily increased from 2000 to 2012. A majority of incident anxiety disorder diagnoses were non-specific anxiety disorders (ICD-9-CM codes: 300.0, 300.00, or 300.09) and over 75 percent of service members diagnosed with non-specific anxiety disorders did not have a more specific anxiety disorder diagnosis during subsequent medical encounters. Incidence rates of anxiety disorders were highest among females, white, non-Hispanics, in the youngest age groups, and among recruits and junior enlisted service members. About one-third of anxiety disorder cases also had a co-occurring diagnosis of either adjustment or depressive disorder within one year before or aft er the incident anxiety disorder encounter., MSMR(Medical Surveillance Monthly rept. v20 n19, 2013e 20,Number 10. The original document contains color images.

How leukemia stem cells gained resistance to radiation and chemotherapy is poorly defined, yet critically determines how leukemia cells tolerate conventional leukemia therapy. Normal hematopoietic stem cells and leukemia initiating cells are known to share many functional properties. Therefore, they are supposed to utilize many common mechanistic pathways for their survival and migration. Using genetically engineered mice we demonstrated the functional roles of P2Y14 in preserving regenerative capacity by constraining senescence induction and molecular events governing it. Since P2Y14 is highly expressed in differentiation-resistant leukemia cells, P2Y14 expression in leukemia cells may also function in modulating the resistance to conventional cancer treatment. Our results strongly suggest that P2Y14/UDP-Glc axis plays an important role in stress-induced senescence and motility of HSPCs. As the expression of P2Y14 is preferentially high in drug-resistant leukemia cells, we anticipate that P2Y14/UDP-Glc axis governs the resistance and motility also in leukemia stem/progenitor cells.

Because aging can lower the fracture resistance of bone in ways that are independent of bone mass, the present project investigated the possibility that transforming growth factor (TGF)-Beta inhibition could improve multiple measurements of fracture resistance in growing, mature adult, and old rodents. TGF-Beta inhibition was achieved with a neutralizing antibody known as 1D11. When administered to growing mice for 4 weeks (13 to 17 weeks of age), 1D11 substantially increased trabecular bone volume fraction. Moreover, treatment-related improvements in trabecular architecture and tissue mineral density translated to stronger vertebral bodies. When administered to adult (6 months) and old rats (22 months) for 6 weeks, 1D11 did not have an appreciable effect on trabecular bone. As another example of differential effects of 1D11 between mice and rats, treatment increased the estimated material strength of cortical bone in mice while it increased the structural strength of cortical bone in old rats with no effects on bone in adult rats. In comparison to control antibody treatment, 1D11 also increased the fracture toughness of bone from growing mice and old rats. These effects appear to be independent of bone mass, and identifying the cause (e.g., changes in collagen crosslinking) is the next step., The original document contains color images.

Patients over the age of 65 are the fastest growing segment of the population, and it is estimated that it comprises 12.5% of the entire population in the developed countries. Advances in medicine, science and healthy lifestyles have promoted substantially increased lifespans, aswell as better quality of life with more physical activity. On the other hand, aging is associated with a variety of physiologic changes that affect orthopedic care. Due to natural involution processes older adults may not have the physiologic reserves necessary to promote healing or to prevent or recover fromcomplications. Degenerative diseases and injuries sustained from trauma in combination with physiologic changes and comorbidity in the aged pose a significant health problem in older adults and a major treatment challenge for an orthopaedic surgeon. This review summarizes some of these unique challenges in care for older orthopaedic patient.

Bone healing after fracture occurs in a well organized manner and involves a multitude of cell types, inflammatory cytokines, growth factors, prostaglandins, and certain vitamins. Some of the means by which alterations in these essential components affect bone repair are understood, whereas others still need to be delineated. Based on clinical experience and basic science research, certain clinical conditions have become associated with delays in bone repair after fracture. These conditions include chronic inflammation, diabetes, hypovitaminosis, aging, and polytrauma. This brief report reviews some of the ways by which these conditions have been shown to negatively influence bone repair., Published in the Journal of Orthopaedic Trauma, v26 n12 p708-711, Dec 2012.

The mRNA cap-binding protein eukaryotic initiation factor 4E (eIF4E) plays a key role in cancer progression. We have recently shown (Furic et al., 2010) that phosphorylation of eIF4E at Ser209 by the MNK family of kinases promotes prostate cancer progression in a mouse model bearing a tissue-specific conditional PTEN deletion in prostatic epithelia. eIF4E activity is regulated at two levels: phosphorylation of Ser209 and binding to a family of small eIF4E-binding proteins aptly termed 4EBPs. Binding of 4E-BPs to eIF4E precludes eIF4G binding thus preventing assembly of the eIF4F complex and recruitment of the ribosome to the messenger RNA. Our most recent data suggests that PTEN interacts genetically with 4E-BPs to induce cellular senescence in prostate cancer. In this report, we also begin to address the effects of simultaneous inhibition of MNK and mTORC1 activity in anchorage-independent prostate cancer cell lines. Our findings will hopefully yield important information for the design of effective therapeutic agents against human prostate cancer., The original document contains color images.

Ovarian cancer ranks first as the cause of death for gynecological cancers. Obviously, there is an urgent need to develop novel treatment methods for ovarian cancer. To do this, we must better understand key events associated with ovarian cancer development. In order to combat cancer, a normal cell's typical response to a tumor-promoting genetic alteration is irreversible growth arrest, consequently preventing the normal human cell from progressing towards becoming a cancer cell. This process is termed senescence. When this process fails, those cells containing tumor-promoting genetic alterations can grow without control and become a tumor. The potential use of cellular senescence for cancer therapy would rely on reactivation of this process in cancer cells. We have previously discovered a pathway that opposes the beneficial process of senescence. This pathway is referred to as the canonical Wnt signaling pathway. Therefore, we hypothesize that canonical Wnt signaling pathway contributes to the development of ovarian cancer through bypassing senescence. The proposed studies may lead to development of strategies for ovarian cancer treatment using reactivation of cellular senescence as a novel mechanism by targeting ovarian cancer promoting canonical Wnt signaling.

Prostate Cancer is the leading cancer diagnosed and the second leading cause of cancer death of men in the United States. The incidence of prostate cancer is closely associated with aging. Recent evidences suggested that the causes of cancer development are not limited to mutations within cancer cells, but also involve in alterations of cancer microenvironment. Senescent cells are irreversibly growth arrested, but remain metabolically active. Senescent cells, especially senescent fibroblasts in the stroma may provide a beneficial environment for tumor growth through secretion of certain factors. In our studies, we found that expression of insulin-like growth factor 1 (IGF-1) and secretory clusterin (sCLU) are increased in senescent fibroblasts, and increasing of sCLU expression in senescent fibroblasts is mediated through IGF-1 signaling pathway and regulated by ATM. Both IGF-1 and sCLU are known tumor promoting factors, and are closely associated with progression of various cancers. Increased IGF-1 signaling is reported to be a poor prognostic factor of breast cancer and overexpression of sCLU protects cells from various stressors induced apoptosis. Thus, we hypothesize that accumulation of senescent fibroblasts would lead to alterations in the microenvironment that could promote cancer growth and progression through secretion of IGF-1 and sCLU. To test this hypothesis, we established an in vivo co-culture mouse model by co-injection of cancer cells with young or senescent normal fibroblasts into mice prostate., The original document contains color images.

iPS reprogramming to model 'disease-in-a-dish has become an attractive approach to study disease mechanisms. However, a frank pathophysiological phenotype in iPSC-derived PD neurons remains to be shown. Objective/Hypothesis: The objective of this proposal is to accelerate the aging process of iPS-derived dopaminergic neurons with the goal of reproducing a Parkinson s disease (PD) specific phenotype in vitro. Specific Aim 1. To generate vector constructs and to establish Dox-inducible iPSC lines that express the Hutchinson-Gilford progeria (HGPS) gene (mutant lamin A with an inframe loss of 150 nucleotides) and differentiate them into dopaminergic neurons. Deliverable of this aim is the introduction of mutant lamin A in iPSC lines and optimization of inducible expression of mutant lamin A in iPSCs and during the differentiation into dopaminergic neurons. Specific Aim 2. To test whether iPSC-derived dopaminergic neurons transduced with mutant lamin A show changes in age-regulated genes at the mRNA and protein levels at different time-points during differentiation, thus exhibiting an accelerated aging. Deliverable of this aim is the assessment of specific age-related aging pattern of gene and protein expression in induced mutant lamin A modified iPSCderived neurons. Specific Aim 3. To test whether induced mutant lamin A cell lines differentiated into dopaminergic neurons exhibit hallmark pathology of PD, such as protein aggregation of alpha-synuclein, posttranslational modification, and signs of mitochondrial pathology. Deliverable of this aim is the assessment of the pathological PD-related phenotype in induced mutant lamin A modified iPSC-derived neurons. Study Design: This is an in vitro study of patient-specific iPSC-derived dopaminergic neurons in which truncated lamin A will be introduced to study cellular phenotypes under the hypothesis that cells under expression of lamin A will age faster than untreated cells., The original document contains color images.

Cerebral ischemia is a common secondary consequence of traumatic brain injury (TBI), including penetrating TBI. Experimental models of closed brain injury (fluid percussion, subdural hematoma, etc.) have demonstrated a neuroprotective effect after perfluorocarbon (PFC) administration, however, there is no data relating to a pharmacological effect of PFC in penetrating ballistic-like brain injury (PBBI;Tortella model) that is characterized by acute, sustained significant hypoxia. In this report we present data on the severity of hypoxia, glucose utilization, histopathology and oxygen metabolism( Vo2) following PBBI, and changes in these parameters following PFC administration in the PBBI model, as well as studies on effect of PFC on blood clotting of normal human blood. The data shows little effect of any of the 3 PFC s on the hypoxia observed in this type of brain injury. In the same PBBI injury model for the first time we observed no effect of PFC s upon VO2 (oxygen consumption) but the studies are incomplete. Surprisingly, the 2 PFc s so far tested significantly improved Glucose utilization (anaerobic glycolysis) but the studies are incomplete. The. We are currently further investigating the effects of PFC administration on this PBBI induced global glucose utilization. The Cell counting study aimed at uncovering any neuroprotective effects of PFC administration on PBBI induced neurodegeneration did not reveal significant global improvement, but the counts are incomplete. Interestingly the three PFCs tested had very different effects on the thromboelastography profile of normal human blood. Only Perftec demonstrated an apparent anticoagulant effect, using Thromboelastography. This data will be used to assess the safety/efficacy profile of each PFC, in the PTBI and closed TBI models. About 60% of experiments are complete, and data analysis is ongoing., The original document contains color images.

Bone is the most common metastatic site for prostate cancer. The growth of the tumor cells in the bone is generally slow and they often become dormant until an appropriate microenviroment is established for their re-growth. The recent stem cell theory predicts that the metastatic cells are a small population of stem-like cells in the primary tumor. However, the precise mechanism of dormancy is virtually unknown, and identifying the responsible factors and understanding their underlining mechanism are crucial for developing a novel therapeutic approach. Our preliminary data indicate that (i) bone morphogenetic protein 7 (BMP7) which is secreted from bone marrow stromal cells is able to induce senescence to prostate tumor cell and (ii) this induction is mediated by activation of the tumor metastasis suppressor gene, N-myc downstream regulated gene 1 (NDRG1). These results strongly suggest that the BMP7-NDRG1axis plays a critical role in dormancy of prostate tumor cells in the bone. The overall goal of this proposal is to elucidate the mechanism of BMP7-induced dormancy in tumor stem cells and explore a possibility of using BMP7 as an anti-metastatic drug for prostate cancer., The original document contains color images.

This thesis examines demographic, social, and economic factors in China and their effect on China's economic growth. The thesis uses Michael Porter's economic development model and various economic indicators to compare China's economic growth from 1978 to 2011 to Japan's economic growth from 1945 to 1978, and to the United States' economic growth from 1919 to 1952. The purpose of this analysis is to identify whether China will become a peer competitor with the United States within the next 20 years. The analysis revealed that China's demographic, social, and economic factors are not likely to significantly undermine its economic growth over the next 20 years. However, although China's economic size will surpass that of the United States within the next decade, China will not become a peer competitor with the United States within the next 20 years. The thesis also found that the largest obstacle to China's long-term economic growth is China's aging population and corruption; these factors have the potential to prevent China from becoming a peer competitor with the United States., The original document contains color images.

Choroid plexus carcinoma (CPC) is a rare malignant brain tumor originating from the epithelial cells lining the cerebral ventricles. CPC represents less than 0.6% of brain tumors in all age groups, yet is more frequent in children (2-4%), especially in infants under the age of 1, accounting for over 20% of brain tumors in this age group (1). The molecular events that drive the malignant progression of this tumor are not well understood, yet this knowledge is crucial to improve patient survival. Surgical resection combined with neo-adjuvant and/or adjuvant therapy remain the primary methods of treatment for CPC; however tumor progression and relapse is observed in 70% of cases (2). Despite improvements on the most current treatment protocols, long-term survival of CPC patients remains under 30% and survivors display significant neurocognitive and/or sensory deficits. (2,3). Identifying altered genes that drive the progression of CPC will refine current diagnostic and prognostic classifications of CPC patients, and promote the implementation of targeted therapies to improve patient survival and reduce long-term side effects. The proposed research aims to identify genetic lesions involved in CPC tumorigenesis in order to implement their use as unique markers for diagnostic and prognostic classification of choroid plexus tumor patients, as well as to promote the creation of personalized molecular targeted therapies. I hypothesize that recurrent genetic lesions accompanied by a significant change in gene expression in CPC, will be drivers of tumorigenesis in this malignant brain tumor. Consequently, this research project will seek to answer the following question: What genes may be used as molecular markers for diagnostic and prognostic classification of CPC, and for which tumor-promoting alterations could CPC therapies be created?, The original document contains color images.

A total of 133 NF1 cases have been collected in the database. Among them, 101 cases are from HFHS site. There are currently 10 individuals with a previous breast cancer diagnosis. However, the analysis has not yet been performed. Two blood samples have been collected from individuals who developed breast cancer. Germline NF1 gene analysis will begin once more samples are collected. Five breast cancer tumor blocks have been collected. Immunohistochemistry validation of the antibodies has been completed; however the analysis of the tumor blocks has not commenced. After successful NF1 knockdown, phospho-ERK1,2 was not increased to reflect the activated Ras in human mammary cell line MCF10A. Primary cells were expected to undergo senescence when exposed to hyperactive Ras. Therefore a senescence assay was attempted to demonstrate this effect. Human mammary epithelial cells (HMEC) derived from breast reduction surgery were then employed. Early observation showed that NF1 knockdown HMEC had the same rate of doubling time as the other Ras activation models, i.e. RB1 and p53-RB1 knockdown cells. Yet again, upregulated Ras could not be demonstrated by phospho-ERK1,2 assay. HMEC may need a longer period of doubling in order to be used to test these again., The original document contains color images.