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Search Results: 1 - 10 of 9145 matches for " Christina Voelkel-Johnson "
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Histone Deacetylase Inhibitors Restore Cell Surface Expression of the Coxsackie Adenovirus Receptor and Enhance CMV Promoter Activity in Castration-Resistant Prostate Cancer Cells
Laura Kasman,Georgiana Onicescu,Christina Voelkel-Johnson
Prostate Cancer , 2012, DOI: 10.1155/2012/137163
Abstract: Adenoviral gene therapy using the death receptor ligand TRAIL as the therapeutic transgene can be safely administered via intraprostatic injection but has not been evaluated for efficacy in patients. Here we investigated the efficacy of adenoviral TRAIL gene therapy in a model of castration resistant prostate cancer and found that intratumoral injections can significantly delay tumor growth but cannot eliminate established lesions. We hypothesized that an underlying cause is inefficient adenoviral delivery. Using the LNCaP progression model of prostate cancer we show that surface CAR expression decreases with increasing tumorigenicity and that castration resistant C4-2b cells were more difficult to transduce with adenovirus than castration sensitive LNCaP cells. Many genes, including CAR, are epigenetically silenced during transformation but a new class of chemotherapeutic agents, known as histone deacetylase inhibitors (HDACi), can reverse this process. We demonstrate that HDACi restore CAR expression and infectivity in C4-2b cells and enhance caspase activation in response to infection with a TRAIL adenovirus. We also show that in cells with high surface CAR expression, HDACi further enhance transgene expression from the CMV promoter. Thus HDACi have multiple beneficial effects, which may enhance not only viral but also non-viral gene therapy of castration resistant prostate cancer. 1. Introduction Epigenetic alterations, such as aberrant activity of histone deacetylases, are frequently observed in malignancies. Acetylation of histones is associated with less condensed chromatin and a transcriptionally active gene status, while deacetylation is associated with transcriptional silencing. Histone deacetylase inhibitors (HDACiS) were originally found to reverse the malignant phenotype of transformed cells and have subsequently been developed as a new group of chemotherapeutic agents. HDACi can affect numerous signaling pathways to inhibit growth or angiogenesis and induce apoptosis or senescence [1, 2]. Using two HDACi under evaluation for the treatment of prostate cancer, we previously demonstrated that both romidepsin (also known as depsipeptide) and MS-275 enhanced the in vitro efficacy of adenoviral TRAIL gene therapy in castration-sensitive LNCaP prostate cancer cells [3]. This effect was selective for the malignant cells as primary cultures of prostate epithelial cells were not adversely affected [3]. TRAIL gene therapy has been evaluated for safety in prostate cancer patients with locally confined disease scheduled for prostatectomy [4]. Although
Adenoviral infectivity of exfoliated viable cells in urine: Implications for the detection of bladder cancer
Anuradha Murali, Laura Kasman, Christina Voelkel-Johnson
BMC Cancer , 2011, DOI: 10.1186/1471-2407-11-168
Abstract: Exfoliated cells from urine were obtained from 36 human subjects (> 40 years old). An adenovirus in which GFP expression is under control of the survivin promoter (Ad.Surv.GFP) was generated. An adenovirus in which GFP is expressed from the CMV promoter served as a control. GFP expression was analyzed by fluorescent microscopy and quantified by flow cytometry.Short-term cultures from exfoliated cells in urine could be established in 16 of 31 samples. These cultures were successfully transduced with Ad.CMV.GFP. Analysis of GFP expression following transduction with Ad.Surv.GFP, indicated that the survivin promoter was preferentially active in UM-UC-3 bladder cancer cells compared to non-malignant UROtsa cells. Interestingly, baseline levels of GFP expression in cultures from exfoliated cells in urine exhibited higher baseline levels than UROtsa following transduction with Ad.Surv.GFP.We demonstrated the feasibility of establishing and analysing short-term cultures isolated from exfoliated cells in voided urine by means of adenoviral transduction, thereby forming the foundation for future studies to determine the specificity and sensitivity of a non-invasive test based on survivin promoter activity.According to the American Cancer Society bladder cancer is the 5th highest in estimated new cases of cancers by site with 14,680 bladder cancer deaths and 70,530 new diagnoses in 2010 [1,2]. Bladder cancer can be categorized into non-muscle-invasive bladder cancer or muscle-invasive bladder cancer where 80% of the newly diagnosed cancers are non-muscle-invasive bladder cancer. Unfortunately, 70% of the patients will have recurrence of the disease and 10-30% will progress to muscle-invasive disease. Bladder cancer is detected as a result of incidental findings or by presenting hematuria. While hematuria is associated with benign conditions such as urinary tract infections and urolithiasis, 10% of the patients with gross hematuria are diagnosed with bladder cancer [3]. Contra
Doxorubicin increases the effectiveness of Apo2L/TRAIL for tumor growth inhibition of prostate cancer xenografts
Ahmed El-Zawahry, John McKillop, Christina Voelkel-Johnson
BMC Cancer , 2005, DOI: 10.1186/1471-2407-5-2
Abstract: In vitro cytotoxic effects of TRAIL were measured using a MTS-based viability assay. For in vivo studies, PC3 prostate carcinoma cells were grown subcutaneously in athymic nude mice and tumor growth was measured following treatment with doxorubicin and/or Apo2L/TRAIL. c-FLIP expression was determined by western blot analysis. Apoptosis in xenografts was detected using TUNEL. Statistical analysis was performed using the student t-test.In vitro experiments show that PC3 cells are partially susceptible to Apo2L/TRAIL and that susceptibility is enhanced by doxorubicin. In mice, doxorubicin did not significantly affect the growth of PC3 xenografts but reduced c-FLIP expression in tumors. Expression of c-FLIP in mouse heart was decreased only at the high doxorubicin concentration (8 mg/kg). Combination of doxorubicin with Apo2L/TRAIL resulted in more apoptotic cell death and tumor growth inhibition than Apo2L/TRAIL alone.Combination of doxorubicin and Apo2L/TRAIL is more effective in growth inhibition of PC3 xenografts in vivo than either agent alone and could present a novel treatment strategy against hormone-refractory prostate cancer. The intracellular mechanism by which doxorubicin enhances the effect of Apo2L/TRAIL on PC3 xenografts may be by reducing expression of c-FLIP.Prostate cancer is a significant health problem among American men. This year about 230,110 men will be diagnosed with the disease and about 30,000 will likely die in this country alone [1]. Treatment options are limited and are associated with significant morbidity and mortality [2]. Localized cancer is treated with radical prostatectomy, brachy- or cryotherapy, and external beam radiation while cancer that has escaped the prostatic capsule is generally treated by androgen ablation. However, the eventual development of an androgen-independent phenotype leads to incurable disease, indicating the need for better treatment strategies. Experimental approaches include delivery of oncolytic viruses, immu
Sphingosine Kinase-2 Maintains Viral Latency and Survival for KSHV-Infected Endothelial Cells
Lu Dai, Karlie Plaisance-Bonstaff, Christina Voelkel-Johnson, Charles D. Smith, Besim Ogretmen, Zhiqiang Qin, Chris Parsons
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0102314
Abstract: Phosphorylation of sphingosine by sphingosine kinases (SphK1 and SphK2) generates sphingosine-1-phosphate (S1P), a bioactive sphingolipid which promotes cancer cell survival and tumor progression in vivo. We have recently reported that targeting SphK2 induces apoptosis for human primary effusion lymphoma (PEL) cell lines infected by the Kaposi’s sarcoma-associated herpesvirus (KSHV), and this occurs in part through inhibition of canonical NF-κB activation. In contrast, pharmacologic inhibition of SphK2 has minimal impact for uninfected B-cell lines or circulating human B cells from healthy donors. Therefore, we designed additional studies employing primary human endothelial cells to explore mechanisms responsible for the selective death observed for KSHV-infected cells during SphK2 targeting. Using RNA interference and a clinically relevant pharmacologic approach, we have found that targeting SphK2 induces apoptosis selectively for KSHV-infected endothelial cells through induction of viral lytic gene expression. Moreover, this effect occurs through repression of KSHV-microRNAs regulating viral latency and signal transduction, including miR-K12-1 which targets IκBα to facilitate activation of NF-κB, and ectopic expression of miR-K12-1 restores NF-κB activation and viability for KSHV-infected endothelial cells during SphK2 inhibition. These data illuminate a novel survival mechanism and potential therapeutic target for KSHV-infected endothelial cells: SphK2-associated maintenance of viral latency.
Preservation of log-concavity on summation
Oliver Johnson,Christina Goldschmidt
Mathematics , 2005, DOI: 10.1051/ps:2006008
Abstract: We extend Hoggar's theorem that the sum of two independent discrete-valued log-concave random variables is itself log-concave. We introduce conditions under which the result still holds for dependent variables. We argue that these conditions are natural by giving some applications. Firstly, we use our main theorem to give simple proofs of the log-concavity of the Stirling numbers of the second kind and of the Eulerian numbers. Secondly, we prove results concerning the log-concavity of the sum of independent (not necessarily log-concave) random variables.
Combining the formative with the summative: the development of a two-stage online test to encourage engagement and provide personal feedback in large classes
Susanne Voelkel
Research in Learning Technology , 2013, DOI: 10.3402/rlt.v21i0.19153
Abstract: The aim of this action research project was to improve student learning by encouraging more “time on task” and to improve self-assessment and feedback through the introduction of weekly online tests in a Year 2 lecture module in biological sciences. Initially voluntary online tests were offered to students and those who participated achieved higher exam marks than those who did not, but completion rate was low. Making the tests compulsory led to high completion rates, but class performance decreased, indicating that using the same assessment for formative and for summative purposes is not always beneficial for learning. Finally, these problems were resolved by introducing a two-stage approach: the first stage of each test was formative and provided prompt feedback. However, students had to achieve 80% to progress to the second summative stage of the test. The two-stage online tests led to significantly improved class performance. This novel test design ensures that students go through at least two attempts and therefore fully benefit from the learning opportunities presented by the formative stage. Two-stage online tests present the opportunity to provide regular feedback in large classes and to improve performance not only of good but also of “weak” students.
Determinants of Modern Contraceptive Use among Women of Reproductive Age in Tanzania: Evidence from Tanzania Demographic and Health Survey Data  [PDF]
Paulo Lino Kidayi, Sia Msuya, Jim Todd, Chuki Christina Mtuya, Tara Mtuy, Michael Johnson Mahande
Advances in Sexual Medicine (ASM) , 2015, DOI: 10.4236/asm.2015.53006
Abstract: Introduction: Tanzania is among of the African countries with high maternal and child mortality rates and fast growing population. It also has high fertility rate and a huge unmet need for family planning. Contraceptive use reported to avert more than 1 million maternal deaths in Sub-Saharan Africa due to decline in fertility rate and thus help to achieve MDG 4 and 5. Therefore, this study aimed to determine factors influencing modern contraceptive use among women aged 15 - 49 years in Tanzania. Methods: This was a secondary analysis of Tanzania Demographic Health Survey (TDHS), 2010. A total of 475 clusters (urban and rural) composed of 9663 households were selected. During the survey, a total of 10,139 women aged 15 - 49 years were interviewed about sexual and reproductive matters using a standardized questionnaire. We restricted our analysis to married/cohabiting women (n = 6412) responded for in individual records and domestic violence (n = 4471). Univariate and multiple logistic regression analyses were performed using Stata version 11.0. Odds ratios with 95% confidence intervals for determinants of modern contraceptive use were estimated. A P value of 5% (2 tails) was considered statistically significant. Results: Women empowerment (OR = 1.4; 95% CI: 1.13 - 1.63), male-female age difference of less or equal to nine (OR = 1.6; 95 CI: 1.01 - 2.66), and advice given at health care facilities on family planning (OR = 1.6; 95 CI: 1.37 - 1.96) were predictors of modern contraceptive use. Woman sexual violence was not associated with modern contraceptive use. Conclusions: The predictors of modern contraceptive use in our study correspond with previous studies in low and middle income countries. Women empowerment, male-female age difference, and child desire were important predictors for modern contraceptive use. This highlights the need to promote contraceptive use among women of reproductive age.
On A^1-fundamental groups of isotropic reductive groups
Konrad Voelkel,Matthias Wendt
Mathematics , 2012,
Abstract: For an isotropic reductive group G satisfying a suitable rank condition over an infinite field k, we show that the sections of the $\mathbb{A}^1$-fundamental group sheaf of G over an extension field L/k can be identified with the second group homology of G(L). For a split group G, we provide explicit loops representing all elements in the $\mathbb{A}^1$-fundamental group. Using $\mathbb{A}^1$-homotopy theory, we deduce a Steinberg relation for these explicit loops.
Primary Human mDC1, mDC2, and pDC Dendritic Cells Are Differentially Infected and Activated by Respiratory Syncytial Virus
Teresa R. Johnson,Christina N. Johnson,Kizzmekia S. Corbett,Gretchen C. Edwards,Barney S. Graham
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0016458
Abstract: Respiratory syncytial virus (RSV) causes recurrent infections throughout life. Vaccine development may depend upon understanding the molecular basis for induction of ineffective immunity. Because dendritic cells (DCs) are critically involved in early responses to infection, their interaction with RSV may determine the immunological outcome of RSV infection. Therefore, we investigated the ability of RSV to infect and activate primary mDCs and pDCs using recombinant RSV expressing green fluorescent protein (GFP). At a multiplicity of infection of 5, initial studies demonstrated ~6.8% of mDC1 and ~0.9% pDCs were infected. We extended these studies to include CD1c?CD141+ mDC2, finding mDC2 infected at similar frequencies as mDC1. Both infected and uninfected cells upregulated phenotypic markers of maturation. Divalent cations were required for infection and maturation, but maturation did not require viral replication. There is evidence that attachment and entry/replication processes exert distinct effects on DC activation. Cell-specific patterns of RSV-induced maturation and cytokine production were detected in mDC1, mDC2, and pDC. We also demonstrate for the first time that RSV induces significant TIMP-2 production in all DC subsets. Defining the influence of RSV on the function of selected DC subsets may improve the likelihood of achieving protective vaccine-induced immunity.
Estrogen exposure, obesity and thyroid disease in women with severe pulmonary hypertension
Lori Sweeney, Norbert F Voelkel
European Journal of Medical Research , 2009, DOI: 10.1186/2047-783x-14-10-433
Abstract: 88 patients attending the Pulmonary Hypertension Association 8th International meeting completed a questionnaire and were interviewed. Information was collected regarding reproductive history, height, weight, and previous diagnosis of thyroid disease.46% met criteria for obesity. 41% reported a diagnosis of thyroid disease. 81% of women reported prior use of hormone therapy. 70% reported greater than 10 years of exogenous hormone use. 74% of female patients reported two or more of potentially disease modifying endocrine factors (obesity, thyroid disease or estrogen therapy).The coexistent high prevalence in our cohort of exogenous estrogen exposure, thyroid disease and obesity suggests that an interaction of multiple endocrine factors might contribute to the pathogenesis of pulmonary hypertension and may represent epigenetic modifiers in genetically-susceptible individuals.Severe pulmonary arterial hypertension continues to be categorized as idiopathic pulmonary arterial hypertension (IPAH) or secondary pulmonary hypertension associated with various disease states (APAH). The WHO pulmonary hypertension classification system includes categories of pulmonary arterial hypertension (PAH), pulmonary hypertension attributable to chronic left heart, lung or thromboembolic disease and "miscellaneous" forms [1]. Whereas thirty years ago idiopathic or then called "primary" pulmonary hypertension was recognized as a disease of young women [2] and the NIH-sponsored pulmonary hypertension registry reported a female to male ratio of 1.7: 1 [3], it appears that in recent years the patient profile has changed. The average patient diagnosed with IPAH is now older and frequently, a postmenopausal woman. The overall number of female patients also appears to have increased or is potentially overrepresented in clinical trials [4]. Data from the 2007 REVEAL registry report that 78% of 1226 patients with PAH were women with a median age of 53 years [5] and a large referral center reported
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