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A Role For Reactive Oxygen Species In Photodynamic Therapy, Michael Price

Wayne State University Dissertations

Photodynamic therapy (PDT) is based on the ability of certain photosensitizing agents to selectively localize in neoplastic cells and their vasculature. Subsequent irradiation at a wavelength corresponding to a photosensitizer absorbance band excites the photosensitizer molecules, leading to energy transfer reactions and fluorescence. It was initially concluded that the phototoxic effect occurred when energy from the excited state of the photosensitizer was transferred to dissolved oxygen to form singlet oxygen. This product has a very brief half-life and will cause cellular damage only in the immediate vicinity of its formation. But an excited-state photosensitizer can also interact with oxygen to …

Hdm2 Small-Molecule Inhibitors For Therapeutic Intervention In B-Cell Lymphoma, Angela Sosin

Wayne State University Dissertations

Lymphomas frequently retain wild-type (wt) p53 function but overexpress HDM2, compromising p53 activity. Therefore, lymphoma is a suitable model for studying therapeutic value of disrupting HDM2-p53 association by small-molecule inhibitors (SMIs). HDM2 SMIs have been developed and are currently under various stages of preclinical and clinical investigation. This study examined various molecular mechanisms associated and biological effects of two different classes of HDM2 SMIs: the spiro-oxindoles (MI-219) and cis-imidazoline (Nutlin-3) in lymphoma cell lines and patient-derived B-lymphoma cells. Surprisingly, results revealed significant quantitative and qualitative differences between these two agents. At the molecular level, effect of Nutlin-3 was generally more …

Substance P And The Host Immune Response, Megan Elizabeth Foldenauer

Wayne State University Dissertations

This body of work examined the mechanism by which SP regulates host immunity, specifically, its control of growth factors and TLR expression in the P. aeruginosa-infected cornea. The role of mTOR and VIP in corneal infection and inflammation also was tested.

SP has a dual role in bacterial infection, unexpectedly upregulating growth factor production. This was accompanied by macrophage-specific upregulation of pro-inflammatory cytokines, downregulation of anti-inflammatory cytokines, and upregulation of anti-apoptotic genes, as well as a decrease in arginase-producing macrophages (M2 cells), important in stromal healing in these mice. All of these lead to worsened disease, despite the stimulatory effects …

Adult Bmi Change And Risk Of Colon Cancer In Postmenopausal Women, Lyla Blake-Gumbs, Zhengyi Chen, Cheryl L. Thompson, Nathan A. Berger, Thomas C. Tucker, Li Li

Markey Cancer Center Faculty Publications

Purpose. We recently reported an association of adult BMI change with colon cancer risk. Here, we sought to further explore this association with respect to postmenopausal HRT use in a larger study population. Methods. We included 1,457 postmenopausal women participating in an ongoing population-based case-control study of colon cancer. Results. We confirmed a previously reported association of adulthood weight gain and increased risk of colon cancer: compared to those with <5 kg/m² change of BMI, women who reported moderate (5–10 kg/m²) and large (>10 kg/m²) BMI changes since their 20s had OR estimates …

Chloroviruses: Not Your Everyday Plant Virus, James L. Van Etten, David D. Dunigan

Nebraska Center for Virology: Faculty Publications

Viruses infecting higher plants are among the smallest viruses known and typically have four to ten protein-encoding genes. By contrast, many viruses that infect algae (classified in the virus family Phycodnaviridae) are among the largest viruses found to date and have up to 600 protein- encoding genes. This brief review focuses on one group of plaque-forming phycodnaviruses that infect unicellular chlorella-like green algae. The prototype chlorovirus PBCV-1 has more than 400 protein-encoding genes and 11 tRNA genes. About 40% of the PBCV-1 encoded proteins resemble proteins of known function including many that are completely unexpected for a virus. In many …

Molecular Genetic And Biochemical Characterization Of The Vaccinia Virus I3 Protein, The Replicative Single-Stranded Dna Binding Protein, Matthew D. Greseth, Kathleen A. Boyle, Matthew S. Bluma, Bethany Unger, Matthew S. Wiebe, Jamaria A. Soares-Martins, Nadi T. Wickramasekera, James Wahlberg, Paula Traktman

Nebraska Center for Virology: Faculty Publications

Vaccinia virus, the prototypic poxvirus, efficiently and faithfully replicates its approximately 200-kb DNA genome within the cytoplasm of infected cells. This intracellular localization dictates that vaccinia virus encodes most, if not all, of its own DNA replication machinery. Included in the repertoire of viral replication proteins is the I3 protein, which binds to single-stranded DNA (ssDNA) with great specificity and stability and has been presumed to be the replicative ssDNA binding protein (SSB). We substantiate here that I3 colocalizes with bromodeoxyuridine (BrdU)-labeled nascent viral genomes and that these genomes accumulate in cytoplasmic factories that are delimited by membranes derived from …

Lineage-Specific Differences Between Human And Simian Immunodeficiency Virus Regulation Of Gp120 Trimer Association And Cd4 Binding, Andrés Finzi, Beatriz Pacheco, Shi-Hua Xiang, Marie Pancera, Alon Herschhorn, Liping Wang, Xing Zeng, Anik Desormeaux, Peter D. Kwong, Joseph Sodroski

Nebraska Center for Virology: Faculty Publications

Metastable conformations of the gp120 and gp41 envelope glycoproteins of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) must be maintained in the unliganded state of the envelope glycoprotein trimer. Binding of gp120 to the primary receptor, CD4, triggers the transition to an open conformation of the trimer, promoting interaction with the CCR5 chemokine receptor and ultimately leading to gp41-mediated virus-cell membrane fusion and entry. Topological layers in the gp120 inner domain contribute to gp120-trimer association in the unliganded state and to CD4 binding. Here we describe similarities and differences between HIV-1 and SIVmac gp120. In both …

Subunit Organization Of The Membrane-Bound Hiv-1 Envelope Glycoprotein Trimer, Youdong Mao, Liping Wang, Christopher Gu, Alon Herschhorn, Shi-Hua Xiang, Hillel Haim, Xinzhen Yang, Joseph Sodroski

Nebraska Center for Virology: Faculty Publications

The trimeric human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) spike is a molecular machine that mediates virus entry into host cells and is the sole target for virus-neutralizing antibodies. The mature Env spike results from cleavage of a trimeric gp160 precursor into three gp120 and three gp41 subunits. Here we describe an ~11-Å cryo-EM structure of the trimeric HIV-1 Env precursor in its unliganded state. The three gp120 and three gp41 subunits form a cage-like structure with an interior void surrounding the trimer axis. Interprotomer contacts are limited to the gp41 transmembrane region, the torus-like gp41 ectodomain, and …

Comparative Analysis Of The Fusion Efficiency Elicited By The Envelope Glycoprotein V1–V5 Regions Derived From Human Immunodeficiency Virus Type 1 Transmitted Perinatally, Hongyan Guo, Levon Abrahamyan, Chang Liu, Mackenzie Waltke, Yunqi Geng, Qimin Chen, Charles Wood, Xiaohong Kong

Nebraska Center for Virology: Faculty Publications

Understanding the properties of viruses preferentially establishing infection during perinatal transmission of human immunodeficiency virus type 1 (HIV-1) is critical for the development of effective measures to prevent transmission. A previous study demonstrated that the newly transmitted viruses (in infants) of chronically infected mother–infant pairs (MIPs) were fitter in terms of growth, which was imparted by their envelope (Env) glycoprotein V1–V5 regions, than those in the corresponding chronically infected mothers. In order to investigate whether the higher fitness of transmitted viruses was conferred by their higher entry efficiency directed by the V1–V5 regions during perinatal transmission, the fusogenicity of Env …

Antibody Responses To Lytic And Latent Human Herpesvirus 8 Antigens Among Hiv-Infected Patients In Central China, Tiejun Zhang, Na He, Yingying Ding, Qingwu Jiang, Charles Wood

Nebraska Center for Virology: Faculty Publications

Human herpesvirus 8 (HHV8) is an important opportunistic infection of HIV/AIDS. However, very little is known about antibody seropositivities to HHV8 lytic and latent antigens among HIVinfected patients in China. Therefore, a cross-sectional study was conducted to explore HHV8 serostatus among 316 HIV-infected patients in a rural area of central China. The antibody seropositivity to HHV8 ORF65 (lytic) and LANA (latent) antigens was 12.7% and 10.4%, respectively. Patients who were naïve to antiretroviral therapy (ART) were more likely to be seropositive for antibodies to ORF65 (OR: 3.79; 95% CI: 1.71–8.42) and LANA (OR: 3.77; 95% CI: 1.55–9.14) than patients receiving …

Heme Oxygenase-1 Regulates The Immune Response To Influenza Virus Infection And Vaccination In Aged Mice, Nathan W. Cummins, Eric A. Weaver, Shannon M. May, Anthony J. Croatt, Oded Foreman, Richard B. Kennedy, Gregory A. Polan, Michael A. Barry, Karl A. Nath, Andrew D. Badley

Nebraska Center for Virology: Faculty Publications

Underlying mechanisms of individual variation in severity of influenza infection and response to vaccination are poorly understood. We investigated the effect of reduced heme oxygenase-1 (HO-1) expression on vaccine response and outcome of influenza infection. HO-1-deficient and wild-type (WT) mice (kingdom, Animalia; phylum, Chordata; genus/species, Mus musculus) were infected with influenza virus A/PR/8/34 with or without prior vaccination with an adenoviral-based influenza vaccine. A genome-wide association study evaluated the expression of single-nucleotide polymorphisms (SNPs) in the HO-1 gene and the response to influenza vaccination in healthy humans. HO-1-deficient mice had decreased survival after influenza infection compared to WT mice (median …

Effects Of Arterial Strain And Stress In The Prediction Of Restenosis Risk: Computer Modeling Of Stent Trials, Shijia Zhao, Linxia Gu, Stacey R. Froemming

Department of Mechanical and Materials Engineering: Faculty Publications

Purpose — In-stenting restenosis is one of the major complications after stenting. Clinical trials of various stent designs have reported different restenosis rates. However, quantitative correlation between stent features and restenosis statistics is scant. In this work, it is hypothesized that stress concentrations on arterial wall caused artery injury, which initiates restenosis. The goal is to assess the correlation between stent-induced arterial stress and strain and the documented restenosis rates.

Methods — Six commercially available stents, including balloon-expandable stents and self-expanding stents, were virtually implanted into the arteries through finite element method. The resulted peak Von Mises stress, principal stress, …

Divergent Functions Of The Myotubularin (Mtm) Homologs Atmtm1 And Atmtm2 In Arabidopsis Thaliana: Evolution Of The Plant Mtm Family, Yong Ding, Ivan Ndamukong, Yang Zhao, Yuannan Xia, Jean-Jack Riethoven, David R. Jones, Nullin Divecha, Zoya Avramova

School of Biological Sciences: Faculty Publications

Myotubularin and myotubularin-related proteins are evolutionarily conserved in eukaryotes. Defects in their function result in muscular dystrophy, neuronal diseases, and leukemia in humans. In contrast to the animal lineage, where genes encoding both active and inactive myotubularins (phosphoinositide 3-phosphatases) have appeared and proliferated in the basal metazoan group, myotubularin genes are not found in the unicellular relatives of green plants. However, they are present in land plants encoding proteins highly similar to the active metazoan enzymes. Despite their remarkable structural conservation, plant and animal myotubularins have significantly diverged in their functions. While loss of myotubularin function causes severe disease phenotypes …

Lymph Node Ratio Is An Important And Independent Prognostic Factor For Patients With Stage Iii Melanoma, Adam C. Berger, Michael Fierro, John C. Kairys, David Berd, Takami Sato, Jocelyn Andrel, Terry Hyslop, Michael J. Mastrangelo

Kimmel Cancer Center Faculty Papers

INTRODUCTION:

The incidence of melanoma is dramatically increasing worldwide. We hypothesized that the ratio of metastatic to examined lymph node ratio (LNR) would be the most important prognostic factor for stage III patients.

METHODS:

We retrospectively reviewed our institutional database of melanoma patients and identified 168 patients who underwent lymph node dissection (LND) for stage III disease between 1993 and 2007. Patients were divided into three groups based on LNR (≤10%, n = 93; 10-≤25%, n = 45; and >25%, n = 30). Univariate and multivariate analysis was performed using Cox proportional hazards model.

RESULTS:

The median survival time of …

Prescient Human Fetuses Thrive, Curt A. Sandman, Elyssia Poggi Davis, Laura M. Glynn

Psychology Faculty Articles and Research

Fetal detection of adversity is a conserved trait that allows many species to adapt their early developmental trajectories to ensure survival. According to the fetal-programming model, exposure to stressful or hostile conditions in utero is associated with compromised development and a lifelong risk of adverse health outcomes. In a longitudinal study, we examined the consequences of prenatal and postnatal exposure to adversity for infant development. We found increased motor and mental development during the 1st year of life among infants whose mothers experienced congruent levels of depressive symptoms during and after pregnancy, even when the levels of symptoms were relatively …

The Role Of The Microenvironment And Th17 Cells In The Carcinogenesis Of Head And Neck Squamous Cell Carcinoma, Danielle Woodford

MUSC Theses and Dissertations

Head and neck cancer is the sixth most common cancer worldwide. Despite advances in diagnosis and treatment, the survival rates for patients with head and neck cancer have remained relatively unchanged for the past 30 years. Head and Neck Squamous Cell Carcinoma is a highly aggressive malignancy with a 5-year survival rate of only 50%. Of the patients diagnosed every year, 5% of head and neck squamous cell carcinoma (HNSCC) patients develop additional primary tumors, an effect that is thought to be associated with the high degree of immune suppression induced by the tumor. During the premalignant stage of HNSCC, …

The Genetics Of Neuroendocrine Prostate Cancers: A Review Of Current And Emerging Candidates, M Hammad Ather, Tahmeena Siddiqui

Department of Surgery Docs

Prostate cancer (PC) displays a strong familial link and genetic factors; genes regulating inflammation may have a pivotal role in the disease. Epigenetic changes control chromosomal integrity, gene functions, and, ultimately, carcinogenesis. The most widely studied epigenetic event in PC is aberrant DNA methylation (hypo- and hypermethylation); besides this, chromatin remodeling and micro RNA (miRNA) are other studied alterations in PC. These all lead to genomic instability and inappropriate gene expression. Causative dysfunction of histone modifying enzymes results in generic and locus-specific changes in chromatin remodeling. miRNA deregulation also contributes to prostate carcinogenesis, including interference with androgen-receptor signaling and apoptosis. …

Determining Efficacy Of Breast Cancer Therapy By Pet Imaging Of Her2 Mrna, Bishnuhari Paudyal, Kaijun Zhang, Changpo Chen, Neil Mehta, Eric Wickstrom, Brian Gray, Jeffrey Mattis, Koon Pak, Mathew L Thakur

Department of Radiology Faculty Papers

No abstract provided.

Optical Imaging For Determination Of Apoptosis Medicated Therapeutic Efficacy, Kaijun Zhang, Bishnuhari Paudyal, Neil Mehta, Brian Gray, Koon Y. Pak, Eric Wickstrom, Mathew L Thakur

Department of Radiology Faculty Papers

No abstract provided.

Macrophage Imbalance (M1 Vs. M2) And Upregulation Of Mast Cells In Wall Of Ruptured Human Cerebral Aneurysms: Preliminary Results., David Hasan, Nohra Chalouhi, Pascal Jabbour, Tomoki Hashimoto

Department of Neurosurgery Faculty Papers

BACKGROUND: M1 and M2 cells are two major subsets of human macrophages that exert opposite effects on the inflammatory response. This study aims to investigate the role of macrophage M1/M2 imbalance and mast cells in the progression of human cerebral aneurysms to rupture.

METHODS: Ten patients with cerebral aneurysms (five ruptured and five unruptured) underwent microsurgical clipping. During the procedure, a segment of the aneurysm dome was resected and immunostained with monoclonal antibodies for M1 cells (anti-HLA DR), M2 cells (anti-CD 163), and mast cells (anti-tryptase clone AA). A segment of the superficial temporal artery (STA) was also removed and …

Nothing As Practical As A Good Theory? The Theoretical Basis Of Hiv Prevention Interventions For Young People In Sub-Saharan Africa: A Systematic Review, Kristien Michielsen, Matthew Chersich, Marleen Temmerman, Tessa Dooms, Ronan Van Rossem

Obstetrics and Gynaecology, East Africa

This paper assesses the extent to which HIV prevention interventions for young people in sub-Saharan Africa are grounded in theory and if theory-based interventions are more effective. Three databases were searched for evaluation studies of HIV prevention interventions for youth. Additional articles were identified on websites of international organisations and through searching references. 34 interventions were included; 25 mentioned the use of theory. Social Cognitive Theory was most prominent (n = 13), followed by Health Belief Model (n = 7), and Theory of Reasoned Action/Planned Behaviour (n = 6). These cognitive behavioural theories assume that cognitions drive sexual behaviour. Reporting …

Is There A Role For The Quantification Of Rrm1 And Ercc1 Expression In Pancreatic Ductal Adenocarcinoma?, Matias E Valsecchi, Thomas Holdbrook, Benjamin E Leiby, Edward Pequignot, Susan J Littman, Charles Yeo, Jonathan Brody, Angieszka Witkiewicz

Department of Medical Oncology Faculty Papers

BACKGROUND: RRM1 and ERCC1 overexpression has been extensively investigated as potential predictive markers of tumor sensitivity to conventional chemotherapy agents, most thoroughly in lung cancer. However, data in pancreatic cancer are scarce.

METHODS: We investigated the mRNA and protein expression of ERCC1 and RRM1 by RT-PCR and immunohistochemistry (IHC) in formalin-fixed, paraffin-embedded pancreatic ductal carcinoma (PDA) tissues. The primary outcome investigated was the association between RRM1 and ERCC1 expression and overall survival (OS) or disease-free survival (DFS).

RESULTS: A total of 94 patients with resected PDA were included in this study. Most of them (87%) received gemcitabine based chemotherapy. Data …

Complementary And Integrative Oncology In The Cross-Cultural Region Of The Middle East And South Asia., Eran Ben-Arye, Barrie Cassileth, Peter Heusser, Fatma Afifi, Bashar Saad, Senthamil R Selvan

Department of Medical Oncology Faculty Papers

No abstract provided.

Perceived Partner Support In Pregnancy Predicts Lower Maternal And Infant Distress, Lynlee R. Tanner Stapleton, Christine Dunkel Schetter, Erika Westling, Christine Rini, Laura M. Glynn, Calvin J. Hobel, Curt A. Sandman

Psychology Faculty Articles and Research

Maternal postpartum emotional distress is quite common and can pose significant risk to mothers and infants. The current study investigated mothers' relationships with their partners during pregnancy and tested the hypotheses that perception of prenatal partner support is a significant predictor of changes in maternal emotional distress from midpregnancy to postpartum, and contributes to maternal ratings of infant distress to novelty. Using a prospective longitudinal design, 272 adult pregnant women were interviewed regarding their partner support, relationship satisfaction, and interpersonal security (attachment style and willingness to seek out support), and they completed standardized measures of prenatal symptoms of depression and …

Gene Expression Signatures Modulated By Epidermal Growth Factor Receptor Activation And Their Relationship To Cetuximab Resistance In Head And Neck Squamous Cell Carcinoma., Elana J Fertig, Qing Ren, Haixia Cheng, Hiromitsu Hatakeyama, Adam Dicker Md, Phd, Ulrich Rodeck, Michael Considine, Michael F Ochs, Christine H Chung

Department of Radiation Oncology Faculty Papers

BACKGROUND: Aberrant activation of signaling pathways downstream of epidermal growth factor receptor (EGFR) has been hypothesized to be one of the mechanisms of cetuximab (a monoclonal antibody against EGFR) resistance in head and neck squamous cell carcinoma (HNSCC). To infer relevant and specific pathway activation downstream of EGFR from gene expression in HNSCC, we generated gene expression signatures using immortalized keratinocytes (HaCaT) subjected to ligand stimulation and transfected with EGFR, RELA/p65, or HRASVal12D.

RESULTS: The gene expression patterns that distinguished the HaCaT variants and conditions were inferred using the Markov chain Monte Carlo (MCMC) matrix factorization algorithm Coordinated Gene Activity …

Genes Adopt Non-Optimal Codon Usage To Generate Cell Cycle-Dependent Oscillations In Protein Levels., Milana Frenkel-Morgenstern, Tamar Danon, Thomas Christian, Takao Igarashi, Lydia Cohen, Ya-Ming Hou, Lars Juhl Jensen

Department of Biochemistry and Molecular Biology Faculty Papers

The cell cycle is a temporal program that regulates DNA synthesis and cell division. When we compared the codon usage of cell cycle-regulated genes with that of other genes, we discovered that there is a significant preference for non-optimal codons. Moreover, genes encoding proteins that cycle at the protein level exhibit non-optimal codon preferences. Remarkably, cell cycle-regulated genes expressed in different phases display different codon preferences. Here, we show empirically that transfer RNA (tRNA) expression is indeed highest in the G2 phase of the cell cycle, consistent with the non-optimal codon usage of genes expressed at this time, and lowest …

Cisplatin-Induced Posterior Reversible Encephalopathy Syndrome And Successful Re-Treatment In A Patient With Non-Seminomatous Germ Cell Tumor: A Case Report, Muhammad Nauman Zahir, Nehal Masood, Munira Shabbir-Moosajee

Department of Radiation Oncology

UNLABELLED: Introduction: Cisplatin is a platinum compound that has revolutionized the treatment of various solid organ tumors. Cisplatin is associated with a variety of side effects and has recently been indicted in the development of posterior reversible encephalopathy syndrome. Posterior reversible encephalopathy syndrome is a potentially reversible condition, with the mainstay of therapy being correction of the underlying cause and withdrawal of the offending drug. However, there are no clear guidelines regarding the possibility of subsequent re-treatment with the causative agent.CASE PRESENTATION: A 23-year-old Asian man presented to our Emergency Department with a four-month history of concomitant abdominal pain and …

Correlates Of Morbidity And Mortality In Severe Necrotizing Pancreatitis, K. M. Pal, Pashtoon Murtaza Kasi, Mohammad Tayyeb, S. M. Faisal Mosharraf, Zafar Fatmi

Community Health Sciences

Acute severe pancreatitis is associated with a high morbidity and mortality and frequently is accompanied by underlying pancreatic parenchymal necrosis. Patients with pancreatic necrosis must be identified, because the morbidity and mortality rate in this subgroup is much higher. Our objective was to compare the clinical outcomes of these patients based on the degree of pancreatic necrosis. A total of 35 patients were noted to have pancreatic necrosis. These were divided into 2 groups based on extent of necrosis: group A had less than 50% necrosis and group B had more than 50% necrosis. The rate of mortality (5% versus …

Extent Of Liver Inflammation In Predicting Response To Interferon Alpha & Ribavirin In Chronic Hepatitis C Patients: A Cohort Study, Shirin Mirza, Amna Rehana Siddiqui, Saeed Hamid, Muhammad Umar, Shaheena Bashir

Community Health Sciences

Background: Liver inflammation due to HCV infection leads to fibrosis, which is an independent predictor of treatment response to interferon therapy in Chronic Hepatitis C (CHC) patients. This relationship has not been studied for liver inflammation on pretreatment liver biopsy and End of Treatment Response (ETR). ALT is a less invasive test than liver biopsy for measuring liver inflammation. Aim of this study was to compare ETR to Interferon alpha (recombinant Interferon) & Ribavirin in CHC patients having higher and lower grades of liver inflammation and to determine the diagnostic accuracy of pretreatment ALT for grades of liver inflammation.Methods: A …

Lymph Node Ratio Is An Important And Independent Prognostic Factor For Patients With Stage Iii Melanoma., Adam C. Berger, Michael Fierro, John C Kairys, David Berd, Takami Sato, Jocelyn Andrel, Terry Hyslop, Michael J Mastrangelo

Department of Surgery Faculty Papers

INTRODUCTION: The incidence of melanoma is dramatically increasing worldwide. We hypothesized that the ratio of metastatic to examined lymph node ratio (LNR) would be the most important prognostic factor for stage III patients.

METHODS: We retrospectively reviewed our institutional database of melanoma patients and identified 168 patients who underwent lymph node dissection (LND) for stage III disease between 1993 and 2007. Patients were divided into three groups based on LNR (≤10%, n = 93; 10-≤25%, n = 45; and >25%, n = 30). Univariate and multivariate analysis was performed using Cox proportional hazards model.

RESULTS: The median survival time of …