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Inhibition Of P73 Function By Pifithrin-Α As Revealed By Studies In Zebrafish Embryos, William R Davidson, Qing Ren, Gabor Kari, Ori Kashi, Adam Dicker Md, Phd, Ulrich Rodeck

Bodine Journal

The p53 family of proteins contains two members that have been implicated in sensitization of cells and organisms to genotoxic stress, i.e., p53 itself and p73. In vitro, lack of either p53 or p73 can protect certain cell types in the adult organism against death upon exposure to DNA damaging agents. The present study was designed to assess the relative contribution of p53 to radiation resistance of an emerging vertebrate model organism, i.e., zebrafish embryos. Consistent with previous reports, suppressing p53 protein expression using antisense morpholino oligonucleotides (MOs) increased survival and reduced gross morphological alterations in zebrafish embryos exposed to …

Vegf Trap In Combination With Radiotherapy Improves Tumor Control In U87 Glioblastoma, Phyllis Wachsberger, Phd, Randy Burd, Phd, Chris Cardi, Ms, Mathew L. Thakur, Constantine Daskalakis, Jocelyn Holash, Phd, George D. Yancopoulos, Phd, Adam Dicker Md, Phd

Bodine Journal

Purpose

To determine the effect of vascular endothelial growth factor VEGF Trap (Regeneron Pharmaceuticals, Tarrytown, NY), a humanized soluble vascular endothelial growth factor (VEGF) receptor protein, and radiation (RT) on tumor growth in U87 glioblastoma xenografts in nude mice.

Methods and Materials

U87 cell suspensions were implanted subcutaneously into hind limbs of nude mice. VEGF Trap (2.5–25 mg/kg) was administered every 3 days for 3 weeks alone or in combination with a single dose of 10 Gy or fractionated RT (3 x 5 Gy). In addition, three scheduling protocols for VEGF Trap plus fractionated RT were examined.

Results

Improved tumor …

Download Entire Bodine Journal Volume 2, Issue 1, 2009

Bodine Journal

No abstract provided.

Flexible Needle-Tissue Interaction Modeling With Depth-Varying Mean Parameter: Preliminary Study, Kai Guo Yan, Tarun Podder, Yan Yu, Tien-I Liu, Christopher W.S. Cheng, Wan Sing Ng

Bodine Journal

Flexible needle steering has aroused a lot of research interest in recent years. It has the potential to correct targeting errors, which may be caused by needle bending, tissue deformation, or error in insertion angle. In addition, control and planning based on a steering model can guide the needle to some areas that are currently not amenable to needles because of obstacles, such as bone or sensitive tissues. Thus, there is a clear motivation for needle steering. In this paper, a spring–beam– damper model is proposed to describe the dynamics during the needle–tissue contact procedure. Considering tissue inhomogeneity, depth-varying mean …

Combination Of Vandetanib, Radiotherapy, And Irinotecan In The Lovo Human Colorectal Cancer Xenograft Model, Phyllis Wachsberger, Phd, Randy Burd, Phd, Anderson Ryan, Phd, Constantine Daskalakis, Phd, Adam Dicker Md, Phd

Bodine Journal

Purpose:

The tumor growth kinetics of the human LoVo colorectal xenograft model was assessed in response to vandetanib, an orally available receptor tyrosine kinase inhibitor, radiotherapy (RT), or irinotecan (CPT-11), as single therapies and in combination.

Methods and Materials:

LoVo cells were injected subcutaneously into the right hind limb (5x106 cells in 100μL phosphate-buffered saline) of athymic NCR NUM mice and tumors were grown to a volume of 200–300mm3 before treatment. Vandetanib was administered at 50 mg/kg daily orally for 14 days starting on Day 1. RT was given as three fractions (3x3 Gy) on Days 1, 2, and 3. …

Nuclear Factor Κb Inhibitors Alleviate And The Proteasome Inhibitor Ps-341 Exacerbates Radiation Toxicity In Zebrafish Embryos, Borbala Daroczi, Gabor Kari, Qing Ren, Adam Dicker Md, Phd, Ulrich Rodeck

Bodine Journal

Inflammatory changes are a major component of the normal tissue response to ionizing radiation, and increased nuclear factor κB (NF-κB) activity is an important mediator of inflammatory responses. Here, we used zebrafish embryos to assess the capacity of two different classes of pharmacologic agents known to target NF-κB to modify radiation toxicity in the vertebrate organism. These were proteasome inhibitors, including lactacystin, MG132, and PS-341 (Bortezomib/VELCADE), and direct inhibitors of NF-κB activity, including ethyl pyruvate (EP) and the synthetic triterpenoid CDDO-TFEA (RTA401), among others. The proteasome inhibitors either did not significantly affect radiation sensitivity of zebrafish embryos (MG132, lactacystin) or …

Caloric Restriction Preserves Memory And Reduces Anxiety Of Aging Mice With Early Enhancement Of Neurovascular Functions, Ishita Parikh, Janet Guo, Kai-Hsiang Chuang, Yu Zhong, Ralf G. Rempe, Jared D. Hoffman, Rachel Armstrong, Björn Bauer, Anika M. S. Hartz, Ai-Ling Lin

Sanders-Brown Center on Aging Faculty Publications

Neurovascular integrity plays an important role in protecting cognitive and mental health in aging. Lifestyle interventions that sustain neurovascular integrity may thus be critical on preserving brain functions in aging and reducing the risk for age-related neurodegenerative disorders. Here we show that caloric restriction (CR) had an early effect on neurovascular enhancements, and played a critical role in preserving vascular, cognitive and mental health in aging. In particular, we found that CR significantly enhanced cerebral blood flow (CBF) and blood-brain barrier function in young mice at 5-6 months of age. The neurovascular enhancements were associated with reduced mammalian target of …

Methods And Systems For Prognosis And Diagnosis Of Brain Damage, Mark A. Lovell, Bert C. Lynn, Melissa A. Bradley-Whitman

Sanders-Brown Center on Aging Faculty Patents

The presently-disclosed subject matter includes methods and devices for diagnosing, prognosing, and treating brain damage in a subject, including brain damage caused by stroke or a traumatic brain injury (TBI). The methods can comprise providing a sample obtained from the subject, exposing the sample to an antibody selective for a visinin-like protein, detecting the presence of a complex that includes the antibody and the visinin-like protein, and diagnosing and/or prognosing the subject as having brain damage if there is the presence of the complex. Embodied methods can also comprise administering a treatment for brain damage if the subject includes the …

Exosome-Mediated Transfer Of Αvβ3 Integrin From Tumorigenic To Nontumorigenic Cells Promotes A Migratory Phenotype., Amrita Singh, Carmine Fedele, Huimin Lu, Marja T. Nevalainen, James H. Keen, Lucia R. Languino

Department of Cancer Biology Faculty Papers

The αvβ3 integrin is known to be highly upregulated during cancer progression and promotes a migratory and metastatic phenotype in many types of tumors. We hypothesized that the αvβ3 integrin is transferred through exosomes and, upon transfer, has the ability to support functional aberrations in recipient cells. Here, for the first time, it is demonstrated that αvβ3 is present in exosomes released from metastatic PC3 and CWR22Pc prostate cancer cells. Exosomal β3 is transferred as a protein from donor to nontumorigenic and tumorigenic cells as β3 protein or mRNA levels remain unaffected upon transcription or translation inhibition in recipient cells. …

Aging-Associated Changes In Microrna Expression Profile Of Internal Anal Sphincter Smooth Muscle: Role Of Microrna-133a., Jagmohan Singh, Boopathi Ettickan, Sankar Addya, Benjamin Philllips, Isidore Rigoutsos, Raymond B. Penn, Satish Rattan

Division of Gastroenterology and Hepatology Faculty Papers

A comprehensive genomic and proteomic, computational, and physiological approach was employed to examine the (previously unexplored) role of microRNAs (miRNAs) as regulators of internal anal sphincter (IAS) smooth muscle contractile phenotype and basal tone. miRNA profiling, genome-wide expression, validation, and network analyses were employed to assess changes in mRNA and miRNA expression in IAS smooth muscles from young vs. aging rats. Multiple miRNAs, including rno-miR-1, rno-miR-340-5p, rno-miR-185, rno-miR-199a-3p, rno-miR-200c, rno-miR-200b, rno-miR-31, rno-miR-133a, and rno-miR-206, were found to be upregulated in aging IAS. qPCR confirmed the upregulated expression of these miRNAs and downregulation of multiple, predicted targets (Eln, Col3a1, Col1a1, Zeb2, …

Symptom Clusters., Andrea M. Barsevick

Department of Medical Oncology Faculty Papers

No abstract provided.

The Targetable Epigenetic Tumor Protein Ezh2 Is Enriched In Intraocular Medulloepithelioma., Sarah E. Avedschmidt, Anna M. Stagner, Ralph C Eagle, George J. Harocopos, Yali Dou, Rajesh C. Rao

Wills Eye Hospital Papers

Purpose: Intraocular medulloepithelioma (IM), the second most common primary neuroepithelial tumor of the eye, can lead to blindness in the affected eye and in rare cases, is deadly. Intraocular medulloepithelioma lacks targetable biomarkers for potential pharmacologic therapy. The purpose of this study was to identify actionable, tumor-specific proteins for potential diagnostic or therapeutic strategies. We hypothesize that the tumor-specific epigenetic enzyme EZH2 is selectively expressed in IM.

Methods: We conducted a retrospective case series study of five IM from five eyes of four children and one adult. Hematoxylin and eosin (H&E) stains of sections from formalin-fixed, paraffin-embedded blocks of IM …

The Relevance Of Sex Differences In Performance Fatigability, Sandra K. Hunter

Exercise Science Faculty Research and Publications

Performance fatigability differs between men and women for a range of fatiguing tasks. Women are usually less fatigable than men, and this is most widely described for isometric fatiguing contractions and some dynamic tasks. The sex difference in fatigability is specific to the task demands so that one mechanism is not universal, including any sex differences in skeletal muscle physiology, muscle perfusion, and voluntary activation. However, there are substantial knowledge gaps about the task dependency of the sex differences in fatigability, the involved mechanisms, and the relevance to clinical populations and with advanced age. The knowledge gaps are in part …

Bleeding With Direct Oral Anticoagulants Vs Warfarin: Clinical Experience., John Eikelboom, Geno J. Merli

Department of Surgery Faculty Papers

The risk of bleeding in the setting of anticoagulant therapy continues to be re-evaluated following the introduction of a new generation of direct oral anticoagulants (DOACs). Interruption of DOAC therapy and supportive care may be sufficient for the management of patients who present with mild or moderate bleeding, but in those with life-threatening bleeding, a specific reversal agent is desirable. We review the phase 3 clinical studies of dabigatran, rivaroxaban, apixaban, and edoxaban in patients with nonvalvular atrial fibrillation, in the context of bleeding risk and management.

Branched Chain Amino Acids Cause Liver Injury In Obese/Diabetic Mice By Promoting Adipocyte Lipolysis And Inhibiting Hepatic Autophagy., Fuyang Zhang, Shihao Zhao, Wenjun Yan, Yunlong Xia, Xiyao Chen, Wei Wang, Jinglong Zhang, Chao Gao, Cheng Peng, Feng Yan, Huishou Zhao, Kun Lian, Yan Lee, Ling Zhang, Wayne Bond Lau, Xin-Liang Ma, Ling Tao

Department of Emergency Medicine Faculty Papers

The Western meat-rich diet is both high in protein and fat. Although the hazardous effect of a high fat diet (HFD) upon liver structure and function is well recognized, whether the co-presence of high protein intake contributes to, or protects against, HF-induced hepatic injury remains unclear. Increased intake of branched chain amino acids (BCAA, essential amino acids compromising 20% of total protein intake) reduces body weight. However, elevated circulating BCAA is associated with non-alcoholic fatty liver disease and injury. The mechanisms responsible for this quandary remain unknown; the role of BCAA in HF-induced liver injury is unclear. Utilizing HFD or …

Evidence Supporting Idarucizumab For The Reversal Of Dabigatran., Charles V. Pollack

Department of Emergency Medicine Faculty Papers

Idarucizumab is a monoclonal antibody fragment specifically targeted to dabigatran. It has demonstrated prompt and durable reversal of the anticoagulant effects of dabigatran in animal studies and phase 1 studies of young, elderly, and renally impaired volunteers. Although elective invasive procedures and most bleeding complications in dabigatran-treated patients can be managed by temporarily stopping dabigatran therapy and using supportive measures, there are rare clinical situations that require urgent reversal of the anticoagulant effect of dabigatran. The effectiveness and safety of 5 g of intravenous idarucizumab is being investigated in a prospective, open-label, single-cohort study in patients with serious bleeding or …

Descriptive Epidemiology Of Karachi Road Traffic Crash Mortality From 2007 To 2014, Rashid Jooma, Masood Ali Shaikh

Department of Surgery Docs

Abstract

According to World Health Organization's estimate for Pakistan, there were 25,781 (95% CI: 20,979-30582) Road Traffic Collision (RTC) fatalities in year 2013. The Road Traffic Injury Research and Prevention Center, collects RTC data on injuries and fatalities from five major public and private hospitals' emergency departments in Karachi. For the eight-year period, from 2007-2014, 9129 fatalities were recorded. Males accounted for 8008 (87.7%) all RTC fatalities. Highest number of fatalities were recorded in the 21-25 age group with 1329 (15.3%) fatalities, while fatalities in 16-30 years old, recorded 3446 (39.7%) of all fatalities out of the total 8684 records …

Toxic Environmental Exposures And Kidney Health In Children., Darcy K. Weidemann, Virginia M. Weaver, Jeffrey J. Fadrowski

Manuscripts, Articles, Book Chapters and Other Papers

High-level exposures to a number of agents are known to have direct nephrotoxic effects in children. A growing body of literature supports the hypothesis that chronic, relatively low-level exposure to various nephrotoxicants may also increase the risk for chronic kidney disease (CKD) or accelerate its progression. In this review we highlight several environmental nephrotoxicants and their association with CKD in children and adolescents. We also discuss unique epidemiological challenges in the use of kidney biomarkers in environmental nephrotoxicology.

Constitutively Activated Pi3k Accelerates Tumor Initiation And Modifies Histopathology Of Breast Cancer, M. R. Sheen, J. D. Marotti, M. J. Allegrezza, M. Rutkowski, J. R. Conejo-Garcia, S. Fiering

Dartmouth Scholarship

The gene encoding phosphatidylinositol 3-kinase catalytic subunit α-isoform (PIK3CA, p110α) is frequently activated by mutation in human cancers. Based on detection in some breast cancer precursors, PIK3CA mutations have been proposed to have a role in tumor initiation. To investigate this hypothesis, we generated a novel mouse model with a Cre-recombinase regulated allele of p110α (myristoylated-p110α, myr-p110α) along with p53fl/fl deletion and KrasG12D also regulated by Cre-recombinase. After instillation of adenovirus-expressing Cre-recombinase into mammary ducts, we found that myr-p110α accelerated breast tumor initiation in a copy number-dependent manner. Breast tumors induced by p53fl/fl;KrasG12D with no or one copy of myr-p110α …

Haploinsufficiency Of The Myc Regulator Mtbp Extends Survival And Delays Tumor Development In Aging Mice., Brian C. Grieb, Kelli Boyd, Ramkrishna Mitra, Christine M. Eischen

Department of Cancer Biology Faculty Papers

Alterations of specific genes can modulate aging. Myc, a transcription factor that regulates the expression of many genes involved in critical cellular functions was shown to have a role in controlling longevity. Decreased expression of Myc inhibited many of the deleterious effects of aging and increased lifespan in mice. Without altering Myc expression, reduced levels of Mtbp, a recently identified regulator of Myc, limit Myc transcriptional activity and proliferation, while increased levels promote Myc-mediated effects. To determine the contribution of Mtbp to the effects of Myc on aging, we studied a large cohort of Mtbp heterozygous mice and littermate matched …

Detrending Changes The Temporal Dynamics Of A Semantic Fluency Task, Steven Lenio, Frances M. Lissemore, Martha Sajatovic, Kathleen A. Smyth, Curtis Tatsuoka, Wojbor A. Woyczynski, Alan J. Lerner

Faculty Scholarship

Objective: To study the dynamics of clustering semantic fluency responses and switching between clusters. Methods: We conducted a cross-sectional study of participants (N = 60) in a study of patient reported outcomes who were given the Saint Louis University Mental Status test. Sixty-second animal naming tests were scored for the timing of responses as well as the clustering of responses into semantic categories. Time scores were detrended to correct for exponential exhaustion and normalize the time scale across individuals. Results: Grouped by number of responses given, low performers (LP; Carter et al., 2012) switched between clusters fewer times than medium …

P70s6k1 (S6k1)-Mediated Phosphorylation Regulates Phosphatidylinositol 4-Phosphate 5-Kinase Type I Γ Degradation And Cell Invasion, Naser Jafari, Qiaodan Zheng, Liqing Li, Wei Li, Lei Qi, Jianyong Xiao, Tianyan Gao, Cai Huang

Markey Cancer Center Faculty Publications

Phosphatidylinositol 4-phosphate 5-kinase type I γ (PIPKIγ90) ubiquitination and subsequent degradation regulate focal adhesion assembly, cell migration, and invasion. However, it is unknown how upstream signals control PIPKIγ90 ubiquitination or degradation. Here we show that p70S6K1 (S6K1), a downstream target of mechanistic target of rapamycin (mTOR), phosphorylates PIPKIγ90 at Thr-553 and Ser-555 and that S6K1-mediated PIPKIγ90 phosphorylation is essential for cell migration and invasion. Moreover, PIPKIγ90 phosphorylation is required for the development of focal adhesions and invadopodia, key machineries for cell migration and invasion. Surprisingly, substitution of Thr-553 and Ser-555 …

When It Isn’T Always Lyme: Expanding The Differential Diagnosis For Acute-Onset Polyarthralgia In The West Virginia Eastern Panhandle, Natalie A. Moffett, Rosemarie Lorenzetti

Marshall Journal of Medicine

This case presentation discusses a 36 year-old female animal care worker presenting with an acute-onset polyarthropathy during the summer months in a Lyme endemic region. Though she appeared to be a good candidate for the diagnosis of Lyme borreliosis, her screening serology reported negative results and alternative diagnoses were considered. Her subsequent diagnosis with parvovirus B19 acts to remind the general practitioner to have confidence in the accuracy of a negative Lyme screen and, upon negative result, to expand the differential to include less common infections including parvovirus B19. It also highlights the need to remember parvovirus B19 in a …

Direct Current-Induced Calcium Trafficking In Different Neuronal Preparations, Andrzej Wieraszko, Zaghloul Ahmed

Publications and Research

The influence of direct current (DC) stimulation on radioactive calcium trafficking in sciatic nerve in vivo and in vitro, spinal cord, and synaptosomes was investigated. The exposure to DC enhanced calcium redistribution in all of these preparations. The effect was dependent on the strength of the stimulation and extended beyond the phase of exposure to DC. The DC-induced increase in calcium sequestration by synaptosomes was significantly reduced by cobalt and rupture of synaptosomes by osmotic shock. Although both anodal and cathodal currents were effective, the experiments with two electrodes of different areas revealed that cathodal stimulation exerted stronger effect. The …

Age-Related Effect Of Viral-Induced Wheezing In Severe Prematurity, Geovanny F. Perez, Amisha Jain, Bassem Kurdi, Rosemary Megalaa, Krishna Pancham, Shehlanoor Huseni, Natalia Isaza, Carlos E. Rodriguez-Martinez, Mary C. Rose, Dinesh Pillai, Gustavo Nino

Pediatrics Faculty Publications

Abstract: Premature children are prone to severe viral respiratory infections in early life, but the age at which susceptibility peaks and disappears for each pathogen is unclear. Methods: A retrospective analysis was performed of the age distribution and clinical features of acute viral respiratory infections in full-term and premature children, aged zero to seven years. Results: The study comprised of a total of 630 hospitalizations (n = 580 children). Sixty-seven percent of these hospitalizations occurred in children born full-term (> 37 weeks), 12% in preterm (32–37 weeks) and 21% in severely premature children (< 32 weeks). The most common viruses identified were rhinovirus (RV; 60%) and respiratory syncytial virus (RSV; 17%). Age-distribution analysis of each virus identified that severely premature children had a higher relative frequency of RV and RSV in their first three years, relative to preterm or full-term children. Additionally, the probability of RV- or RSV-induced wheezing was higher overall in severely premature children less than three years old. Conclusions: Our results indicate that the …

A Proteogenomic Approach To Understanding Myc Function In Metastatic Medulloblastoma Tumors., Jerome A Staal, Yanxin Pei, Brian R. Rood

Pediatrics Faculty Publications

Brain tumors are the leading cause of cancer-related deaths in children, and medulloblastoma is the most prevalent malignant childhood/pediatric brain tumor. Providing effective treatment for these cancers, with minimal damage to the still-developing brain, remains one of the greatest challenges faced by clinicians. Understanding the diverse events driving tumor formation, maintenance, progression, and recurrence is necessary for identifying novel targeted therapeutics and improving survival of patients with this disease. Genomic copy number alteration data, together with clinical studies, identifies c-MYC amplification as an important risk factor associated with the most aggressive forms of medulloblastoma with marked metastatic potential. Yet despite …

Interleukin-17a Promotes Cd8 T Cell Cytotoxicity To Facilitate West Nile Virus Clearance, Amber M. Paul, Dhiraj Acharya, Penghua Wang, Jianfeng Dai, David Gate

Publications

CD8 T cells are crucial components of immunity and play a vital role in recovery from West Nile virus (WNV) infection. Here, we identify a previously unrecognized function of interleukin-17A (IL-17A) in inducing cytotoxic-mediator gene expression and promoting CD8 T cell cytotoxicity against WNV infection in mice. We find that IL-17A-deficient (Il17a/) mice are more susceptible to WNV infection and develop a higher viral burden than wild-type (WT) mice. Interestingly, the CD8 T cells isolated from Il17a/ mice are less cytotoxic and express lower levels of cytotoxic-mediator genes, which can be restored by supplying recombinant IL-17A in vitro and in …

Pleckstrin Homology (Ph) Domain Leucine-Rich Repeat Protein Phosphatase Controls Cell Polarity By Negatively Regulating The Activity Of Atypical Protein Kinase C, Xiaopeng Xiong, Xin Li, Yang-An Wen, Tianyan Gao

Markey Cancer Center Faculty Publications

The proper establishment of epithelial polarity allows cells to sense and respond to signals that arise from the microenvironment in a spatiotemporally controlled manner. Atypical PKCs (aPKCs) are implicated as key regulators of epithelial polarity. However, the molecular mechanism underlying the negative regulation of aPKCs remains largely unknown. In this study, we demonstrated that PH domain leucine-rich repeat protein phosphatase (PHLPP), a novel family of Ser/Thr protein phosphatases, plays an important role in regulating epithelial polarity by controlling the phosphorylation of both aPKC isoforms. Altered expression of PHLPP1 or PHLPP2 disrupted polarization of Caco2 cells grown in 3D cell cultures …

Neuromodulation, Stephen Silberstein

Department of Neurology Faculty Papers

Neuromodulation is a new promising treatment for headache disorders. It consists of peripheral nerve neurostimulation and central neurostimulation. © 2016, Touch Briefings. All rights reserved.

Il-10 Plays An Important Role In The Control Of Inflammation But Not In The Bacterial Burden In S. Epidermidis Cns Catheter Infection., Yenis M. Gutierrez-Murgas, Gwenn Skar, Danielle Ramirez, Matthew Beaver, Jessica N. Snowden

Journal Articles: Pathology and Microbiology

BACKGROUND: Shunt infection is a frequent and serious complication in the surgical treatment in hydrocephalus. Previous studies have shown an attenuated immune response to these biofilm-mediated infections. We proposed that IL-10 reduces the inflammatory response to Staphylococcus epidermidis (S. epidermidis) CNS catheter infection.

METHODS: In this study, a murine model of catheter-associated S. epidermidis biofilm infection in the CNS was generated based on a well-established similar model for S. aureus. The catheters were pre-coated with a clinically derived biofilm-forming strain of S. epidermidis (strain 1457) which were then stereotactically implanted into the lateral left ventricle of 8-week-old C57BL/6 and IL-10 …