Digital Commons Network^™

Year In Review, Scott A. Waldman, Andre Terzic

Department of Pharmacology and Experimental Therapeutics Faculty Papers

If examination of journal performance is a surrogate for the vitality of a discipline, the continued ascension of Clinical Pharmacology and Therapeutics (CPT) bodes well for the evolution and practice of human therapeutics in this decade. CPT has excelled as the authoritative, cross-disciplinary journal in experimental and clinical medicine devoted to publishing advances in the nature, action, efficacy and evaluation of therapeutics in humans. Building on a foundation that established the core tenets, and a framework providing the structural integrity for the field, CPT was conceived by visionary precedent editors and editorial teams who were themselves leaders of …

Kidney Injury Molecule-1 (Kim-1) As An Early Detection Tool For Acute Kidney Injury And Other Renal Diseases, John Fontanilla, Md, Won K. Han, M.D

Department of Medicine Faculty Papers

Introduction: Although serum creatinine is the standard metric tool for the detection of renal injury, its lack of sensitivity has made the early diagnosis of acute kidney injury (AKI) very difficult.  In fact, the absence of sensitive AKI biomarkers has impaired progress in the nephrology field and had a detrimental effect on the design and outcome of AKI clinical trials.  Recently, several proteins have shown potential in the early detection of acute and chronic kidney injuries.

Areas covered: This review discusses the current status of kidney injury molecule-1 (KIM-1) as a potential diagnostic tool in patients with various acute …

Expression Of Aldehyde Dehydrogenase In Dysplastic Lesions Arising From Inflammatory Bowel Disease, Adam D. Toll, Bruce M. Boman, Juan P. Palazzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Conclusion: Our study demonstrates ALDH1 is significantly expressed in dysplatic lesions arising from IBD. ALDH1-expression in cancer stem cells suggest an important causative role in the progression to cancer in IBD. Although we found high sensitivity for dysplasia, the specificity was poor. In addition to neoplasia, ALDH1-expressing stem cells proliferate in response to chronic inflammation, accounting for the cases of inflammatory atypia with positive ALDHI1 expression.

Fus Transgenic Rats Develop The Phenotypes Of Amyotrophic Lateral Sclerosis And Frontotemporal Lobar Degeneration., Cao Huang, Hongxia Zhou, Jianbin Tong, Han Chen, Yong-Jian Liu, Dian Wang, Xiaotao Wei, Xu-Gang Xia

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Fused in Sarcoma (FUS) proteinopathy is a feature of frontotemporal lobar dementia (FTLD), and mutation of the fus gene segregates with FTLD and amyotrophic lateral sclerosis (ALS). To study the consequences of mutation in the fus gene, we created transgenic rats expressing the human fus gene with or without mutation. Overexpression of a mutant (R521C substitution), but not normal, human FUS induced progressive paralysis resembling ALS. Mutant FUS transgenic rats developed progressive paralysis secondary to degeneration of motor axons and displayed a substantial loss of neurons in the cortex and hippocampus. This neuronal loss was accompanied by ubiquitin aggregation and …

Adrenal Activity During Repeated Long-Access Cocaine Self-Administration Is Required For Later Crf-Induced And Crf-Dependent Stressor-Induced Reinstatement In Rats, Evan N. Graf, Michael A. Hoks, Jean Baumgardner, Jose Sierra, Oliver Vranjkovic, Colin Bohr, David A. Baker, John R. Mantsch

Biomedical Sciences Faculty Research and Publications

Understanding the neurobiological processes that contribute to the establishment and expression of stress-induced regulation of cocaine use in addicted individuals is important for the development of new and better treatment approaches. It has been previously shown that rats self-administering cocaine under long-access conditions (6 h daily) display heightened susceptibility to the reinstatement of extinguished cocaine seeking by a stressor, electric footshock, or i.c.v. administration of the stressor-responsive neuropeptide, corticotropin-releasing factor (CRF). This study tested the hypothesis that adrenal responsiveness during earlier long-access cocaine self-administration (SA) is necessary for the establishment of later CRF-dependent stress-induced reinstatement. Reinstatement by footshock, but not …

Repeated N-Acetyl Cysteine Reduces Cocaine Seeking In Rodents And Craving In Cocaine-Dependent Humans, Shelley L. Amen, Linda B. Piacentine, Muhammad E. Ahmad, Shi-Jiang Li, John R. Mantsch, Robert C. Risinger, David A. Baker

Biomedical Sciences Faculty Research and Publications

Addiction is a chronic relapsing disorder hypothesized to be produced by drug-induced plasticity that renders individuals vulnerable to craving-inducing stimuli such as re-exposure to the drug of abuse. Drug-induced plasticity that may result in the addiction phenotype includes increased excitatory signaling within corticostriatal pathways that correlates with craving in humans and is necessary for reinstatement in rodents. Reduced cystine–glutamate exchange by system x_c– appears to contribute to heightened excitatory signaling within the striatum, thereby posing this as a novel target in the treatment of addiction. In the present report, we examined the impact of repeated N-acetyl cysteine, …

Hedgehog Inhibition Promotes A Switch From Type Ii To Type I Cell Death Receptor Signaling In Cancer Cells., Satoshi Kurita, Justin L. Mott, Sophie C. Cazanave, Christian D. Fingas, Maria E. Guicciardi, Steve F. Bronk, Lewis R. Roberts, Martin E. Fernandez-Zapico, Gregory J. Gores

Journal Articles: Biochemistry & Molecular Biology

TRAIL is a promising therapeutic agent for human malignancies. TRAIL often requires mitochondrial dysfunction, referred to as the Type II death receptor pathway, to promote cytotoxicity. However, numerous malignant cells are TRAIL resistant due to inhibition of this mitochondrial pathway. Using cholangiocarcinoma cells as a model of TRAIL resistance, we found that Hedgehog signaling blockade sensitized these cancer cells to TRAIL cytotoxicity independent of mitochondrial dysfunction, referred to as Type I death receptor signaling. This switch in TRAIL requirement from Type II to Type I death receptor signaling was demonstrated by the lack of functional dependence on Bid/Bim and Bax/Bak, …

Differential Subcellular Distribution Of Rat Brain Dopamine Receptors And Subtype-Specific Redistribution Induced By Cocaine., Pamela J Voulalas, John Schetz, Ashiwel S Undieh

College of Pharmacy Faculty Papers

We investigated the subcellular distribution of dopamine D(1), D(2) and D(5) receptor subtypes in rat frontal cortex, and examined whether psychostimulant-induced elevation of synaptic dopamine could alter the receptor distribution. Differential detergent solubilization and density gradient centrifugation were used to separate various subcellular fractions, followed by semi-quantitative determination of the relative abundance of specific receptor proteins in each fraction. D(1) receptors were predominantly localized to detergent-resistant membranes, and a portion of these receptors also floated on sucrose gradients. These properties are characteristic of proteins found in lipid rafts and caveolae. D(2) receptors exhibited variable distribution between cytoplasmic, detergent-soluble and detergent-resistant …

Correlation Of P16ink4a Expression And Hpv Copy Number With Cellular Ftir Spectroscopic Signatures Of Cervical Cancer Cells, Kamila Ostrowska, Amaya Garcia, Aidan Meade, Alison Malkin, Ifeoluwapo Okewumi, John O’Leary, Cara Martin, Hugh Byrne, Fiona Lyng

Articles

Cervical cancer, a potentially preventable disease, has its main aetiology in infection by high risk human papillomavirus (HR-HPV). Approaches to improving cervical cancer screening and diagnostic methodologies include molecular biological analysis, targeting of biomarker proteins, but also exploration and implementation of new techniques such as vibrational spectroscopy. This study correlates the biomarker protein p16^INK4A expression levels dependent on HPV copy number with the infrared absorption spectral signatures of the cervical cancer cell lines, HPV negative C33A, HPV-16 positive SiHa and CaSki and HPV-18 positive HeLa. Confocal fluorescence microscopy demonstrated that p16^INK4A is expressed in all investigated cell lines …

Epidermal Growth Factor Receptor Overexpression In Resected Pancreatic Cancer, Amit Mahipal, Mary J. Mcdonald, Agnieszka Witkiewicz, Brian I. Carr

Department of Medical Oncology Faculty Papers

Conclusions:

Membrane EGFR overexpression is associated with poorer clinical outcomes in patients with pancreatic cancer receiving adjuvant therapy post resection.

Cytoplasmic EGFR overexpression is not associated with clinical outcomes.

Low Levels Of Hydrogen Peroxide Stimulate Corneal Epithelial Cell Adhesion, Migration, And Wound Healing, Qing Pan, Wen-Ya Qiu, Ya-Nan Huo, Yu-Feng Yao, Marjorie F. Lou

School of Veterinary and Biomedical Sciences: Faculty Publications

PURPOSE. Intracellular reactive oxygen species have been reported to associate with growth factor and integrin signalings in promoting cell adhesion in many cell types. This study is to explore if exogenous H2O2 at low levels can be beneficial to cell adhesion, migration, and wound healing.

METHODS. Primary rabbit corneal epithelial cells treated with 0–70 M H2O2 were tested for viability by MTT assay, adhesion by centrifugation assay, focal contacts of vinculin and F-actin by immunofluorescence, activated Src(pY416), EGF receptor (pY845), vinculin(pY1065), FAK(pY397), and FAK(pY576) by immunoblotting. Cell migration was examined with 0–50 M H2O2 using the scratch wound technique. Corneal …

Posterior Reversible Encephalopathic Syndrome: Treating The Puzzling Syndrome Of Pres, Lorraine Valeriano Bsn, Rn, Cnrn

Patient Care Services / Nursing

No abstract provided.

Improving Outcomes For Hispanic Patients Undergoing Peginterferon/Ribavirin Therapy For Chronic Hepatitis C In An Internist-Led, Multidisciplinary, Multi-Cultural Practice: A Unique Application Of The Medical, Joseph L. Yozviak Do, Facp, Orlando J. Penaloza Md, Facp, Judith A. Knoop

Department of Medicine

No abstract provided.

Open To The Public: Meeting The Nursing Challenge Of A Diverse America, Bonnie Wasilowsky Rn, Bspa-Hca, Cnrn

Patient Care Services / Nursing

No abstract provided.

Igf2 Promotes Activation Of Estrogen Receptors In Basal-Like Breast Cancer Cells, Angelique Richardson

Loma Linda University Electronic Theses, Dissertations & Projects

The autocrine-paracrine effects of IGF2 are important in the growth and differentiation of normal breast. In breast cancer (BC), IGF2 is initially stimulated by estrogen, progesterone and prolactin to regulate proliferation and cancer progression. These actions are mediated by the IGF-1R and insulin receptor A (IR-A) both members of the tyrosine- kinase receptors family. The activation of Estrogen Receptor (ER) is also very important in BC growth and progression. As BC progresses to estrogen-independent growth, the IGF-1R and the estrogen receptor (ER) interact in crosstalk mechanisms that are synergistic and results in enhanced activation of both receptors signaling cascades. This …

A Pilot Study Of The Prevalence Of Leg Pain Among Women With Endometriosis, Stacey A. Missmer, Geoffrey M. Bove

Biomedical Sciences Faculty Publications

Radiating leg pain is a common symptom presenting in manual therapy practices. Although this symptom has been reported as a complication of endometriosis, its prevalence and characteristics have not been studied. We surveyed members of a national endometriosis support group with endometriosis using a self-administered, mailed questionnaire. The main outcome measures were the prevalence and characteristics of leg pain. Of 94 respondents, leg pain was reported by 48 women (51%), and was bilateral in 59% of these symptomatic women. The likelihood of experiencing leg pain was related to weight gain since age 18, age, and height. The most common treatments …

Optimality In Neural Adaptation, Adrienne Fairhall

Systems Science Friday Noon Seminar Series

Nervous systems tune themselves to the statistical structure of the stimuli they encounter. This sensitivity to statistics appears in phenomena ranging over many timescales, from the adaptation of vision to a rapid change in light level to the loss of ability to distinguish the sounds of non-native languages. While multiple neural mechanisms contribute to this on-line learning of stimulus distributions, we show that the intrinsic nonlinearities of single neurons provide them with the ability to represent time-varying stimuli optimally. While such sensitivity to stimulus statistics does not require learning, slower timescales of adaptation are consistent with optimal inference of statistical …

Rho Activation Of Mdia Formins Is Modulated By An Interaction With Inverted Formin 2 (Inf2), Hua Sun, Johannes S. Schlondorff, Elizabeth J. Brown, Henry N. Higgs, Martin R. Pollak

Dartmouth Scholarship

Inverted formin 2 (INF2) encodes a member of the diaphanous subfamily of formin proteins. Mutations in INF2 cause human kidney disease characterized by focal and segmental glomerulosclerosis. Disease-causing mutations occur only in the diaphanous inhibitory domain (DID), suggesting specific roles for this domain in the pathogenesis of disease. In a yeast two-hybrid screen, we identified the diaphanous autoregulatory domains (DADs) of the mammalian diaphanous-related formins (mDias) mDia1, mDia2, and mDia 3 as INF2_DID-interacting partners. The mDias are Rho family effectors that regulate actin dynamics. We confirmed in vitro INF2_DID/mDia_DAD binding by biochemical assays, confirmed the in vivo interaction of these …

Transcriptional Profiling Of Peripheral Blood Mononuclear Cells In Pancreatic Cancer Patients Identifies Novel Genes With Potential Diagnostic Utility., Michael J. Baine, Subhankar Chakraborty, Lynette M. Smith, Kavita Mallya, Aaron R. Sasson, Randall E. Brand, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

BACKGROUND: It is well known that many malignancies, including pancreatic cancer (PC), possess the ability to evade the immune system by indirectly downregulating the mononuclear cell machinery necessary to launch an effective immune response. This knowledge, in conjunction with the fact that the trancriptome of peripheral blood mononuclear cells has been shown to be altered in the context of many diseases, including renal cell carcinoma, lead us to study if any such alteration in gene expression exists in PC as it may have diagnostic utility.

METHODS AND FINDINGS: PBMC samples from 26 PC patients and 33 matched healthy controls were …

Impaired Memory Cd8 T-Cell Responses Against An Immunodominant Retroviral Cryptic Epitope, Melanie R. Rutkowski, Cynthia A. Stevens, William R. Green

Dartmouth Scholarship

The immunodominant cryptic epitope SYNTGRFPPL, encoded within open reading frame 2 of the LP-BM5 retroviral gag gene, is critical for protection against retroviral-induced pathogenesis. The goal of this study was to dissect the memory response against this unique immunodominant cryptic epitope. Unlike the protective acute effector population of SYNTGRFPPL-specific CD8 T cells, long-lived SYNTGRFPPL-specific CD8 T cells lacked the ability to protect susceptible mice infected with LP-BM5 retrovirus. Compared to memory CD8 T cells against a conventional epitope with similar MHC-I specificity, primed and restimulated using similar conditions, long-lived SYNTGRFPPL-specific CD8 T cells were impaired in their ability to recall …

Pressure Distribution Over The Palm Region During Forward Falls On The Outstretched Hands, Woochol J. Choi, Stephen N. Robinovitch

Physical Therapy Faculty Articles and Research

Falls on the outstretched hands are the cause of over 90% of wrist fractures, yet little is known about bone loading during this event. We tested how the magnitude and distribution of pressure over the palm region during a forward fall is affected by foam padding (simulating a glove) and arm configuration, and by the faller’s body mass index (BMI) and thickness of soft tissues over the palm region.

Thirteen young women with high (n=7) or low (n=6) BMI participated in a “torso release experiment” that simulated falling on both outstretched hands with the arm inclined either at 20° or …

Patterns Of Microrna Expression In Normal And Early Alzheimer's Disease Human Temporal Cortex: White Matter Versus Gray Matter, Wang-Xia Wang, Qingwei Huang, Yanling Hu, Arnold J. Stromberg, Peter T. Nelson

Pathology and Laboratory Medicine Faculty Publications

MicroRNA (miRNA) expression was assessed in human cerebral cortical gray matter (GM) and white matter (WM) in order to provide the first insights into the difference between GM and WM miRNA repertoires across a range of Alzheimer's disease (AD) pathology. RNA was isolated separately from GM and WM portions of superior and middle temporal cerebral cortex (N = 10 elderly females, postmortem interval < 4 h). miRNA profiling experiments were performed using state-of-the-art Exiqon^© LNA-microarrays. A subset of miRNAs that appeared to be strongly expressed according to the microarrays did not appear to be conventional miRNAs according to Northern blot analyses. Some well-characterized miRNAs were substantially enriched in WM …

Clinical Translational Science 2020: Disruptive Innovation Redefines The Discovery-Application Enterprise, Scott A. Waldman, Andre Terzic

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Vaccines, analgesia, and antibiotics embody some of the most

enduring therapeutic breakthroughs that have transformed

medicine. Building on such fine paradigms of biomedical

innovation, the evolution of technologies has increasingly

sparked spectacular advances across the continuum of wellness

and disease-spanning medical and surgical specialties. Discovery

science—fueled by government and private sector resources—has

systematically instituted the principles of modern healthcare

delivery ensuring that medical practice is based on up-to-date

scientifi c evidence. Th e harmony between science, technology,

and resources has culminated in a golden age of discovery and

translation, eradicating infections, curing cancers, and palliating

endocrine and metabolic diseases. Indeed, …

Comparative Gender Analysis Of The Efficacy And Safety Of Atazanavir/Ritonavir And Lopinavir/Ritonavir At 96 Weeks In The Castle Study., Kathleen E Squires, Margaret Johnson, Rong Yang, Jonathan Uy, Louise Sheppard, Judith Absalon, Donnie Mcgrath

Department of Medicine Faculty Papers

OBJECTIVES: To examine whether the overall results of the CASTLE study pertain to both genders, we analysed the efficacy and safety of atazanavir/ritonavir and lopinavir/ritonavir in 277 female and 606 male patients in the open-label, multinational trial over 96 weeks. The trial is registered with ClinicalTrials.gov, number NCT00272779.

METHODS: Treatment-naive patients aged ≥ 18 years with HIV-1 RNA ≥ 5000 copies/mL were randomized to receive either atazanavir/ritonavir 300/100 mg once daily or lopinavir/ritonavir 400/100 mg twice daily, with fixed-dose tenofovir/emtricitabine 300/200 mg once daily.

RESULTS: At week 96, confirmed virological response rates (HIV RNA <50 copies>/mL; intent-to-treat analysis) were higher in …

Three Dimensional Projection Environment For Molecular Design And Surgical Simulation, Matthew Wampole, Eric Wickstrom, Chang-Po Chen, Devakumar Devadhas, Yuan-Yuan Jin, Jeffrey M. Sanders, John C. Kairys, Martha L. Ankeny, Rui Hu, Kenneth E. Barner, Karl V. Steiner, Mathew L. Thakur

Department of Biochemistry and Molecular Biology Faculty Papers

Poster presented at "Medicine Meets Virtual Reality" conference February 8-12, 2011 in Newport Beach, California.

Conclusions:

Turning 2D CT/PET slices into 3D objects assists in understanding the topology surrounding tumor masses. Incorporating the visual and physical characteristics of a patient’s anatomy will provide surgeons with an informative pre-operative tool to plan and practice the operation before the first incision. Including haptic feedback provides a familiar 'feel' to surgeons as they palpate the target organ, trying to locate the tumor and determine how large a margin of resection will be needed. The development of genetic PET imaging and contrast CT into …

Follicle-Stimulating Hormone Promotes Rank Expression On Human Monocytes, Joseph G. Cannon, Barbara Kraj, Gloria Sloan

School of Medical Diagnostics & Translational Sciences Publications

Elevated serum concentrations of follicle-stimulating hormone (FSH) are associated with diminished bone density in women, beginning years before menopause and the decline in estradiol. We hypothesized that FSH promotes development of myeloid cells toward the bone-resorbing osteoclast phenotype. This was tested by isolating peripheral blood mononuclear cells from nine healthy adults, incubating them in the presence of FSH at three different concentrations spanning the physiological range, and then measuring the expression of receptor activator for NF-κB (RANK, a surface marker for osteoclasts) on CD14+ cells by flow cytometry. In the absence of FSH, 3.3±0.5% of the cells expressed high levels …

Serum 25-Hydroxyvitamin D Level And Acute-Phase Reaction Following Initial Intravenous Bisphosphonate., Tarak Srivastava, Hongying Dai, Connie J. Haney, Uri S. Alon

Manuscripts, Articles, Book Chapters and Other Papers

No abstract provided.

Correction: Epistatic Interactions In Genetic Regulation Of T-Pa And Pai-1 Levels In A Ghanaian Population, Nadia M. Penrod, Kwabena A. Poku, Douglas E. Vaughn, Folkert W. Asselbergs, Nancy J. Brown, Jason H. Moore, Scott M. Williams

Dartmouth Scholarship

The proteins, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1), act in concert to balance thrombus formation and degradation, thereby modulating the development of arterial thrombosis and excessive bleeding. PAI-1 is upregulated by the renin-angiotensin system (RAS), specifically by angiotensin II, the product of angiotensin converting enzyme (ACE) cleavage of angiotensin I, which is produced by the cleavage of angiotensinogen (AGT) by renin (REN). ACE indirectly stimulates the release of t-PA which, in turn, activates the corresponding fibrinolytic system. Single polymorphisms in these pathways have been shown to significantly impact plasma levels of t-PA and PAI-1 differently in …

Aberrant Promoter Cpg Methylation Is A Mechanism For Impaired Phd3 Expression In A Diverse Set Of Malignant Cells., Trenton L. Place, Matthew P. Fitzgerald, Sujatha Venkataraman, Sabine U. Vorrink, Adam J. Case, Melissa L.T. Teoh, Frederick E. Domann

Journal Articles: Cellular & Integrative Physiology

BACKGROUND: The prolyl-hydroxylase domain family of enzymes (PHD1-3) plays an important role in the cellular response to hypoxia by negatively regulating HIF-α proteins. Disruption of this process can lead to up-regulation of factors that promote tumorigenesis. We observed decreased basal expression of PHD3 in prostate cancer tissue and tumor cell lines representing diverse tissues of origin. Furthermore, some cancer lines displayed a failure of PHD3 mRNA induction when introduced to a hypoxic environment. This study explores the mechanism by which malignancies neither basally express PHD3 nor induce PHD3 under hypoxic conditions.

METHODOLOGY/PRINCIPAL FINDINGS: Using bisulfite sequencing and methylated DNA enrichment …

Prolactin-Induced Mouse Mammary Carcinomas Model Estrogen Resistant Luminal Breast Cancer., Lisa M Arendt, Debra E Rugowski, Tara A Grafwallner-Huseth, Maria Jose Garcia-Barchino, Hallgeir Rui, Linda A Schuler

Kimmel Cancer Center Faculty Papers

INTRODUCTION: Tumors that express estrogen receptor alpha (ERα+) comprise 75% of breast cancers in women. While treatments directed against this receptor have successfully lowered mortality rates, many primary tumors initially or later exhibit resistance. The paucity of murine models of this "luminal" tumor subtype has hindered studies of factors that promote their pathogenesis and modulate responsiveness to estrogen-directed therapeutics. Since epidemiologic studies closely link prolactin and the development of ERα+ tumors in women, we examined characteristics of the aggressive ERα+ and ERα- carcinomas which develop in response to mammary prolactin in a murine transgenic model (neu-related lipocalin- prolactin (NRL-PRL)). To …