Digital Commons Network^™

Effect Of Kidney Function On Drug Kinetics And Dosing In Neonates, Infants, And Children., Frederique Rodieux, Melanie Wilbaux, Johannes N. Van Den Anker, Marc Pfister

Pediatrics Faculty Publications

Neonates, infants, and children differ from adults in many aspects, not just in age, weight, and body composition. Growth, maturation and environmental factors affect drug kinetics, response and dosing in pediatric patients. Almost 80% of drugs have not been studied in children, and dosing of these drugs is derived from adult doses by adjusting for body weight/size. As developmental and maturational changes are complex processes, such simplified methods may result in subtherapeutic effects or adverse events. Kidney function is impaired during the first 2 years of life as a result of normal growth and development. Reduced kidney function during childhood …

Multi-Ancestry Genome-Wide Association Study Of 21,000 Cases And 95,000 Controls Identifies New Risk Loci For Atopic Dermatitis, Lavinia Paternoster, Marie Standl, Johannes Waage, Hansjörg Baurecht, Melanie Hotze, David P. Strachan, John A. Curtin, Klaus Bønnelykke, Chao Tian, Atsushi Takahashi, Jorge Esparza-Gordillo, Alexessander C. Alves, Jacob P. Thyssen, Herman T. Den Dekker, Manuel A. Ferreira, Elisabeth Altmaier, Patrick M. Sleiman, Feng Li Xiao, Juan R. Gonzalez, Ingo Marenholz, Birgit Kalb, Maria Pino Yanes, Cheng-Jian Xu, Lisbeth Carstensen, Maria M. Groen-Blokhuis, Cristina Venturini, Craig E. Pennell, Sheila J. Barton, Albert M. Levin, Ivan Curjuric, Mariona Bustamante, Eskil Kreiner-Møller, Gabrielle A. Lockett, Jonas Bacelis, Supinda Bunyavanich, Rachel A. Myers, Anja Matanovic, Ashish Kumar, Joyce Y. Tung, Tomomitsu Hirota, Michiaki Kubo, Wendy L. Mcardle, A J. Henderson, John P. Kemp, Jie Zheng, George Davey Smith, Franz Rüschendorf, Anja Bauerfeind, Min Ae Lee-Kirsch, Andreas Arnold, Georg Homuth, Carsten O. Schmidt, Elisabeth Mangold, Sven Cichon, Thomas Keil, Elke Rodríguez, Annette Peters, Andre Franke, Wolfgang Lieb, Natalija Novak, Regina Fölster-Holst, Momoko Horikoshi, Juha Pekkanen, Sylvain Sebert, Lise L. Husemoen, Niels Grarup, Johan C. De Jongste, Fernando Rivadeneira, Albert Hofman, Vincent Jaddoe, Suzanne Gma Pasmans, Niels J. Elbert, André G. Uitterlinden, Guy B. Marks, Philip J. Thompson, Melanie C. Matheson, Colin F. Robertson, Janina S. Ried, Jin Li, Xian Bo Zuo, Xiao Dong Zheng, Xian Yong Yin, Liang Dan Sun, Maeve A. Mcaleer, Grainne M O'Regan, Caoimhe Fahy, Linda E. Campbell, Milan Macek, Michael Kurek, Donglei Hu, Celeste Eng, Dirkje S. Postma, Bjarke Feenstra, Frank Geller, Jouke Jan Hottenga, Christel M. Middeldorp, Pirro Hysi, Veronique Bataille, Tim Spector, Carla Mt Tiesler, Elisabeth Thiering, Badri Pahukasahasram, James J. Yang, Medea Imboden, Scott Huntsman, Natàlia Vilor-Tejedor, Caroline L Relton, Ronny Myhre, Wenche Nystad, Adnan Custovic, Scott T Weiss, Deborah A Meyers, Cilla Söderhäll, Erik Melén, Carole Ober, Benjamin A Raby, Angela Simpson, Bo Jacobsson, John W Holloway, Hans Bisgaard, Jordi Sunyer, Nicole M Probst Hensch, Keoki L. Williams, Keith M Godfrey, Carol A Wang, Dorret I Boomsma, Mads Melbye, Gerard H Koppelman, Deborah Jarvis, Wh Irwin Mclean, Alan D Irvine, Xue Jun Zhang, Hakon Hakonarson, Christian Gieger, Esteban G Burchard, Nicholas G Martin, Liesbeth Duijts, Allan Linneberg, Marjo-Riitta Jarvelin, Markus M Noethen, Susanne Lau, Norbert Hübner, Young-Ae Lee, Mayumi Tamari, David A Hinds, Daniel Glass, Sara J Brown, Joachim Heinrich, David M Evans, Stephan Weidinger

Center for Health Policy and Health Services Research Articles

Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with …

Emerging Biomarkers In Psoriatic Arthritis, So Yeon Paek, Ling Han, Matthew Weiland, Chuan-Jian Lu, Kathleen Maksimowicz-Mckinnon, Li Zhou, Henry W. Lim, James T. Elder, Qing-Sheng Mi

Dermatology Articles

Psoriasis is an immune-mediated skin disease which affects 2-4% of the worldwide population. Approximately 20-30% of patients with psoriasis develop psoriatic arthritis (PsA), a frequently destructive and disabling condition. As skin manifestations precede joint symptoms in nearly all patients with PsA, identification of biomarkers for early prediction of joint damage is an important clinical need. Because not all patients with PsA respond to treatment in the same fashion, identification of biomarkers capable of predicting therapeutic response is also imperative. Here, we review existing literature and discuss current investigations to identify potential biomarkers for PsA disease activity, with particular emphasis on …

New Insights Into Micrornas In Skin Wound Healing, Fatima Fahs, Xinling Bi, Fu-Shin Yu, Li Zhou, Qing-Sheng Mi

Dermatology Articles

Chronic wounds are a major burden to overall healthcare cost and patient morbidity. Chronic wounds affect a large portion of the US, and billions of healthcare dollars are spent in their treatment and management. microRNAs (miRNAs) are small, noncoding double-stranded RNAs that post-transcriptionally downregulate the expression of protein-coding genes. Studies have identified miRNAs involved in all three phases of wound healing including inflammation, proliferation, and remodeling. Some miRNAs have been demonstrated in vitro with primary keratinocyte wound healing model and in vivo with mouse wound healing model through regulation of miRNA expression to affect the wound healing process. This review …

Safety And Immunogenicity Of Human Serum Albumin-Free Mmr Vaccine In Us Children Aged 12-15 Months., Maurice A. Mufson, Clemente Diaz, Michael Leonardi, Christopher J. Harrison, Stanley Grogg, Antonio Carbayo, Simon Carlo-Torres, Robert Jeanfreau, Ana Quintero-Del-Rio, Gisele Bautista, Michael Povey, Christopher Da Costa, Ouzama Nicholson, Bruce L. Innis

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: M-M-R(TM)II (MMRII; Merck & Co) is currently the only measles-mumps-rubella (MMR) vaccine licensed in the United States. Another licensed vaccine would reinforce MMR supply. This study assessed the immunogenicity of a candidate vaccine (Priorix(TM), GlaxoSmithKline Vaccines [MMR-RIT]) when used as a first dose among eligible children in the United States.

METHODS: In this exploratory Phase-2, multicenter, observer-blind study, 1220 healthy subjects aged 12-15 months were randomized (3:3:3:3) and received 1 dose of 1 of 3 MMR-RIT lots with differing mumps virus titers (MMR-RIT-1 [4.8 log10]; MMR-RIT-2 [4.1 log10]; MMR-RIT-3 [3.7 log10] CCID50) or MMRII co-administered with hepatitis A vaccine …

Multivariate Criteria Most Accurately Distinguish Cardiac From Noncardiac Causes Of Dyspnea, Mirza Nubair Ahmad, Syed Hasan Yusuf, Rafath Ullah, Mirza Mujadil Ahmad, Mary K Ellis, Haroon Yousaf, Timothy E Paterick, Khawaja Afzal Ammar

The Texas Heart Institute Journal

Cardiopulmonary exercise testing provides oxygen pulse as a continuous measure of stroke volume, which is superior to other stress-testing methods in which systolic function is measured at baseline and at peak stress. However, the optimal peak oxygen pulse criterion for distinguishing cardiac from noncardiac causes of exercise limitation is unknown.

In comparing several peak oxygen pulse criteria against the clinical standard of cardiopulmonary exercise testing, we retrospectively studied 54 consecutive patients referred for cardiopulmonary exercise testing. These exercise tests included measurement of oxygen consumption, carbon dioxide production, breathing reserve, arterial blood gases at baseline and at peak stress, exercise electrocardiogram, …

Actin Filaments Target The Oligomeric Maturation Of The Dynamin Gtpase Drp1 To Mitochondrial Fission Sites, Wei-Ke Ji, Anna L. Hatch, Ronald A. Merrill, Stefan Strack, Henry N. Higgs

Dartmouth Scholarship

While the dynamin GTPase Drp1 plays a critical role during mitochondrial fission, mechanisms controlling its recruitment to fission sites are unclear. A current assumption is that cytosolic Drp1 is recruited directly to fission sites immediately prior to fission. Using live-cell microscopy, we find evidence for a different model, progressive maturation of Drp1 oligomers on mitochondria through incorporation of smaller mitochondrially-bound Drp1 units. Maturation of a stable Drp1 oligomer does not forcibly lead to fission. Drp1 oligomers also translocate directionally along mitochondria. Ionomycin, a calcium ionophore, causes rapid mitochondrial accumulation of actin filaments followed by Drp1 accumulation at the fission site, …

Cyclin-Dependent Kinase Inhibitor P1446a Induces Apoptosis In A Jnk/P38 Mapk-Dependent Manner In Chronic Lymphocytic Leukemia B-Cells, Cody Paiva, J. Claire Godbersen, Ryan S. Soderquist, Taylor Rowland, Sumner Kilmarx

Dartmouth Scholarship

CDK (cyclin-dependent kinase) inhibitors have shown remarkable activity in CLL, where its efficacy has been linked to inhibition of the transcriptional CDKs (7 and 9) and deregulation of RNA polymerase and short-lived pro-survival proteins such as MCL1. Furthermore, ER (endoplasmic reticulum) stress has been implicated in CDK inhibition in CLL. Here we conducted a pre-clinical study of a novel orally active kinase inhibitor P1446A in CLL B-cells. P1446A inhibited CDKs at nanomolar concentrations and induced rapid apoptosis of CLL cells in vitro, irrespective of chromosomal abnormalities or IGHV mutational status. Apoptosis preceded inactivation of RNA polymerase, and was accompanied by …

Progressive Hearing Loss In Mice Carrying A Mutation In Usp53, Marcin Kazmierczak, Suzan L. Harris, Piotr Kazmierczak, Prahar Shah, Valentin Starovoytov, Kevin K. Ohlemiller, Martin Schwander

Open Access Publications

UNLABELLED: Disordered protein ubiquitination has been linked to neurodegenerative disease, yet its role in inner ear homeostasis and hearing loss is essentially unknown. Here we show that progressive hearing loss in the ethylnitrosourea-generated mambo mouse line is caused by a mutation in Usp53, a member of the deubiquitinating enzyme family. USP53 contains a catalytically inactive ubiquitin-specific protease domain and is expressed in cochlear hair cells and a subset of supporting cells. Although hair cell differentiation is unaffected in mambo mice, outer hair cells degenerate rapidly after the first postnatal week. USP53 colocalizes and interacts with the tight junction scaffolding proteins …

Systematic Analysis Of Hematopoietic Gene Expression Profiles For Prognostic Prediction In Acute Myeloid Leukemia, Frederick S. Varn, Erik H. Andrews, Chao Cheng

Dartmouth Scholarship

Acute myeloid leukemia (AML) is a hematopoietic disorder initiated by the leukemogenic transformation of myeloid cells into leukemia stem cells (LSCs). Preexisting gene expression programs in LSCs can be used to assess their transcriptional similarity to hematopoietic cell types. While this relationship has previously been examined on a small scale, an analysis that systematically investigates this relationship throughout the hematopoietic hierarchy has yet to be implemented. We developed an integrative approach to assess the similarity between AML patient tumor profiles and a collection of 232 murine hematopoietic gene expression profiles compiled by the Immunological Genome Project. The resulting lineage similarity …

Role Of Micrornas In Alcohol-Induced Multi-Organ Injury., Sathish Kumar Natarajan, Joseph M. Pachunka, Justin L. Mott

Journal Articles: Biochemistry & Molecular Biology

Alcohol consumption and its abuse is a major health problem resulting in significant healthcare cost in the United States. Chronic alcoholism results in damage to most of the vital organs in the human body. Among the alcohol-induced injuries, alcoholic liver disease is one of the most prevalent in the United States. Remarkably, ethanol alters expression of a wide variety of microRNAs that can regulate alcohol-induced complications or dysfunctions. In this review, we will discuss the role of microRNAs in alcoholic pancreatitis, alcohol-induced liver damage, intestinal epithelial barrier dysfunction, and brain damage including altered hippocampus structure and function, and neuronal loss, …

Emerging Immunopharmacological Targets In Multiple Sclerosis., Mojtaba Farjam, Guang-Xian Zhang, Bogoljub Ciric, Abdolmohamad Rostami

Department of Neurology Faculty Papers

Inflammatory demyelination of the central nervous system (CNS) is the hallmark of multiple sclerosis (MS), a chronic debilitating disease that affects more than 2.5 million individuals worldwide. It has been widely accepted, although not proven, that the major pathogenic mechanism of MS involves myelin-reactive T cell activation in the periphery and migration into the CNS, which subsequently triggers an inflammatory cascade that leads to demyelination and axonal damage. Virtually all MS medications now in use target the immune system and prevent tissue damage by modulating neuroinflammatory processes. Although current therapies such as commonly prescribed disease-modifying medications decrease the relapse rate …

A Forward Genetic Screen Reveals Novel Independent Regulators Of Ulbp1, An Activating Ligand For Natural Killer Cells, Benjamin G Gowen, Bryan Chim, Caleb D. Marceau, Trever T Greene, Patrick Burr, Jeanmarie R. Gonzalez, Charles Hesser, Peter A. Dietzen, Teal Russell, Alexandre Iannello, Laurent Coscoy, Charles L. Sentman

Dartmouth Scholarship

Recognition and elimination of tumor cells by the immune system is crucial for limiting tumor growth. Natural killer (NK) cells become activated when the receptor NKG2D is engaged by ligands that are frequently upregulated in primary tumors and on cancer cell lines. However, the molecular mechanisms driving NKG2D ligand expression on tumor cells are not well defined. Using a forward genetic screen in a tumor-derived human cell line, we identified several novel factors supporting expression of the NKG2D ligand ULBP1. Our results show stepwise contributions of independent pathways working at multiple stages of ULBP1 biogenesis. Deeper investigation of selected hits …

A Cytosolic Multiprotein Complex Containing P85Α Is Required For Β-Catenin Activation In Colitis And Colitis-Associated Cancer, Tatiana Goretsky, Emily M. Bradford, Hyunji Ryu, Maryam Tahir, Mary Pat Moyer, Tianyan Gao, Linheng Li, Terrence A. Barrett

Internal Medicine Faculty Publications

Wnt/β-catenin signaling is required for crypt structure maintenance. We previously observed nuclear accumulation of Ser-552 phosphorylated β-catenin (pβ-Cat^Ser-552) in intestinal epithelial cells (IEC) during colitis and colitis-associated cancer. Data here delineate a novel multiprotein cytosolic complex (MCC) involved in β-catenin signaling in the intestine. The MCC contains p85α, the class IA subunit of PI3K, along with β-catenin, 14-3-3ζ, Akt, and p110α. MCC levels in IEC increase in colitis and colitis-associated cancer patients. IEC-specific p85α-deficient (p85^ΔIEC) mice develop more severe dextran sodium …

Age-Associated Methylation Suppresses Spry1, Leading To A Failure Of Re-Quiescence And Loss Of The Reserve Stem Cell Pool In Elderly Muscle., Anne Bigot, William J Duddy, Zamalou G Ouandaogo, Elisa Negroni, Virginie Mariot, Svetlana Ghimbovschi, Brennan Harmon, Aurore Wielgosik, Camille Loiseau, Joseph Devaney, Julie Dumonceaux, Gillian Butler-Browne, Vincent Mouly, Stéphanie Duguez

Genomics and Precision Medicine Faculty Publications

The molecular mechanisms by which aging affects stem cell number and function are poorly understood. Murine data have implicated cellular senescence in the loss of muscle stem cells with aging. Here, using human cells and by carrying out experiments within a strictly pre-senescent division count, we demonstrate an impaired capacity for stem cell self-renewal in elderly muscle. We link aging to an increased methylation of the SPRY1 gene, a known regulator of muscle stem cell quiescence. Replenishment of the reserve cell pool was modulated experimentally by demethylation or siRNA knockdown of SPRY1. We propose that suppression of SPRY1 by age-associated …

Propagated Infra-Slow Intrinsic Brain Activity Reorganizes Across Wake And Slow Wave Sleep, Anish Mitra, Abraham Z. Snyder, Enzo Tagliazucchi, Helmut Laufs, Marcus E. Raichle

Open Access Publications

Propagation of slow intrinsic brain activity has been widely observed in electrophysiogical studies of slow wave sleep (SWS). However, in human resting state fMRI (rs-fMRI), intrinsic activity has been understood predominantly in terms of zero-lag temporal synchrony (functional connectivity) within systems known as resting state networks (RSNs). Prior rs-fMRI studies have found that RSNs are generally preserved across wake and sleep. Here, we use a recently developed analysis technique to study propagation of infra-slow intrinsic blood oxygen level dependent (BOLD) signals in normal adults during wake and SWS. This analysis reveals marked changes in propagation patterns in SWS vs. wake. …

Serum Iron Level Is Associated With Time To Antibiotics In Cystic Fibrosis, Alex H. Gifford, Dana B. Dorman, Lisa A. Moulton, Jennifer E. Helm, Mary M. Griffin, Todd A. Mackenzie

Dartmouth Scholarship

Background:

Serum levels of hepcidin‐25, a peptide hormone that reduces blood iron content, are elevated when patients with cystic fibrosis (CF) develop pulmonary exacerbation (PEx). Because hepcidin‐25 is unavailable as a clinical laboratory test, we questioned whether a one‐time serum iron level was associated with the subsequent number of days until PEx, as defined by the need to receive systemic antibiotics (ABX) for health deterioration.

Methods:

Clinical, biochemical, and microbiological parameters were simultaneously checked in 54 adults with CF. Charts were reviewed to determine when they first experienced a PEx after these parameters were assessed. Time to ABX was compared …

Antioncogenic And Oncogenic Properties Of Nrf2 In Arsenic-Induced Carcinogenesis, Young-Ok Son, Poyil Pratheeshkumar, Ram Vinod Roy, Andrew Hitron, Lei Wang, Sasidharan Padmaja Divya, Mei Xu, Jia Luo, Gang Chen, Zhuo Zhang, Xianglin Shi

Center for Research on Environmental Disease Faculty Publications

Arsenic (As³⁺) is a carcinogen with considerable environmental and occupational relevancy. The present study shows that As³⁺-transformed human lung bronchial epithelial BEAS-2B cells (AsT cells) exhibit the property of apoptosis resistance. The level of basal reactive oxygen species (ROS) is very low in AsT cells in correlation with elevated expressions of both antioxidant enzymes and antiapoptotic proteins. Nuclear factor erythroid 2-related factor (Nrf2) and p62 are constitutively expressed. These two proteins up-regulate antioxidant enzymes and antiapoptotic proteins. The knockdown of Nrf2 or p62 by small interfering RNA (siRNA) enhanced both ROS levels and As³⁺-induced …

Integrin Α6Β4 Promotes Autocrine Epidermal Growth Factor Receptor (Egfr) Signaling To Stimulate Migration And Invasion Toward Hepatocyte Growth Factor (Hgf), Brittany L. Carpenter, Min Chen, Teresa Knifley, Kelley A. Davis, Susan M.W. Harrison, Rachel L. Stewart, Kathleen O'Connor

Markey Cancer Center Faculty Publications

Integrin α6β4 is up-regulated in pancreatic adenocarcinomas where it contributes to carcinoma cell invasion by altering the transcriptome. In this study, we found that integrin α6β4 up-regulates several genes in the epidermal growth factor receptor (EGFR) pathway, including amphiregulin (AREG), epiregulin (EREG), and ectodomain cleavage protease MMP1, which is mediated by promoter demethylation and NFAT5. The correlation of these genes with integrin α6β4 was confirmed in The Cancer Genome Atlas Pancreatic Cancer Database. Based on previous observations that integrin α6β4 cooperates with c-Met in pancreatic cancers, we examined the impact of EGFR signaling on hepatocyte growth factor (HGF)-stimulated migration and …

Fizzy: Feature Subset Selection For Metagenomics., Gregory Ditzler, J Calvin Morrison, Yemin Lan, Gail L Rosen

Henry M. Rowan College of Engineering Departmental Research

BACKGROUND: Some of the current software tools for comparative metagenomics provide ecologists with the ability to investigate and explore bacterial communities using α- & β-diversity. Feature subset selection--a sub-field of machine learning--can also provide a unique insight into the differences between metagenomic or 16S phenotypes. In particular, feature subset selection methods can obtain the operational taxonomic units (OTUs), or functional features, that have a high-level of influence on the condition being studied. For example, in a previous study we have used information-theoretic feature selection to understand the differences between protein family abundances that best discriminate between age groups in the …

‘The Thing Is Not Knowing’: Patients' Perspectives On Surveillance Of An Indeterminate Pulmonary Nodule, Renda Soylemez Wiener, Michael K. Gould, Steven Woloshin, Lisa M. Schwartz, Jack Clark

Dartmouth Scholarship

Background: The hundreds of thousands of patients found to have a potentially malignant pulmonary nodule each year are faced with tremendous uncertainty regarding what the nodule is and how it should be evaluated.

Objective: To explore patients' responses to the detection and evaluation of a pulmonary nodule.

Vascular Access: Inukshuk, Jerry Yee

Nephrology Articles

No abstract provided.

Abcc9/Sur2 In The Brain: Implications For Hippocampal Sclerosis Of Aging And A Potential Therapeutic Target, Peter T. Nelson, Gregory A. Jicha, Wang-Xia Wang, Eseosa T. Ighodaro, Sergey C. Artiushin, Colin G. Nichols, David W. Fardo

Sanders-Brown Center on Aging Faculty Publications

The ABCC9 gene and its polypeptide product, SUR2, are increasingly implicated in human neurologic disease, including prevalent diseases of the aged brain. SUR2 proteins are a component of the ATP-sensitive potassium (“K _ATP ”) channel, a metabolic sensor for stress and/or hypoxia that has been shown to change in aging. The K _ATP channel also helps regulate the neurovascular unit. Most brain cell types express SUR2, including neurons, astrocytes, oligodendrocytes, microglia, vascular smooth muscle, pericytes, and endothelial cells. Thus it is not surprising that ABCC9 gene variants are associated with risk for human brain diseases. For example, Cantu syndrome is …

Clear Cell Renal Cell Carcinoma With Borderline Features Of Clear Cell Papillary Renal Cell Carcinoma: Combined Morphologic, Immunohistochemical, And Cytogenetic Analysis, Sean R. Williamson, Nilesh S. Gupta, John N. Eble, Craig G. Rogers, Susan Michalowski, Shaobo Zhang, Mingsheng Wang, David J. Grignon, Liang Cheng

Pathology and Laboratory Medicine Articles

Clear cell papillary renal cell carcinoma is increasingly recognized as a distinct tumor with unique morphology, immunohistochemistry, and cytogenetics. Histopathology often mimics clear cell renal cell carcinoma; however, metastasis has not been reported, emphasizing the clinical value of recognizing these likely nonaggressive tumors. We studied tumors with borderline morphology of clear cell papillary renal cell carcinoma, utilizing immunohistochemistry and fluorescence in situ hybridization or karyotyping. Tumors from 22 patients (ages 33 to 82 y) were analyzed. Clear cell papillary renal cell carcinoma-like morphology varied from 10% to 90% of the tumor (median 25%). Sources of resemblance included: branched glands (95%), …

Identification Of Regions Of Normal Grey Matter And White Matter From Pathologic Glioblastoma And Necrosis In Frozen Sections Using Raman Imaging, Rachel Kast, Gregory Auner, Sally Yurgelevic, Brandy Broadbent, Aditya Raghunathan, Laila M. Poisson, Tom Mikkelsen, Mark L. Rosenblum, Steven N. Kalkanis

Neurosurgery Articles

In neurosurgical applications, a tool capable of distinguishing grey matter, white matter, and areas of tumor and/or necrosis in near-real time could greatly aid in tumor resection decision making. Raman spectroscopy is a non-destructive spectroscopic technique which provides molecular information about the tissue under examination based on the vibrational properties of the constituent molecules. With careful measurement and data processing, a spatial step and repeat acquisition of Raman spectra can be used to create Raman images. Forty frozen brain tissue sections were imaged in their entirety using a 300-µm-square measurement grid, and two or more regions of interest within each …

Enos Transfection Of Adipose-Derived Stem Cells Yields Bioactive Nitric Oxide Production And Improved Results In Vascular Tissue Engineering., Stephen Mcilhenny, Ping Zhang, Thomas Tulenko, Jason Comeau, Sarah Fernandez, Aleksandra Policha, Matthew Ferroni, Elizabeth J Faul, Gabor Bagameri, Irving Shapiro, Paul J. Dimuzio

Department of Surgery Faculty Papers

This study evaluates the durability of a novel tissue engineered blood vessel (TEBV) created by seeding a natural vascular tissue scaffold (decellularized human saphenous vein allograft) with autologous adipose-derived stem cells (ASC) differentiated into endothelial-like cells. Previous work with this model revealed the graft to be thrombogenic, likely due to inadequate endothelial differentiation as evidenced by minimal production of nitric oxide (NO). To evaluate the importance of NO expression by the seeded cells, we created TEBV using autologous ASC transfected with the endothelial nitric oxide synthase (eNOS) gene to produce NO. We found that transfected ASC produced NO at levels …

Beyond The One-Locus-One-Mirna Paradigm: Microrna Isoforms Enable Deeper Insights Into Breast Cancer Heterogeneity., Aristeidis G Telonis, Phillipe Loher, Yi Jing, Eric R Londin, Isidore Rigoutsos

Computational Medicine Center Faculty Papers

Here we describe our study of miRNA isoforms (isomiRs) in breast cancer (BRCA) and normal breast data sets from the Cancer Genome Atlas (TCGA) repository. We report that the full isomiR profiles, from both known and novel human-specific miRNA loci, are particularly rich in information and can distinguish tumor from normal tissue much better than the archetype miRNAs. IsomiR expression is also dependent on the patient's race, exemplified by miR-183-5p, several isomiRs of which are upregulated in triple negative BRCA in white but not black women. Additionally, we find that an isomiR's 5' endpoint and length, but not the genomic …

Dna-Repair Defects And Olaparib In Metastatic Prostate Cancer., Joaquin Mateo, Suzanne Carreira, Shahneen Sandhu, Susana Miranda, Helen Mossop, Raquel Perez-Lopez, Daniel Nava Rodrigues, Dan Robinson, Aurelius Omlin, Nina Tunariu, Gunther Boysen, Nuria Porta, Penny Flohr, Alexa Gillman, Ines Figueiredo, Claire Paulding, George Seed, Suneil Jain, Christy Ralph, Andrew Protheroe, Syed Hussain, Robert Jones, Tony Elliott, Ursula Mcgovern, Diletta Bianchini, Jane Goodall, Zafeiris Zafeiriou, Chris T Williamson, Roberta Ferraldeschi, Ruth Riisnaes, Bernardette Ebbs, Gemma Fowler, Desamparados Roda, Wei Yuan, Yi-Mi Wu, Xuhong Cao, Rachel Brough, Helen Pemberton, Roger A'Hern, Amanda Swain, Lakshmi P Kunju, Rosalind Eeles, Gerhardt Attard, Christopher J Lord, Alan Ashworth, Mark A Rubin, Karen E Knudsen, Felix Y Feng, Arul M Chinnaiyan, Emma Hall, Johann S De Bono

Department of Medicine Faculty Papers

BACKGROUND: Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib.

METHODS: We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. The primary end point was the response rate, defined either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the …

A Piece Of My Mind. A Piece Of My Mind--Actually., Herbert M. Adler

Department of Psychiatry and Human Behavior Faculty Papers

No abstract provided.

Mannitol Does Not Enhance Tobramycin Killing Of Pseudomonas Aeruginosa In A Cystic Fibrosis Model System Of Biofilm Formation, Katherine E. Price, Giulia Orazi, Kathryn L. Ruoff, Wesley P. Hebert, George A. O'Toole, Paul Mastoridis

Dartmouth Scholarship

Cystic Fibrosis (CF) is a human genetic disease that results in the accumulation of thick, sticky mucus in the airways, which results in chronic, life-long bacterial biofilm infections that are difficult to clear with antibiotics. Pseudomonas aeruginosa lung infection is correlated with worsening lung disease and P. aeruginosa transitions to an antibiotic tolerant state during chronic infections. Tobramycin is an aminoglycoside currently used to combat lung infections in individuals with CF. While tobramycin is effective at eradicating P. aeruginosa in the airways of young patients, it is unable to completely clear the chronic P. aeruginosa infections in …