Digital Commons Network^™

In Situ Capture Of Chromatin Interactions By Biotinylated Dcas9., Xin Liu, Yuannyu Zhang, Yong Chen, Mushan Li, Feng Zhou, Kailong Li, Hui Cao, Min Ni, Yuxuan Liu, Zhimin Gu, Kathryn E Dickerson, Shiqi Xie, Gary C Hon, Zhenyu Xuan, Michael Q Zhang, Zhen Shao, Jian Xu

College of Science & Mathematics Departmental Research

Cis-regulatory elements (CREs) are commonly recognized by correlative chromatin features, yet the molecular composition of the vast majority of CREs in chromatin remains unknown. Here, we describe a CRISPR affinity purification in situ of regulatory elements (CAPTURE) approach to unbiasedly identify locus-specific chromatin-regulating protein complexes and long-range DNA interactions. Using an in vivo biotinylated nuclease-deficient Cas9 protein and sequence-specific guide RNAs, we show high-resolution and selective isolation of chromatin interactions at a single-copy genomic locus. Purification of human telomeres using CAPTURE identifies known and new telomeric factors. In situ capture of individual constituents of the enhancer cluster controlling human β-globin …

Smartscope2: Simultaneous Imaging And Reconstruction Of Neuronal Morphology., Brian Long, Zhi Zhou, Ali Cetin, Jonathan Ting, Ryder Gwinn, Bosiljka Tasic, Tanya Daigle, Ed Lein, Hongkui Zeng, Peter Saggau, Michael Hawrylycz, Hanchuan Peng

Articles, Abstracts, and Reports

Quantitative analysis of neuronal morphology is critical in cell type classification and for deciphering how structure gives rise to function in the brain. Most current approaches to imaging and tracing neuronal 3D morphology are data intensive. We introduce SmartScope2, the first open source, automated neuron reconstruction machine integrating online image analysis with automated multiphoton imaging. SmartScope2 takes advantage of a neuron's sparse morphology to improve imaging speed and reduce image data stored, transferred and analyzed. We show that SmartScope2 is able to produce the complex 3D morphology of human and mouse cortical neurons with six-fold reduction in image data requirements …

Calcium-Mediated Control Of S100 Proteins: Allosteric Communication Via An Agitator/Signal Blocking Mechanism., Yiming Xiao, Gary S Shaw, Lars Konermann

Chemistry Publications

Allosteric proteins possess dynamically coupled residues for the propagation of input signals to distant target binding sites. The input signals usually correspond to "effector is present" or "effector is not present". Many aspects of allosteric regulation remain incompletely understood. This work focused on S100A11, a dimeric EF-hand protein with two hydrophobic target binding sites. An annexin peptide (Ax) served as the target. Target binding is allosterically controlled by Ca²⁺ over a distance of ∼26 Å. Ca²⁺ promotes formation of a [Ca₄ S100 Ax₂] complex, where the Ax peptides are accommodated between helices III/IV and III'/IV'. …

Mentalizing Skills Do Not Differentiate Believers From Non-Believers, But Credibility Enhancing Displays Do, David L. R. Maij, Frenk Van Harreveld, Will M. Gervais, Yann Schrag, Christine Mohr, Michiel Van Elk

Psychology Faculty Publications

The ability to mentalize has been marked as an important cognitive mechanism enabling belief in supernatural agents. In five studies we cross-culturally investigated the relationship between mentalizing and belief in supernatural agents with large sample sizes (over 67,000 participants in total) and different operationalizations of mentalizing. The relative importance of mentalizing for endorsing supernatural beliefs was directly compared with credibility enhancing displays–the extent to which people observed credible religious acts during their upbringing. We also compared autistic with neurotypical adolescents. The empathy quotient and the autism-spectrum quotient were not predictive of belief in supernatural agents in all countries (i.e., The …

Growth And Weight Gain In Children With Juvenile Idiopathic Arthritis: Results From The Reacch-Out Cohort., Jaime Guzman, Tristan Kerr, Leanne M Ward, Jinhui Ma, Kiem Oen, Alan M Rosenberg, Brian M Feldman, Gilles Boire, Kristin Houghton, Paul Dancey, Rosie Scuccimarri, Alessandra Bruns, Adam M Huber, Karen Watanabe Duffy, Natalie J Shiff, Roberta A Berard, Deborah M Levy, Elizabeth Stringer, Kimberly Morishita, Nicole Johnson, David A Cabral, Maggie Larché, Ross E Petty, Ronald M Laxer, Earl Silverman, Paivi Miettunen, Anne-Laure Chetaille, Elie Haddad, Lynn Spiegel, Stuart E Turvey, Heinrike Schmeling, Bianca Lang, Janet Ellsworth, Suzanne E Ramsey, Johannes Roth, Sarah Campillo, Susanne Benseler, Gaëlle Chédeville, Rayfel Schneider, Shirley M L Tse, Roxana Bolaria, Katherine Gross, Debbie Feldman, Bonnie Cameron, Roman Jurencak, Jean Dorval, Claire Leblanc, Claire St Cyr, Michele Gibbon, Rae S M Yeung, Ciarán M Duffy, Lori B Tucker

Paediatrics Publications

BACKGROUND: With modern treatments, the effect of juvenile idiopathic arthritis (JIA) on growth may be less than previously reported. Our objective was to describe height, weight and body mass index (BMI) development in a contemporary JIA inception cohort.

METHODS: Canadian children newly-diagnosed with JIA 2005-2010 had weight and height measurements every 6 months for 2 years, then yearly up to 5 years. These measurements were used to calculate mean age- and sex-standardized Z-scores, and estimate prevalence and cumulative incidence of growth impairments, and the impact of disease activity and corticosteroids on growth.

RESULTS: One thousand one hundred forty seven children …

Effect Of Natriuretic Peptide-Guided Therapy On Hospitalization Or Cardiovascular Mortality In High-Risk Patients With Heart Failure And Reduced Ejection Fraction: A Randomized Clinical Trial., G. Michael Felker, Kevin J. Anstrom, Kirkwood F. Adams, Justin A Ezekowitz, Mona Fiuzat, Nancy Houston-Miller, James L. Januzzi, Daniel B. Mark, Ileana L. Piña, Gayle Passmore, David J. Whellan, Hongqiu Yang, Lawton S. Cooper, Eric S. Leifer, Patrice Desvigne-Nickens, Christopher M O'Connor

Department of Medicine Faculty Papers

Importance: The natriuretic peptides are biochemical markers of heart failure (HF) severity and predictors of adverse outcomes. Smaller studies have evaluated adjusting HF therapy based on natriuretic peptide levels ("guided therapy") with inconsistent results.

Objective: To determine whether an amino-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided treatment strategy improves clinical outcomes vs usual care in high-risk patients with HF and reduced ejection fraction (HFrEF).

Design, Settings, and Participants: The Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT) study was a randomized multicenter clinical trial conducted between January 16, 2013, and September 20, 2016, at 45 clinical sites in …

Multi-Laboratory Assessment Of Reproducibility, Qualitative And Quantitative Performance Of Swath-Mass Spectrometry., Ben C Collins, Christie L Hunter, Yansheng Liu, Birgit Schilling, George Rosenberger, Samuel L Bader, Daniel W Chan, Bradford W Gibson, Anne-Claude Gingras, Jason M Held, Mio Hirayama-Kurogi, Guixue Hou, Christoph Krisp, Brett Larsen, Liang Lin, Siqi Liu, Mark P Molloy, Robert L Moritz, Sumio Ohtsuki, Ralph Schlapbach, Nathalie Selevsek, Stefani N Thomas, Shin-Cheng Tzeng, Hui Zhang, Ruedi Aebersold

Articles, Abstracts, and Reports

Quantitative proteomics employing mass spectrometry is an indispensable tool in life science research. Targeted proteomics has emerged as a powerful approach for reproducible quantification but is limited in the number of proteins quantified. SWATH-mass spectrometry consists of data-independent acquisition and a targeted data analysis strategy that aims to maintain the favorable quantitative characteristics (accuracy, sensitivity, and selectivity) of targeted proteomics at large scale. While previous SWATH-mass spectrometry studies have shown high intra-lab reproducibility, this has not been evaluated between labs. In this multi-laboratory evaluation study including 11 sites worldwide, we demonstrate that using SWATH-mass spectrometry data acquisition we can consistently …

Strategies To Improve Interdisciplinary Communication In An Acute Care Inpatient Pediatric Unit, Sarah Thompson, Haley Pelletier, Barbara Bush Children's Hospital-Inpatient, Maine Medical Center, Suneela Nayak, Ruth Hanselman, Stephen Tyzik

MaineHealth Maine Medical Center

Interdisciplinary patient rounding has been shown to improve patient and family satisfaction as well as reduce patient length of stay and readmission rates. In an acute care inpatient pediatric unit, baseline metrics demonstrated that 100% of the time, nursing was not included in these rounds thus resulting in sub optimal communication.

The goal of this performance improvement project was to attain increased nursing participation. Data collection demonstrated several reasons for lack of participation and corrective actions were instituted. After undertaking this KPI goal and utilizing operational excellence, 95% of the time, nurses were called to morning rounds with the medical …

Strategies To Improve Control Of Blood A1c In Diabetics, Jennifer Aronson, Leanne Bellino, Elizabeth Eisenhardt, Diane Bryant, Haley Pelletier, Internal Medicine Team, Adult Outpatient Clinic

MaineHealth Maine Medical Center

A1c monitoring is an important aspect of controlling the health of a diabetic patient. An adult internal medicine clinic noted that the percentage of their diabetic patients who had an A1c higher than 9 or no reading within the past year exceeded the national average. As a result, operational excellence methods were implemented with the overall goal to reduce their percentage to 18% or less.

A root cause analysis identified several deficiencies to includelack of essential equipment, variations in

staff education and the absence of daily reminders.

Post KPI implementations, an overall decrease in the percentage of patients with poorly …

Identification Strategies For The Very High Fall Risk Patient In An Acute Inpatient Psychiatric Unit, P6 Inpatient Geri-Med Psychiatry, Haley Pelletier, Suneela Nayak, Stephen Tyzik, Ruth Hanselman

MaineHealth Maine Medical Center

Patients falling as a result of geriatric and psychiatric impairments are at a much higher risk than the average patient population. An acute care inpatient psychiatric team used baseline metrics to demonstrate increasing fall rates per month that surpassed the unit’s target number. As a result, a quality improvement project around falls was felt to be warranted.

The overall goal of this study was to improve patient safety by reducing falls for their very high risk fall population. A root cause analysis determined that this population was not being properly identified and several tools were developed and employed to better …

Improving Type And Screen Specimen Collection Prior To Elective Surgery, Nordx Blood Bank Staff, Haley Pelletier, Suneela Nayak, Stephen Tyzik, Ruth Hanselman

MaineHealth Maine Medical Center

To avoid delays in the availability of compatible blood for elective surgery patients requiring transfusion, a type and screen specimen should be completed at least 24 hours prior to surgery. Baseline metrics in an acute care inpatient blood bank demonstrated a significant number of cases with no type or screen completed.

The objective of this KPI was to prevent any delays in providing compatible blood products to scheduled surgical patients. Several internal and external system issues were identified as a result of a root cause analysis and a number of actions were initiated.

Outcomes have been positive. Data collection post …

Delirium Reduction Strategies For The Critically Ill, June Chaves, Sam Canonico, Will Cheney, Tammy Corey, Gil Fraser, Alex Kowalewski, Jen Low, Cardiac Intensive Care Unit, Haley Pelletier, Cathy Palleschi, Stephen Tyzik, Suneela Nayak, Ruth Hanselman

MaineHealth Maine Medical Center

Delirium, an acute and fluctuating disturbance of consciousness and cognition, is a common manifestation of acute brain dysfunction in critically ill patients. Patients with delirium have longer hospital stays and a lower 6-month survival rate than do patients without delirium. Preliminary research suggests that delirium may be associated with cognitive impairment that persists months to years after discharge.

In a large acute care hospital, the cardiac intensive care staff became interested in mitigating their unit’s high delirium rate of ventilated patients. At baseline, many members of the healthcare team did not believe that delirium could be prevented and the predominant …

Improving Cardiology Patient Flow In Nuclear Medicine, Kelly Haar, Hannah Sullivan, Kathryn Laverdiere, Nuclear Medicine Department, Haley Pelletier, Stephen Tyzik, Suneela Nayak, Ruth Hanselman

MaineHealth Maine Medical Center

At baseline, a nuclear medicine department found it difficult to complete cardiac stress tests within scheduled times. Using the performance improvement process, a nuclear medicine department looked to improve patient experience related to wait times for this test.

Two goals were identified and a root cause analysis was initiated. After identifying some process issues, two KPIs were developed to address them.

A root cause analysis identified some processing issues and two KPIs were instituted to address them.

As a result, one outcome was to hire an additional physician assistant to address the barrier of inadequate cardiology coverage. Next steps include …

Communication Of Medication Side Effects In An Acute Care Hospital, Deb Bachand, Rachel Caiola, R6 Neurology Med-Surg Unit, Haley Pelletier, Brendan Lilley, Suneela Nayak, Ruth Hanselman, Stephen Tyzik

MaineHealth Maine Medical Center

COMMUNICATION OF MEDICATION SIDE EFFECTS IN AN ACUTE CARE HOSPITAL

Effective patient education of prescribed medication side effects improves patient safety and reduces overall risk. On an acute care hospital unit, nursing staff felt previous attempts at this education had been ineffective as demonstrated by their HCAHPs scores for communication about medications.

A root cause analysis demonstrated some flaws and several countermeasures were instituted. The goal of this KPI project was to attain a higher than national average for the specific HCAHPs score.

Post KPI inception, the unit’s HCAHPs data showed steady improvement. Within one month, the goal of an …

Rational Confederation Of Genes And Diseases: Ngs Interpretation Via Genecards, Malacards And Varelect., Noa Rappaport, Simon Fishilevich, Ron Nudel, Michal Twik, Frida Belinky, Inbar Plaschkes, Tsippi Iny Stein, Dana Cohen, Danit Oz-Levi, Marilyn Safran, Doron Lancet

Articles, Abstracts, and Reports

BACKGROUND: A key challenge in the realm of human disease research is next generation sequencing (NGS) interpretation, whereby identified filtered variant-harboring genes are associated with a patient's disease phenotypes. This necessitates bioinformatics tools linked to comprehensive knowledgebases. The GeneCards suite databases, which include GeneCards (human genes), MalaCards (human diseases) and PathCards (human pathways) together with additional tools, are presented with the focus on MalaCards utility for NGS interpretation as well as for large scale bioinformatic analyses.

RESULTS: VarElect, our NGS interpretation tool, leverages the broad information in the GeneCards suite databases. MalaCards algorithms unify disease-related terms and annotations from 69 …

Human Milk And Allergic Diseases: An Unsolved Puzzle, Daniel Munblit, Diego G. Peroni, Alba Boix-Amorós, Peter S. Hsu, Belinda Van't Land, Melvin C. L. Gay, Anastasia Kolotilina, Chrysanthi Skevaki, Robert J. Boyle, Maria C. Collado, Johan Garssen, Donna T. Geddes, Ralph Nanan, Carolyn Slupsky, Ganesa Wegienka, Anita L. Kozyrskyj, John O. Warner

Public Health Sciences Articles

There is conflicting evidence on the protective role of breastfeeding in relation to the development of allergic sensitisation and allergic disease. Studies vary in methodology and definition of outcomes, which lead to considerable heterogeneity. Human milk composition varies both within and between individuals, which may partially explain conflicting data. It is known that human milk composition is very complex and contains variable levels of immune active molecules, oligosaccharides, metabolites, vitamins and other nutrients and microbial content. Existing evidence suggests that modulation of human breast milk composition has potential for preventing allergic diseases in early life. In this review, we discuss …

Tia1 Mutations In Amyotrophic Lateral Sclerosis And Frontotemporal Dementia Promote Phase Separation And Alter Stress Granule Dynamics., Ian R. Mackenzie, Alexandra M. Nicholson, Mohona Sarkar, James Messing, Maria D. Purice, Cyril Pottier, Kavya Annu, Matt Baker, Ralph B. Perkerson, Aishe Kurti, Billie J. Matchett, Tanja Mittag, Jamshid Temirov, Ging-Yuek R. Hsiung, Charles Krieger, Melissa E. Murray, Masato Kato, John D. Fryer, Leonard Petrucelli, Lorne Zinman, Sandra Weintraub, Marsel Mesulam, Julia Keith, Sasha A. Zivkovic, Veronica Hirsch-Reinshagen, Raymond P. Roos, Stephan Züchner, Neill R. Graff-Radford, Ronald C. Petersen, Richard J. Caselli, Zbigniew K. Wszolek, Elizabeth Finger, Carol Lippa, David Lacomis, Heather Stewart, Dennis W. Dickson, Hong Joo Kim, Ekaterina Rogaeva, Eileen Bigio, Kevin B. Boylan, J. Paul Taylor, Rosa Rademakers

Department of Neurology Faculty Papers

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative disorders with shared genetic etiologies and overlapping clinical and pathological features. Here we studied a novel ALS/FTD family and identified the P362L mutation in the low-complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1). Subsequent genetic association analyses showed an increased burden of TIA1 LCD mutations in ALS patients compared to controls (p = 8.7 × 10

Interleukin-6 (Il-6) Rs1800796 And Cyclin Dependent Kinase Inhibitor (Cdkn2a/Cdkn2b) Rs2383207 Are Associated With Ischemic Stroke In Indigenous West African Men, Rufus Akinyemi, Donna K. Arnett, Hemant K. Tiwari, Bruce Ovbiagele, Fred Sarfo, Vinodh Srinivasasainagendra, Marguerite Ryan Irvin, Abiodun Adeoye, Rodney T. Perry, Albert Akpalu, Carolyn Jenkins, Lukman Owolabi, Reginald Obiako, Kolawole Wahab, Emmanuel Sanya, Morenikeji Komolafe, Michael Fawale, Philip Adebayo, Godwin Osaigbovo, Taofiki Sunmonu, Paul Olowoyo, Innocent Chukwuonye, Yahaya Obiabo, Onoja Akpa, Sylvia Melikam, Raelle Saulson, Raj Kalaria, Adesola Ogunniyi, Mayowa Owolabi

Epidemiology and Environmental Health Faculty Publications

Background—Inherited genetic variations offer a possible explanation for the observed peculiarities of stroke in sub – Saharan African populations. Interleukin–6 polymorphisms have been previously associated with ischemic stroke in some non-African populations.

Aim—Herein we investigated, for the first time, the association of genetic polymorphisms of IL-6 and CDKN2A- CDKN2B and other genes with ischemic stroke among indigenous West African participants in the Stroke Investigative Research and Education Network (SIREN) Study.

Methods—Twenty-three previously identified single nucleotide polymorphisms (SNPs) in 14 genes of relevance to the neurobiology of ischemic stroke were investigated. Logistic regression models adjusting for known …

Epigenetic Regulation Of Kpc1 Ubiquitin Ligase Affects The Nf-Κb Pathway In Melanoma., Yuuki Iida, Aaron Ciechanover, Diego M Marzese, Keisuke Hata, Matias Bustos, Shigeshi Ono, Jinhua Wang, Matthew P Salomon, Kevin Tran, Stella Lam, Sandy Hsu, Nellie Nelson, Yelena Kravtsova-Ivantsiv, Gordon B Mills, Michael A Davies, Dave S B Hoon

Articles, Abstracts, and Reports

Purpose: Abnormal activation of the NF-κB pathway induces a more aggressive phenotype of cutaneous melanoma. Understanding the mechanisms involved in melanoma NF-κB activation may identify novel targets for this pathway. KPC1, an E3 ubiquitin ligase, is a regulator of the NF-κB pathway. The objective of this study was to investigate the mechanisms regulating KPC1 expression and its clinical impact in melanoma.Experimental Design: The clinical impact of KPC1 expression and its epigenetic regulation were assessed in large cohorts of clinically well-annotated melanoma tissues (tissue microarrays; n = 137, JWCI cohort; n = 40) and The Cancer Genome Atlas database (TCGA …

Selective Inhibitors Of Human Mpges-1 From Structure-Based Computational Screening, Ziyuan Zhou, Yaxia Yuan, Shuo Zhou, Kai Ding, Fang Zheng, Chang-Guo Zhan

Molecular Modeling and Biopharmaceutical Center Faculty Publications

Human mPGES-1 is recognized as a promising target for next generation of anti-inflammatory drugs. Although various mPGES-1 inhibitors have been reported in literature, few have entered clinical trials and none has been proven clinically useful so far. It is highly desired for developing the next generation of therapeutics for inflammation-related diseases to design and discover novel inhibitors of mPGES-1 with new scaffolds. Here, we report the identification of a series of new, potent and selective inhibitors of human mPGES-1 with diverse scaffolds through combined computational and experimental studies. The computationally modeled binding structures of these new inhibitors with mPGES-1 provide …

Estimation Of Exposure Distribution Adjusting For Association Between Exposure Level And Detection Limit, Yuchen Yang, Brent J. Shelton, Thomas Tucker, Li Li, Richard Kryscio, Li Chen

Statistics Faculty Publications

In environmental exposure studies, it is common to observe a portion of exposure measurements to fall below experimentally determined detection limits (DLs). The reverse Kaplan–Meier estimator, which mimics the well‐known Kaplan–Meier estimator for right‐censored survival data with the scale reversed, has been recommended for estimating the exposure distribution for the data subject to DLs because it does not require any distributional assumption. However, the reverse Kaplan–Meier estimator requires the independence assumption between the exposure level and DL and can lead to biased results when this assumption is violated. We propose a kernel‐smoothed nonparametric estimator for the exposure distribution without imposing …

Posttranscriptional Upregulation Of Idh1 By Hur Establishes A Powerful Survival Phenotype In Pancreatic Cancer Cells., Mahsa Zarei, Shruti Lal, Seth J. Parker, Avinoam Nevler, Ali Vaziri-Gohar, Katerina Dukleska, Nicole C. Mambelli-Lisboa, Cynthia Moffat, Fernando F Blanco, Saswati N. Chand, Masaya Jimbo, Joseph A. Cozzitorto, Wei Jiang, Charles J. Yeo, Eric R. Londin, Erin L. Seifert, Christian M. Metallo, Jonathan R. Brody, Jordan M. Winter

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Cancer aggressiveness may result from the selective pressure of a harsh nutrient-deprived microenvironment. Here we illustrate how such conditions promote chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Glucose or glutamine withdrawal resulted in a 5- to 10-fold protective effect with chemotherapy treatment. PDAC xenografts were less sensitive to gemcitabine in hypoglycemic mice compared with hyperglycemic mice. Consistent with this observation, patients receiving adjuvant gemcitabine (n = 107) with elevated serum glucose levels (HgbA1C > 6.5%) exhibited improved survival. We identified enhanced antioxidant defense as a driver of chemoresistance in this setting. ROS levels were doubled in vitro by either nutrient withdrawal …

Integrative Analysis Identifies Four Molecular And Clinical Subsets In Uveal Melanoma., A Gordon Robertson, Juliann Shih, Christina Yau, Ewan A Gibb, Junna Oba, Karen L Mungall, Julian M Hess, Vladislav Uzunangelov, Vonn Walter, Ludmila Danilova, Tara M Lichtenberg, Melanie Kucherlapati, Patrick K Kimes, Ming Tang, Alexander Penson, Ozgun Babur, Rehan Akbani, Christopher A Bristow, Katherine A Hoadley, Lisa Iype, Matthew T Chang, Andrew D Cherniack, Christopher Benz, Gordon B Mills, Roel G W Verhaak, Klaus G Griewank, Ina Felau, Jean C Zenklusen, Jeffrey E Gershenwald, Lynn Schoenfield, Alexander J Lazar, Mohamed H Abdel-Rahman, Sergio Roman-Roman, Marc-Henri Stern, Colleen M Cebulla, Michelle D Williams, Martine J Jager, Sarah E Coupland, Bita Esmaeli, Cyriac Kandoth, Scott E Woodman

Articles, Abstracts, and Reports

Comprehensive multiplatform analysis of 80 uveal melanomas (UM) identifies four molecularly distinct, clinically relevant subtypes: two associated with poor-prognosis monosomy 3 (M3) and two with better-prognosis disomy 3 (D3). We show that BAP1 loss follows M3 occurrence and correlates with a global DNA methylation state that is distinct from D3-UM. Poor-prognosis M3-UM divide into subsets with divergent genomic aberrations, transcriptional features, and clinical outcomes. We report change-of-function SRSF2 mutations. Within D3-UM, EIF1AX- and SRSF2/SF3B1-mutant tumors have distinct somatic copy number alterations and DNA methylation profiles, providing insight into the biology of these low- versus intermediate-risk clinical mutation subtypes.

Building Virtual Communities Of Practice For Health, Bruce Struminger, Sanjeev Arora, Sarah Zalud-Cerrato, David Lowrance, Tedd Ellerbrock

Project ECHO Bibliography

No abstract provided.

Abl Kinase Regulation By Braf/Erk And Cooperation With Akt In Melanoma, Aditi Jain, Rakshamani Tripathi, Courtney P. Turpin, Chi Wang, Rina Plattner

Pharmacology and Nutritional Sciences Faculty Publications

The melanoma incidence continues to increase, and the disease remains incurable for many due to its metastatic nature and high rate of therapeutic resistance. In particular, melanomas harboring BRAF^V600E and PTEN mutations often are resistant to current therapies, including BRAF inhibitors (BRAFi) and immune checkpoint inhibitors. Abl kinases (Abl/Arg) are activated in melanomas and drive progression; however, their mechanism of activation has not been established. Here we elucidate a novel link between BRAF^V600E/ERK signaling and Abl kinases. We demonstrate that BRAF^V600E/ERK play a critical role in binding, phosphorylating and regulating Abl localization and Abl/Arg activation …

Determining The Optimal Target Blood Pressure After Thrombectomy: High Or Low?, Katja E. Wartenberg, Stephan A. Mayer

Neurology Articles

No abstract provided.

Polymer Nanoassemblies With Hydrophobic Pendant Groups In The Core Induce False Positive Sirna Transfection In Luciferase Reporter Assays, Steven Rheiner, Derek Alexander Reichel, Piotr G. Rychahou, Tadahide Izumi, Hsin-Sheng Yang, Younsoo Bae

Pharmaceutical Sciences Faculty Publications

Poly(ethylene glycol)-conjugated polyethylenimine (PEG-PEI) is a widely studied cationic polymer used to develop non-viral vectors for siRNA therapy of genetic disorders including cancer. Cell lines stably expressing luciferase reporter protein typically evaluate the transfection efficacy of siRNA/PEG-PEI complexes, however recent findings revealed that PEG-PEI can reduce luciferase expression independent of siRNA. This study elucidates a cause of the false positive effect in luciferase assays by using polymer nanoassemblies (PNAs) made from PEG, PEI, poly-(L-lysine) (PLL), palmitate (PAL), and deoxycholate (DOC): PEG-PEI (2P), PEG-PEI-PAL (3P), PEG-PLL (2P′), PEG-PLL-PAL (3P′), and PEG-PEI-DOC (2PD). In vitro transfection and western blot assays of luciferase …

Recognizing The Continuous Nature Of Expression Heterogeneity And Clinical Outcomes In Clear Cell Renal Cell Carcinoma, Xiaona Wei, Yukti Choudhury, Weng-Khong Lim, John Anema, Richard J. Kahnoski, Brian Lane, John Ludlow, Masayuki Takahashi, Hiro-Omi Kanayama, Arie Belldegrun, Hyung L. Kim, Craig G. Rogers, David Nicol, Bin T. Teh, Min-Han Tan

Urology Articles

Clear cell renal cell carcinoma (ccRCC) has been previously classified into putative discrete prognostic subtypes by gene expression profiling. To investigate the robustness of these proposed subtype classifications, we evaluated 12 public datasets, together with a new dataset of 265 ccRCC gene expression profiles. Consensus clustering showed unstable subtype and principal component analysis (PCA) showed a continuous spectrum both within and between datasets. Considering the lack of discrete delineation and continuous spectrum observed, we developed a continuous quantitative prognosis score (Continuous Linear Enhanced Assessment of RCC, or CLEAR score). Prognostic performance was evaluated in independent cohorts from The Cancer Genome …

In Vivo Study Of Plasmodium Falciparum Chloroquine Susceptibility In Three Departments Of Haiti, Christian P. Raccurt, Philippe Brasseur, Micheline Cicéron, Dana M. Parke, Marcus J. Zervos, Jacques Boncy

Global Health Initiative Articles

BACKGROUND: Malaria is considered a public health priority in Haiti, with a goal to eliminate by year 2020. Chloroquine is the first-line treatment recommended by the Ministry of Public Health and Population. In order to verify the suitability of chloroquine for uncomplicated malaria treatment, an in vivo study of susceptibility of Plasmodium falciparum to chloroquine was conducted from January 2013 to March 2015 in six localities in the south of Haiti.

RESULTS: Sixty-one patients who presented with confirmed P. falciparum malaria were included in the study and followed until day 28 after having taken 25 mg/kg of chloroquine orally over …

Heterozygous De Novo Ubtf Gain-Of-Function Variant Is Associated With Neurodegeneration In Childhood., Simon Edvardson, Claudia M Nicolae, Pankaj B Agrawal, Cyril Mignot, Katelyn Payne, Asuri Narayan Prasad, Chitra Prasad, Laurie Sadler, Caroline Nava, Thomas E Mullen, Amber Begtrup, Berivan Baskin, Zöe Powis, Avraham Shaag, Boris Keren, George-Lucian Moldovan, Orly Elpeleg

Paediatrics Publications

Ribosomal RNA (rRNA) is transcribed from rDNA by RNA polymerase I (Pol I) to produce the 45S precursor of the 28S, 5.8S, and 18S rRNA components of the ribosome. Two transcription factors have been defined for Pol I in mammals, the selectivity factor SL1, and the upstream binding transcription factor (UBF), which interacts with the upstream control element to facilitate the assembly of the transcription initiation complex including SL1 and Pol I. In seven unrelated affected individuals, all suffering from developmental regression starting at 2.5-7 years, we identified a heterozygous variant, c.628G>A in UBTF, encoding p.Glu210Lys in UBF, which …