Digital Commons Network^™

Phase 1 Dose Escalation Study Of The Allosteric Akt Inhibitor Bay 1125976 In Advanced Solid Cancer-Lack Of Association Between Activating Akt Mutation And Akt Inhibition-Derived Efficacy, Andreas Schneeweiss, Dagmar Hess, Markus Joerger, Andrea Varga, Stacy Moulder, Apostolia M Tsimberidou, Cynthia Ma, Sara A Hurvitz, Christine Rentzsch, Marion Rudolph, Silke Thiele, Oliver Boix, Gary Wilkinson, Eleni Lagkadinou, Matthias Ocker

Open Access Publications

This open-label, phase I first-in-human study (NCT01915576) of BAY 1125976, a highly specific and potent allosteric inhibitor of AKT1/2, aimed to evaluate the safety, pharmacokinetics, and maximum tolerated dose of BAY 1125976 in patients with advanced solid tumors. Oral dose escalation was investigated with a continuous once daily (QD) treatment (21 days/cycle) and a twice daily (BID) schedule. A dose expansion in 28 patients with hormone receptor-positive metastatic breast cancer, including nine patients harboring the

Mechanisms Underlying Bone Loss Associated With Gut Inflammation, Ke Ke, Manoj Arra, Yousef Abu-Amer

Open Access Publications

Patients with gastrointestinal diseases frequently suffer from skeletal abnormality, characterized by reduced bone mineral density, increased fracture risk, and/or joint inflammation. This pathological process is characterized by altered immune cell activity and elevated inflammatory cytokines in the bone marrow microenvironment due to disrupted gut immune response. Gastrointestinal disease is recognized as an immune malfunction driven by multiple factors, including cytokines and signaling molecules. However, the mechanism by which intestinal inflammation magnified by gut-residing actors stimulates bone loss remains to be elucidated. In this article, we discuss the main risk factors potentially contributing to intestinal disease-associated bone loss, and summarize current …

A Review Of The Immunomodulating Components Of Maternal Breast Milk And Protection Against Necrotizing Enterocolitis, Lila S Nolan, Olivia B Parks, Misty Good

Open Access Publications

Breast milk contains immunomodulating components that are beneficial to newborns during maturation of their immune system. Human breast milk composition is influenced by an infant's gestational and chronological age, lactation stage, and the mother and infant's health status. Major immunologic components in human milk, such as secretory immunoglobulin A (IgA) and growth factors, have a known role in regulating gut barrier integrity and microbial colonization, which therefore protect against the development of a life-threatening gastrointestinal illness affecting newborn infants called necrotizing enterocolitis (NEC). Breast milk is a known protective factor in the prevention of NEC when compared with feeding with …

The Zebrafish Xenograft Platform-A Novel Tool For Modeling Kshv-Associated Diseases, Eric S Pringle, Jaime Wertman, Nicole Melong, Andrew J Coombs, Andrew L Young, David O'Leary, Chansey Veinotte, Carolyn-Ann Robinson, Michael N Ha, Graham Dellaire, Todd E Druley, Craig Mccormick, Jason N Berman

Open Access Publications

Kaposi's sarcoma associated-herpesvirus (KSHV, also known as human herpesvirus-8) is a gammaherpesvirus that establishes life-long infection in human B lymphocytes. KSHV infection is typically asymptomatic, but immunosuppression can predispose KSHV-infected individuals to primary effusion lymphoma (PEL); a malignancy driven by aberrant proliferation of latently infected B lymphocytes, and supported by pro-inflammatory cytokines and angiogenic factors produced by cells that succumb to lytic viral replication. Here, we report the development of the first

Changes In Food Cravings And Eating Behavior After A Dietary Carbohydrate Restriction Intervention Trial, Katherene O-B Anguah, Majid M Syed-Abdul, Qiong Hu, Miriam Jacome-Sosa, Colette Heimowitz, Vicki Cox, Elizabeth J Parks

Open Access Publications

Compared to low-fat diets, low-carbohydrate (CHO) diets cause weight loss (WL) over a faster time frame; however, it is unknown how changes in food cravings and eating behavior contribute to this more rapid WL in the early phases of dieting. We hypothesized that reductions in food cravings and improved eating behaviors would be evident even after a relatively short (4-week) duration of CHO-restriction, and that these changes would be associated with WL. Adult participants (

Trpv1 Activity And Substance P Release Are Required For Corneal Cold Nociception, Fengxian Li, Weishan Yang, Haowu Jiang, Changxiong Guo, Andrew J.W. Huang, Hongzhen Hu, Qin Liu

Open Access Publications

No abstract provided.

Gna11 Brain Somatic Pathogenic Variant In An Individual With Phacomatosis Pigmentovascularis, Joseph M. Sliepka, Yi-Shan Lee, Et Al.

Open Access Publications

No abstract provided.

Selective Small Molecule Parg Inhibitor Causes Replication Fork Stalling And Cancer Cell Death, Jerry H. Houl, Roderick A. Stegeman, Tom Ellenberger, In-Kwon Kim, Et Al.

Open Access Publications

No abstract provided.

Diffusion Basis Spectrum Imaging Provides Insights Into Ms Pathology, Peng Sun, Ajit George, Dana C. Perantie, Kathryn Trinkaus, Zezhong Ye, Robert T. Naismith, Sheng-Kwei Song, Anne H. Cross

Open Access Publications

No abstract provided.

Resolution Of Secondary Hemophagocytic Lymphohistiocytosis After Treatment With The Jak1/2 Inhibitor Ruxolitinib, Scott R. Goldsmith, Sana Saif Ur Rehman, Cara L. Shirai, Kiran Vij, John F. Dipersio

Open Access Publications

No abstract provided.

New Statistical Method Identifes Cytokines That Distinguish Stool Microbiomes, Dake Yang, Jethro Johnson, Xin Zhou, Elena Deych, Berkley Shands, Blake Hanson, Erica Sodergren, George Weinstock, William D. Shannon

Open Access Publications

No abstract provided.

De Novo Assembly Of The Brugia Malayi Genome Using Long Reads From A Single Minion Flowcell, Joseph R. Fauver, John Martin, Gary J. Weil, Makedonka Mitreva, Peter U. Fischer

Open Access Publications

No abstract provided.

The Epigenomic Landscape Of Transposable Elements Across Normal Human Development And Anatomy, Erica C. Pehrsson, Mayank N.K. Choudhary, Vasavi Sundaram, Ting Wang

Open Access Publications

No abstract provided.

Report From A Multidisciplinary Meeting On Anxiety As A Non-Motor Manifestation Of Parkinson’S Disease, Gregory M. Pontone, Eric J. Lenze, Et Al.

Open Access Publications

No abstract provided.

Infammatory Bowel Disease-Associated Ubiquitin Ligase Rnf183 Promotes Lysosomal Degradation Of Dr5 And Trail-Induced Caspase Activation, Yan Wu, Yuka Kimura, Takumi Okamoto, Koji Matsuhisa, Rie Asada, Atsushi Saito, Fumika Sakaue, Kazunori Imaizumi, Masayuki Kaneko

Open Access Publications

No abstract provided.

Microstructural Abnormalities In Deep And Superficial White Matter In Youths With Mild Traumatic Brain Injury, Sonja Stojanovski, Arash Nazeri, Christian Lepage, Stephanie Ameis, Aristotle N Voineskos, Anne L Wheeler

Open Access Publications

BACKGROUND: Diffusion Tensor Imaging (DTI) studies of traumatic brain injury (TBI) have focused on alterations in microstructural features of deep white matter fibers (DWM), though post-mortem studies have demonstrated that injured axons are often observed at the gray-white matter interface where superficial white matter fibers (SWM) mediate local connectivity.

OBJECTIVES: To examine microstructural alterations in SWM and DWM in youths with a history of mild TBI and examine the relationship between white matter alterations and attention.

METHODS: Using DTIDWM fractional anisotropy (FA) and SWM FA in youths with mild TBI (TBI, n=63) were compared to typically developing and psychopathology matched …

Mr Diffusion Changes In The Perimeter Of The Lateral Ventricles Demonstrate Periventricular Injury In Post-Hemorrhagic Hydrocephalus Of Prematurity, Albert M Isaacs, Christopher D Smyser, Rachel E Lean, Dimitrios Alexopoulos, Rowland H Han, Jeffrey J Neil, Sophia A Zimbalist, Cynthia E Rogers, Yan Yan, Joshua S Shimony, David D Limbrick

Open Access Publications

OBJECTIVES: Injury to the preterm lateral ventricular perimeter (LVP), which contains the neural stem cells responsible for brain development, may contribute to the neurological sequelae of intraventricular hemorrhage (IVH) and post-hemorrhagic hydrocephalus of prematurity (PHH). This study utilizes diffusion MRI (dMRI) to characterize the microstructural effects of IVH/PHH on the LVP and segmented frontal-occipital horn perimeters (FOHP).

STUDY DESIGN: Prospective study of 56 full-term infants, 72 very preterm infants without brain injury (VPT), 17 VPT infants with high-grade IVH without hydrocephalus (HG-IVH), and 13 VPT infants with PHH who underwent dMRI at term equivalent. LVP and FOHP dMRI measures and …

Evaluating Glial And Neuronal Blood Biomarkers Gfap And Uch-L1 As Gradients Of Brain Injury In Concussive, Subconcussive And Non-Concussive Trauma: A Prospective Cohort Study, Linda Papa, Mark R Zonfrillo, Robert D Welch, Lawrence M Lewis, Carolina F Braga, Ciara N Tan, Neema J Ameli, Marco A Lopez, Crystal A Haeussler, Diego Mendez Giordano, Philip A Giordano, Jose Ramirez, Manoj K Mittal

Open Access Publications

Objectives: To evaluate the ability of glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase (UCH-L1) to detect concussion in children and adult trauma patients with a normal mental status and assess biomarker concentrations over time as gradients of injury in concussive and non-concussive head and body trauma.

Design: Large prospective cohort study.

Setting: Three level I trauma centres in the USA.

Participants: Paediatric and adult trauma patients of all ages, with and without head trauma, presenting with a normal mental status (Glasgow Coma Scale score of 15) within 4 hours of injury. Rigorous screening for concussive symptoms was conducted. …

The Effect Of Gut Microbiome Composition On Human Immune Responses: An Exploration Of Interference By Helminth Infections, Ivonne Martin, Maria M M Kaisar, Aprilianto E Wiria, Firdaus Hamid, Yenny Djuardi, Erliyani Sartono, Bruce A Rosa, Makedonka Mitreva, Taniawati Supali, Jeanine J Houwing-Duistermaat, Maria Yazdanbakhsh, Linda J Wammes

Open Access Publications

No abstract provided.

Vaccine-Induced Skewing Of T Cell Responses Protects Against Chikungunya Virus Disease, Rebecca M Broeckel, Nicole Haese, Takeshi Ando, Igor Dmitriev, Craig N Kreklywich, John Powers, Michael Denton, Patricia Smith, Thomas E Morrison, Mark Heise, Victor Defilippis, Ilhem Messaoudi, David T Curiel, Daniel N Streblow

Open Access Publications

Chikungunya virus (CHIKV) infections can cause severe and debilitating joint and muscular pain that can be long lasting. Current CHIKV vaccines under development rely on the generation of neutralizing antibodies for protection; however, the role of T cells in controlling CHIKV infection and disease is still unclear. Using an overlapping peptide library, we identified the CHIKV-specific T cell receptor epitopes recognized in C57BL/6 infected mice at 7 and 14 days post-infection. A fusion protein containing peptides 451, 416, a small region of nsP4, peptide 47, and an HA tag (CHKVf5) was expressed using adenovirus and cytomegalovirus-vectored vaccines. Mice vaccinated with …

Thromboelastography Variables, Immune Markers, And Endothelial Factors Associated With Shock And Npmods In Children With Severe Sepsis, Arun Saini, Philip C Spinella, Steven P Ignell, John C Lin

Open Access Publications

No abstract provided.

Attribution Of Ghrelin To Cancer; Attempts To Unravel An Apparent Controversy, Saeed Soleyman-Jahi, Fatemeh Sadeghi, Amin Pastaki Khoshbin, Leila Khani, Venus Roosta, Kazem Zendehdel

Open Access Publications

Ghrelin is an endogenous peptide hormone mainly produced in the stomach. It has been known to regulate energy homeostasis, stimulate secretion of growth hormone, and mediate many other physiologic effects. Various effects attributed to ghrelin contribute to many aspects of cancer development and progression. Accordingly, a large body of evidence has emerged about the association of ghrelin with several types of cancer in scales of cell-line, animal, and human studies. However, existing data are controversial. This controversy occurs in two main domains: one is the controversial results in local effects of ghrelin on different types of human cancer cell-lines; the …

22q11.2 Duplication: A Review Of Neuropsychiatric Correlates And A Newly Observed Case Of Prototypic Sociopathy, Sonam Vyas, John N Constantino, Dustin Baldridge

Open Access Publications

Callous-unemotional (CU) traits are highly disabling behavioral characteristics, common predictors of delinquency and criminality, and pathognomonic for antisocial personality disorder. They are highly heritable, but their specific molecular genetic causes are unknown. Here, we briefly review the literature on neuropsychiatric correlates of 22q11.2 duplication and describe a newly identified case of a 737-kb microduplication within the low copy repeat (LCR) B-D region, involving a 13-yr-old early adoptee with mild developmental delay and severe, chronic antisocial behavior of early childhood onset. When psychiatric symptoms have been reported in relation to duplications in this specific region, 19% of the reports feature aggression-but …

The Impact Of The Geometric Correction Scheme On Meg Functional Topology At Rest, Stefania Della Penna, Maurizio Corbetta, Vincent Wens, Francesco De Pasquale

Open Access Publications

Spontaneous activity is correlated across brain regions in large scale networks (RSN) closely resembling those recruited during several behavioral tasks and characterized by functional specialization and dynamic integration. Specifically, MEG studies revealed a set of central regions (dynamic core) possibly facilitating communication among differently specialized brain systems. However, source projected MEG signals, due to the fundamentally ill-posed inverse problem, are affected by spatial leakage, leading to the estimation of spurious, blurred connections that may affect the topological properties of brain networks and their integration. To reduce leakage effects, several correction schemes have been proposed including the Geometric Correction Scheme (GCS) …

Ureteropelvic Junction Obstruction Caused By Metastatic Cholangiocarcinoma, Nicholas A Pickersgill, Alec J Wright, Robert S Figenshau

Open Access Publications

We describe the rare case of a 61-year-old female with right ureteropelvic junction (UPJ) obstruction caused by metastatic cholangiocarcinoma. Her past medical history was notable for cholangiocarcinoma treated with neoadjuvant chemoradiation and two orthotopic liver transplants six years earlier. Urology was consulted when she presented with flank pain and urinary tract infection. Diagnostic workup demonstrated right UPJ obstruction. She was managed acutely with percutaneous nephrostomy. She subsequently underwent robotic pyeloplasty and intrinsic obstruction of the UPJ was discovered. Histological examination revealed adenocarcinoma, consistent with systemic recurrence of the patient's known cholangiocarcinoma.

Proteomic And Phosphoproteomic Analysis Reveals That Neurokinin-1 Receptor (Nk1r) Blockade With Aprepitant In Human Keratinocytes Activates A Distinct Subdomain Of Egfr Signaling: Implications For The Anti-Pruritic Activity Of Nk1r Antagonists, Shawn G Kwatra, Emily Boozalis, Amy H Huang, Cory Nanni, Raveena Khanna, Kyle A Williams, Yevgeniy R Semenov, Callie M Roberts, Robert F Burns, Madison Krischak, Madan M Kwatra

Open Access Publications

No abstract provided.

Confronting The Opioid Crisis: Practical Pain Management And Strategies: Aoa 2018 Critical Issues Symposium, Hassan R Mir, Anna N Miller, William T Obremskey, A Alex Jahangir, Joseph R Hsu

Open Access Publications

The United States is in the midst of an opioid crisis. Clinicians have been part of the problem because of overprescribing of narcotics for perioperative pain management. Clinicians need to understand the pathophysiology and science of addiction to improve perioperative management of pain for their patients. Multiple modalities for pain management exist that decrease the use of narcotics. Physical strategies, cognitive strategies, and multimodal medication can all provide improved pain relief and decrease the use of narcotics. National medical societies are developing clinical practice guidelines for pain management that incorporate multimodal strategies and multimodal medication. Changes to policy that improve …

Mechanisms Of Reactivation Of Latent Tuberculosis Infection Due To Siv Coinfection, Allison N Bucşan, Ayan Chatterjee, Dhiraj K Singh, Taylor W Foreman, Tae-Hyung Lee, Breanna Threeton, Melanie G Kirkpatrick, Mushtaq Ahmed, Nadia Golden, Xavier Alvarez, James A Hoxie, Smriti Mehra, Jyothi Rengarajan, Shabaana A Khader, Deepak Kaushal

Open Access Publications

HIV is a major driver of tuberculosis (TB) reactivation. Depletion of CD4+ T cells is assumed to be the basis behind TB reactivation in individuals with latent tuberculosis infection (LTBI) coinfected with HIV. Nonhuman primates (NHPs) coinfected with a mutant simian immunodeficiency virus (SIVΔGY) that does not cause depletion of tissue CD4+ T cells during infection failed to reactivate TB. To investigate the contribution of CD4+ T cell depletion relative to other mechanisms of SIV-induced reactivation of LTBI, we used CD4R1 antibody to deplete CD4+ T cells in animals with LTBI without lentiviral infection. The mere depletion of CD4+ T …

Impact Of An Electronic Hard-Stop Clinical Decision Support Tool To Limit Repeat Clostridioides Difficile Toxin Enzyme Immunoassay Testing On Test Utilization, Jennie H Kwon, Kimberly A Reske, Tiffany Hink, Ronald Jackups, Carey-Ann D Burnham, Erik R Dubberke

Open Access Publications

We performed an intervention evaluating the impact of an electronic hard-stop clinical decision support tool on repeat Clostridioides difficile (CD) toxin enzyme immunoassay (T-EIA) testing. The CD testing rate and number of admissions with repeat tests decreased significantly postintervention (P < .01 for both); the percentage of positive tests was unchanged (P = .27).

Foxm1 Drives Proximal Tubule Proliferation During Repair From Acute Ischemic Kidney Injury, Monica Chang-Panesso, Farid F Kadyrov, Matthew Lalli, Haojia Wu, Shiyo Ikeda, Eirini Kefaloyianni, Mai M Abdelmageed, Andreas Herrlich, Akio Kobayashi, Benjamin D Humphreys

Open Access Publications

The proximal tubule has a remarkable capacity for repair after acute injury, but the cellular lineage and molecular mechanisms underlying this repair response are incompletely understood. Here, we developed a Kim1-GFPCreERt2 knockin mouse line (Kim1-GCE) in order to perform genetic lineage tracing of dedifferentiated cells while measuring the cellular transcriptome of proximal tubule during repair. Acutely injured genetically labeled clones coexpressed KIM1, VIMENTIN, SOX9, and KI67, indicating a dedifferentiated and proliferative state. Clonal analysis revealed clonal expansion of Kim1+ cells, indicating that acutely injured, dedifferentiated proximal tubule cells, rather than fixed tubular progenitor cells, account for repair. Translational profiling during …