Digital Commons Network^™

Mri Radiomic Signature Of White Matter Hyperintensities Is Associated With Clinical Phenotypes, Martin Bretzner, Laura Heitsch, Chia-Ling Phuah, Et Al

Open Access Publications

Objective: Neuroimaging measurements of brain structural integrity are thought to be surrogates for brain health, but precise assessments require dedicated advanced image acquisitions. By means of quantitatively describing conventional images, radiomic analyses hold potential for evaluating brain health. We sought to: (1) evaluate radiomics to assess brain structural integrity by predicting white matter hyperintensities burdens (WMH) and (2) uncover associations between predictive radiomic features and clinical phenotypes.

Methods: We analyzed a multi-site cohort of 4,163 acute ischemic strokes (AIS) patients with T2-FLAIR MR images with total brain and WMH segmentations. Radiomic features were extracted from normal-appearing brain tissue (brain mask-WMH …

The Fidelity Of Dna Replication, Particularly On Gc-Rich Templates, Is Reduced By Defects Of The Fe-S Cluster In Dna Polymerase Δ, Denis A. Kiktev, Margaret Dominska, Tony Zhang, Joseph Dahl, Elena I. Stepchenkova, Piotr Mieczkowski, Peter M. Burgers, Scott Lujan, Adam Burkholder, Thomas A. Kunkel, Thomas D. Petes

Open Access Publications

Iron-sulfur clusters (4Fe-4S) exist in many enzymes concerned with DNA replication and repair. The contribution of these clusters to enzymatic activity is not fully understood. We identified the MET18 (MMS19) gene of Saccharomyces cerevisiae as a strong mutator on GC-rich genes. Met18p is required for the efficient insertion of iron-sulfur clusters into various proteins. met18 mutants have an elevated rate of deletions between short flanking repeats, consistent with increased DNA polymerase slippage. This phenotype is very similar to that observed in mutants of POL3 (encoding the catalytic subunit of Pol δ) that weaken binding of the iron-sulfur cluster. Comparable mutants …

Maturation Of Heterogeneity In Afferent Synapse Ultrastructure In The Mouse Cochlea, Shelby A Payne, Matthew S Joens, Heather Chung, Natalie Skigen, Adam Frank, Sonali Gattani, Kya Vaughn, Allison Schwed, Matt Nester, Atri Bhattacharyya, Guhan Iyer, Bethany Davis, Jason Carlquist, Honey Patel, James A J Fitzpatrick, Mark A Rutherford

Open Access Publications

Auditory nerve fibers (ANFs) innervating the same inner hair cell (IHC) may have identical frequency tuning but different sound response properties. In cat and guinea pig, ANF response properties correlate with afferent synapse morphology and position on the IHC, suggesting a causal structure-function relationship. In mice, this relationship has not been fully characterized. Here we measured the emergence of synaptic morphological heterogeneities during maturation of the C57BL/6J mouse cochlea by comparing postnatal day 17 (p17, ∼3 days after hearing onset) with p34, when the mouse cochlea is mature. Using serial block face scanning electron microscopy and three-dimensional reconstruction we measured …

Cancer-Associated Mesothelial Cells Promote Ovarian Cancer Chemoresistance Through Paracrine Osteopontin Signaling, Jin Qian, Bauer L Lesavage, Kelsea M Hubka, Chenkai Ma, Suchitra Natarajan, Joshua T Eggold, Yiren Xiao, Katherine C Fuh, Venkatesh Krishnan, Annika Enejder, Sarah C Heilshorn, Oliver Dorigo, Erinn B Rankin

Open Access Publications

Ovarian cancer is the leading cause of gynecological malignancy-related deaths, due to its widespread intraperitoneal metastases and acquired chemoresistance. Mesothelial cells are an important cellular component of the ovarian cancer microenvironment that promote metastasis. However, their role in chemoresistance is unclear. Here, we investigated whether cancer-associated mesothelial cells promote ovarian cancer chemoresistance and stemness in vitro and in vivo. We found that osteopontin is a key secreted factor that drives mesothelial-mediated ovarian cancer chemoresistance and stemness. Osteopontin is a secreted glycoprotein that is clinically associated with poor prognosis and chemoresistance in ovarian cancer. Mechanistically, ovarian cancer cells induced osteopontin expression …

Mab Das-1 Recognizes 3'-Sulfated Lewis A/C, Which Is Aberrantly Expressed During Metaplastic And Oncogenic Transformation Of Several Gastrointestinal Epithelia, Jeffrey W. Brown, Koushik K. Das, Vasilios Kalas, Kiron M. Das, Jason C. Mills

Open Access Publications

INTRODUCTION: Multiple previous studies have shown the monoclonal antibody Das-1 (formerly called 7E12H12) is specifically reactive towards metaplastic and carcinomatous lesions in multiple organs of the gastrointestinal system (e.g. Barrett's esophagus, intestinal-type metaplasia of the stomach, gastric adenocarcinoma, high-grade pancreatic intraepithelial neoplasm, and pancreatic ductal adenocarcinoma) as well as in other organs (bladder and lung carcinomas). Beyond being a useful biomarker in tissue, mAb Das-1 has recently proven to be more accurate than current paradigms for identifying cysts harboring advanced neoplasia. Though this antibody has been used extensively for clinical, basic science, and translational applications for decades, its epitope has …

Innovations In Md-Only Physician-Scientist Training: Experiences From The Burroughs Wellcome Fund Physician-Scientist Institutional Award Initiative, Allison T Mcelvaine, Jacqueline A Hawkins-Salsbury, Wayne M Yokoyama, Et Al

Open Access Publications

No abstract provided.

Activated Microglia Mitigate Aβ-Associated Tau Seeding And Spreading, Maud Gratuze, Yun Chen, Samira Parhizkar, Nimansha Jain, Michael R. Strickland, Javier Remolina Serrano, Marco Colonna, Jason D. Ulrich, David M. Holtzman

Open Access Publications

In Alzheimer's disease (AD) models, AD risk variants in the microglial-expressed TREM2 gene decrease Aβ plaque-associated microgliosis and increase neuritic dystrophy as well as plaque-associated seeding and spreading of tau aggregates. Whether this Aβ-enhanced tau seeding/spreading is due to loss of microglial function or a toxic gain of function in TREM2-deficient microglia is unclear. Depletion of microglia in mice with established brain amyloid has no effect on amyloid but results in less spine and neuronal loss. Microglial repopulation in aged mice improved cognitive and neuronal deficits. In the context of AD pathology, we asked whether microglial removal and repopulation decreased …

Dengue And The Lectin Pathway Of The Complement System, Romchat Kraivong, Nuntaya Punyadee, M Kathryn Liszewski, John P Atkinson, Panisadee Avirutnan

Open Access Publications

Dengue is a mosquito-borne viral disease causing significant health and economic burdens globally. The dengue virus (DENV) comprises four serotypes (DENV1-4). Usually, the primary infection is asymptomatic or causes mild dengue fever (DF), while secondary infections with a different serotype increase the risk of severe dengue disease (dengue hemorrhagic fever, DHF). Complement system activation induces inflammation and tissue injury, contributing to disease pathogenesis. However, in asymptomatic or primary infections, protective immunity largely results from the complement system's lectin pathway (LP), which is activated through foreign glycan recognition. Differences in N-glycans displayed on the DENV envelope membrane influence the lectin pattern …

Single Cell Transcriptional And Chromatin Accessibility Profiling Redefine Cellular Heterogeneity In The Adult Human Kidney, Yoshiharu Muto, Parker C. Wilson, Nicolas Ledru, Haojia Wu, Henrik Dimke, Sushrut S. Waikar, Benjamin D. Humphreys

Open Access Publications

No abstract provided.

A Microfluidic-Based Filtration System To Enrich For Bone Marrow Disseminated Tumor Cells From Breast Cancer Patients, Sreeraj G. Pillai, Chidananda M. Siddappa, Cynthia Ma, Jackie Snider, Madhurima Kaushal, Mark A. Watson, Rebecca Aft

Open Access Publications

Disseminated tumors cells (DTCs) present in the bone marrow (BM) are believed to be the progenitors of distant metastatic spread, a major cause of mortality in breast cancer patients. To better understand the behavior and therapeutic vulnerabilities of these rare cell populations, unbiased methods for selective cell enrichment are required. In this study, we have evaluated a microfluidic-based filtration system (ParsortixR, Angle PLC), previously demonstrated for use in circulating tumor cell (CTC) capture, to capture BM DTCs. Performance using BM samples was also compared directly to enrichment of CTCs in the peripheral blood (PB) from both metastatic and non-metastatic breast …

Humanized Neurofibroma Model From Induced Pluripotent Stem Cells Delineates Tumor Pathogenesis And Developmental Origins, Juan Mo, Corina Anastasaki, Zhiguo Chen, Tracey Shipman, Jason Papke, Kevin Yin, David H Gutmann, Lu Q Le

Open Access Publications

Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome caused by NF1 gene mutation, in which affected patients develop Schwann cell lineage peripheral nerve sheath tumors (neurofibromas). To investigate human neurofibroma pathogenesis, we differentiated a series of isogenic, patient-specific NF1-mutant human induced pluripotent stem cells (hiPSCs) into Schwannian lineage cells (SLCs). We found that, although WT and heterozygous NF1-mutant hiPSCs-SLCs did not form tumors following mouse sciatic nerve implantation, NF1-null SLCs formed bona fide neurofibromas with high levels of SOX10 expression. To confirm that SOX10+ SLCs contained the cells of origin for neurofibromas, both Nf1 alleles were inactivated in …

The Transcriptional Landscape Of Shh Medulloblastoma, Patryk Skowron, Joshua B. Rubin, Et Al.

Open Access Publications

No abstract provided.

Odontoblast Trpc5 Channels Signal Cold Pain In Teeth, Laura Bernal, Allen Sclaroff, John D Pfeifer, Et Al

Open Access Publications

Teeth are composed of many tissues, covered by an inflexible and obdurate enamel. Unlike most other tissues, teeth become extremely cold sensitive when inflamed. The mechanisms of this cold sensation are not understood. Here, we clarify the molecular and cellular components of the dental cold sensing system and show that sensory transduction of cold stimuli in teeth requires odontoblasts. TRPC5 is a cold sensor in healthy teeth and, with TRPA1, is sufficient for cold sensing. The odontoblast appears as the direct site of TRPC5 cold transduction and provides a mechanism for prolonged cold sensing via TRPC5's relative sensitivity to intracellular …

Thousands Of High‑Quality Sequencing Samples Fail To Show Meaningful Correlation Between 5s And 45s Ribosomal Dna Arrays In Humans, Ashley N. Hall, Tychele N. Turner, Christine Queitsch

Open Access Publications

No abstract provided.

Are Prescription Misuse And Illicit Drug Use Etiologically Distinct? A Genetically-Informed Analysis Of Opioids And Stimulants, Genevieve F Dash, Nicholas G Martin, Arpana Agrawal, Michael T Lynskey, Wendy S Slutske

Open Access Publications

BACKGROUND: Drug classes are grouped based on their chemical and pharmacological properties, but prescription and illicit drugs differ in other important ways. Potential differences in genetic and environmental influences on the (mis)use of prescription and illicit drugs that are subsumed under the same class should be examined. Opioid and stimulant classes contain prescription and illicit forms differentially associated with salient risk factors (common route of administration, legality), making them useful comparators for addressing this etiological issue.

METHODS: A total of 2410 individual Australian twins [Mage = 31.77 (s.d. = 2.48); 67% women] were interviewed about prescription misuse and illicit use …

Plasma Amyloid-Beta Levels In A Pre-Symptomatic Dutch-Type Hereditary Cerebral Amyloid Angiopathy Pedigree: A Cross-Sectional And Longitudinal Investigation, Pratishtha Chatterjee, Anne M Fagan, Chengjie Xiong, Tammie L S Benzinger, John C Morris, Randall J Bateman, Et Al

Open Access Publications

Plasma amyloid-beta (Aβ) has long been investigated as a blood biomarker candidate for Cerebral Amyloid Angiopathy (CAA), however previous findings have been inconsistent which could be attributed to the use of less sensitive assays. This study investigates plasma Aβ alterations between pre-symptomatic Dutch-type hereditary CAA (D-CAA) mutation-carriers (MC) and non-carriers (NC) using two Aβ measurement platforms. Seventeen pre-symptomatic members of a D-CAA pedigree were assembled and followed up 3-4 years later (NC = 8; MC = 9). Plasma Aβ1-40 and Aβ1-42 were cross-sectionally and longitudinally analysed at baseline (T1) and follow-up (T2) and were found to be lower in MCs …

The Role Of Mental Imagery In Parkinson's Disease Rehabilitation, Amit Abraham, Ryan P Duncan, Gammon M Earhart

Open Access Publications

Parkinson's disease (PD) is a disabling neurodegenerative disease whose manifestations span motor, sensorimotor, and sensory domains. While current therapies for PD include pharmacological, invasive, and physical interventions, there is a constant need for developing additional approaches for optimizing rehabilitation gains. Mental imagery is an emerging field in neurorehabilitation and has the potential to serve as an adjunct therapy to enhance patient function. Yet, the literature on this topic is sparse. The current paper reviews the motor, sensorimotor, and sensory domains impacted by PD using gait, balance, and pain as examples, respectively. Then, mental imagery and its potential for PD motor …

Bempedoic Acid For Heterozygous Familial Hypercholesterolemia: From Bench To Bedside, Anandita Agarwala, Renato Quispe, Anne C Goldberg, Erin D Michos

Open Access Publications

Bempedoic acid is a first-in-class, oral, inhibitor of cholesterol biosynthesis that is approved for use in patients with atherosclerotic cardiovascular disease (ASCVD) and for primary prevention in individuals with heterozygous familial hypercholesterolemia (HeFH) by the United States Food and Drug Administration. Pooled data from the phase III clinical trials, CLEAR Harmony and CLEAR Wisdom, have demonstrated the safety and efficacy of bempedoic acid with regard to lowering of low-density lipoprotein cholesterol (LDL-C) in patients with HeFH as an adjunct or alternative to currently existing lipid-lowering therapies. CLEAR Outcomes is a cardiovascular outcomes trial that is currently underway that will provide …

A Synthetic Mechanogenetic Gene Circuit For Autonomous Drug Delivery In Engineered Tissues, Robert J Nims, Lara Pferdehirt, Noelani B Ho, Alireza Savadipour, Jeremiah Lorentz, Sima Sohi, Jordan Kassab, Alison K Ross, Christopher J O'Conor, Wolfgang B Liedtke, Bo Zhang, Amy L Mcnulty, Farshid Guilak

Open Access Publications

Mechanobiologic signals regulate cellular responses under physiologic and pathologic conditions. Using synthetic biology and tissue engineering, we developed a mechanically responsive bioartificial tissue that responds to mechanical loading to produce a preprogrammed therapeutic biologic drug. By deconstructing the signaling networks induced by activation of the mechanically sensitive ion channel transient receptor potential vanilloid 4 (TRPV4), we created synthetic TRPV4-responsive genetic circuits in chondrocytes. We engineered these cells into living tissues that respond to mechanical loading by producing the anti-inflammatory biologic drug interleukin-1 receptor antagonist. Chondrocyte TRPV4 is activated by osmotic loading and not by direct cellular deformation, suggesting that tissue …

Microglia Control Small Vessel Calcification Via Trem2, Yvette Zarb, Sucheta Sridhar, Sina Nassiri, Sebastian Guido Utz, Johanna Schaffenrath, Upasana Maheshwari, Elisabeth J Rushing, K Peter R Nilsson, Mauro Delorenzi, Marco Colonna, Melanie Greter, Annika Keller

Open Access Publications

Microglia participate in central nervous system (CNS) development and homeostasis and are often implicated in modulating disease processes. However, less is known about the role of microglia in the biology of the neurovascular unit (NVU). In particular, data are scant on whether microglia are involved in CNS vascular pathology. In this study, we use a mouse model of primary familial brain calcification,

Exploring Social Media Recruitment Strategies And Preliminary Acceptability Of An Mhealth Tool For Teens With Eating Disorders, Erin Kasson, Melissa M Vázquez, Christine Doroshenko, Ellen E Fitzsimmons-Craft, Denise E Wilfley, C Barr Taylor, Patricia A Cavazos-Rehg

Open Access Publications

(1) Background: The current study leveraged social media to connect with teens with EDs to identify population specific characteristics and to gather feedback on an mHealth intervention. (2) Methods: We recruited teens with EDs from social media in two phases: (1) Discovery Group, (2) Testing Group. The Discovery Group (

Interleukin 33 Triggers Early Eosinophil-Dependent Events Leading To Metaplasia In A Chronic Model Of Gastritis-Prone Mice, Carlo De Salvo, Jason C. Mills, Et Al

Open Access Publications

No abstract provided.

Defining Surgical Terminology And Risk For Brain Computer Interface Technologies, Eric C Leuthardt, Daniel W Moran, Tim R Mullen

Open Access Publications

With the emergence of numerous brain computer interfaces (BCI), their form factors, and clinical applications the terminology to describe their clinical deployment and the associated risk has been vague. The terms "minimally invasive" or "non-invasive" have been commonly used, but the risk can vary widely based on the form factor and anatomic location. Thus, taken together, there needs to be a terminology that best accommodates the surgical footprint of a BCI and their attendant risks. This work presents a semantic framework that describes the BCI from a procedural standpoint and its attendant clinical risk profile. We propose extending the common …

Metformin Ameliorates The Severity Of Experimental Alport Syndrome, Kohei Omachi, Jeffrey H. Miner, Et Al.

Open Access Publications

No abstract provided.

Get Privacy Trending: Best Practices For The Social Media Educator, Sara W. Dong, Nathanial S. Nolan, Miguel A. Chavez, Yijia Li, Gerome V. Escota, Wendy Stead

Open Access Publications

Social media is an increasingly popular forum for medical education. Many educators, including those in infectious diseases, are now creating and sharing unique and educational patient cases online. Unfortunately, some educators unknowingly threaten patient privacy and open themselves to legal liability. Further, the use of published figures or tables creates risk of copyright infringement. As more and more infectious diseases physicians engage in social media, it is imperative to create best practices to protect both patients and physicians. This summary will define the legal requirements of patient de-identification as well as other practical recommendations as they relate to use of …

Predicting Outcomes In Patients Undergoing Pancreatectomy Using Wearable Technology And Machine Learning: Prospective Cohort Study, Heidy Cos, Dingwen Li, Gregory Williams, Jeffrey Chininis, Ruixuan Dai, Jingwen Zhang, Rohit Srivastava, Lacey Raper, Dominic Sanford, William Hawkins, Chenyang Lu, Chet W Hammill

Open Access Publications

BACKGROUND: Pancreatic cancer is the third leading cause of cancer-related deaths, and although pancreatectomy is currently the only curative treatment, it is associated with significant morbidity.

OBJECTIVE: The objective of this study was to evaluate the utility of wearable telemonitoring technologies to predict treatment outcomes using patient activity metrics and machine learning.

METHODS: In this prospective, single-center, single-cohort study, patients scheduled for pancreatectomy were provided with a wearable telemonitoring device to be worn prior to surgery. Patient clinical data were collected and all patients were evaluated using the American College of Surgeons National Surgical Quality Improvement Program surgical risk calculator …

Thermoneutrality Alters Gastrointestinal Antigen Passage Patterning And Predisposes To Oral Antigen Sensitization In Mice, Taeko K Noah, Jee-Boong Lee, Christopher A Brown, Amnah Yamani, Sunil Tomar, Varsha Ganesan, Rodney D Newberry, Gary B Huffnagle, Senad Divanovic, Simon P Hogan

Open Access Publications

Food allergy is an emerging epidemic, and the underlying mechanisms are not well defined partly due to the lack of robust adjuvant free experimental models of dietary antigen sensitization. As housing mice at thermoneutrality (Tn) - the temperature of metabolic homeostasis (26-30°C) - has been shown to improve modeling various human diseases involved in inflammation, we tested the impact of Tn housing on an experimental model of food sensitization. Here we demonstrate that WT BALB/c mice housed under standard temperature (18-20°C, Ts) conditions translocated the luminal antigens in the small intestine (SI) across the epithelium

Ontogenetic Oxycodone Exposure Affects Early Life Communicative Behaviors, Sensorimotor Reflexes, And Weight Trajectory In Mice, Elena Minakova, Simona Sarafinovska, Marwa O Mikati, Kia M Barclay, Katherine B Mccullough, Joseph D Dougherty, Ream Al-Hasani, Susan E Maloney

Open Access Publications

Nationwide, opioid misuse among pregnant women has risen four-fold from 1999 to 2014, with commensurate increase in neonates hospitalized for neonatal abstinence syndrome (NAS). NAS occurs when a fetus exposed to opioids

Apathy, Cognitive Impairment, And Social Support Contribute To Participation In Cognitively Demanding Activities Poststroke, Amy Ho, Marjorie L. Nicholas, Chaitali Dagli, Lisa Tabor Connor

Open Access Publications

No abstract provided.

Mr-Guided Adaptive Radiotherapy For Bladder Cancer, Adham Hijab, Boris Tocco, Ian Hanson, Hanneke Meijer, Christina Junker Nyborg, Anders Smedegaard Bertelsen, Robert Jan Smeenk, Gillian Smith, Jeff Michalski, Brian C Baumann, Shaista Hafeez

Open Access Publications

Radiotherapy has an important role in the curative and palliative treatment settings for bladder cancer. As a target for radiotherapy the bladder presents a number of technical challenges. These include poor tumor visualization and the variability in bladder size and position both between and during treatment delivery. Evidence favors the use of magnetic resonance imaging (MRI) as an important means of tumor visualization and local staging. The availability of hybrid systems incorporating both MRI scanning capabilities with the linear accelerator (MR-Linac) offers opportunity for in-room and real-time MRI scanning with ability of plan adaption at each fraction while the patient …