Digital Commons Network^™

Tet2 And Dnmt3a Mutations Exert Divergent Effects On Dna Repair And Sensitivity Of Leukemia Cells To Parp Inhibitors, Silvia Maifrede, Bac Viet Le, Margaret Nieborowska-Skorska, Konstantin Golovine, Katherine Sullivan-Reed, Wangisa M B Dunuwille, Joseph Nacson, Michael Hulse, Kelsey Keith, Jozef Madzo, Lisa Beatrice Caruso, Zachary Gazze, Zhaorui Lian, Antonella Padella, Kumaraswamy N. Chitrala, Boris A. Bartholdy, Ksenia Matlawska-Wasowska, Daniela Di Marcantonio, Giorgia Simonetti, Georg Greiner, Stephen M Sykes, Peter Valent, Elisabeth M. Paietta, Martin S. Tallman, Hugo F. Fernandez, Mark R. Litzow, Mark D. Minden, Jian Huang, Giovanni Martinelli, George S. Vassiliou, Italo Tempera, Katarzyna Piwocka, Neil Johnson, Grant A. Challen, Tomasz Skorski

Pediatrics Research and Scholarship

Somatic variants in TET2 and DNMT3A are founding mutations in hematological malignancies that affect the epigenetic regulation of DNA methylation. Mutations in both genes often co-occur with activating mutations in genes encoding oncogenic tyrosine kinases such as FLT3ITD, BCR-ABL1, JAK2V617F , and MPLW515L , or with mutations affecting related signaling pathways such as NRASG12D and CALRdel52 . Here, we show that TET2 and DNMT3A mutations exert divergent roles in regulating DNA repair activities in leukemia cells expressing these oncogenes. Malignant TET2-deficient cells displayed downregulation of BRCA1 and LIG4, resulting in reduced activity of BRCA1/2-mediated homologous recombination (HR) and DNA-PK-mediated non-homologous …

Ethics Of Ai In Pathology: Current Paradigms And Emerging Issues, Chhavi Chauhan, Rama R. Gullapalli

Pathology Research and Scholarship

Deep learning has rapidly advanced artificial intelligence (AI) and algorithmic decision-making (ADM) paradigms, affecting many traditional fields of medicine, including pathology, which is a heavily data-centric specialty of medicine. The structured nature of pathology data repositories makes it highly attractive to AI researchers to train deep learning models to improve health care delivery. Additionally, there are enormous financial incentives driving adoption of AI and ADM due to promise of increased efficiency of the health care delivery process. AI, if used unethically, may exacerbate existing inequities of health care, especially if not implemented correctly. There is an urgent need to harness …

Initial Laparotomy Versus Peritoneal Drainage In Extremely Low Birthweight Infants With Surgical Necrotizing Enterocolitis Or Isolated Intestinal Perforation: A Multicenter Randomized Clinical Trial, Martin L Blakely, Jon E Tyson, Kevin P Lally, Susan R Hintz, Barry Eggleston, David K Stevenson, Gail E Besner, Abhik Das, Robin K Ohls, William E Truog, Leif D Nelin, Brenda B Poindexter, Claudia Pedroza, Michele C Walsh, Barbara J Stoll, Rachel Geller, Kathleen A Kennedy, Reed A Dimmitt, Waldemar A Carlo, C Michael Cotten, Abbot R Laptook, Krisa P Van Meurs, Kara L Calkins, Gregory M Sokol, Pablo J Sanchez, Myra H Wyckoff, Ravi M Patel, Ivan D Frantz, Seetha Shankaran, Carl T D'Angio, Bradley A Yoder, Edward F Bell, Kristi L Watterberg, Colin A Martin, Carroll M Harmon, Henry Rice, Arlet G Kurkchubasche, Karl Sylvester, James C Y Dunn, Troy A Markel, Diana L Diesen, Amina M Bhatia, Alan Flake, Walter J Chwals, Rebeccah Brown, Kathryn D Bass, Shawn D St Peter, Christina M Shanti, Walter Pegoli, David Skarda, Joel Shilyansky, David G Lemon, Ricardo A Mosquera, Myriam Peralta-Carcelen, Ricki F Goldstein, Betty R Vohr, Isabell B Purdy, Abbey C Hines, Nathalie L Maitre, Roy J Heyne, Sara B Demauro, Elisabeth C Mcgowan, Kimberly Yolton, Howard W Kilbride, Girija Natarajan, Kelley Yost, Sarah Winter, Tarah T Colaizy, Matthew M Laughon, Satyanarayana Lakshminrusimha, Rosemary D Higgins, Eunice Kennedy Shriver National Institute Of Child Health And Human Development Neonatal Research Network

Faculty, Staff and Student Publications

OBJECTIVE: The aim of this study was to determine which initial surgical treatment results in the lowest rate of death or neurodevelopmental impairment (NDI) in premature infants with necrotizing enterocolitis (NEC) or isolated intestinal perforation (IP).

SUMMARY BACKGROUND DATA: The impact of initial laparotomy versus peritoneal drainage for NEC or IP on the rate of death or NDI in extremely low birth weight infants is unknown.

METHODS: We conducted the largest feasible randomized trial in 20 US centers, comparing initial laparotomy versus peritoneal drainage. The primary outcome was a composite of death or NDI at 18 to 22 months corrected …

A Human Ipsc-Derived Inducible Neuronal Model Of Niemann-Pick Disease, Type C1, Anika V Prabhu, Insung Kang, Raffaella De Pace, Christopher A Wassif, Hideji Fujiwara, Pamela Kell, Xuntian Jiang, Daniel S Ory, Juan S Bonifacino, Michael E Ward, Forbes D Porter

2020-Current year OA Pubs

BACKGROUND: Niemann-Pick disease, type C (NPC) is a childhood-onset, lethal, neurodegenerative disorder caused by autosomal recessive mutations in the genes NPC1 or NPC2 and characterized by impaired cholesterol homeostasis, a lipid essential for cellular function. Cellular cholesterol levels are tightly regulated, and mutations in either NPC1 or NPC2 lead to deficient transport and accumulation of unesterified cholesterol in the late endosome/lysosome compartment, and progressive neurodegeneration in affected individuals. Previous cell-based studies to understand the NPC cellular pathophysiology and screen for therapeutic agents have mainly used patient fibroblasts. However, these do not allow modeling the neurodegenerative aspect of NPC disease, highlighting …

Structure Of Venezuelan Equine Encephalitis Virus In Complex With The Ldlrad3 Receptor, Katherine Basore, Hongming Ma, Natasha M Kafai, Samantha Mackin, Arthur S Kim, Christopher A Nelson, Michael S Diamond, Daved H Fremont

Open Access Publications

LDLRAD3 is a recently defined attachment and entry receptor for Venezuelan equine encephalitis virus (VEEV)

Initial Laparotomy Versus Peritoneal Drainage In Extremely Low Birthweight Infants With Surgical Necrotizing Enterocolitis Or Isolated Intestinal Perforation: A Multicenter Randomized Clinical Trial, Martin L Blakely, Jon E Tyson, Kevin P Lally, Susan R Hintz, Barry Eggleston, David K Stevenson, Gail E Besner, Abhik Das, Robin K Ohls, William E Truog, Leif D Nelin, Brenda B Poindexter, Claudia Pedroza, Michele C Walsh, Barbara J Stoll, Rachel Geller, Kathleen A Kennedy, Reed A Dimmitt, Waldemar A Carlo, C Michael Cotten, Abbot R Laptook, Krisa P Van Meurs, Kara L Calkins, Gregory M Sokol, Pablo J Sanchez, Myra H Wyckoff, Ravi M Patel, Ivan D Frantz, Seetha Shankaran, Carl T D'Angio, Bradley A Yoder, Edward F Bell, Kristi L Watterberg, Colin A Martin, Carroll M Harmon, Henry Rice, Arlet G Kurkchubasche, Karl Sylvester, James C Y Dunn, Troy A Markel, Diana L Diesen, Amina M Bhatia, Alan Flake, Walter J Chwals, Rebeccah Brown, Kathryn D Bass, Shawn D St Peter, Christina M Shanti, Walter Pegoli, David Skarda, Joel Shilyansky, David G Lemon, Ricardo A Mosquera, Myriam Peralta-Carcelen, Ricki F Goldstein, Betty R Vohr, Isabell B Purdy, Abbey C Hines, Nathalie L Maitre, Roy J Heyne, Sara B Demauro, Elisabeth C Mcgowan, Kimberly Yolton, Howard W Kilbride, Girija Natarajan, Kelley Yost, Sarah Winter, Tarah T Colaizy, Matthew M Laughon, Satyanarayana Lakshminrusimha, Rosemary D Higgins, Eunice Kennedy Shriver National Institute Of Child Health And Human Development Neonatal Research Network

Faculty, Staff and Student Publications

OBJECTIVE: The aim of this study was to determine which initial surgical treatment results in the lowest rate of death or neurodevelopmental impairment (NDI) in premature infants with necrotizing enterocolitis (NEC) or isolated intestinal perforation (IP).

SUMMARY BACKGROUND DATA: The impact of initial laparotomy versus peritoneal drainage for NEC or IP on the rate of death or NDI in extremely low birth weight infants is unknown.

METHODS: We conducted the largest feasible randomized trial in 20 US centers, comparing initial laparotomy versus peritoneal drainage. The primary outcome was a composite of death or NDI at 18 to 22 months corrected …

Organophosphate Pesticides And Progression Of Chronic Kidney Disease Among Children: A Prospective Cohort Study., Melanie H. Jacobson, Yinxiang Wu, Mengling Liu, Kurunthachalam Kannan, Adela Jing Li, Morgan Robinson, Bradley A. Warady, Susan Furth, Howard Trachtman, Leonardo Trasande

Manuscripts, Articles, Book Chapters and Other Papers

Background: Growing evidence suggests that exposure to environmental chemicals, such as pesticides, impacts renal function and chronic kidney disease (CKD). However, it is not clear if pesticides may affect CKD progression and no studies exist in children.

Objectives: The objective of this study was to examine associations between serially measured urinary OP pesticide metabolites and clinical and laboratory measures of kidney function over time among children with CKD.

Methods: This study used data on 618 participants enrolled in the CKD in Children study (CKiD), a cohort study of pediatric CKD patients from the US and Canada. Children were followed over …

Clinical Trial And Postmarketing Safety Of Onasemnogene Abeparvovec Therapy, John W Day, Jerry R Mendell, Eugenio Mercuri, Richard S Finkel, Kevin A Strauss, Aaron Kleyn, Sitra Tauscher-Wisniewski, Francis Fonyuy Tukov, Sandra P Reyna, Deepa H Chand

2020-Current year OA Pubs

INTRODUCTION: This is the first description of safety data for intravenous onasemnogene abeparvovec, the only approved systemically administered gene-replacement therapy for spinal muscular atrophy.

OBJECTIVE: We comprehensively assessed the safety of intravenous onasemnogene abeparvovec from preclinical studies, clinical studies, and postmarketing data.

METHODS: Single-dose toxicity studies were performed in neonatal mice and juvenile or neonatal cynomolgus nonhuman primates (NHPs). Data presented are from a composite of preclinical studies, seven clinical trials, and postmarketing sources (clinical trials, n = 102 patients; postmarketing surveillance, n = 665 reported adverse event [AE] cases). In clinical trials, safety was assessed through AE monitoring, vital-sign …

Rare Variants In Kdr, Encoding Vegf Receptor 2, Are Associated With Tetralogy Of Fallot., Doris Škorić-Milosavljević, Najim Lahrouchi, Fernanda M. Bosada, Gregor Dombrowsky, Simon G. Williams, Robert Lesurf, Fleur V Y Tjong, Roddy Walsh, Ihssane El Bouchikhi, Jeroen Breckpot, Enrique Audain, Aho Ilgun, Leander Beekman, Ilham Ratbi, Alanna Strong, Maximilian Muenke, Solveig Heide, Alison M. Muir, Mariam Hababa, Laura A. Cross, Dihong Zhou, T Pastinen, German Competence Network For Congenital Heart Defects, Elaine Zackai, Samir Atmani, Karim Ouldim, Najlae Adadi, Katharina Steindl, Anita Rauch, David Brook, Anna Wilsdon, Irene Kuipers, Nico A. Blom, Barbara J. Mulder, Heather C. Mefford, Boris Keren, Pascal Joset, Paul Kruszka, Isabelle Thiffault, Sarah E. Sheppard, Amy Roberts, Elisabeth M. Lodder, Bernard D. Keavney, Sally-Ann B. Clur, Seema Mital, Marc-Philip Hitz, Vincent M. Christoffels, Alex V. Postma, Connie R. Bezzina

Manuscripts, Articles, Book Chapters and Other Papers

Purpose: Rare genetic variants in KDR, encoding the vascular endothelial growth factor receptor 2 (VEGFR2), have been reported in patients with tetralogy of Fallot (TOF). However, their role in disease causality and pathogenesis remains unclear.

Methods: We conducted exome sequencing in a familial case of TOF and large-scale genetic studies, including burden testing, in >1,500 patients with TOF. We studied gene-targeted mice and conducted cell-based assays to explore the role of KDR genetic variation in the etiology of TOF.

Results: Exome sequencing in a family with two siblings affected by TOF revealed biallelic missense variants in KDR. Studies in knock-in …

Activation Of The Innate Immune System In Children With Irritable Bowel Syndrome Evidenced By Increased Fecal Human Β-Defensin-2, Robert J Shulman, Sridevi Devaraj, Margaret Heitkemper

Children’s Nutrition Research Center Staff Publications

Background & aims: The role of the innate immune system in functional gastrointestinal pain disorders is unclear. We investigated the role of β-defensin-2 and gut permeability in childhood irritable bowel syndrome (IBS) and functional abdominal pain (FAP) symptom generation.

Methods: Fecal β-defensin-2 (and in a subset, gut permeability) was measured in children with IBS (n = 116), FAP (n = 33), and healthy control (HC) children (n = 72). IBS and FAP patients were recruited from tertiary and primary care, and HCs were recruited from primary care.

Results: β-defensin-2 concentration was greater in children with IBS (P = .003) and …

Real-World Assessment Of Asthma Specialist Visits Among U.S. Patients With Severe Asthma., Jessica F Most, Christopher S Ambrose, Yen Chung, James L Kreindler, Aimee Near, Stephen Brunton, Yao Cao, Huan Huang, Xiaohui Zhao

Division of Pulmonary, Allergy, and Critical Care Medicine Faculty Papers

BACKGROUND: U.S. guidelines recommend that patients with severe asthma be referred to specialists (allergists/immunologists or pulmonologists) for systematic assessment or comanagement; however, contemporary, real-world data on the frequency and impact of specialist care among U.S. severe asthma patients are lacking.

OBJECTIVES: To quantify the frequency of asthma specialist visits among U.S. patients with severe asthma, identify patient demographic and clinical characteristics associated with specialist visits and describe health outcomes following specialist care.

METHODS: Severe asthma patients aged 6 years or older were identified between January 1, 2015, and December 31, 2017, in the IQVIA PharMetrics® Plus database of commercially insured …

Flowcharts Improve Periodontal Diagnosis By Dental And Dental Hygiene Students, Karo Parsegian, Srinivas Ayilavarapu, Tulsi Patel, Harold A Henson, Nikola Angelov

Faculty, Staff and Student Publications

BACKGROUND: In 2017, the American Academy of Periodontology and the European Federation of Periodontology updated the classification of periodontal and peri-implant diseases and conditions. The goal of the present crossover study was to develop straightforward, illustrative flowcharts and determine their impact on the accuracy and speed of diagnosing periodontal conditions by predoctoral dental students (DS) and dental hygiene students (DHS).

METHODS: Two flowcharts (a decision-tree flowchart and one based on the periodontal disease/condition entity) were developed using updated diagnostic determinants proposed by the 2017 classification. A total of 26 second-, third-, and fourth-year DS (DS2, DS3, and DS4, respectively) and …

Immune Responses To Injury And Their Links To Eye Disease., Mary Ann Stepp, A Sue Menko

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The eye is regarded as an immune privileged site. Since the presence of a vasculature would impair vision, the vasculature of the eye is located outside of the central light path. As a result, many regions of the eye evolved mechanisms to deliver immune cells to sites of dysgenesis, injury, or in response to the many age-related pathologies. While the purpose of these immune responses is reparative or protective, cytokines released by immune cells compromise visual acuity by inducing inflammation and fibrosis. The response to traumatic or pathological injury is distinct in different regions of the eye. Age-related diseases impact …

Bone Mineral Density Changes Associated With Pregnancy, Lactation, And Medical Treatments In Premenopausal Women And Effects Later In Life., Nelson B Watts, Neil Binkley, Charlotte D Owens, Ayman Al-Hendy, Elizabeth E Puscheck, Mohamad Shebley, William Schlaff, Md, James A Simon

Department of Obstetrics and Gynecology Faculty Papers

Bone mineral density (BMD) changes during the life span, increasing rapidly during adolescence, plateauing in the third decade of life, and subsequently entering a phase of age-related decline. In women, menopause leads to accelerated bone loss and an increase in fracture risk. Between peak bone mass attainment and menopause, BMD is generally stable and the risk of fracture is typically low. This time period is marked by life events such as pregnancy and lactation, which transiently decrease BMD, yet their long-term effects on fracture risk are less certain. BMD may also be altered by exposure to medications that affect bone …

Advances In Optical Gastrointestinal Endoscopy: A Technical Review, Yubo Tang, Sharmila Anandasabapathy, Rebecca Richards-Kortum

Faculty, Staff and Students Publications

Optical endoscopy is the primary diagnostic and therapeutic tool for management of gastrointestinal (GI) malignancies. Most GI neoplasms arise from precancerous lesions; thus, technical innovations to improve detection and diagnosis of precancerous lesions and early cancers play a pivotal role in improving outcomes. Over the last few decades, the field of GI endoscopy has witnessed enormous and focused efforts to develop and translate accurate, user-friendly, and minimally invasive optical imaging modalities. From a technical point of view, a wide range of novel optical techniques is now available to probe different aspects of light-tissue interaction at macroscopic and microscopic scales, complementing …

Transmission Event Of Sars-Cov-2 Delta Variant Reveals Multiple Vaccine Breakthrough Infections, Timothy Farinholt, Harsha Doddapaneni, Xiang Qin, Vipin Menon, Qingchang Meng, Ginger Metcalf, Hsu Chao, Marie-Claude Gingras, Vasanthi Avadhanula, Paige Farinholt, Charu Agrawal, Donna M Muzny, Pedro A Piedra, Richard A Gibbs, Joseph Petrosino

Faculty, Staff and Students Publications

BACKGROUND: This study aims to identify the causative strain of SARS-CoV-2 in a cluster of vaccine breakthroughs. Vaccine breakthrough by a highly transmissible SARS-CoV-2 strain is a risk to global public health.

METHODS: Nasopharyngeal swabs from suspected vaccine breakthrough cases were tested for SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) by qPCR (quantitative polymerase chain reaction) for Wuhan-Hu1 and alpha variant. Positive samples were then sequenced by Swift Normalase Amplicon Panels to determine the causal variant. GATK (genome analysis toolkit) variants were filtered with allele fraction ≥80 and min read depth 30x.

RESULTS: Viral sequencing revealed an infection cluster of …

Adjuvant Platinum-Based Chemotherapy In Radically Resected Adrenocortical Carcinoma: A Cohort Study, Otilia Kimpel, Sara Bedrose, Felix Megerle, Alfredo Berruti, Massimo Terzolo, Matthias Kroiss, Knut Mai, Olaf M Dekkers, Mouhammed Amir Habra, Martin Fassnacht

Faculty, Staff and Students Publications

BACKGROUND: After radical resection, patients with adrenocortical carcinoma (ACC) frequently experience recurrence and, therefore, effective adjuvant treatment is urgently needed. The aim of the study was to investigate the role of adjuvant platinum-based therapy.

METHODS: In this retrospective multicentre cohort study, we identified patients treated with adjuvant platinum-based chemotherapy after radical resection and compared them with patients without adjuvant chemotherapy. Recurrence-free and overall survival (RFS/OS) were investigated in a matched group analysis and by applying a propensity score matching using the full control cohort (n = 268). For both approaches, we accounted for immortal time bias.

RESULTS: Of the 31 …

Prevention And Screening Of Hpv Malignancies, Kristina R Dahlstrom, Andrew T Day, Erich M Sturgis

Faculty, Staff and Students Publications

It is estimated that 5% of the global cancer burden, or approximately 690,000 cancer cases annually, is attributable to human papillomavirus (HPV). Primary prevention through prophylactic vaccination is the best option for reducing the burden of HPV-related cancers. Most high-income countries (HICs) have introduced the HPV vaccine and are routinely vaccinating adolescent boys and girls. Unfortunately, although they suffer the greatest morbidity and mortality due to HPV-related cancers, many lower- and middle-income countries (LMICs) have been unable to initiate and sustain vaccination programs. Secondary prevention in the form of screening has led to substantial declines in cervical cancer incidence in …

Pancreatic Differentiation Of Stem Cells Reveals Pathogenesis Of A Syndrome Of Ketosis-Prone Diabetes, Diane Yang, Sanjeet Patel, Wojciech J Szlachcic, Jolanta Chmielowiec, Diane Scaduto, Nagireddy Putluri, Arun Sreekumar, James Suliburk, Michael Metzker, Ashok Balasubramanyam, Malgorzata Borowiak

Faculty, Staff and Students Publications

Genetic analysis of an adult patient with an unusual course of ketosis-prone diabetes (KPD) and lacking islet autoantibodies demonstrated a nucleotide variant in the 5′-untranslated region (UTR) of PDX1, a β-cell development gene. When differentiated to the pancreatic lineage, his induced pluripotent stem cells stalled at the definitive endoderm (DE) stage. Metabolomics analysis of the cells revealed that this was associated with leucine hypersensitivity during transition from the DE to the pancreatic progenitor (PP) stage, and RNA sequencing showed that defects in leucine-sensitive mTOR pathways contribute to the differentiation deficiency. CRISPR/Cas9 manipulation of the PDX1 variant demonstrated that it …

Gut Microbiota-Derived Short-Chain Fatty Acids Protect Against The Progression Of Endometriosis, Sangappa B Chadchan, Pooja Popli, Chandrasekhar R Ambati, Eric Tycksen, Sang Jun Han, Serdar E Bulun, Nagireddy Putluri, Scott W Biest, Ramakrishna Kommagani

2020-Current year OA Pubs

Worldwide, ∼196 million are afflicted with endometriosis, a painful disease in which endometrial tissue implants and proliferates on abdominal peritoneal surfaces. Theories on the origin of endometriosis remained inconclusive. Whereas up to 90% of women experience retrograde menstruation, only 10% develop endometriosis, suggesting that factors that alter peritoneal environment might contribute to endometriosis. Herein, we report that whereas some gut bacteria promote endometriosis, others protect against endometriosis by fermenting fiber to produce short-chain fatty acids. Specifically, we found that altered gut microbiota drives endometriotic lesion growth and feces from mice with endometriosis contained less of short-chain fatty acid and n-butyrate …

Thrombolytic Enzymes Of Microbial Origin: A Review, Deepti Diwan, Zeba Usmani, Minaxi Sharma, James W Nelson, Vijay Kumar Thakur, Graham Christie, Gustavo Molina, Vijai Kumar Gupta

2020-Current year OA Pubs

Enzyme therapies are attracting significant attention as thrombolytic drugs during the current scenario owing to their great affinity, specificity, catalytic activity, and stability. Among various sources, the application of microbial-derived thrombolytic and fibrinolytic enzymes to prevent and treat vascular occlusion is promising due to their advantageous cost-benefit ratio and large-scale production. Thrombotic complications such as stroke, myocardial infarction, pulmonary embolism, deep venous thrombosis, and peripheral occlusive diseases resulting from blood vessel blockage are the major cause of poor prognosis and mortality. Given the ability of microbial thrombolytic enzymes to dissolve blood clots and prevent any adverse effects, their use as …

Genetic Characterization, Current Model Systems And Prognostic Stratification In Pax Fusion-Negative Vs. Pax Fusion-Positive Rhabdomyosarcoma, Carina A Dehner, Amy E Armstrong, Marielle Yohe, Jack F Shern, Angela C Hirbe

Open Access Publications

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents and accounts for approximately 2% of soft tissue sarcomas in adults. It is subcategorized into distinct subtypes based on histological features and fusion status (

Genomic Biomarkers Of Meningioma: A Focused Review, Jacob A. Pawloski, Hassan A. Fadel, Yi-Wen Huang, Ian Y. Lee

Neurosurgery Articles

Meningiomas represent a phenotypically and genetically diverse group of tumors which often behave in ways that are not simply explained by their pathologic grade. The genetic landscape of meningiomas has become a target of investigation as tumor genomics have been found to impact tumor location, recurrence risk, and malignant potential. Additionally, targeted therapies are being developed that in the future may provide patients with personalized chemotherapy based on the genetic aberrations within their tumor. This review focuses on the most common genetic mutations found in meningiomas of all grades, with an emphasis on the impact on tumor location and clinically …

Rapidiron: Reducing Anaemia In Pregnancy In India-A 3-Arm, Randomized-Controlled Trial Comparing The Effectiveness Of Oral Iron With Single-Dose Intravenous Iron In The Treatment Of Iron Deficiency Anaemia In Pregnant Women And Reducing Low Birth Weight Deliveries., Richard J. Derman, Shivaprasad S. Goudar, Simal Thind, Sudhir Bhandari, Zubair H. Aghai, Michael Auerbach, Rupsa Boelig, Umesh S. Charantimath, Rosemary Frasso, M. S. Ganachari, Kusum Lata Gaur, Michael K. Georgieff, Frances Jaeger, S. Yogeshkumar, Parth Lalakia, Benjamin Leiby, Mita Majumdar, Amarjeet Mehta, Seema Mehta, Sudhir Mehta, Stephen T. Mennemeyer, Amit P. Revankar, Dharmesh Kumar Sharma, Vanessa Short, Manjunath S Somannavar, Dennis Wallace, Hemang Shah, Manjula Singh, Sufia Askari, Mrutyunjaya B. Bellad, Rapidiron Trial Group

Department of Obstetrics and Gynecology Faculty Papers

BACKGROUND: Anaemia is a worldwide problem and iron deficiency is the most common cause. In pregnancy, anaemia increases the risk of adverse maternal, foetal and neonatal outcomes. India's anaemia rate is among the highest in the world with India's National Family Health Survey indicating over 50% of pregnant women were affected by anaemia. India's Anaemia Mukt Bharat-Intensified National Iron Plus Initiative aims to reduce the prevalence of anaemia among reproductive-age women, adolescents and children by 3% per year and facilitate the achievement of a Global World Health Assembly 2025 objective to achieve a 50% reduction of anaemia among women of …

The Dynamic Proteome Of Lyme Disease Borrelia, Anahita Fouladzadeh, Mohsen Dorraki, Kay Khine Myo Min, Michaelia P Cockshell, Emma J Thompson, Johan W Verjans, Andrew Allison, Claudine S Bonder, Derek Abbott

Faculty, Staff and Student Publications

The growth of solid tumours relies on an ever-increasing supply of oxygen and nutrients that are delivered via vascular networks. Tumour vasculature includes endothelial cell lined angiogenesis and the less common cancer cell lined vasculogenic mimicry (VM). To study and compare the development of vascular networks formed during angiogenesis and VM (represented here by breast cancer and pancreatic cancer cell lines) a number of in vitro assays were utilised. From live cell imaging, we performed a large-scale automated extraction of network parameters and identified properties not previously reported. We show that for both angiogenesis and VM, the characteristic network path …

Discovery Of Potent Bet Bromodomain 1 Stereoselective Inhibitors Using Dna-Encoded Chemical Library Selections, Rajesh Sharma, Kyoung-Jae Choi, My Diem Quan, Sonum Sharma, Banumathi Sankaran, Hyekyung Park, Anel Lagrone, Jean J Kim, Kevin R Mackenzie, Allan Chris M Ferreon, Choel Kim, Josephine C Ferreon

Faculty, Staff and Students Publications

Expression of a few master transcription factors can reprogram the epigenetic landscape and three-dimensional chromatin topology of differentiated cells and achieve pluripotency. During reprogramming, thousands of long-range chromatin contacts are altered, and changes in promoter association with enhancers dramatically influence transcription. Molecular participants at these sites have been identified, but how this re-organization might be orchestrated is not known. Biomolecular condensation is implicated in subcellular organization, including the recruitment of RNA polymerase in transcriptional activation. Here, we show that reprogramming factor KLF4 undergoes biomolecular condensation even in the absence of its intrinsically disordered region. Liquid-liquid condensation of the isolated KLF4 …

Transcatheter Aortic Valve Replacement With Self-Expandable Supra-Annular Valves For Degenerated Surgical Bioprostheses: Insights From Transcatheter Valve Therapy Registry., Luis Augusto P Dallan, John K Forrest, Michael J Reardon, Wilson Y Szeto, Isaac George, Susheel Kodali, Neal S Kleiman, Steven J Yakubov, Kendra J Grubb, Fang Liu, Cristian Baeza, Guilherme F Attizzani

Heart and Vascular Articles

Background Transcatheter aortic valve replacement with supra-annular transcatheter heart valves has been adopted in patients with degenerated surgical aortic valves. The next generation self-expanding Evolut PRO valve has not been evaluated in patients with surgical valve failure. Methods and Results Patients undergoing transcatheter aortic valve replacement in degenerated surgical aortic valve procedures using the Evolut R or Evolut PRO transcatheter heart valves in the Society of Thoracic Surgeons and American College of Cardiology Transcatheter Valve Therapy Registry between April 2015 and June 2019 were evaluated. Transcatheter valve performance was evaluated by clinical site echocardiography. In-hospital, 30-day, and 1-year clinical outcomes …

Metformin Selectively Dampens The Acute Inflammatory Response Through An Ampk-Dependent Mechanism, Thomas S Postler, Vincent Peng, Dev M Bhatt, Sankar Ghosh

2020-Current year OA Pubs

Metformin is a first-line drug in the treatment of type-2 diabetes mellitus (T2DM). In addition to its antigluconeogenic and insulin-sensitizing properties, metformin has emerged as a potent inhibitor of the chronic inflammatory response of macrophages. In particular, metformin treatment has been shown to reduce expression of interleukin (IL-) 1β during long-term exposure to the pro-inflammatory stimulus lipopolysaccharide (LPS) through a reduction in reactive oxygen species (ROS), which decreases the levels of the hypoxia-inducible factor (HIF) 1-α, and through enhanced expression of IL-10. However, the effect of metformin on the acute inflammatory response, before significant levels of ROS accumulate in the …

Increased Blood Pressure Variability And The Risk Of Probable Dementia Or Mild Cognitive Impairment: A Post Hoc Analysis Of The Sprint Mind Trial, Adam De Havenon, Mohammad Anadani, Shyam Prabhakaran, Ka-Ho Wong, Shadi Yaghi, Natalia Rost

Open Access Publications

Background Increased systolic blood pressure variability (BPV) is associated with stroke, cardiovascular disease, and dementia and mild cognitive impairment. However, prior studies assessing the relationship between BPV and dementia or mild cognitive impairment had infrequent measurement of blood pressure or suboptimal blood pressure control. Methods and Results We performed a post hoc analysis of the SPRINT (Systolic Blood Pressure Intervention Trial) MIND (Memory and Cognition in Decreased Hypertension) trial. The primary outcome was probable dementia during follow-up. We defined our exposure period, during which blood pressures were collected, as the first 600 days of the trial, and outcomes were ascertained …

Validation Of An Electronic Trigger To Measure Missed Diagnosis Of Stroke In Emergency Departments, Viralkumar Vaghani, Li Wei, Umair Mushtaq, Dean F Sittig, Andrea Bradford, Hardeep Singh

Faculty, Staff and Students Publications

OBJECTIVE: Diagnostic errors are major contributors to preventable patient harm. We validated the use of an electronic health record (EHR)-based trigger (e-trigger) to measure missed opportunities in stroke diagnosis in emergency departments (EDs).

METHODS: Using two frameworks, the Safer Dx Trigger Tools Framework and the Symptom-disease Pair Analysis of Diagnostic Error Framework, we applied a symptom-disease pair-based e-trigger to identify patients hospitalized for stroke who, in the preceding 30 days, were discharged from the ED with benign headache or dizziness diagnoses. The algorithm was applied to Veteran Affairs National Corporate Data Warehouse on patients seen between 1/1/2016 and 12/31/2017. Trained …