Open Access. Powered by Scholars. Published by Universities.®

Diseases Commons

Open Access. Powered by Scholars. Published by Universities.®

Pediatrics

Institution
Keyword
Publication Year
Publication
Publication Type
File Type

Articles 961 - 990 of 1416

Full-Text Articles in Diseases

Stress And Negative Affect As Mediators In The Association Between Parental Social Support And Lung Function In Adolescents With Asthma, Amber Osorno, Eric Sternlicht, Pornchai Tirakitsoontorn, Azucena Talamantes, Anchalee Yuengsrigul, Zeev N. Kain, Brooke Jenkins Aug 2020

Stress And Negative Affect As Mediators In The Association Between Parental Social Support And Lung Function In Adolescents With Asthma, Amber Osorno, Eric Sternlicht, Pornchai Tirakitsoontorn, Azucena Talamantes, Anchalee Yuengsrigul, Zeev N. Kain, Brooke Jenkins

SURF Posters and Papers

Asthma is the leading chronic condition amongst children in the United States as 7.5% of children are diagnosed with asthma. Studies have shown that positive social support is associated with positive asthma management. A strong social support system predicts good management of asthma symptoms; however, current literature has not yet examined how social support impacts lung function as opposed to merely symptom management. Stress and negative affect have been revealed to be associated with worse asthma control, as well as exacerbation of symptoms. Stressful situations, such as the death of a family member, unemployment, and familial tensions lead to worsening …


Fosl1 Is A Novel Mediator Of Endotoxin/Lipopolysaccharide-Induced Pulmonary Angiogenic Signaling., Christopher R. Nitkin, Sheng Xia, Heather Menden, Wei Yu, Min Xiong, Daniel P. Heruth, Shui Qing Ye, Venkatesh Sampath Aug 2020

Fosl1 Is A Novel Mediator Of Endotoxin/Lipopolysaccharide-Induced Pulmonary Angiogenic Signaling., Christopher R. Nitkin, Sheng Xia, Heather Menden, Wei Yu, Min Xiong, Daniel P. Heruth, Shui Qing Ye, Venkatesh Sampath

Manuscripts, Articles, Book Chapters and Other Papers

Systemic sepsis is a known risk factor for bronchopulmonary dysplasia (BPD) in premature infants, a disease characterized by dysregulated angiogenesis and impaired vascular and alveolar development. We have previoulsy reported that systemic endotoxin dysregulates pulmonary angiogenesis resulting in alveolar simplification mimicking BPD in neonatal mice, but the underlying mechanisms remain unclear. We undertook an unbiased discovery approach to identify novel signaling pathways programming sepsis-induced deviant lung angiogenesis. Pulmonary endothelial cells (EC) were isolated for RNA-Seq from newborn C57BL/6 mice treated with intraperitoneal lipopolysaccharide (LPS) to mimic systemic sepsis. LPS significantly differentially-regulated 269 genes after 6 h, and 1,934 genes after …


Intussusception In An Infant As A Manifestation Of Covid-19, Zorays Moazzam, Areej Saleem, Alina Ashraf, Fyezah Jehan, Muhammad Arshad Aug 2020

Intussusception In An Infant As A Manifestation Of Covid-19, Zorays Moazzam, Areej Saleem, Alina Ashraf, Fyezah Jehan, Muhammad Arshad

Medical College Documents

Gastrointestinal manifestations of COVID-19 are rare and have primarily been limited to diarrhea or vomiting. Intussusception is the most common cause of bowel obstruction in infants, with up to 30% of pediatric intussusception cases having a preceding viral illness. We present the rare case of intussusception in a SARS-CoV-2 positive infant. This is the first documented case of survival in a SARS-CoV-2 positive patient presenting with intussusception as the primary manifestation. As our knowledge of this disease evolves, surgeons need to remain suspicious for possible gastrointestinal manifestations of COVID-19.


The Efficacy Of Different Type Of Phototherapy Light Devices For Neonatal Jaundice Treatment, Ismail Mohammad Hanafi Aug 2020

The Efficacy Of Different Type Of Phototherapy Light Devices For Neonatal Jaundice Treatment, Ismail Mohammad Hanafi

Student Works (2020-2029)

It has been reported that 60% of term neonates and 80% of the pre-terms develop jaundice in the first week of life and the proportion of jaundice in Malaysia is on the rise. As phototherapy light is the primary source of treatment for jaundice, it is crucial for hospital to have the best phototherapy light devices which can help to treat jaundice effectively. This would help to shorten neonate patient hospital stay, reduce staff workload as well as increasing treatment capacity of the hospital. Hospitals in Malaysia are using several type of phototherapy devices in their wards. The most commonly …


The Use Of Animal-Assisted Therapeutic Interventions In The Hospital Setting During The Covid-19 Pandemic, Alicia Cesare Aug 2020

The Use Of Animal-Assisted Therapeutic Interventions In The Hospital Setting During The Covid-19 Pandemic, Alicia Cesare

Graduate Theses/Dissertations

Handlers of therapy and/or facility dogs working within hospital settings have experienced various barriers and challenges within their practice during the COVID-19 pandemic. Animal-assisted interventions, specifically therapeutic working dogs, are a valued source of support to individuals, communities, hospital settings, and disaster sites during times of community distress. The purpose of this study was to identify barriers and solutions to the continued use of animal-assisted therapeutic interventions in support of patients and families within the hospital setting during the COVID-19 pandemic. This researcher’s position within the research is the knowledge and experience of being a facility dog handler within the …


The Surveillance For Enteric Fever In Asia Project (Seap), Severe Typhoid Fever Surveillance In Africa (Seta), Surveillance Of Enteric Fever In India (Sefi), And Strategic Typhoid Alliance Across Africa And Asia (Strataa) Population-Based Enteric Fever Studies: A Review Of Methodological Similarities And Differences, Megan E. Carey, William R. Macwrigh, Justin Im, James E. Meiring, Malick M. Gibani, Se Eun Park, Ashley Longley, Hyon Jin Jeon, Caitlin Hemlock, Mohammad Tahir Yousafzai, Farah Qamar Jul 2020

The Surveillance For Enteric Fever In Asia Project (Seap), Severe Typhoid Fever Surveillance In Africa (Seta), Surveillance Of Enteric Fever In India (Sefi), And Strategic Typhoid Alliance Across Africa And Asia (Strataa) Population-Based Enteric Fever Studies: A Review Of Methodological Similarities And Differences, Megan E. Carey, William R. Macwrigh, Justin Im, James E. Meiring, Malick M. Gibani, Se Eun Park, Ashley Longley, Hyon Jin Jeon, Caitlin Hemlock, Mohammad Tahir Yousafzai, Farah Qamar

Department of Paediatrics and Child Health

Building on previous multicountry surveillance studies of typhoid and others salmonelloses such as the Diseases of the Most Impoverished program and the Typhoid Surveillance in Africa Project, several ongoing blood culture surveillance studies are generating important data about incidence, severity, transmission, and clinical features of invasive Salmonella infections in sub-Saharan Africa and South Asia. These studies are also characterizing drug resistance patterns in their respective study sites. Each study answers a different set of research questions and employs slightly different methodologies, and the geographies under surveillance differ in size, population density, physician practices, access to healthcare facilities, and access to …


Elective Tracheostomy In Critically Ill Children: A 10-Year Single-Center Experience From A Lower-Middle Income Country, Sidra Ishaque, Anwarul Haque, Saqib Hamid Qazi, Hamdan Mallick, Saad Nasir Jul 2020

Elective Tracheostomy In Critically Ill Children: A 10-Year Single-Center Experience From A Lower-Middle Income Country, Sidra Ishaque, Anwarul Haque, Saqib Hamid Qazi, Hamdan Mallick, Saad Nasir

Department of Paediatrics and Child Health

Objective: Tracheostomy is a commonly performed procedure amongst critically ill patients, especially in cases of prolonged mechanical ventilation (PMV). This study aimed to describe the indications, clinical characteristics, and outcomes of elective pediatric tracheostomies in critically ill children at our center.
Methods: A retrospective review of medical records of children who underwent elective tracheostomies in our pediatric intensive care unit (PICU) was conducted from January 2009 to June 2018. Data were extracted based on demographics, indications of tracheostomy, and patient outcomes. Results were reported as mean with standard deviation and as frequencies with percentage.
Results: Of the 3,200 patients admitted …


Failure To Thrive - An Overlooked Manifestation Of Kmt2b-Related Dystonia: A Case Presentation., Andrew Ng, Serena Galosi, Lisa Salz, Terence Wong, Caitlin Schwager, Shivarajan Amudhavalli, Rose N. Gelineau-Morel, Shimul Chowdhury, Rady Children’S Institute For Genomic Medicine Investigators, Jennifer Friedman Jun 2020

Failure To Thrive - An Overlooked Manifestation Of Kmt2b-Related Dystonia: A Case Presentation., Andrew Ng, Serena Galosi, Lisa Salz, Terence Wong, Caitlin Schwager, Shivarajan Amudhavalli, Rose N. Gelineau-Morel, Shimul Chowdhury, Rady Children’S Institute For Genomic Medicine Investigators, Jennifer Friedman

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: KMT2B-related dystonia is a recently described form of childhood onset dystonia that may improve with deep brain stimulation. Prior reports have focused on neurologic features including prominent bulbar involvement without detailing general health consequences that may result from orolingual dysfunction. We describe a family with novel KMT2B mutation with several members with failure to thrive to highlight this non-neurologic, but consequential impact of mutation in this gene.

CASE PRESENTATION: We present a case of a 15-year old female who was admitted and evaluated for failure to thrive. On exam, she had severe speech dysfluency, limited ability to protrude the …


Investigation Of Japanese Encephalitis Virus As A Cause Of Acute Encephalitis In Southern Pakistan, April 2015-January 2018, Tazeen Fatima, Abida Rais, Erum Khan, Susan L. Hills, Trudy V. Chambers, Aneeta Hotwani, Shahida Qureshi, Saad Shafqat, Saima Malik, Farah Qamar, Fatima Mir, Anthony A. Marfin, Anita K. M. Zaidi, Asif Raza Khowaja, Sadia Shakoor Jun 2020

Investigation Of Japanese Encephalitis Virus As A Cause Of Acute Encephalitis In Southern Pakistan, April 2015-January 2018, Tazeen Fatima, Abida Rais, Erum Khan, Susan L. Hills, Trudy V. Chambers, Aneeta Hotwani, Shahida Qureshi, Saad Shafqat, Saima Malik, Farah Qamar, Fatima Mir, Anthony A. Marfin, Anita K. M. Zaidi, Asif Raza Khowaja, Sadia Shakoor

Department of Pathology and Laboratory Medicine

Background: Japanese encephalitis (JE) occurs in fewer than 1% of JE virus (JEV) infections, often with catastrophic sequelae including death and neuropsychiatric disability. JEV transmission in Pakistan was documented in 1980s and 1990s, but recent evidence is lacking. Our objective was to investigate JEV as a cause of acute encephalitis in Pakistan.
Methods: Persons aged ≥1 month with possible JE admitted to two acute care hospitals in Karachi, Pakistan from April 2015 to January 2018 were enrolled. Cerebrospinal fluid (CSF) or serum samples were tested for JEV immunoglobulin M (IgM) using the InBios JE DetectTM assay. Positive or equivocal samples …


Facing Real-World Challenges Of Immunogenicity In Pediatric Inflammatory Bowel Disease., Kyle Gress, Julie A. Bass, Ryan S Funk, Ryan Morrow, Rachel Hasenkamp, Valentina Shakhnovich Jun 2020

Facing Real-World Challenges Of Immunogenicity In Pediatric Inflammatory Bowel Disease., Kyle Gress, Julie A. Bass, Ryan S Funk, Ryan Morrow, Rachel Hasenkamp, Valentina Shakhnovich

Manuscripts, Articles, Book Chapters and Other Papers

No abstract provided.


Change In Sex Of Rearing In Individuals With Disorders Of Sex Development, Michelle Knoll May 2020

Change In Sex Of Rearing In Individuals With Disorders Of Sex Development, Michelle Knoll

Research Days

No abstract provided.


Isolated Polymorphic Ventricular Tachycardia: An Unusual Presentation Of Acute Myocarditis, Natalie S. Shwaish May 2020

Isolated Polymorphic Ventricular Tachycardia: An Unusual Presentation Of Acute Myocarditis, Natalie S. Shwaish

Research Days

No abstract provided.


Unusual Echocardiographic Findings Of Myocarditis Mimicking An Aortic Run-Off Lesion, Sarah Studyvin, Barbara A. Pahud, Christine Symes May 2020

Unusual Echocardiographic Findings Of Myocarditis Mimicking An Aortic Run-Off Lesion, Sarah Studyvin, Barbara A. Pahud, Christine Symes

Research Days

No abstract provided.


Heart Rate Recovery Following Exercise Testing In Pediatric Patients With Acyanotic Repaired Congenital Heart Disease, Natalie S. Shwaish May 2020

Heart Rate Recovery Following Exercise Testing In Pediatric Patients With Acyanotic Repaired Congenital Heart Disease, Natalie S. Shwaish

Research Days

No abstract provided.


Atrioventricular Nodal Reentrant Tachycardia In Patients With Complex Congenital Heart Disease And Twin Atrioventricular Nodes., John Papagiannis, Christopher Mathis, Lindsey Malloy-Walton, Svjetlana Tisma-Dupanovic May 2020

Atrioventricular Nodal Reentrant Tachycardia In Patients With Complex Congenital Heart Disease And Twin Atrioventricular Nodes., John Papagiannis, Christopher Mathis, Lindsey Malloy-Walton, Svjetlana Tisma-Dupanovic

Manuscripts, Articles, Book Chapters and Other Papers

No abstract provided.


Maternal Education And Cockroach Sensitization In Asthmatic Children, Jessica S. Van Mason, Ryan Allenbrand, David Williams, Kevin Kennedy, Salman Aljubran May 2020

Maternal Education And Cockroach Sensitization In Asthmatic Children, Jessica S. Van Mason, Ryan Allenbrand, David Williams, Kevin Kennedy, Salman Aljubran

Research Days

No abstract provided.


Same-Day Discharge And Quality Of Life For Primary Laparoscopic Rectopexy For Rectal Prolapse In Children- A 10-Year Experience, Obiyo O. Osuchukwu May 2020

Same-Day Discharge And Quality Of Life For Primary Laparoscopic Rectopexy For Rectal Prolapse In Children- A 10-Year Experience, Obiyo O. Osuchukwu

Research Days

No abstract provided.


Similac Special Care And Elecare Cause Neonatal Gut Injury In Mice, Karishma Rao, Heather L. Menden, Wei Yu, Inamul Haque, Susana Chavez-Bueno, Alain C. Cuna, Shahid Umar, Venkatesh Sampath May 2020

Similac Special Care And Elecare Cause Neonatal Gut Injury In Mice, Karishma Rao, Heather L. Menden, Wei Yu, Inamul Haque, Susana Chavez-Bueno, Alain C. Cuna, Shahid Umar, Venkatesh Sampath

Research Days

No abstract provided.


Methotrexate Polyglutamates As Biomarkers Of Treatment Response In Ibd Vs. Jia, Ryan Morrow May 2020

Methotrexate Polyglutamates As Biomarkers Of Treatment Response In Ibd Vs. Jia, Ryan Morrow

Research Days

No abstract provided.


Clinical Validation And Diagnostic Rate/Outcomes Of A Dual Molecular Diagnostic Assay For Myotonic Dystrophy 1., Maxime Cadieux-Dion, Isabelle Thiffault, Midhat S. Farooqi, Joseph Alaimo May 2020

Clinical Validation And Diagnostic Rate/Outcomes Of A Dual Molecular Diagnostic Assay For Myotonic Dystrophy 1., Maxime Cadieux-Dion, Isabelle Thiffault, Midhat S. Farooqi, Joseph Alaimo

Research Days

No abstract provided.


Angiopoietin 1 Protects Against Lps-Induced Acute Lung Injury And Alveolar Remodeling In Neonatal Mice, Umar Salimi May 2020

Angiopoietin 1 Protects Against Lps-Induced Acute Lung Injury And Alveolar Remodeling In Neonatal Mice, Umar Salimi

Research Days

No abstract provided.


Polysubstance Exposure And Its Relationship To Pharmacological Treatment Characteristics, Parker Miller May 2020

Polysubstance Exposure And Its Relationship To Pharmacological Treatment Characteristics, Parker Miller

Undergraduate Honors Theses

Neonatal Abstinence Syndrome (NAS) remains an ever-growing public health issue and a continued avenue for future research. The research question for this retrospective study was whether polysubstance exposure is related to the dose of medication the infant received or to the number of opioid-medications required to treat the infants’ withdrawal symptoms? The hypothesis for the retrospective study was there will be a significant relationship between polysubstance exposure and the dose of medication the infant received as well as the number of opioid-medications required to treat the infants’ withdrawal symptoms. A bivariate correlational indicated that there was not a significant association …


Impact Of Slco1b1 Genetic Variation On Rosuvastatin Systemic Exposure In Pediatric Hypercholesterolemia., Jonathan B. Wagner, Susan M. Abdel-Rahman, Andrea Gaedigk, R Gaedigk, Geetha Raghuveer, Vincent S. Staggs, Leon Van Haandel, J Steven Leeder May 2020

Impact Of Slco1b1 Genetic Variation On Rosuvastatin Systemic Exposure In Pediatric Hypercholesterolemia., Jonathan B. Wagner, Susan M. Abdel-Rahman, Andrea Gaedigk, R Gaedigk, Geetha Raghuveer, Vincent S. Staggs, Leon Van Haandel, J Steven Leeder

Manuscripts, Articles, Book Chapters and Other Papers

This study investigated the impact of SLCO1B1 genotype on rosuvastatin systemic exposure in hypercholesterolemic children and adolescents. Participants (8-21 years) with at least one allelic variant of SLCO1B1 c.521T>C (521TC, n = 13; 521CC, n = 2) and wild type controls (521TT, n = 13) completed a single oral dose pharmacokinetic study. The variability contributed by SLCO1B1 c.521 sequence variation to rosuvastatin (RVA) systemic exposure among our pediatric cohort was comparable to previous studies in adults. RVA concentration-time curve from 0-24 hours (AUC


Challenges Of Pediatric Disease In Adulthood, Dennis J. Baumgardner, Brian Chicoine Apr 2020

Challenges Of Pediatric Disease In Adulthood, Dennis J. Baumgardner, Brian Chicoine

Journal of Patient-Centered Research and Reviews

Some chronic diseases — such as the rare bone disease X-linked hypophosphatemia, the impetus for a study reported within Volume 7, Issue 2 of the Journal of Patient-Centered Research and Reviews — are diagnosed in childhood but become more symptomatic in adulthood. In this editorial, the challenges, pitfalls, and opportunities regarding the care of adults with childhood-onset chronic diseases are examined using Down syndrome, cystic fibrosis, congenital heart disease, and Hirschsprung disease as examples.


Tetralogy Of Fallot: A Clinical Review, Jacob Wooten, Joshua Bahos Silva Apr 2020

Tetralogy Of Fallot: A Clinical Review, Jacob Wooten, Joshua Bahos Silva

Student Scholar Showcase

Tetralogy of Fallot is a congenital heart disease that is associated with structural abnormalities during fetal development 1. The incidence of Tetralogy of Fallot in the United States is approximately 3-5 cases per 10,000 live births and is considered one of the most common cyanotic congenital heart diseases 2. The exact etiology of Tetralogy of Fallot is unknown, however it is thought to be associated with untreated maternal diabetes, maternal use of retinoids, as well as chromosomal abnormalities 2. The main components of this disease state include a right ventricular outflow obstruction, interventricular communication in the form of a ventricular …


Delivering Non-Communicable Disease Interventions To Women And Children In Conflict Settings: A Systematic Review, Shailja Shah, Mariella Munyuzangabo, Michelle F. Gaffey, Mahdis Kamali, Reena P. Jain, Daina Als, Sarah Meteke, Amruta Radhakrishnan, Fahad J. Siddiqui, Anushka Ataullahjan, Zulfiqar Ahmed Bhutta Apr 2020

Delivering Non-Communicable Disease Interventions To Women And Children In Conflict Settings: A Systematic Review, Shailja Shah, Mariella Munyuzangabo, Michelle F. Gaffey, Mahdis Kamali, Reena P. Jain, Daina Als, Sarah Meteke, Amruta Radhakrishnan, Fahad J. Siddiqui, Anushka Ataullahjan, Zulfiqar Ahmed Bhutta

Woman and Child Health

Background: Non-communicable diseases (NCDs) are the leading cause of death worldwide. In the context of conflict settings, population displacement, disrupted treatment, infrastructure damage and other factors impose serious NCD intervention delivery challenges, but relatively little attention has been paid to addressing these challenges. Here we synthesise the available indexed and grey literature reporting on the delivery of NCD interventions to conflict-affected women and children in low- and middle-income countries (LMICs).
Methods: A systematic search in MEDLINE, Embase, CINAHL and PsycINFO databases for indexed articles published between 1 January 1990 and 31 March 2018 was conducted, and publications reporting on NCD …


Global Burden Of Respiratory Infections Associated With Seasonal Influenza In Children Under 5 Years In 2018: A Systematic Review And Modelling Study, Xin Wang, You Li, Katherine L. O'Brien, Qalab Abbas, Syed Asad Ali, Respiratory Virus Global Epidemiology Network, Mohammad Tahir Yousafzai, Zulfiqar Ahmed Bhutta, Sajid Bashir Soofi, Anita K. M. Zaidi Apr 2020

Global Burden Of Respiratory Infections Associated With Seasonal Influenza In Children Under 5 Years In 2018: A Systematic Review And Modelling Study, Xin Wang, You Li, Katherine L. O'Brien, Qalab Abbas, Syed Asad Ali, Respiratory Virus Global Epidemiology Network, Mohammad Tahir Yousafzai, Zulfiqar Ahmed Bhutta, Sajid Bashir Soofi, Anita K. M. Zaidi

Department of Paediatrics and Child Health

Background: Seasonal influenza virus is a common cause of acute lower respiratory infection (ALRI) in young children. In 2008, we estimated that 20 million influenza-virus-associated ALRI and 1 million influenza-virus-associated severe ALRI occurred in children under 5 years globally. Despite this substantial burden, only a few low-income and middle-income countries have adopted routine influenza vaccination policies for children and, where present, these have achieved only low or unknown levels of vaccine uptake. Moreover, the influenza burden might have changed due to the emergence and circulation of influenza A/H1N1pdm09. We aimed to incorporate new data to update estimates of the global …


Paediatric Respiratory Isolation: A Challenge For A Secondary Care Hospital! A Service Innovation Project, Nadia Mohammad, Shireen Mohammad, Arjumand Sohaila, Syed Mohammad Yousuf, Adnan Khan, Rahila Meghani, Kashif Sajwani, Khalil Ahmad, Ali Faisal Saleem Dr, Pawan Vash Apr 2020

Paediatric Respiratory Isolation: A Challenge For A Secondary Care Hospital! A Service Innovation Project, Nadia Mohammad, Shireen Mohammad, Arjumand Sohaila, Syed Mohammad Yousuf, Adnan Khan, Rahila Meghani, Kashif Sajwani, Khalil Ahmad, Ali Faisal Saleem Dr, Pawan Vash

Department of Paediatrics and Child Health

Objective: The aim of this project was to broaden the secondary care hospital's scope of services and provide safe, effective and quality care for the patient presenting with measles.
Methods: Six Sigma DMAIC [define measure, analyze, improve, and control (DMAIC)] methodology was used in this quality improvement project. The quality project was started in October 2015 using a Gantt chart quality tool.
Results: The paediatric team with the support of administration of the hospital has established isolation rooms and devised a policy for the care and management of patient with airborne infection to avoid cross transmission. During six months period …


Management Of Childhood Migraine By Headache Specialist Versus Non-Headache Specialists, Kelly Valentini, Radhika Gutta, Gunjanpreet Kaur, Ahmad Farooqi, Lalitha Sivaswamy Mar 2020

Management Of Childhood Migraine By Headache Specialist Versus Non-Headache Specialists, Kelly Valentini, Radhika Gutta, Gunjanpreet Kaur, Ahmad Farooqi, Lalitha Sivaswamy

Medical Student Research Symposium

This study aims to compare the management practices of a headache specialist with non-headache specialists in the treatment of pediatric migraine. The use of appropriate rescue medications and prophylactic agents, application of neuro-imaging, and short-term outcomes are compared in children treated by the two groups of physicians. A retrospective cohort study was conducted utilizing the electronic medical records of children 3-18 years of age with migraine, who were evaluated at a tertiary care children’s hospital from 2016-2018. Of the 849 patients that met the study criteria, 469 were classified as having chronic migraine or high-frequency episodic migraine and were followed …


Atrx Loss In Pediatric Glioma Results In Epigenetic Dysregulation Of G2/M Checkpoint Maintenance And Sensitivity To Atm Inhibition, Brendan Mullan, Tingting Qin, Ruby Siada, Carla Danussi, Jacqueline Brosnan-Cashman, Drew Pratt, Taylor Garcia, Viveka Nand Yadav, Xinyi Zhao, Meredith Morgan, Sriram Venneti, Alan Meeker, Alnawaz Rehemtulla, Pedro Lowenstein, Maria Castro, Carl Koschmann Mar 2020

Atrx Loss In Pediatric Glioma Results In Epigenetic Dysregulation Of G2/M Checkpoint Maintenance And Sensitivity To Atm Inhibition, Brendan Mullan, Tingting Qin, Ruby Siada, Carla Danussi, Jacqueline Brosnan-Cashman, Drew Pratt, Taylor Garcia, Viveka Nand Yadav, Xinyi Zhao, Meredith Morgan, Sriram Venneti, Alan Meeker, Alnawaz Rehemtulla, Pedro Lowenstein, Maria Castro, Carl Koschmann

Medical Student Research Symposium

ATRX is a histone chaperone protein recurrently mutated in pediatric glioma. The mechanism which mediates the proliferative advantage of ATRX loss in pediatric glioma remains unexplained. Recent data revealed a distinct pattern of DNA binding sites of the ATRX protein using ChIP-seq in mouse neuronal precursor cells (mNPCs). Using the ATRX peaks identified in p53-/- mNPCs, we confirmed that ATRX binding sites were significantly enriched in gene promoters (p < 0.0001) and CpG islands (p < 0.0001) compared with random regions. Gene set enrichment (GSE) analysis identified that cell cycle and regulation of cell cycle were among the most significantly enriched gene sets (p=2.52e-16 and 1.61e-9, respectively). We found that ATRX loss resulted in dysfunction of G2/M checkpoint maintenance: (1) ATRX-deficient pediatric glioblastoma (GBM) cells exhibited a seven-fold increase in mitotic index at 16 hours after sub-lethal radiation, and (2) murine GBM cells with ATRX knockdown demonstrated impaired pChk1 signaling on western blot at multiple time points after radiation compared to controls (p=0.0187). Notably, the ATM signaling (pChk2) remained intact in those cells, suggesting a potential therapeutic target. ATRX-deficient mouse cells were uniquely sensitive to ATM inhibitors at 1 uM alongside 8 Gy radiation compared to controls with intact ATRX (AZD0156: p=0.0027 and AZD01390: p=0.0436). Mice intra-cranially implanted with ATRX-deficient GBM cells showed improved survival (n=10, p=0.0018) when treated with AZD0156 combined with radiation. Our findings suggest that ATRX loss in glioma results in unique sensitivity to ATM inhibition via epigenetic dysregulation of G2/M checkpoint maintenance.