Medicine and Health Sciences Commons^™

Precision Medicine In Pediatric Cancer: Current Applications And Future Prospects., Atif Ahmed, Divya S. Vundamati, Midhat S. Farooqi, Erin M. Guest

Manuscripts, Articles, Book Chapters and Other Papers

Precision oncologic medicine is an emerging approach for cancer treatment that has recently taken giant steps in solid clinical practice. Recent advances in molecular diagnostics that can analyze the individual tumor's variability in genes have provided greater understanding and additional strategies to treat cancers. Although tumors can be tested by several molecular methods, the use of next-generation sequencing (NGS) has greatly facilitated our understanding of pediatric cancer and identified additional therapeutic opportunities. Pediatric tumors have a different genetic make-up, with a fewer number of actionable targets than adult tumors. Nevertheless, precision oncology in the pediatric population has greatly improved the …

Bafopathies' Dna Methylation Epi-Signatures Demonstrate Diagnostic Utility And Functional Continuum Of Coffin-Siris And Nicolaides-Baraitser Syndromes., Erfan Aref-Eshghi, Eric G Bend, Rebecca L Hood, Laila C Schenkel, Deanna Alexis Carere, Rana Chakrabarti, Sandesh C S Nagamani, Sau Wai Cheung, Philippe M Campeau, Chitra Prasad, Victoria Mok Siu, Lauren Brady, Mark A Tarnopolsky, David J Callen, A Micheil Innes, Susan M White, Wendy S Meschino, Andrew Y Shuen, Guillaume Paré, Dennis E Bulman, Peter J Ainsworth, Hanxin Lin, David I Rodenhiser, Raoul C Hennekam, Kym M Boycott, Charles E Schwartz, Bekim Sadikovic

Paediatrics Publications

Coffin-Siris and Nicolaides-Baraitser syndromes (CSS and NCBRS) are Mendelian disorders caused by mutations in subunits of the BAF chromatin remodeling complex. We report overlapping peripheral blood DNA methylation epi-signatures in individuals with various subtypes of CSS (ARID1B, SMARCB1, and SMARCA4) and NCBRS (SMARCA2). We demonstrate that the degree of similarity in the epi-signatures of some CSS subtypes and NCBRS can be greater than that within CSS, indicating a link in the functional basis of the two syndromes. We show that chromosome 6q25 microdeletion syndrome, harboring ARID1B deletions, exhibits a similar CSS/NCBRS methylation profile. Specificity of this epi-signature was confirmed across …

App21 Transgenic Rats Develop Age-Dependent Cognitive Impairment And Microglia Accumulation Within White Matter Tracts., Nina Weishaupt, Qingfan Liu, Sheojung Shin, Ramandeep Singh, Yuksel Agca, Cansu Agca, Vladimir Hachinski, Shawn Narain Whitehead

Paediatrics Publications

Background

Most of the animal models commonly used for preclinical research into Alzheimer's disease (AD) largely fail to address the pathophysiology, including the impact of known risk factors, of the widely diagnosed sporadic form of the disease. Here, we use a transgenic rat (APP21) that does not develop AD-like pathology spontaneously with age, but does develop pathology following vascular stress. To further the potential of this novel rat model as a much-needed pre-clinical animal model of sporadic AD, we characterize APP21 transgenic rats behaviorally and histologically up to 19 months of age.

Methods

The open field test was used as …

Peripheral Blood Epi-Signature Of Claes-Jensen Syndrome Enables Sensitive And Specific Identification Of Patients And Healthy Carriers With Pathogenic Mutations In Kdm5c, Laila C Schenkel, Erfan Aref-Eshghi, Cindy Skinner, Peter Ainsworth, Hanxin Lin, Guillaume Paré, David I Rodenhiser, Charles Schwartz, Bekim Sadikovic

Paediatrics Publications

Background

Claes-Jensen syndrome is an X-linked inherited intellectual disability caused by mutations in the

Results

Genome-wide DNA methylation analysis of 7 male patients affected with Claes-Jensen syndrome and 56 age- and sex-matched controls identified a specific DNA methylation defect (epi-signature) in the peripheral blood of these patients, including 1769 individual CpGs and 9 genomic regions. Six healthy female carriers showed less pronounced but distinctive changes in the same regions enabling their differentiation from both patients and controls. Highly specific computational model using the most significant methylation changes demonstrated 100% accuracy in differentiating patients, carriers, and controls in the training cohort, …

Fasoracetam In Adolescents With Adhd And Glutamatergic Gene Network Variants Disrupting Mglur Neurotransmitter Signaling., Josephine Elia, Grace Ungal, Charlly Kao, Alexander Ambrosini, Nilsa De Jesus-Rosario, Lene Larsen, Rosetta Chiavacci, Tiancheng Wang, Christine Kurian, Kanani Titchen, Brian Sykes, Sharon Hwang, Bhumi Kumar, Jacqueline Potts, Joshua Davis, Jeffrey Malatack, Emma Slattery, Ganesh Moorthy, Athena Zuppa, Andrew Weller, Enda Byrne, Yun R. Li, Walter K. Kraft, Hakon Hakonarson

Department of Pediatrics Faculty Papers

The glutamatergic neurotransmitter system may play an important role in attention-deficit hyperactivity disorder (ADHD). This 5-week, open-label, single-blind, placebo-controlled study reports the safety, pharmacokinetics and responsiveness of the metabotropic glutamate receptor (mGluR) activator fasoracetam (NFC-1), in 30 adolescents, age 12-17 years with ADHD, harboring mutations in mGluR network genes. Mutation status was double-blinded. A single-dose pharmacokinetic profiling from 50-800 mg was followed by a single-blind placebo at week 1 and subsequent symptom-driven dose advancement up to 400 mg BID for 4 weeks. NFC-1 treatment resulted in significant improvement. Mean Clinical Global Impressions-Improvement (CGI-I) and Severity (CGI-S) scores were, respectively, 3.79 …