Medicine and Health Sciences Commons^™

Integrated Pathologic Score Effectively Stratifies Patients With Pancreatic Ductal Adenocarcinoma Who Received Neoadjuvant Therapy And Pancreaticoduodenectomy, Aaron J Sohn, Mehran Taherian, Matthew H G Katz, Laura R Prakash, Deyali Chatterjee, Hua Wang, Michael Kim, Ching-Wei D Tzeng, Jeffrey E Lee, Naruhiko Ikoma, Asif Rashid, Robert A Wolff, Dan Zhao, Eugene J Koay, Ryan Sun, Anirban Maitra, Huamin Wang

Faculty, Staff and Student Publications

Neoadjuvant therapy is increasingly used to treat patients with pancreatic ductal adenocarcinoma (PDAC). Pathologic parameters of treated PDAC, including tumor (ypT) and lymph node (ypN) stage, and tumor response grading (TRG) are important prognostic factors in this group of patients. To our knowledge, a multifactorial prognostic score combining pathologic features including ypT, ypN, and TRG in treated PDAC patients has not been reported. Our cohort consisted of 398 PDAC patients who received neoadjuvant therapy and underwent pancreaticoduodenectomy at our institution. All pancreaticoduodenectomy specimens were grossly and microscopically evaluated using a standard protocol. The integrated pathologic score (IPS) was calculated as …

Data Partitioning And Statistical Considerations For Association Of Radiomic Features To Biological Underpinnings: What Is Needed, Michael A Jacobs

Faculty, Staff and Student Publications

No abstract provided.

Patient Radiation Doses In Interventional Radiology Procedures: Comparison Of Fluoroscopy Dose Indices Between The American College Of Radiology Dose Index Registry-Fluoroscopy Pilot And The Radiation Doses In Interventional Radiology Study, A Kyle Jones, Kevin A Wunderle, Tom Fruscello, Michael Simanowith, Brendan Cline, Shalmali Dharmadhikari, Xinhui Duan, Jeremy C Durack, David Hirschl, Don-Soo Kim, Usman Mahmood, Steve D Mann, Charles Martin, Zeyad Metwalli, Jeffrey M Moirano, Rebecca A Neill, Janice Newsome, Horacio Padua, Alan H Schoenfeld, Donald L Miller

Faculty, Staff and Student Publications

Purpose: To compare radiation dose index distributions for fluoroscopically guided interventions in interventional radiology from the American College of Radiology (ACR) Fluoroscopy Dose Index Registry (DIR-Fluoro) pilot to those from the Radiation Doses in Interventional Radiology (RAD-IR) study.

Materials and methods: Individual and grouped ACR Common identification numbers (procedure types) from the DIR-Fluoro pilot were matched to procedure types in the RAD-IR study. Fifteen comparisons were made. Distribution parameters, including the 10th, 25th, 50th, 75th, and 95th percentiles, were compared for fluoroscopy time (FT), cumulative air kerma (Ka,r), and kerma area product (PKA). Two derived indices were computed using median …

Patient Radiation Doses In Ir Procedures: The American College Of Radiology Dose Index Registry-Fluoroscopy Pilot, A Kyle Jones, Kevin A Wunderle, Tom Fruscello, Michael Simanowith, Brendan Cline, Shalmali Dharmadhikari, Xinhui Duan, Jeremy C Durack, David Hirschl, Don-Soo Kim, Usman Mahmood, Steve D Mann, Charles Martin, Zeyad Metwalli, Jeffrey M Moirano, Rebecca A Neill, Janice Newsome, Horacio Padua, Alan H Schoenfeld, Donald L Miller

Faculty, Staff and Student Publications

Purpose: To update normative data on fluoroscopy dose indices in the United States for the first time since the Radiation Doses in Interventional Radiology study in the late 1990s.

Materials and methods: The Dose Index Registry-Fluoroscopy pilot study collected data from March 2018 through December 2019, with 50 fluoroscopes from 10 sites submitting data. Primary radiation dose indices including fluoroscopy time (FT), cumulative air kerma (Ka,r), and kerma area product (PKA) were collected for interventional radiology fluoroscopically guided interventional (FGI) procedures. Clinical facility procedure names were mapped to the American College of Radiology (ACR) common procedure lexicon. Distribution parameters including …

Letter To The Editor: Quality Criteria For Computational Models Predicting Individual Outcomes In Car-T Cell Therapy, Anna M Mc Laughlin, Cassian Yee

Faculty, Staff and Student Publications

No abstract provided.

Long-Term Outcomes Of Allogeneic Hematopoietic Cell Transplantation In Patients With Newly Diagnosed Multiple Myeloma, Aimaz Afrough, Leonard C Alsfeld, Denái R Milton, Ruby Delgado, Uday R Popat, Yago Nieto, Partow Kebriaei, Betul Oran, Neeraj Saini, Samer Srour, Chitra Hosing, Faisal H Cheema, Sairah Ahmed, Elisabet E Manasanch, Hans C Lee, Gregory P Kaufman, Krina K Patel, Donna M Weber, Robert Z Orlowski, Chelsea C Pinnix, Bouthaina S Dabaja, Sheeba K Thomas, Richard E Champlin, Elizabeth J Shpall, Muzaffar H Qazilbash, Qaiser Bashir

Faculty, Staff and Student Publications

Despite remarkable progress in survival with the availability of novel agents, an overwhelming majority of patients with multiple myeloma (MM) have disease that relapses. Allogeneic (allo-) hematopoietic cell transplantation (HCT) is a potentially curative option for a subgroup of patients with high-risk MM. This study assessed the long-term outcome of MM patients who underwent allo-HCT while in first remission as consolidation treatment. Thirty-three patients with newly diagnosed MM who underwent allo-HCT as part of consolidation therapy between 1994 and 2016 were reviewed retrospectively. Of these patients, 70% underwent autologous HCT before allo-HCT. All patients were chemosensitive and achieved at least …

Quality Assurance Assessment Of Intra-Acquisition Diffusion-Weighted And T2-Weighted Magnetic Resonance Imaging Registration And Contour Propagation For Head And Neck Cancer Radiotherapy, Mohamed A Naser, Kareem A Wahid, Sara Ahmed, Vivian Salama, Cem Dede, Benjamin W Edwards, Ruitao Lin, Brigid Mcdonald, Travis C Salzillo, Renjie He, Yao Ding, Moamen Abobakr Abdelaal, Daniel Thill, Nicolette O'Connell, Virgil Willcut, John P Christodouleas, Stephen Y Lai, Clifton D Fuller, Abdallah S R Mohamed

Faculty, Staff and Student Publications

BACKGROUND/PURPOSE: Adequate image registration of anatomical and functional magnetic resonance imaging (MRI) scans is necessary for MR-guided head and neck cancer (HNC) adaptive radiotherapy planning. Despite the quantitative capabilities of diffusion-weighted imaging (DWI) MRI for treatment plan adaptation, geometric distortion remains a considerable limitation. Therefore, we systematically investigated various deformable image registration (DIR) methods to co-register DWI and T2-weighted (T2W) images.

MATERIALS/METHODS: We compared three commercial (ADMIRE, Velocity, Raystation) and three open-source (Elastix with default settings [Elastix Default], Elastix with parameter set 23 [Elastix 23], Demons) post-acquisition DIR methods applied to T2W and DWI MRI images acquired during the same …

Effect Of The Physical Fibrillated Sweet Potato (Ipomoea Batatas) Stem On The Plant-Based Patty Analogues, Suyoon Lee, You Young Lee, Yang Kim, Seung Hwan Ham, Min Gyu Lee, Jungwoo Hahn, Young Jin Choi

Faculty, Staff and Student Publications

In this study, a dietary fiber extracted from sweet potato stems (Ipomoea batatas, PS) was evaluated for its ability to improve the quality of vegetable patty analogues. A patty analogues containing 0–50 wt% dietary fiber were prepared to analyze the utilized dietary fiber's performance. To evaluate the manufactured patty analogues, texture profile analysis, color analysis, emulsion stability, and microstructural analysis were conducted. As the PS increased, the hardness decreased, while the total expressible fluids tended to increase. The color analysis revealed that the a* value, which represents red, declined as the PS content increased, and heterogeneous colors showed …

Covid-19 And Employee Job Performance Trajectories: The Moderating Effect Of Different Sources Of Status, Xin Liu, Xiaoming Zheng, Byron Y Lee, Yu Yu, Mengyi Zhang

Faculty, Staff and Student Publications

This study investigates the impact of the COVID-19 pandemic on employee job performance trajectories, and further examines the moderating effects of different sources of status. Drawing from event system theory (EST), we propose that employee job performance decreases upon COVID-19 onset, but gradually increases during the postonset period. Furthermore, we argue that status from society, occupation, and workplace functions to moderate such performance trajectories. We test our hypotheses with a unique dataset of 708 employees that combines survey responses and job performance archival data over 21 consecutive months (10,808 observations) spanning the preonset, onset, and postonset periods of the initial …

Prediction Of Survival With Lower Intensity Therapy Among Older Patients With Acute Myeloid Leukemia, Koji Sasaki, Farhad Ravandi, Tapan M Kadia, Gautam Borthakur, Nicholas J Short, Nitin Jain, Naval G Daver, Elias J Jabbour, Guillermo Garcia-Manero, Sanam Loghavi, Keyur P Patel, Guillermo Montalban-Bravo, Lucia Masarova, Courtney D Dinardo, Hagop M Kantarjian

Faculty, Staff and Student Publications

BACKGROUND: The aim of this study was to develop a prognostic model for survival in older/unfit patients with newly diagnosed acute myeloid leukemia (AML) who were treated with lower-intensity chemotherapy regimens.

METHODS: The authors reviewed all older/unfit patients with newly diagnosed AML who received lower-intensity chemotherapy from 2000 until 2020 at their institution. A total of 1462 patients were included. They were divided (3:1 basis) into a training (n = 1088) and a validation group (n = 374).

RESULTS: In the training cohort of 1088 patients (median age, 72 years), the multivariate analysis identified 11 consistent independent adverse factors associated …

The Outcomes Of Patients With Chronic Myeloid Leukemia Treated With Third-Line Bcr::Abl1 Tyrosine Kinase Inhibitors, Elias J Jabbour, Koji Sasaki, Fadi G Haddad, Ghayas C Issa, Guillermo Garcia-Manero, Tapan M Kadia, Nitin Jain, Musa Yilmaz, Courtney D Dinardo, Keyur P Patel, Rashmi Kanagal-Shamanna, Richard Champlin, Issa F Khouri, Sara Dellasala, Sherry A Pierce, Hagop Kantarjian

Faculty, Staff and Student Publications

The BCR::ABL1 tyrosine kinase inhibitors (TKIs) have improved the outcomes of patients with chronic myeloid leukemia (CML). After failing second-generation TKI (2G-TKI), the optimal third-line therapy in chronic phase CML (CML-CP) is not well established. We analyzed 354 patients with CML-CP treated with a third-line BCR::ABL1 TKI at our institution, and in the PACE and OPTIC trials, and evaluated the outcome after alternate 2G-TKIs or ponatinib. We performed a propensity score matching analysis to compare outcomes and multivariate analysis to identify variables associated with survival. One hundred seventy-three (49%) patients received 2G-TKIs and 181 (51%) ponatinib. Patients in the ponatinib …

Tissue Specificity And Spatio-Temporal Dynamics Of The P53 Transcriptional Program, Vinod Pant, Chang Sun, Guillermina Lozano

Faculty, Staff and Student Publications

Transcription factors regulate hundreds of genes and p53 is no exception. As a stress responsive protein, p53 transactivates an array of downstream targets which define its role in maintaining physiological functions of cells/tissues. Despite decades of studies, our understanding of the p53 in vivo transcriptional program is still incomplete. Here we discuss some of the physiological stressors that activate p53, the pathological and physiological implications of p53 activation and the molecular profiling of the p53 transcriptional program in maintaining tissue homeostasis. We argue that the p53 transcriptional program is spatiotemporally regulated in a tissue-specific manner and define a p53 target …

A Non-Antibiotic-Disrupted Gut Microbiome Is Associated With Clinical Responses To Cd19-Car-T Cell Cancer Immunotherapy, Christoph K Stein-Thoeringer, Neeraj Y Saini, Eli Zamir, Viktoria Blumenberg, Maria-Luisa Schubert, Uria Mor, Matthias A Fante, Sabine Schmidt, Eiko Hayase, Tomo Hayase, Roman Rohrbach, Chia-Chi Chang, Lauren Mcdaniel, Ivonne Flores, Rogier Gaiser, Matthias Edinger, Daniel Wolff, Martin Heidenreich, Paolo Strati, Ranjit Nair, Dai Chihara, Luis E Fayad, Sairah Ahmed, Swaminathan P Iyer, Raphael E Steiner, Preetesh Jain, Loretta J Nastoupil, Jason Westin, Reetakshi Arora, Michael L Wang, Joel Turner, Meghan Menges, Melanie Hidalgo-Vargas, Kayla Reid, Peter Dreger, Anita Schmitt, Carsten Müller-Tidow, Frederick L Locke, Marco L Davila, Richard E Champlin, Christopher R Flowers, Elizabeth J Shpall, Hendrik Poeck, Sattva S Neelapu, Michael Schmitt, Marion Subklewe, Michael D Jain, Robert R Jenq, Eran Elinav

Faculty, Staff and Student Publications

Increasing evidence suggests that the gut microbiome may modulate the efficacy of cancer immunotherapy. In a B cell lymphoma patient cohort from five centers in Germany and the United States (Germany, n = 66; United States, n = 106; total, n = 172), we demonstrate that wide-spectrum antibiotics treatment ('high-risk antibiotics') prior to CD19-targeted chimeric antigen receptor (CAR)-T cell therapy is associated with adverse outcomes, but this effect is likely to be confounded by an increased pretreatment tumor burden and systemic inflammation in patients pretreated with high-risk antibiotics. To resolve this confounding effect and gain insights into antibiotics-masked microbiome signals …

Comparative Analysis Of Opioid Use Between Robotic And Open Pancreatoduodenectomy, Russell G Witt, Yuki Hirata, Laura R Prakash, Timothy E Newhook, Jessica E Maxwell, Michael P Kim, Hop S Tran Cao, Jeffrey E Lee, Jean-Nicolas Vauthey, Matthew H G Katz, Ching-Wei D Tzeng, Naruhiko Ikoma

Faculty, Staff and Student Publications

BACKGROUND/PURPOSE: Risk-stratified pancreatectomy clinical pathways using regional anesthesia and multimodality analgesia have decreased overall opioid use, but the additional benefits of robotic surgery in opioid reduction for pancreatoduodenectomy (PD) are unknown. We compared the inpatient opioid use between robotic PD and open PD.

METHODS: Patients undergoing open PD within a protocol evaluating preincisional regional anesthetic block bundles were compared to consecutively-treated patients undergoing robotic PD identified from a prospectively maintained single-institutional database. Clinical characteristics, operative outcomes, pain scores and inpatient oral morphine equivalent (OME) use were compared between patients treated with robotic or open PD. Patients with a history of …

Five-Year Survivors From Brain Metastases Treated With Stereotactic Radiosurgery: Biology, Improving Treatments, Or Just Plain Luck?, Jane B Pearce, Fang-Chi Hsu, Claire M Lanier, Christina K Cramer, Jimmy Ruiz, Hui-Wen Lo, Fei Xing, Margaret Smith, Wencheng Li, Christopher Whitlow, Jaclyn J White, Stephen B Tatter, Adrian W Laxton, Michael D Chan

Faculty, Staff and Student Publications

BACKGROUND: Improvements in therapies have led to an increasing number of long-term survivors of brain metastases. The present series compares a population of 5-year survivors of brain metastases to a generalized brain metastases population to assess for factors attributable to long-term survival.

METHODS: A single institution retrospective review was performed to identify 5-year survivors of brain metastases who received stereotactic radiosurgery (SRS). A historical control population of 737 patients with brain metastases was used to assess similarities and differences between the long-term survivor population and the general population treated with SRS.

RESULTS: A total of 98 patients with brain metastases …

Advancing Car T Cell Therapy Through The Use Of Multidimensional Omics Data, Jingwen Yang, Yamei Chen, Ying Jing, Michael R Green, Leng Han

Faculty, Staff and Student Publications

Despite the notable success of chimeric antigen receptor (CAR) T cell therapies in the treatment of certain haematological malignancies, challenges remain in optimizing CAR designs and cell products, improving response rates, extending the durability of remissions, reducing toxicity and broadening the utility of this therapeutic modality to other cancer types. Data from multidimensional omics analyses, including genomics, epigenomics, transcriptomics, T cell receptor-repertoire profiling, proteomics, metabolomics and/or microbiomics, provide unique opportunities to dissect the complex and dynamic multifactorial phenotypes, processes and responses of CAR T cells as well as to discover novel tumour targets and pathways of resistance. In this Review, …

Integrated Analysis Of Racial Disparities In Genomic Architecture Identifies A Trans-Ancestry Prognostic Subtype In Bladder Cancer, Baifeng Zhang, Peilin Jia, Jiayin Wang, Guangsheng Pei, Changxi Wang, Shimei Pei, Xiangchun Li, Zhongming Zhao, Xin Yi, Xin-Yuan Guan, Yi Huang

Faculty, Staff and Student Publications

The incidence of bladder cancer and patient survival vary greatly among different populations, but the influence of the associated molecular features and evolutionary processes on its clinical treatment and prognostication remains unknown. Here, we analyze the genomic architectures of 505 bladder cancer patients from Asian/Black/White populations. We identify a previously unknown association between AHNAK mutations and activity of the APOBEC-a mutational signature, the activity of which varied substantially across populations. All significantly mutated genes but only half of arm-level somatic copy number alterations (SCNAs) are enriched with clonal events, indicating large-scale SCNAs as rich sources of bladder cancer clonal diversities. …

Clinical Outcomes Of Immune Checkpoint Inhibitor Diabetes Mellitus At A Comprehensive Cancer Center, Rebecca Jeun, Priyanka C Iyer, Conor Best, Victor Lavis, Jeena M Varghese, Sireesha Yedururi, Veronica Brady, Isabella C Glitza Oliva, Ramona Dadu, Denai R Milton, Kristy Brock, Sonali Thosani

Faculty, Staff and Student Publications

Introduction: Immune checkpoint inhibitor-associated diabetes mellitus (ICI-DM) is a rare adverse event. In this study, we characterize clinical outcomes of patients with ICI-DM and evaluate survival impact of this complication on melanoma patients.

Research design & methods: We conducted a retrospective review of 76 patients diagnosed with ICI-DM from April 2014 to December 2020.

Results: 68% of patients presented in diabetic ketoacidosis, 16% had readmissions for hyperglycemia, and hypoglycemia occurred in 70% of patients after diagnosis. Development of ICI-DM did not impact overall survival or progression-free survival in melanoma patients.

Conclusion: Development of ICI-DM is associated with long-term insulin dependence …

Axicabtagene Ciloleucel In Relapsed Or Refractory Large B-Cell Lymphoma Patients In Complete Metabolic Response, Andrew P Jallouk, Sushanth Gouni, Jason Westin, Lei Feng, Haleigh Mistry, Raphael E Steiner, Jinsu James, Mansoor Noorani, Sandra Horowitz, Nahum Puebla-Osorio, Luis E Fayad, Swaminathan P Iyer, Misha Hawkins, Christopher R Flowers, Sairah Ahmed, Loretta J Nastoupil, Partow Kebriaei, Elizabeth J Shpall, Sattva S Neelapu, Yago Nieto, Paolo Strati

Faculty, Staff and Student Publications

No abstract provided.

Inconsistent Partitioning And Unproductive Feature Associations Yield Idealized Radiomic Models, Mishka Gidwani, Ken Chang, Jay Biren Patel, Katharina Viktoria Hoebel, Syed Rakin Ahmed, Praveer Singh, Clifton David Fuller, Jayashree Kalpathy-Cramer

Faculty, Staff and Student Publications

Background Radiomics is the extraction of predefined mathematic features from medical images for the prediction of variables of clinical interest. While some studies report superlative accuracy of radiomic machine learning (ML) models, the published methodology is often incomplete, and the results are rarely validated in external testing data sets. Purpose To characterize the type, prevalence, and statistical impact of methodologic errors present in radiomic ML studies. Materials and Methods Radiomic ML publications were reviewed for the presence of performance-inflating methodologic flaws. Common flaws were subsequently reproduced with randomly generated features interpolated from publicly available radiomic data sets to demonstrate the …

Ablative Margins Of Colorectal Liver Metastases Using Deformable Ct Image Registration And Autosegmentation, Yuan-Mao Lin, Iwan Paolucci, Caleb S O'Connor, Brian M Anderson, Bastien Rigaud, Bryan M Fellman, Kyle A Jones, Kristy K Brock, Bruno C Odisio

Faculty, Staff and Student Publications

Background

Confirming ablation completeness with sufficient ablative margin is critical for local tumor control following colorectal liver metastasis (CLM) ablation. An image-based confirmation method considering patient- and ablation-related biomechanical deformation is an unmet need.

Purpose

To evaluate a biomechanical deformable image registration (DIR) method for three-dimensional (3D) minimal ablative margin (MAM) quantification and the association with local disease progression following CT-guided CLM ablation.

Materials and Methods

This single-institution retrospective study included patients with CLM treated with CT-guided microwave or radiofrequency ablation from October 2015 to March 2020. A biomechanical DIR method with AI-based autosegmentation of liver, tumors, and ablation zones …

Moral Injury To Inform Analysis Of Post-Traumatic Stress Disorder, Amanda Julia Manea

Senior Theses

Post-traumatic stress disorder (PTSD) is a mental health condition that almost one out of ten veterans struggle with. Although the National Center for PTSD has made extensive progress in characterizing and developing new treatments for PTSD, most veterans still experience symptoms of PTSD following treatment. Novel avenues of investigation, such as developing algorithms to review electronic health record (EHR) data and better understanding moral injury, are being pursued to address the gap that still exists when it comes to treating veterans. Moral injury is the individual evaluation of exposure to a potentially morally injurious event (PMIE) and can lead to …

Natural History Of Tango2 Deficiency Disorder: Baseline Assessment Of 73 Patients, Christina Y Miyake, Erica J Lay, Claudia Soler-Alfonso, Kevin E Glinton, Kimberly M Houck, Mustafa Tosur, Nancy E Moran, Sara B Stephens, Fernando Scaglia, Taylor S Howard, Jeffrey J Kim, Tam Dam Pham, Santiago O Valdes, Na Li, Chaya N Murali, Lilei Zhang, Maina Kava, Deane Yim, Cheyenne Beach, Gregory Webster, Leonardo Liberman, Christopher M Janson, Prince J Kannankeril, Samantha Baxter, Moriel Singer-Berk, Jordan Wood, Samuel J Mackenzie, Michael Sacher, Lina Ghaloul-Gonzalez, Claudia Pedroza, Shaine A Morris, Saad A Ehsan, Mahshid S Azamian, Seema R Lalani

Faculty, Staff and Students Publications

PURPOSE: TANGO2 deficiency disorder (TDD), an autosomal recessive disease first reported in 2016, is characterized by neurodevelopmental delay, seizures, intermittent ataxia, hypothyroidism, and life-threatening metabolic and cardiac crises. The purpose of this study was to define the natural history of TDD.

METHODS: Data were collected from an ongoing natural history study of patients with TDD enrolled between February 2019 and May 2022. Data were obtained through phone or video based parent interviews and medical record review.

RESULTS: Data were collected from 73 patients (59% male) from 57 unrelated families living in 16 different countries. The median age of participants at …

Dnmt3a-Coordinated Splicing Governs The Stem State Switch Towards Differentiation In Embryonic And Haematopoietic Stem Cells, Raghav Ramabadran, Jarey H Wang, Jaime M Reyes, Anna G Guzman, Sinjini Gupta, Carina Rosas, Lorenzo Brunetti, Michael C Gundry, Ayala Tovy, Hali Long, Tianpeng Gu, Sean M Cullen, Siddhartha Tyagi, Danielle Rux, Jean J Kim, Steven M Kornblau, Michael Kyba, Fabio Stossi, Rachel E Rau, Koichi Takahashi, Thomas F Westbrook, Margaret A Goodell

Faculty, Staff and Student Publications

Upon stimulation by extrinsic stimuli, stem cells initiate a programme that enables differentiation or self-renewal. Disruption of the stem state exit has catastrophic consequences for embryogenesis and can lead to cancer. While some elements of this stem state switch are known, major regulatory mechanisms remain unclear. Here we show that this switch involves a global increase in splicing efficiency coordinated by DNA methyltransferase 3α (DNMT3A), an enzyme typically involved in DNA methylation. Proper activation of murine and human embryonic and haematopoietic stem cells depends on messenger RNA processing, influenced by DNMT3A in response to stimuli. DNMT3A coordinates splicing through recruitment …

Wwox P47t Partial Loss-Of-Function Mutation Induces Epilepsy, Progressive Neuroinflammation, And Cerebellar Degeneration In Mice Phenocopying Human Scar12, Tabish Hussain, Kevin Sanchez, Jennifer Crayton, Dhurjhoti Saha, Collene Jeter, Yue Lu, Martin Abba, Ryan Seo, Jeffrey L Noebels, Laura Fonken, C Marcelo Aldaz

Faculty, Staff and Student Publications

WWOX gene loss-of-function (LoF) has been associated with neuropathologies resulting in developmental, epileptic, and ataxic phenotypes of varying severity based on the level of WWOX dysfunction. WWOX gene biallelic germline variant p.Pro47Thr (P47T) has been causally associated with a new form of autosomal recessive cerebellar ataxia with epilepsy and intellectual disability (SCAR12, MIM:614322). This mutation affecting the WW1 protein binding domain of WWOX, impairs its interaction with canonical proline-proline-X-tyrosine motifs in partner proteins. We generated a mutant knock-in mouse model of Wwox P47T mutation that phenocopies human SCAR12. Wwox

Machine Learning And Health Care: Potential Benefits And Issues, J Graham Atkinson, Elizabeth G Atkinson

Faculty, Staff and Students Publications

We discuss the potential for machine learning (ML) and artificial intelligence (AI) to improve health care, while detailing caveats and important considerations to ensure unbiased and equitable implementation. If disparities exist in the data used to train ML algorithms, they must be recognized and accounted for, so they do not bias performance accuracy or are not interpreted by the algorithm as simply a lack of need. We pay particular attention to an area in which bias in data composition is particularly striking, that is in large-scale genetics databases, as people of European descent are vastly overrepresented in the existing resources.

Loss Of Neuron Navigator 2 Impairs Brain And Cerebellar Development, Andrea Accogli, Shenzhao Lu, Ilaria Musante, Paolo Scudieri, Jill A Rosenfeld, Mariasavina Severino, Simona Baldassari, Michele Iacomino, Antonella Riva, Ganna Balagura, Gianluca Piccolo, Carlo Minetti, Denis Roberto, Fan Xia, Razaali Razak, Emily Lawrence, Mohamed Hussein, Emmanuel Yih-Herng Chang, Michelle Holick, Elisa Calì, Emanuela Aliberto, Rosalba De-Sarro, Antonio Gambardella, Undiagnosed Diseases Network, Synaps Study Group, Lisa Emrick, Peter J A Mccaffery, Margaret Clagett-Dame, Paul C Marcogliese, Hugo J Bellen, Seema R Lalani, Federico Zara, Pasquale Striano, Vincenzo Salpietro

Faculty, Staff and Students Publications

Cerebellar hypoplasia and dysplasia encompass a group of clinically and genetically heterogeneous disorders frequently associated with neurodevelopmental impairment. The Neuron Navigator 2 (NAV2) gene (MIM: 607,026) encodes a member of the Neuron Navigator protein family, widely expressed within the central nervous system (CNS), and particularly abundant in the developing cerebellum. Evidence across different species supports a pivotal function of NAV2 in cytoskeletal dynamics and neurite outgrowth. Specifically, deficiency of Nav2 in mice leads to cerebellar hypoplasia with abnormal foliation due to impaired axonal outgrowth. However, little is known about the involvement of the NAV2 gene in human disease phenotypes. In …

Molecular Function And Contribution Of Tbx4 In Development And Disease, Justyna A Karolak, Carrie L Welch, Christian Mosimann, Katarzyna Bzdęga, James D West, David Montani, Mélanie Eyries, Mary P Mullen, Steven H Abman, Matina Prapa, Stefan Gräf, Nicholas W Morrell, Anna R Hemnes, Frédéric Perros, Rizwan Hamid, Malcolm P O Logan, Jeffrey Whitsett, Csaba Galambos, Paweł Stankiewicz, Wendy K Chung, Eric D Austin

Faculty, Staff and Students Publications

Over the past decade, recognition of the profound impact of the TBX4 (T-box 4) gene, which encodes a member of the evolutionarily conserved family of T-box–containing transcription factors, on respiratory diseases has emerged. The developmental importance of TBX4 is emphasized by the association of TBX4 variants with congenital disorders involving respiratory and skeletal structures; however, the exact role of TBX4 in human development remains incompletely understood. Here, we discuss the developmental, tissue-specific, and pathological TBX4 functions identified through human and animal studies and review the published TBX4 variants resulting in variable disease phenotypes. We also outline future research …

Kcna1 Gain-Of-Function Epileptic Encephalopathy Treated With 4-Aminopyridine, Peter Müller, Danielle S Takacs, Ulrike B S Hedrich, Rohini Coorg, Laura Masters, Kevin E Glinton, Hongzheng Dai, Jon A Cokley, James J Riviello, Holger Lerche, Edward C Cooper

Faculty, Staff and Students Publications

Precision medicine for Mendelian epilepsy is rapidly developing. We describe an early infant with severely pharmacoresistant multifocal epilepsy. Exome sequencing revealed the de novo variant p.(Leu296Phe) in the gene KCNA1, encoding the voltage‐gated K+ channel subunit KV1.1. So far, loss‐of‐function variants in KCNA1 have been associated with episodic ataxia type 1 or epilepsy. Functional studies of the mutated subunit in oocytes revealed a gain‐of‐function caused by a hyperpolarizing shift of voltage dependence. Leu296Phe channels are sensitive to block by 4‐aminopyridine. Clinical use of 4‐aminopyridine was associated with reduced seizure burden, enabled simplification of co‐medication and prevented rehospitalization.

Temporal Single-Cell Atlas Of Non-Neuronal Retinal Cells Reveals Dynamic, Coordinated Multicellular Responses To Central Nervous System Injury, Inbal Benhar, Jiarui Ding, Wenjun Yan, Irene E Whitney, Anne Jacobi, Malika Sud, Grace Burgin, Karthik Shekhar, Nicholas M Tran, Chen Wang, Zhigang He, Joshua R Sanes, Aviv Regev

Faculty, Staff and Students Publications

Non-neuronal cells are key to the complex cellular interplay that follows central nervous system insult. To understand this interplay, we generated a single-cell atlas of immune, glial and retinal pigment epithelial cells from adult mouse retina before and at multiple time points after axonal transection. We identified rare subsets in naive retina, including interferon (IFN)-response glia and border-associated macrophages, and delineated injury-induced changes in cell composition, expression programs and interactions. Computational analysis charted a three-phase multicellular inflammatory cascade after injury. In the early phase, retinal macroglia and microglia were reactivated, providing chemotactic signals concurrent with infiltration of CCR2+ monocytes from …