Digital Commons Network^™

Biochemical, Biophysical, And Immunological Characterization Of Respiratory Secretions In Severe Sars-Cov-2 Infections, Michael J Kratochvil, Gernot Kaber, Sally Demirdjian, Pamela C Cai, Elizabeth B Burgener, Nadine Nagy, Graham L Barlow, Medeea Popescu, Mark R Nicolls, Michael G Ozawa, Donald P Regula, Ana E Pacheco-Navarro, Samuel Yang, Vinicio A De Jesus Perez, Harry Karmouty-Quintana, Andrew M Peters, Bihong Zhao, Maximilian L Buja, Pamela Y Johnson, Robert B Vernon, Thomas N Wight, Carlos E Milla, Angela J Rogers, Andrew J Spakowitz, Sarah C Heilshorn, Paul L Bollyky

Faculty, Staff and Student Publications

Thick, viscous respiratory secretions are a major pathogenic feature of COVID-19, but the composition and physical properties of these secretions are poorly understood. We characterized the composition and rheological properties (i.e., resistance to flow) of respiratory secretions collected from intubated COVID-19 patients. We found the percentages of solids and protein content were greatly elevated in COVID-19 compared with heathy control samples and closely resembled levels seen in cystic fibrosis, a genetic disease known for thick, tenacious respiratory secretions. DNA and hyaluronan (HA) were major components of respiratory secretions in COVID-19 and were likewise abundant in cadaveric lung tissues from these …

Antigenic Landscapes On Staphylococcus Aureus Pore-Forming Toxins Reveal Insights Into Specificity And Cross-Neutralization, Shweta Kailasan, Ravi Kant, Madeleine Noonan-Shueh, Tulasikumari Kanipakala, Grant Liao, Sergey Shulenin, Daisy W Leung, Richard A Alm, Rajan P Adhikari, Gaya K Amarasinghe, Michael L Gross, M Javad Aman

2020-Current year OA Pubs

No abstract provided.

A Pathogenic Mechanism Associated With Myopathies And Structural Birth Defects Involves Tpm2-Directed Myogenesis, Jennifer Mcadow, Shuo Yang, Tiffany Ou, Gary Huang, Matthew B. Dobbs, Christina A. Gurnett, Michael J. Greenberg, Aaron N. Johnson

2020-Current year OA Pubs

Nemaline myopathy (NM) is the most common congenital myopathy, characterized by extreme weakness of the respiratory, limb, and facial muscles. Pathogenic variants in Tropomyosin 2 (TPM2), which encodes a skeletal muscle-specific actin binding protein essential for sarcomere function, cause a spectrum of musculoskeletal disorders that include NM as well as cap myopathy, congenital fiber type disproportion, and distal arthrogryposis (DA). The in vivo pathomechanisms underlying TPM2-related disorders are unknown, so we expressed a series of dominant, pathogenic TPM2 variants in Drosophila embryos and found 4 variants significantly affected muscle development and muscle function. Transient overexpression of the 4 variants also …

Fine-Tuning Cardiac Insulin-Like Growth Factor 1 Receptor Signaling To Promote Health And Longevity, Mahmoud Abdellatif, Tobias Pendl, Sebastian J Hofer, Moydul Islam, Abhinav Diwan, Tobias Eisenberg, Frank Madeo, Et Al

2020-Current year OA Pubs

BACKGROUND: The insulin-like growth factor 1 (IGF1) pathway is a key regulator of cellular metabolism and aging. Although its inhibition promotes longevity across species, the effect of attenuated IGF1 signaling on cardiac aging remains controversial.

METHODS: We performed a lifelong study to assess cardiac health and lifespan in 2 cardiomyocyte-specific transgenic mouse models with enhanced versus reduced IGF1 receptor (IGF1R) signaling. Male mice with human IGF1R overexpression or dominant negative phosphoinositide 3-kinase mutation were examined at different life stages by echocardiography, invasive hemodynamics, and treadmill coupled to indirect calorimetry. In vitro assays included cardiac histology, mitochondrial respiration, ATP synthesis, autophagic …

The Microbiome Restrains Melanoma Bone Growth By Promoting Intestinal Nk And Th1 Cell Homing To Bone, Subhashis Pal, Daniel S. Perrien, Tetsuya Yumoto, Roberta Faccio, Andreea Stoica, Jonathan Adams, Craig M. Coopersmith, Rheinallt M. Jones, M. Neale Weitzmann, Roberto Pacifici

2020-Current year OA Pubs

Bone metastases are frequent complications of malignant melanoma leading to reduced quality of life and significant morbidity. Regulation of immune cells by the gut microbiome influences cancer progression, but the role of the microbiome in tumor growth in bone is unknown. Using intracardiac or intratibial injections of B16-F10 melanoma cells into mice, we showed that gut microbiome depletion by broad-spectrum antibiotics accelerated intraosseous tumor growth and osteolysis. Microbiome depletion blunted melanoma-induced expansion of intestinal NK cells and Th1 cells and their migration from the gut to tumor-bearing bones. Demonstrating the functional relevance of immune cell trafficking from the gut to …

Anxiety Symptoms And Suicidal Thoughts And Behaviors Among Patients With Mood Disorders, Marsal Sanches, Linh K Nguyen, Tong Han Chung, Paul Nestadt, Holly C Wilcox, William H Coryell, Jair C Soares, Sudhakar Selvaraj

Faculty, Staff and Student Publications

Background: Though the association between anxiety disorders and suicidal behavior is well-described, the impact of anxiety symptoms on suicidal thoughts and behaviors (STB) across different mood disorders is still unclear.

Methods: We performed a registry-based retrospective study utilizing outcome measure data collected by the National Network of Depression Centers (NNDC), a nationwide nonprofit consortium of 26 leading clinical and academic member centers in the United States. The sample consisted of 2607 outpatients with mood disorders (major depressive disorder or bipolar disorders). Demographic and clinical variables were compared based on the presence or absence of STB and severity of anxiety symptoms …

B- And T-Cell Subset Abnormalities In Monogenic Common Variable Immunodeficiency, Saba Fekrvand, Shaghayegh Khanmohammadi, Hassan Abolhassani, Reza Yazdani

Department of Neurology Faculty Papers

Common variable immunodeficiency (CVID) is a heterogeneous group of inborn errors of immunity characterized by reduced serum concentrations of different immunoglobulin isotypes. CVID is the most prevalent symptomatic antibody deficiency with a broad range of infectious and non-infectious clinical manifestations. Various genetic and immunological defects are known to be involved in the pathogenesis of CVID. Monogenic defects account for the pathogenesis of about 20-50% of CVID patients, while a variety of cases do not have a defined genetic background. Deficiencies in molecules of B cell receptor signaling or other pathways involving B-cell development, activation, and proliferation could be associated with …

Challenges And Opportunities For Advancing Patient-Centered Clinical Decision Support: Findings From A Horizon Scan, Prashila Dullabh, Shana F Sandberg, Krysta Heaney-Huls, Lauren S Hovey, David F Lobach, Aziz Boxwala, Priyanka J Desai, Elise Berliner, Chris Dymek, Michael I Harrison, James Swiger, Dean F Sittig

Faculty, Staff and Student Publications

OBJECTIVE: We conducted a horizon scan to (1) identify challenges in patient-centered clinical decision support (PC CDS) and (2) identify future directions for PC CDS.

MATERIALS AND METHODS: We engaged a technical expert panel, conducted a scoping literature review, and interviewed key informants. We qualitatively analyzed literature and interview transcripts, mapping findings to the 4 phases for translating evidence into PC CDS interventions (Prioritizing, Authoring, Implementing, and Measuring) and to external factors.

RESULTS: We identified 12 challenges for PC CDS development. Lack of patient input was identified as a critical challenge. The key informants noted that patient input is critical …

Assessing Covid-19 Testing Strategies In K-12 Schools In Underserved Populations: Study Protocol For A Cluster-Randomized Trial, Samantha Hayes, Sara Malone, Brittany Bonty, Nancy Mueller, Summer M Reyes, Sydney A Reyes, Christina Evans, Myisha Wilcher-Roberts, Tremayne Watterson, Sewuese Akuse, Jamee Shelley, Grace Yuan, Ian Lackey, Jasmine Prater, Brock Montgomery, Cynthia Williams, Sheretta T Butler-Barnes, Kelly Harris, Charlene Caburnay, Nikole Lobb Dougherty, Jingxia Liu, Albert Lai, Julie Neidich, Stephanie Fritz, Jason G Newland

2020-Current year OA Pubs

BACKGROUND: Since March 2020, COVID-19 has disproportionately impacted communities of color within the United States. As schools have shifted from virtual to in-person learning, continual guidance is necessary to understand appropriate interventions to prevent SARS-CoV-2 transmission. Weekly testing of students and staff for SARS-CoV-2 within K-12 school setting could provide an additional barrier to school-based transmission, especially within schools unable to implement additional mitigation strategies and/or are in areas of high transmission. This study seeks to understand the role that weekly SARS-CoV-2 testing could play in K-12 schools. In addition, through qualitative interviews and listening sessions, this research hopes to …

Estimating Circadian Phase In Elementary School Children: Leveraging Advances In Physiologically Informed Models Of Circadian Entrainment And Wearable Devices, Jennette P Moreno, Kevin M Hannay, Olivia Walch, Hafza Dadabhoy, Jessica Christian, Maurice Puyau, Abeer El-Mubasher, Fida Bacha, Sarah R Grant, Rebekah Julie Park, Philip Cheng

Faculty, Staff and Students Publications

STUDY OBJECTIVES: Examine the ability of a physiologically based mathematical model of human circadian rhythms to predict circadian phase, as measured by salivary dim light melatonin onset (DLMO), in children compared to other proxy measurements of circadian phase (bedtime, sleep midpoint, and wake time).

METHODS: As part of an ongoing clinical trial, a sample of 29 elementary school children (mean age: 7.4 ± .97 years) completed 7 days of wrist actigraphy before a lab visit to assess DLMO. Hourly salivary melatonin samples were collected under dim light conditions (<5 >lx). Data from actigraphy were used to generate predictions of circadian …

A Long-Acting Interleukin-7, Rhil-7-Hyfc, Enhances Car T Cell Expansion, Persistence, And Anti-Tumor Activity, Miriam Y Kim, Reyka Jayasinghe, Jessica M Devenport, Julie K Ritchey, Michael P Rettig, Julie O'Neal, Karl W Staser, Krista M Kennerly, Alun J Carter, Feng Gao, Byung Ha Lee, Matthew L Cooper, John F Dipersio

Open Access Publications

Chimeric antigen receptor (CAR) T cell therapy is routinely used to treat patients with refractory hematologic malignancies. However, a significant proportion of patients experience suboptimal CAR T cell cytotoxicity and persistence that can permit tumor cell escape and disease relapse. Here we show that a prototype pro-lymphoid growth factor is able to enhance CAR T cell efficacy. We demonstrate that a long-acting form of recombinant human interleukin-7 (IL-7) fused with hybrid Fc (rhIL-7-hyFc) promotes proliferation, persistence and cytotoxicity of human CAR T cells in xenogeneic mouse models, and murine CAR T cells in syngeneic mouse models, resulting in long-term tumor-free …

Antigen Glycosylation Regulates Efficacy Of Car T Cells Targeting Cd19, Amanda Heard, Jack H Landmann, Ava R Hansen, Yu-Sung Hsu, Mehmet Emrah Selli, John M Warrington, John Lattin, Jufang Chang, Helen Ha, Balraj Doray, Abby M Green, Nathan Singh, Et Al

Open Access Publications

While chimeric antigen receptor (CAR) T cells targeting CD19 can cure a subset of patients with B cell malignancies, most patients treated will not achieve durable remission. Identification of the mechanisms leading to failure is essential to broadening the efficacy of this promising platform. Several studies have demonstrated that disruption of CD19 genes and transcripts can lead to disease relapse after initial response; however, few other tumor-intrinsic drivers of CAR T cell failure have been reported. Here we identify expression of the Golgi-resident intramembrane protease Signal peptide peptidase-like 3 (SPPL3) in malignant B cells as a potent regulator of resistance …

Electronic Health Record-Based Recruitment And Retention And Mobile Health App Usage: Multisite Cohort Study., Janelle W Coughlin, Lindsay M Martin, Di Zhao, Attia Goheer, Thomas B Woolf, Katherine Holzhauer, Harold P Lehmann, Michelle R. Lent, Kathleen M Mctigue, Jeanne M Clark, Wendy L Bennett

PCOM Scholarly Works

BACKGROUND: To address the obesity epidemic, there is a need for novel paradigms, including those that address the timing of eating and sleep in relation to circadian rhythms. Electronic health records (EHRs) are an efficient way to identify potentially eligible participants for health research studies. Mobile health (mHealth) apps offer available and convenient data collection of health behaviors, such as timing of eating and sleep.

OBJECTIVE: The aim of this descriptive analysis was to report on recruitment, retention, and app use from a 6-month cohort study using a mobile app called Daily24.

METHODS: Using an EHR query, adult patients from …

A Reference Tissue Atlas For The Human Kidney, Jens Hansen, Sanjay Jain, Et Al

2020-Current year OA Pubs

Kidney Precision Medicine Project (KPMP) is building a spatially specified human kidney tissue atlas in health and disease with single-cell resolution. Here, we describe the construction of an integrated reference map of cells, pathways, and genes using unaffected regions of nephrectomy tissues and undiseased human biopsies from 56 adult subjects. We use single-cell/nucleus transcriptomics, subsegmental laser microdissection transcriptomics and proteomics, near-single-cell proteomics, 3D and CODEX imaging, and spatial metabolomics to hierarchically identify genes, pathways, and cells. Integrated data from these different technologies coherently identify cell types/subtypes within different nephron segments and the interstitium. These profiles describe cell-level functional organization of …

Context Matters: Preliminary Evidence That The Association Between Positive Affect And Adiposity In Infancy Varies In Social Vs Non-Social Situations, Alexis C Wood, Shabnam R Momin, Mackenzie K Senn, David J Bridgett

Children’s Nutrition Research Center Staff Publications

Previous studies have suggested that infants high in negative affect have higher levels of adiposity, arising in part via changes in nutrition (e.g., “feeding to soothe”). Few studies have examined whether positive affect shows similar or inverse associations with adiposity. The current study examined cross-sectional and longitudinal relationships between adiposity and observations of positive affect in both a social and a non-social context, using data from infants at four (n = 125) and 12 (n = 80) months of age. Our analyses did not find any cross-sectional associations between positive affect and adiposity (all p > 0.05). However, in the longitudinal …

Challenges Created By The Covid-19 Pandemic: Pediatric Emergency Medicine And Disaster Management Perspectives, Thomas E Tanner, Nichole R Davis, Brent D Kaziny, Erin E Endom, Esther M Sampayo

Faculty, Staff and Students Publications

OBJECTIVE: The coronavirus disease (COVID-19) pandemic has presented unique challenges to pediatric emergency medicine (PEM) departments. The purpose of this study was to identify these challenges and ascertain how centers overcame barriers in creating solutions to continue to provide high-quality care and keep their workforce safe during the early pandemic.

METHODS: This is a qualitative study based on semi-structured interviews with physicians in leadership positions who have disaster or emergency management experience. Participants were identified through purposive sampling. Interviews were recorded and transcribed electronically. Themes and codes were extracted from the transcripts by 2 independent coders. Constant comparison analysis was …

Deep Learning Features Encode Interpretable Morphologies Within Histological Images., Ali Foroughi Pour, Brian S White, Jonghanne Park, Todd B Sheridan, Jeffrey H Chuang

Faculty Research 2022

Convolutional neural networks (CNNs) are revolutionizing digital pathology by enabling machine learning-based classification of a variety of phenotypes from hematoxylin and eosin (H&E) whole slide images (WSIs), but the interpretation of CNNs remains difficult. Most studies have considered interpretability in a post hoc fashion, e.g. by presenting example regions with strongly predicted class labels. However, such an approach does not explain the biological features that contribute to correct predictions. To address this problem, here we investigate the interpretability of H&E-derived CNN features (the feature weights in the final layer of a transfer-learning-based architecture). While many studies have incorporated CNN features …

Decoding The Pitx2-Controlled Genetic Network In Atrial Fibrillation, Jeffrey D Steimle, Francisco J Grisanti Canozo, Minjun Park, Zachary A Kadow, Md Abul Hassan Samee, James F Martin

Faculty, Staff and Students Publications

Atrial fibrillation (AF), the most common sustained cardiac arrhythmia and a major risk factor for stroke, often arises through ectopic electrical impulses derived from the pulmonary veins (PVs). Sequence variants in enhancers controlling expression of the transcription factor PITX2, which is expressed in the cardiomyocytes (CMs) of the PV and left atrium (LA), have been implicated in AF predisposition. Single nuclei multiomic profiling of RNA and analysis of chromatin accessibility combined with spectral clustering uncovered distinct PV- and LA-enriched CM cell states. Pitx2-mutant PV and LA CMs exhibited gene expression changes consistent with cardiac dysfunction through cell type-distinct, PITX2-directed, cis-regulatory …

A Peptide Blocking The Adora1-Neurabin Interaction Is Anticonvulsant And Inhibits Epilepsy In An Alzheimer's Model, Shalini Saggu, Yunjia Chen, Liping Chen, Diana Pizarro, Sandipan Pati, Wen Jing Law, Lori Mcmahon, Kai Jiao, Qin Wang

Faculty, Staff and Student Publications

Epileptic seizures are common sequelae of stroke, acute brain injury, and chronic neurodegenerative diseases, including Alzheimer's disease (AD), and cannot be effectively controlled in approximately 40% of patients, necessitating the development of novel therapeutic agents. Activation of the A1 receptor (A1R) by endogenous adenosine is an intrinsic mechanism to self-terminate seizures and protect neurons from excitotoxicity. However, targeting A1R for neurological disorders has been hindered by side effects associated with its broad expression outside the nervous system. Here we aim to target the neural-specific A1R/neurabin/regulator of G protein signaling 4 (A1R/neurabin/RGS4) complex that dictates A1R signaling strength and response outcome …

Precise Topology Of Adjacent Domain-General And Sensory-Biased Regions In The Human Brain, Moataz Assem, Sneha Shashidhara, Matthew F Glasser, John Duncan

2020-Current year OA Pubs

Recent functional MRI studies identified sensory-biased regions across much of the association cortices and cerebellum. However, their anatomical relationship to multiple-demand (MD) regions, characterized as domain-general due to their coactivation during multiple cognitive demands, remains unclear. For a better anatomical delineation, we used multimodal MRI techniques of the Human Connectome Project to scan subjects performing visual and auditory versions of a working memory (WM) task. The contrast between hard and easy WM showed strong domain generality, with essentially identical patterns of cortical, subcortical, and cerebellar MD activity for visual and auditory materials. In contrast, modality preferences were shown by contrasting …

Serotonin Type 3 Receptor Subunit Gene Polymorphisms Associated With Psychosomatic Symptoms In Irritable Bowel Syndrome: A Multicenter Retrospective Study, Sabrina Berens, Gregory Sayuk, Et Al

2020-Current year OA Pubs

BACKGROUND: Single-nucleotide polymorphisms (SNPs) of the serotonin type 3 receptor subunit (

AIM: To assess the association of

METHODS: In this retrospective study, 623 participants with IBS were recruited from five specialty centers in Germany, Sweden, the United States, the United Kingdom, and Ireland. Depressive, anxiety, and somatization symptoms and sociodemographic characteristics were collected. Four functional SNPs -

RESULTS: Depressive and anxiety symptoms significantly worsened with increasing numbers of minor

CONCLUSION: We have provided the first evidence that

Cetuximab And Anemia Prevention In Head And Neck Cancer Patients Undergoing Radiotherapy, Lucas G. Maahs, Ahmed I. Ghanem, Radhika Gutta, Amy Tang, Swarn Arya, Zaid Al-Saheli, Haythem Y. Ali, Steven S. Chang, Samantha Tam, Vivian Wu, Farzan Siddiqui, Jawad Z. Sheqwara

Hematology/Oncology Articles

BACKGROUND: Epidermal growth factor receptor (EGFR) activation is associated with increased production of interleukin 6 (IL6), which is intensified by radiotherapy (RT) induced inflammatory response. Elevated IL6 levels intensifies RT-induced anemia by upregulating hepcidin causing functional iron deficiency. Cetuximab, an EGFR inhibitor, has been associated with lower rates of anemia for locally advanced head and neck squamous cell carcinoma (HNSCC). We hypothesized that concomitant cetuximab could prevent RT-induced anemia.

METHODS: We queried our institutional head and neck cancers database for non-metastatic HNSCC cases that received RT with concomitant cetuximab or RT-only between 2006 and 2018. Cetuximab was administered for some …

Political Environment And Mortality Rates In The United States, 2001-19: Population Based Cross Sectional Analysis, Haider J Warraich, Pankaj Kumar, Khurram Nasir, Karen E Joynt Maddox, Rishi K Wadhera

Open Access Publications

OBJECTIVE: To assess recent trends in age adjusted mortality rates (AAMRs) in the United States based on county level presidential voting patterns.

DESIGN: Cross sectional study.

SETTING: USA, 2001-19.

PARTICIPANTS: 99.8% of the US population.

MAIN OUTCOME MEASURES: AAMR per 100 000 population and average annual percentage change (APC).

METHODS: The Centers for Disease Control and Prevention WONDER database was linked to county level data on US presidential elections. County political environment was classified as either Democratic or Republican for the four years that followed a November presidential election. Additional sensitivity analyses analyzed AAMR trends for counties that voted only …

Temporal Changes In Gastrointestinal Fungi And The Risk Of Autoimmunity During Early Childhood: The Teddy Study, Thomas A Auchtung, Christopher J Stewart, Daniel P Smith, Eric W Triplett, Daniel Agardh, William A Hagopian, Anette G Ziegler, Marian J Rewers, Jin-Xiong She, Jorma Toppari, Åke Lernmark, Beena Akolkar, Jeffrey P Krischer, Kendra Vehik, Jennifer M Auchtung, Nadim J Ajami, Joseph F Petrosino

Faculty, Staff and Students Publications

Fungal infections are a major health problem that often begin in the gastrointestinal tract. Gut microbe interactions in early childhood are critical for proper immune responses, yet there is little known about the development of the fungal population from infancy into childhood. Here, as part of the TEDDY (The Environmental Determinants of Diabetes in the Young) study, we examine stool samples of 888 children from 3 to 48 months and find considerable differences between fungi and bacteria. The metagenomic relative abundance of fungi was extremely low but increased while weaning from milk and formula. Overall fungal diversity remained constant over …

Latent Linguistic Motifs In Social Media Postings Resisting Covid-19 Misinformation, Tavleen Singh, Sofia Olivares, Sahiti Myneni

Faculty, Staff and Student Publications

Social media has become a predominant source of information for many health care consumers. However, false and misleading information is a pervasive problem in this context. Specifically, health-related misinformation has become a significant public health challenge, impeding the effectiveness of public health awareness campaigns and resulting in suboptimal responsiveness to the communication of legitimate risk-related information. Little is known about the mechanisms driving the seeding and spreading of such information. In this paper, we specifically examine COVID-19 tweets which attempt to correct misinformation. We employ a mixed-methods approach comprising qualitative coding, deep learning classification, and computerized text analysis to understand …

Prefrontal Cortex Supports Speech Perception In Listeners With Cochlear Implants, Arefeh Sherafati, Noel Dwyer, Aahana Bajracharya, Mahlega Samira Hassanpour, Adam T Eggebrecht, Jill B Firszt, Joseph P Culver, Jonathan E Peelle

2020-Current year OA Pubs

Cochlear implants are neuroprosthetic devices that can restore hearing in people with severe to profound hearing loss by electrically stimulating the auditory nerve. Because of physical limitations on the precision of this stimulation, the acoustic information delivered by a cochlear implant does not convey the same level of acoustic detail as that conveyed by normal hearing. As a result, speech understanding in listeners with cochlear implants is typically poorer and more effortful than in listeners with normal hearing. The brain networks supporting speech understanding in listeners with cochlear implants are not well understood, partly due to difficulties obtaining functional neuroimaging …

De Novo Fzr1 Loss-Of-Function Variants Cause Developmental And Epileptic Encephalopathies, Sathiya N Manivannan, Jolien Roovers, Noor Smal, Candace T Myers, Dilsad Turkdogan, Filip Roelens, Oguz Kanca, Hyung-Lok Chung, Tasja Scholz, Katharina Hermann, Tatjana Bierhals, Hande S Caglayan, Hannah Stamberger, Mae Working Group Of Euroepinomics Res Consortium, Heather Mefford, Peter De Jonghe, Shinya Yamamoto, Sarah Weckhuysen, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

FZR1, which encodes the Cdh1 subunit of the anaphase-promoting complex, plays an important role in neurodevelopment by regulating the cell cycle and by its multiple post-mitotic functions in neurons. In this study, evaluation of 250 unrelated patients with developmental and epileptic encephalopathies and a connection on GeneMatcher led to the identification of three de novo missense variants in FZR1. Whole-exome sequencing in 39 patient-parent trios and subsequent targeted sequencing in an additional cohort of 211 patients was performed to identify novel genes involved in developmental and epileptic encephalopathy. Functional studies in Drosophila were performed using three different mutant alleles of …

Precision Combination Therapies Based On Recurrent Oncogenic Coalterations, Xubin Li, Elisabeth K Dowling, Gonghong Yan, Zeynep Dereli, Behnaz Bozorgui, Parisa Imanirad, Jacob H Elnaggar, Augustin Luna, David G Menter, Patrick G Pilié, Timothy A Yap, Scott Kopetz, Chris Sander, Anil Korkut

Faculty, Staff and Student Publications

UNLABELLED: Cancer cells depend on multiple driver alterations whose oncogenic effects can be suppressed by drug combinations. Here, we provide a comprehensive resource of precision combination therapies tailored to oncogenic coalterations that are recurrent across patient cohorts. To generate the resource, we developed Recurrent Features Leveraged for Combination Therapy (REFLECT), which integrates machine learning and cancer informatics algorithms. Using multiomic data, the method maps recurrent coalteration signatures in patient cohorts to combination therapies. We validated the REFLECT pipeline using data from patient-derived xenografts, in vitro drug screens, and a combination therapy clinical trial. These validations demonstrate that REFLECT-selected combination therapies …

Predictive Performance Of Different Ntcp Techniques For Radiation-Induced Esophagitis In Nsclc Patients Receiving Proton Radiotherapy, Mei Chen, Zeming Wang, Shengpeng Jiang, Jian Sun, Li Wang, Narayan Sahoo, G Brandon Gunn, Steven J Frank, Cheng Xu, Jiayi Chen, Quynh-Nhu Nguyen, Joe Y Chang, Zhongxing Liao, X Ronald Zhu, Xiaodong Zhang

Faculty, Staff and Student Publications

This study aimed to compare the predictive performance of different modeling methods in developing normal tissue complication probability (NTCP) models for predicting radiation-induced esophagitis (RE) in non-small cell lung cancer (NSCLC) patients receiving proton radiotherapy. The dataset was composed of 328 NSCLC patients receiving passive-scattering proton therapy and 41.6% of the patients experienced ≥ grade 2 RE. Five modeling methods were used to build NTCP models: standard Lyman-Kutcher-Burman (sLKB), generalized LKB (gLKB), multivariable logistic regression using two variable selection procedures-stepwise forward selection (Stepwise-MLR), and least absolute shrinkage and selection operator (LASSO-MLR), and support vector machines (SVM). Predictive performance was internally …

Evolutionarily Stable Gene Clusters Shed Light On The Common Grounds Of Pathogenicity In The Acinetobacter Calcoaceticus-Baumannii Complex, Bardya Djahanschiri, Gisela Di Venanzio, Jesus S. Distel, Jennifer Breisch, Marius Alfred Dieckmann, Alexander Goesmann, Beate Averhoff, Stephan Göttig, Gottfried Wilharm, Mario F. Feldman, Ingo Ebersberger

Open Access Publications

Nosocomial pathogens of the Acinetobacter calcoaceticus-baumannii (ACB) complex are a cautionary example for the world-wide spread of multi- and pan-drug resistant bacteria. Aiding the urgent demand for novel therapeutic targets, comparative genomics studies between pathogens and their apathogenic relatives shed light on the genetic basis of human-pathogen interaction. Yet, existing studies are limited in taxonomic scope, sensing of the phylogenetic signal, and resolution by largely analyzing genes independent of their organization in functional gene clusters. Here, we explored more than 3,000 Acinetobacter genomes in a phylogenomic framework integrating orthology-based phylogenetic profiling and microsynteny conservation analyses. We delineate gene clusters in …