Digital Commons Network^™

Improving Pharmacist-Led Pediatric Patient Education On Oral Chemotherapy At Home, Anika Patel, Christopher M. Nguyen, Kristin Willins, Elsabella Y. Wang, Grace Magedman, Sun Yang

Pharmacy Faculty Articles and Research

Oral chemotherapy (OC) has been increasingly used in pediatric patients diagnosed with cancer, which is primarily managed in the outpatient setting. Different from adults, pediatric patients face unique challenges in administering these hazardous medications at home. Because of the complexity of pediatric pharmaceutical care and the hazardous nature of chemotherapy agents, comprehensive patient education is imperative to mitigate the potential safety risks associated with OC administration at home. Pharmacists play a vital role in patient education and medication consultations. However, the lack of practice guidelines and limited resources supporting OC counseling are noted. Additional barriers include insufficient knowledge and training …

Multiphoton In Vivo Microscopy Of Embryonic Thrombopoiesis Reveals The Generation Of Platelets Through Budding, Huan Liu, Hellen Ishikawa-Ankerhold, Julia Winterhalter, Michael Lorenz, Mykhailo Vladymyrov, Steffen Massberg, Christian Schulz, Mathias Orban

Faculty, Staff and Student Publications

Platelets are generated by specialized cells called megakaryocytes (MKs). However, MK's origin and platelet release mode have remained incompletely understood. Here, we established direct visualization of embryonic thrombopoiesis in vivo by combining multiphoton intravital microscopy (MP-IVM) with a fluorescence switch reporter mouse model under control of the platelet factor 4 promoter (Pf4CreRosa26mTmG). Using this microscopy tool, we discovered that fetal liver MKs provide higher thrombopoietic activity than yolk sac MKs. Mechanistically, fetal platelets were released from MKs either by membrane buds or the formation of proplatelets, with the former constituting the key process. In E14.5 c-Myb-deficient …

High-Fat Diet, But Not Duration Of Lactation, Increases Mammary Gland Lymphatic Vessel Function And Subsequent Growth Of Inflammatory Breast Cancer Cells, Wintana Balema, Janelle Morton, Richard A Larson, Li Li, Fred Christian Velasquez, Natalie W Fowlkes, Savitri Krishnamurthy, Bisrat G Debeb, Eva Sevick-Muraca, Wendy A Woodward

Faculty, Staff and Student Publications

Inflammatory breast cancer (IBC) presents as rapid-onset swelling and breast skin changes caused by tumor emboli in the breast and breast skin lymphatics. IBC has been linked with obesity and duration of breastfeeding, but how these factors affect IBC tumor progression is not clear. We modeled the simultaneous effects of diet and weaning in mice on in vivo lymphatic function; on IBC tumor growth; and on aspects of the mammary gland microenvironment before and after IBC (SUM149) xenograft inoculation. We hypothesized that weaning status and diet would have synergistic effects on lymphatic function and the breast microenvironment to enhance IBC …

Epigenomic Signature Of Major Congenital Heart Defects In Newborns With Down Syndrome, Julia S Mouat, Shaobo Li, Swe Swe Myint, Benjamin I Laufer, Philip J Lupo, Jeremy M Schraw, John P Woodhouse, Adam J De Smith, Janine M Lasalle

Faculty, Staff and Students Publications

BACKGROUND: Congenital heart defects (CHDs) affect approximately half of individuals with Down syndrome (DS), but the molecular reasons for incomplete penetrance are unknown. Previous studies have largely focused on identifying genetic risk factors associated with CHDs in individuals with DS, but comprehensive studies of the contribution of epigenetic marks are lacking. We aimed to identify and characterize DNA methylation differences from newborn dried blood spots (NDBS) of DS individuals with major CHDs compared to DS individuals without CHDs.

METHODS: We used the Illumina EPIC array and whole-genome bisulfite sequencing (WGBS) to quantitate DNA methylation for 86 NDBS samples from the …

Genomic Variant Benchmark: If You Cannot Measure It, You Cannot Improve It, Sina Majidian, Daniel Paiva Agustinho, Chen-Shan Chin, Fritz J Sedlazeck, Medhat Mahmoud

Faculty, Staff and Students Publications

Genomic benchmark datasets are essential to driving the field of genomics and bioinformatics. They provide a snapshot of the performances of sequencing technologies and analytical methods and highlight future challenges. However, they depend on sequencing technology, reference genome, and available benchmarking methods. Thus, creating a genomic benchmark dataset is laborious and highly challenging, often involving multiple sequencing technologies, different variant calling tools, and laborious manual curation. In this review, we discuss the available benchmark datasets and their utility. Additionally, we focus on the most recent benchmark of genes with medical relevance and challenging genomic complexity.

Literature-Based Predictions Of Mendelian Disease Therapies, Cole A Deisseroth, Won-Seok Lee, Jiyoen Kim, Hyun-Hwan Jeong, Ryan S Dhindsa, Julia Wang, Huda Y Zoghbi, Zhandong Liu

Faculty, Staff and Students Publications

In the effort to treat Mendelian disorders, correcting the underlying molecular imbalance may be more effective than symptomatic treatment. Identifying treatments that might accomplish this goal requires extensive and up-to-date knowledge of molecular pathways-including drug-gene and gene-gene relationships. To address this challenge, we present "parsing modifiers via article annotations" (PARMESAN), a computational tool that searches PubMed and PubMed Central for information to assemble these relationships into a central knowledge base. PARMESAN then predicts putatively novel drug-gene relationships, assigning an evidence-based score to each prediction. We compare PARMESAN's drug-gene predictions to all of the drug-gene relationships displayed by the Drug-Gene Interaction …

Global Effect Of Modifiable Risk Factors On Cardiovascular Disease And Mortality, Global Cardiovascular Risk Consortium, Christina Magnussen, Francisco M Ojeda, Darryl P Leong, Jesus Alegre-Diaz, Philippe Amouyel, Larissa Aviles-Santa, Dirk De Bacquer, Christie M Ballantyne, Antonio Bernabé-Ortiz, Martin Bobak, Hermann Brenner, Rodrigo M Carrillo-Larco, James De Lemos, Annette Dobson, Marcus Dörr, Chiara Donfrancesco, Wojciech Drygas, Robin P Dullaart, Gunnar Engström, Marco M Ferrario, Jean Ferrières, Giovanni De Gaetano, Uri Goldbourt, Clicerio Gonzalez, Guido Grassi, Allison M Hodge, Kristian Hveem, Licia Iacoviello, M Kamran Ikram, Vilma Irazola, Modou Jobe, Pekka Jousilahti, Pontiano Kaleebu, Maryam Kavousi, Frank Kee, Davood Khalili, Wolfgang Koenig, Anna Kontsevaya, Kari Kuulasmaa, Karl J Lackner, David M Leistner, Lars Lind, Allan Linneberg, Thiess Lorenz, Magnus Nakrem Lyngbakken, Reza Malekzadeh, Sofia Malyutina, Ellisiv B Mathiesen, Olle Melander, Andres Metspalu, J Jaime Miranda, Marie Moitry, Joseph Mugisha, Mahdi Nalini, Vijay Nambi, Toshiharu Ninomiya, Karen Oppermann, Eleonora D'Orsi, Andrzej Pająk, Luigi Palmieri, Demosthenes Panagiotakos, Arokiasamy Perianayagam, Annette Peters, Hossein Poustchi, Andrew M Prentice, Eva Prescott, Ulf Risérus, Veikko Salomaa, Susana Sans, Satoko Sakata, Ben Schöttker, Aletta E Schutte, Sadaf G Sepanlou, Sanjib Kumar Sharma, Jonathan E Shaw, Leon A Simons, Stefan Söderberg, Abdonas Tamosiunas, Barbara Thorand, Hugh Tunstall-Pedoe, Raphael Twerenbold, Diego Vanuzzo, Giovanni Veronesi, Julia Waibel, S Goya Wannamethee, Masafumi Watanabe, Philipp S Wild, Yao Yao, Yi Zeng, Andreas Ziegler, Stefan Blankenberg

Faculty, Staff and Students Publications

BACKGROUND: Five modifiable risk factors are associated with cardiovascular disease (CVD) and all-cause mortality. The regional and sex-specific prevalence of these modifiable risk factors and their impact on CVD and all-cause mortality have not been evaluated using individual-level data.

METHODS: The Global Cardiovascular Risk Consortium harmonized individual-level data from 112 cohort studies conducted in 34 countries and 8 geographic regions. Associations between body-mass index, systolic blood pressure, non-high-density lipoprotein cholesterol, smoking, and diabetes with incident CVD and all-cause mortality were examined using Cox regression analyses and stratified by geographic region, age and sex. Population-attributable fractions were estimated for 10-year incident …

Disease-Modifying Therapies And Features Linked To Treatment Response In Type 1 Diabetes Prevention: A Systematic Review, Jamie L Felton, Kurt J Griffin, Richard A Oram, Cate Speake, S Alice Long, Suna Onengut-Gumuscu, Stephen S Rich, Gabriela S F Monaco, Carmella Evans-Molina, Linda A Dimeglio, Heba M Ismail, Andrea K Steck, Dana Dabelea, Randi K Johnson, Marzhan Urazbayeva, Stephen Gitelman, John M Wentworth, Maria J Redondo, Emily K Sims, Ada/Easd Pmdi

Faculty, Staff and Students Publications

BACKGROUND: Type 1 diabetes (T1D) results from immune-mediated destruction of insulin-producing beta cells. Prevention efforts have focused on immune modulation and supporting beta cell health before or around diagnosis; however, heterogeneity in disease progression and therapy response has limited translation to clinical practice, highlighting the need for precision medicine approaches to T1D disease modification.

METHODS: To understand the state of knowledge in this area, we performed a systematic review of randomized-controlled trials with ≥50 participants cataloged in PubMed or Embase from the past 25 years testing T1D disease-modifying therapies and/or identifying features linked to treatment response, analyzing bias using a …

An Intrinsically Disordered Region Controlling Condensation Of A Circadian Clock Component And Rhythmic Transcription In The Liver, Kun Zhu, Isaac J Celwyn, Dongyin Guan, Yang Xiao, Xiang Wang, Wenxiang Hu, Chunjie Jiang, Lan Cheng, Rafael Casellas, Mitchell A Lazar

Faculty, Staff and Students Publications

Circadian gene transcription is fundamental to metabolic physiology. Here we report that the nuclear receptor REV-ERBα, a repressive component of the molecular clock, forms circadian condensates in the nuclei of mouse liver. These condensates are dictated by an intrinsically disordered region (IDR) located in the protein's hinge region which specifically concentrates nuclear receptor corepressor 1 (NCOR1) at the genome. IDR deletion diminishes the recruitment of NCOR1 and disrupts rhythmic gene transcription in vivo. REV-ERBα condensates are located at high-order transcriptional repressive hubs in the liver genome that are highly correlated with circadian gene repression. Deletion of the IDR disrupts transcriptional …

Rare Variants In Long Non-Coding Rnas Are Associated With Blood Lipid Levels In The Topmed Whole-Genome Sequencing Study, Yuxuan Wang, Margaret Sunitha Selvaraj, Xihao Li, Zilin Li, Jacob A Holdcraft, Donna K Arnett, Joshua C Bis, John Blangero, Eric Boerwinkle, Donald W Bowden, Brian E Cade, Jenna C Carlson, April P Carson, Yii-Der Ida Chen, Joanne E Curran, Paul S De Vries, Susan K Dutcher, Patrick T Ellinor, James S Floyd, Myriam Fornage, Barry I Freedman, Stacey Gabriel, Soren Germer, Richard A Gibbs, Xiuqing Guo, Jiang He, Nancy Heard-Costa, Bertha Hildalgo, Lifang Hou, Marguerite R Irvin, Roby Joehanes, Robert C Kaplan, Sharon Lr Kardia, Tanika N Kelly, Ryan Kim, Charles Kooperberg, Brian G Kral, Daniel Levy, Changwei Li, Chunyu Liu, Don Lloyd-Jone, Ruth Jf Loos, Michael C Mahaney, Lisa W Martin, Rasika A Mathias, Ryan L Minster, Braxton D Mitchell, May E Montasser, Alanna C Morrison, Joanne M Murabito, Take Naseri, Jeffrey R O'Connell, Nicholette D Palmer, Michael H Preuss, Bruce M Psaty, Laura M Raffield, Dabeeru C Rao, Susan Redline, Alexander P Reiner, Stephen S Rich, Muagututi'a Sefuiva Ruepena, Wayne H-H Sheu, Jennifer A Smith, Albert Smith, Hemant K Tiwari, Michael Y Tsai, Karine A Viaud-Martinez, Zhe Wang, Lisa R Yanek, Wei Zhao, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Jerome I Rotter, Xihong Lin, Pradeep Natarajan, Gina M Peloso

Faculty, Staff and Student Publications

Long non-coding RNAs (lncRNAs) are known to perform important regulatory functions in lipid metabolism. Large-scale whole-genome sequencing (WGS) studies and new statistical methods for variant set tests now provide an opportunity to assess more associations between rare variants in lncRNA genes and complex traits across the genome. In this study, we used high-coverage WGS from 66,329 participants of diverse ancestries with measurement of blood lipids and lipoproteins (LDL-C, HDL-C, TC, and TG) in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program to investigate the role of lncRNAs in lipid variability. We aggregated rare variants …

Pls3 Missense Variants Affecting The Actin-Binding Domains Cause X-Linked Congenital Diaphragmatic Hernia And Body-Wall Defects, Florence Petit, Mauro Longoni, Julie Wells, Richard S Maser, Eric L Bogenschutz, Matthew J Dysart, Hannah T M Contreras, Frederic Frénois, Barbara R Pober, Robin D Clark, Philip F Giampietro, Hilger H Ropers, Hao Hu, Maria Loscertales, Richard Wagner, Xingbin Ai, Harrison Brand, Anne-Sophie Jourdain, Marie-Ange Delrue, Brigitte Gilbert-Dussardier, Louise Devisme, Boris Keren, David J Mcculley, Lu Qiao, Rebecca Hernan, Julia Wynn, Tiana M Scott, Daniel G Calame, Zeynep Coban-Akdemir, Patricia Hernandez, Andres Hernandez-Garcia, Hagith Yonath, James R Lupski, Yufeng Shen, Wendy K Chung, Daryl A Scott, Carol J Bult, Patricia K Donahoe, Frances A High

Faculty, Staff and Student Publications

Congenital diaphragmatic hernia (CDH) is a relatively common and genetically heterogeneous structural birth defect associated with high mortality and morbidity. We describe eight unrelated families with an X-linked condition characterized by diaphragm defects, variable anterior body-wall anomalies, and/or facial dysmorphism. Using linkage analysis and exome or genome sequencing, we found that missense variants in plastin 3 (PLS3), a gene encoding an actin bundling protein, co-segregate with disease in all families. Loss-of-function variants in PLS3 have been previously associated with X-linked osteoporosis (MIM: 300910), so we used in silico protein modeling and a mouse model to address these seemingly disparate clinical …

Analysis And Prediction Of Liver Volume Change Maps Derived From Computational Tomography Scans Acquired Pre- And Post-Radiation Therapy, Guillaume Cazoulat, Aashish C Gupta, Mais M Al Taie, Eugene J Koay, Kristy K Brock

Faculty, Staff and Student Publications

External beam radiation therapy (EBRT) of liver cancers can cause local liver atrophy as a result of tissue damage or hypertrophy as a result of liver regeneration. Predicting those volumetric changes would enable new strategies for liver function preservation during treatment planning. However, understanding of the spatial dose/volume relationship is still limited. This study leverages the use of deep learning-based segmentation and biomechanical deformable image registration (DIR) to analyze and predict this relationship. Pre- and Post-EBRT imaging data were collected for 100 patients treated for hepatocellular carcinomas, cholangiocarcinoma or CRC with intensity-modulated radiotherapy (IMRT) with prescription doses ranging from 50 …

Detection Of Early Myocardial Dysfunction By Imaging Biomarkers In Cancer Patients Undergoing Photon Beam Vs Proton Beam Radiotherapy: A Prospective Study, Muhannad Aboud Abbasi, Giulia Bruno, Cristina Di Stefano, Laura Garcia Bello, Nadia N Laack, Kimberly S Corbin, Thomas J Whitaker, Patricia A Pellikka, Robert W Mutter, Hector R Villarraga

Faculty, Staff and Student Publications

1. Background: We sought to determine acute and subacute changes in cardiac function after proton beam (PBT) and photon beam (PhT) radiotherapy (RT) using conventional and two-dimensional speckle tracking echocardiography (2D-STE) in patients with malignant breast and thoracic tumors. 2. Methods: Between March 2016 and March 2017, 70 patients with breast or thoracic cancer were prospectively enrolled and underwent transthoracic echocardiography with comprehensive strain analysis at pretreatment, mid-treatment, end of treatment, and 3 months after RT. 3. Results: PBT was used to treat 44 patients; PhT 26 patients. Mean ± SD age was 55 ± 12 years; most patients (93%) …

Gut Microbiota Aggravates Neutrophil Extracellular Traps-Induced Pancreatic Injury In Hypertriglyceridemic Pancreatitis, Guanqun Li, Liwei Liu, Tianqi Lu, Yuhang Sui, Can Zhang, Yongwei Wang, Tao Zhang, Yu Xie, Peng Xiao, Zhongjie Zhao, Chundong Cheng, Jisheng Hu, Hongze Chen, Dongbo Xue, Hua Chen, Gang Wang, Rui Kong, Hongtao Tan, Xuewei Bai, Zhibo Li, Florencia Mcallister, Le Li, Bei Sun

Faculty, Staff and Student Publications

Hypertriglyceridemic pancreatitis (HTGP) is featured by higher incidence of complications and poor clinical outcomes. Gut microbiota dysbiosis is associated with pancreatic injury in HTGP and the mechanism remains unclear. Here, we observe lower diversity of gut microbiota and absence of beneficial bacteria in HTGP patients. In a fecal microbiota transplantation mouse model, the colonization of gut microbiota from HTGP patients recruits neutrophils and increases neutrophil extracellular traps (NETs) formation that exacerbates pancreatic injury and systemic inflammation. We find that decreased abundance of Bacteroides uniformis in gut microbiota impairs taurine production and increases IL-17 release in colon that triggers NETs formation. …

Hemizygous Variants In Protein Phosphatase 1 Regulatory Subunit 3f (Ppp1r3f) Are Associated With A Neurodevelopmental Disorder Characterized By Developmental Delay, Intellectual Disability And Autistic Features, Zhigang Liu, Baozhong Xin, Iris N Smith, Valerie Sency, Julia Szekely, Anna Alkelai, Alan Shuldiner, Stephanie Efthymiou, Farrah Rajabi, Stephanie Coury, Catherine A Brownstein, Sabine Rudnik-Schöneborn, Ange-Line Bruel, Julien Thevenon, Shimriet Zeidler, Parul Jayakar, Axel Schmidt, Kirsten Cremer, Hartmut Engels, Sophia O Peters, Maha S Zaki, Ruizhi Duan, Changlian Zhu, Yiran Xu, Chao Gao, Tania Sepulveda-Morales, Reza Maroofian, Issam A Alkhawaja, Mariam Khawaja, Hunaida Alhalasah, Henry Houlden, Jill A Madden, Valentina Turchetti, Dana Marafi, Pankaj B Agrawal, Ulrich Schatz, Ari Rotenberg, Joshua Rotenberg, Grazia M S Mancini, Somayeh Bakhtiari, Michael Kruer, Isabelle Thiffault, Steffen Hirsch, Maja Hempel, Lara G Stühn, Tobias B Haack, Jennifer E Posey, James R Lupski, Hyunpil Lee, Nicholas B Sarn, Charis Eng, Claudia Gonzaga-Jauregui, Bin Zhang, Heng Wang

Faculty, Staff and Students Publications

Protein phosphatase 1 regulatory subunit 3F (PPP1R3F) is a member of the glycogen targeting subunits (GTSs), which belong to the large group of regulatory subunits of protein phosphatase 1 (PP1), a major eukaryotic serine/threonine protein phosphatase that regulates diverse cellular processes. Here, we describe the identification of hemizygous variants in PPP1R3F associated with a novel X-linked recessive neurodevelopmental disorder in 13 unrelated individuals. This disorder is characterized by developmental delay, mild intellectual disability, neurobehavioral issues such as autism spectrum disorder, seizures and other neurological findings including tone, gait and cerebellar abnormalities. PPP1R3F variants segregated with disease in affected hemizygous males …

Effect Of Preoperative Programmed Death-1 Or Programmed Death Ligand-1 Immune Check Point Inhibition On Complications After Surgery For Primary Head And Neck Cancer, Ramez Philips, Angela Alnemri, Dev Amin, Jena Patel, Michael C. Topf, Jennifer M. Johnson, Voichita Bar-Ad, Rita Axelrod, Athanassios Argiris, Christopher Fundakowski, Adam J. Luginbuhl, David M. Cognetti, Joseph M. Curry

Jefferson Hospital Staff Papers and Presentations

BACKGROUND: There is sparse literature on the effect of preoperative immunotherapy on complications after surgery for primary head and neck squamous cell carcinoma (HNSCC). The objectives are to compare complication rates in patients receiving surgery with and without neoadjuvant immune checkpoint inhibitors (nICI) for primary HNSCC and to evaluate factors associated with increased odds of surgical complications.

METHODS: A retrospective review of patients who underwent ablation and free flap reconstruction or transoral robotic surgery (TORS) for primary HNSCC between 2017-2021 was conducted. Complications were compared between patients who underwent surgery with or without nICI before and after propensity score matching. …

Report Of The Assay Guidance Workshop On 3-Dimensional Tissue Models For Antiviral Drug Development, Robert Jordan, Stephanie L Ford-Scheimer, Rodolfo M Alarcon, Anthony Atala, Jeffrey T Borenstein, Kyle R Brimacombe, Sara Cherry, Hans Clevers, Mindy I Davis, Simon G P Funnell, Lee Gehrke, Linda G Griffith, Abigail C Grossman, Thomas Hartung, Donald E Ingber, Nicole C Kleinstreuer, Calvin J Kuo, Emily M Lee, Christine L Mummery, Thames E Pickett, Sasirekha Ramani, Edwin A Rosado-Olivieri, Evi B Struble, Zhengpeng Wan, Mark S Williams, Matthew D Hall, Marc Ferrer, Sarine Markossian

Faculty, Staff and Students Publications

The National Center for Advancing Translational Sciences (NCATS) Assay Guidance Manual (AGM) Workshop on 3D Tissue Models for Antiviral Drug Development, held virtually on 7-8 June 2022, provided comprehensive coverage of critical concepts intended to help scientists establish robust, reproducible, and scalable 3D tissue models to study viruses with pandemic potential. This workshop was organized by NCATS, the National Institute of Allergy and Infectious Diseases, and the Bill and Melinda Gates Foundation. During the workshop, scientific experts from academia, industry, and government provided an overview of 3D tissue models' utility and limitations, use of existing 3D tissue models for antiviral …

Quality Of Life In Male Breast Cancer: Prospective Study Of The International Male Breast Cancer Program (Eortc10085/Tbcrc029/Big2-07/Nabcg), Carolien P Schröder, Elise Van Leeuwen-Stok, Fatima Cardoso, Barbro Linderholm, Coralie Poncet, Antonio C Wolff, Vesna Bjelic-Radisic, Gustavo Werutsky, Miguel H Abreu, Ivana Bozovic-Spasojevic, Irma Den Hoed, Aafke H Honkoop, Maartje Los, Jose P Leone, Nicola S Russell, Tineke J Smilde, Annette W G Van Der Velden, Catherine Van Poznak, Marije M Vleugel, Rachel L Yung, Corneel Coens, Sharon H Giordano, Kathryn J Ruddy

Faculty, Staff and Student Publications

INTRODUCTION: Prospective data about quality of life (QoL) in men with breast cancer (BC) are lacking. A prospective registry (EORTC10085) of men with all BC stages, including a QoL correlative study, was performed as part of the International Male Breast Cancer Program.

METHODS: Questionnaires at BC diagnosis included the EORTC QLQ-C30 and BR23 (BC specific module), adapted for men. High functioning and global health/QoL scores indicate high functioning levels/high QoL; high symptom-focused measures scores indicate high symptoms/problems levels. EORTC reference data for healthy men and women with BC were used for comparisons.

RESULTS: Of 422 men consenting to participate, 363 …

An Update On Strategies To Deliver Protein And Peptide Drugs To The Eye, Sai H S Boddu, Devarshi Acharya, Vivek Hala, Harshil Jani, Sonal Pande, Chirag Patel, Moyad Shahwan, Renukuntla Jwala, Ketan M Ranch

Faculty, Staff and Student Publications

In the past few decades, advancements in protein engineering, biotechnology, and structural biochemistry have resulted in the discovery of various techniques that enhanced the production yield of proteins, targetability, circulating half-life, product purity, and functionality of proteins and peptides. As a result, the utilization of proteins and peptides has increased in the treatment of many conditions, including ocular diseases. Ocular delivery of large molecules poses several challenges due to their high molecular weight, hydrophilicity, unstable nature, and poor permeation through cellular and enzymatic barriers. The use of novel strategies for delivering protein and peptides such as glycoengineering, PEGylation, Fc-fusion, chitosan …

Comparative Genomic Landscape Of Urothelial Carcinoma Of The Bladder Among Patients Of East And South Asian Genomic Ancestry, Taylor Peak, Philippe E Spiess, Roger Li, Petros Grivas, Andrea Necchi, Dean Pavlick, Richard S P Huang, Douglas Lin, Natalie Danziger, Joseph M Jacob, Gennady Bratslavsky, Jeffrey S Ross

Faculty, Staff and Student Publications

BACKGROUND: Despite the low rate of urothelial carcinoma of the bladder (UCB) in patients of South Asian (SAS) and East Asian (EAS) descent, they make up a significant portion of the cases worldwide. Nevertheless, these patients are largely under-represented in clinical trials. We queried whether UCB arising in patients with SAS and EAS ancestry would have unique genomic features compared to the global cohort.

METHODS: Formalin-fixed, paraffin-embedded tissue was obtained for 8728 patients with advanced UCB. DNA was extracted and comprehensive genomic profiling was performed. Ancestry was classified using a proprietary calculation algorithm. Genomic alterations (GAs) were determined using a …

The Breast Cancer Proteome And Precision Oncology, Jonathan T Lei, Eric J Jaehnig, Hannah Smith, Matthew V Holt, Xi Li, Meenakshi Anurag, Matthew J Ellis, Gordon B Mills, Bing Zhang, Marilyne Labrie

Faculty, Staff and Students Publications

The goal of precision oncology is to translate the molecular features of cancer into predictive and prognostic tests that can be used to individualize treatment leading to improved outcomes and decreased toxicity. Success for this strategy in breast cancer is exemplified by efficacy of trastuzumab in tumors overexpressing ERBB2 and endocrine therapy for tumors that are estrogen receptor positive. However, other effective treatments, including chemotherapy, immune checkpoint inhibitors, and CDK4/6 inhibitors are not associated with strong predictive biomarkers. Proteomics promises another tier of information that, when added to genomic and transcriptomic features (proteogenomics), may create new opportunities to improve both …

Scribbledom: Using Scribble-Annotated Histology Images To Identify Domains In Spatial Transcriptomics Data, Mohammad Nuwaisir Rahman, Abdullah Al Noman, Abir Mohammad Turza, Mohammed Abid Abrar, Md Abul Hassan Samee, M Saifur Rahman

Faculty, Staff and Students Publications

Motivation

Spatial domain identification is a very important problem in the field of spatial transcriptomics. The state-of-the-art solutions to this problem focus on unsupervised methods, as there is lack of data for a supervised learning formulation. The results obtained from these methods highlight significant opportunities for improvement.

Results

In this article, we propose a potential avenue for enhancement through the development of a semi-supervised convolutional neural network based approach. Named “ScribbleDom”, our method leverages human expert’s input as a form of semi-supervision, thereby seamlessly combines the cognitive abilities of human experts with the computational power of machines. ScribbleDom incorporates a …

Spa-Stocsy: An Automated Tool For Identifying Annotated And Non-Annotated Metabolites In High-Throughput Nmr Spectra, Xu Han, Wanli Wang, Li-Hua Ma, Ismael Ai-Ramahi, Juan Botas, Kevin Mackenzie, Genevera I Allen, Damian W Young, Zhandong Liu, Mirjana Maletic-Savatic

Faculty, Staff and Students Publications

MOTIVATION: Nuclear magnetic resonance spectroscopy (NMR) is widely used to analyze metabolites in biological samples, but the analysis requires specific expertise, it is time-consuming, and can be inaccurate. Here, we present a powerful automate tool, SPatial clustering Algorithm-Statistical TOtal Correlation SpectroscopY (SPA-STOCSY), which overcomes challenges faced when analyzing NMR data and identifies metabolites in a sample with high accuracy.

RESULTS: As a data-driven method, SPA-STOCSY estimates all parameters from the input dataset. It first investigates the covariance pattern among datapoints and then calculates the optimal threshold with which to cluster datapoints belonging to the same structural unit, i.e. the metabolite. …

Deep Learning For Fully Automatic Tumor Segmentation On Serially Acquired Dynamic Contrast-Enhanced Mri Images Of Triple-Negative Breast Cancer, Zhan Xu, David E Rauch, Rania M Mohamed, Sanaz Pashapoor, Zijian Zhou, Bikash Panthi, Jong Bum Son, Ken-Pin Hwang, Benjamin C Musall, Beatriz E Adrada, Rosalind P Candelaria, Jessica W T Leung, Huong T C Le-Petross, Deanna L Lane, Frances Perez, Jason White, Alyson Clayborn, Brandy Reed, Huiqin Chen, Jia Sun, Peng Wei, Alastair Thompson, Anil Korkut, Lei Huo, Kelly K Hunt, Jennifer K Litton, Vicente Valero, Debu Tripathy, Wei Yang, Clinton Yam, Jingfei Ma

Faculty, Staff and Student Publications

Accurate tumor segmentation is required for quantitative image analyses, which are increasingly used for evaluation of tumors. We developed a fully automated and high-performance segmentation model of triple-negative breast cancer using a self-configurable deep learning framework and a large set of dynamic contrast-enhanced MRI images acquired serially over the patients' treatment course. Among all models, the top-performing one that was trained with the images across different time points of a treatment course yielded a Dice similarity coefficient of 93% and a sensitivity of 96% on baseline images. The top-performing model also produced accurate tumor size measurements, which is valuable for …

Intraperitoneal Paclitaxel Is A Safe And Effective Therapeutic Strategy For Treating Mucinous Appendiceal Adenocarcinoma, Ichiaki Ito, Abdelrahman M G Yousef, Saikat Chowdhury, Princess N Dickson, Zahra A Naini, Michael G White, Karianne G Fleten, Kjersti Flatmark, Keith F Fournier, Natalie W Fowlkes, John Paul Shen

Faculty, Staff and Student Publications

Appendiceal adenocarcinomas (AAs) are a rare and heterogeneous mix of tumors for which few preclinical models exist. The rarity of AA has made performing prospective clinical trials difficult, which has partly contributed to AA remaining an orphan disease with no chemotherapeutic agents approved by the FDA for its treatment. AA has a unique biology in which it frequently forms diffuse peritoneal metastases but almost never spreads via a hematogenous route and rarely spreads to lymphatics. Given the localization of AA to the peritoneal space, intraperitoneal (IP) delivery of chemotherapy could be an effective treatment strategy. Here, we tested the efficacy …

Abemaciclib Is Effective In Palbociclib-Resistant Hormone Receptor-Positive Metastatic Breast Cancers, Juliana Navarro-Yepes, Nicole M Kettner, Xiayu Rao, Cassandra Santaella Bishop, Tuyen N Bui, Hannah F Wingate, Akshara Singareeka Raghavendra, Yan Wang, Jing Wang, Aysegul A Sahin, Funda Meric-Bernstam, Kelly K Hunt, Senthil Damodaran, Debu Tripathy, Khandan Keyomarsi

Faculty, Staff and Student Publications

Cyclin-dependent kinases 4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) is standard of care for patients with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (MBC). However, resistance to CDK4/6is plus ET remains a clinical problem with limited therapeutic options following disease progression. Different CDK4/6is might have distinct mechanisms of resistance, and therefore using them sequentially or targeting their differentially altered pathways could delay disease progression. To understand pathways leading to resistance to the CDK4/6is palbociclib and abemaciclib, we generated multiple in vitro models of palbociclib-resistant (PR) and abemaciclib-resistant (AR) cell lines as well as in vivo patient-derived xenografts (PDX) and ex …

Endocrine Therapy Synergizes With Smac Mimetics To Potentiate Antigen Presentation And Tumor Regression In Hormone Receptor-Positive Breast Cancer, Francisco Hermida-Prado, Yingtian Xie, Shira Sherman, Zsuzsanna Nagy, Douglas Russo, Tara Akhshi, Zhengtao Chu, Avery Feit, Marco Campisi, Minyue Chen, Agostina Nardone, Cristina Guarducci, Klothilda Lim, Alba Font-Tello, Irene Lee, Juana García-Pedrero, Israel Cañadas, Judith Agudo, Ying Huang, Tal Sella, Qingchun Jin, Nabihah Tayob, Elizabeth A Mittendorf, Sara M Tolaney, Xintao Qiu, Henry Long, William F Symmans, Jia-Ren Lin, Sandro Santagata, Isabelle Bedrosian, Denise A Yardley, Ingrid A Mayer, Edward T Richardson, Giacomo Oliveira, Catherine J Wu, Eugene F Schuster, Mitch Dowsett, Alana L Welm, David Barbie, Otto Metzger, Rinath Jeselsohn

Faculty, Staff and Student Publications

Immunotherapies have yet to demonstrate significant efficacy in the treatment of hormone receptor-positive (HR+) breast cancer. Given that endocrine therapy (ET) is the primary approach for treating HR+ breast cancer, we investigated the effects of ET on the tumor immune microenvironment (TME) in HR+ breast cancer. Spatial proteomics of primary HR+ breast cancer samples obtained at baseline and after ET from patients enrolled in a neoadjuvant clinical trial (NCT02764541) indicated that ET upregulated β2-microglobulin and influenced the TME in a manner that promotes enhanced immunogenicity. To gain a deeper understanding of the underlying mechanisms, the intrinsic effects of …

Safety And Tolerability Of A Novel Anti-Her2 Antibody-Drug Conjugate (Pf-06804103) In Patients With Her2-Expressing Solid Tumors: A Phase 1 Dose-Escalation Study, Funda Meric-Bernstam, Emiliano Calvo, Keun Seok Lee, Victor Moreno, Yeon Hee Park, Sun Young Rha, Pavani Chalasani, Wei Zhong, Li Zhou, Steven Pirie-Shepherd, Abraham C F Leung, Giuseppe Curigliano

Faculty, Staff and Student Publications

PF-06804103 is an anti-HER2 antibody–drug conjugate with auristatin payload. We evaluated its safety, tolerability, and antitumor activity in patients with advanced/unresectable or metastatic breast and gastric cancers. This multicenter, open-label, first-in-human, phase 1 study (NCT03284723) comprised dose escalation (P1) and dose expansion (P2). In P1, adults with HER2+ breast or gastric cancer received PF-06804103 0.15–5.0 mg/kg intravenously once/21 days (Q3W); in P2, patients with HER2+ or HER2-low (IHC 1+ or IHC 2+/ISH−) breast cancer received 3.0 or 4.0 mg/kg Q3W. The primary endpoints were dose-limiting toxicities (DLT) and safety (P1), and objective response rate (ORR) assessed using RECIST v1.1 (P2). …

Setd2 Loss And Atr Inhibition Synergize To Promote Cgas Signaling And Immunotherapy Response In Renal Cell Carcinoma, Xian-De Liu, Yan-Ting Zhang, Daniel J Mcgrail, Xuesong Zhang, Truong Lam, Anh Hoang, Elshad Hasanov, Ganiraju Manyam, Christine B Peterson, Haifeng Zhu, Shwetha V Kumar, Rehan Akbani, Patrick G Pilie, Nizar M Tannir, Guang Peng, Eric Jonasch

Faculty, Staff and Student Publications

PURPOSE: Immune checkpoint blockade (ICB) demonstrates durable clinical benefits in a minority of patients with renal cell carcinoma (RCC). We aimed to identify the molecular features that determine the response and develop approaches to enhance it.

EXPERIMENTAL DESIGN: We investigated the effects of SET domain-containing protein 2 (SETD2) loss on the DNA damage response pathway, the cytosolic DNA-sensing pathway, the tumor immune microenvironment, and the response to ataxia telangiectasia and rad3-related (ATR) and checkpoint inhibition in RCC.

RESULTS: ATR inhibition activated the cyclic GMP-AMP synthase (cGAS)-interferon regulatory factor 3 (IRF3)-dependent cytosolic DNA-sensing pathway, resulting in the concurrent expression of inflammatory …

Single-Cell Characterization Of Pulmonary Nodules Implicates Suppression Of Immunosurveillance Across Early Stages Of Lung Adenocarcinoma, Jane Yanagawa, Linh M Tran, Ramin Salehi-Rad, Raymond J Lim, Camelia Dumitras, Eileen Fung, William D Wallace, Ashley E Prosper, Gregory Fishbein, Conor Shea, Rui Hong, Bitta Kahangi, John J Deng, Adam C Gower, Bin Liu, Joshua D Campbell, Sarah A Mazzilli, Jennifer E Beane, Humam Kadara, Marc E Lenburg, Avrum E Spira, Denise R Aberle, Kostyantyn Krysan, Steven M Dubinett

Faculty, Staff and Student Publications

UNLABELLED: A greater understanding of molecular, cellular, and immunological changes during the early stages of lung adenocarcinoma development could improve diagnostic and therapeutic approaches in patients with pulmonary nodules at risk for lung cancer. To elucidate the immunopathogenesis of early lung tumorigenesis, we evaluated surgically resected pulmonary nodules representing the spectrum of early lung adenocarcinoma as well as associated normal lung tissues using single-cell RNA sequencing and validated the results by flow cytometry and multiplex immunofluorescence (MIF). Single-cell transcriptomics revealed a significant decrease in gene expression associated with cytolytic activities of tumor-infiltrating natural killer and natural killer T cells. This …