Biomedical Informatics Commons^™

Biomolecular Condensation: A New Phase In Cancer Research, Anupam K Chakravarty, Daniel J Mcgrail, Thomas M Lozanoski, Brandon S Dunn, David J H Shih, Kara M Cirillo, Sueda H Cetinkaya, Wenjin Jim Zheng, Gordon B Mills, S Stephen Yi, Daniel F Jarosz, Nidhi Sahni

Faculty, Staff and Student Publications

Multicellularity was a watershed development in evolution. However, it also meant that individual cells could escape regulatory mechanisms that restrict proliferation at a severe cost to the organism: cancer. From the standpoint of cellular organization, evolutionary complexity scales to organize different molecules within the intracellular milieu. The recent realization that many biomolecules can "phase-separate" into membraneless organelles, reorganizing cellular biochemistry in space and time, has led to an explosion of research activity in this area. In this review, we explore mechanistic connections between phase separation and cancer-associated processes and emerging examples of how these become deranged in malignancy.

SIGNIFICANCE: One …

Chd1 Promotes Sensitivity To Aurora Kinase Inhibitors By Suppressing Interaction Of Aurka With Its Coactivator Tpx2, Haoyan Li, Yin Wang, Kevin Lin, Varadha Balaji Venkadakrishnan, Martin Bakht, Wei Shi, Chenling Meng, Jie Zhang, Kaitlyn Tremble, Xin Liang, Jian H Song, Xu Feng, Vivien Van, Pingna Deng, Jared K Burks, Ana Aparicio, Khandan Keyomarsi, Junjie Chen, Yue Lu, Himisha Beltran, Di Zhao

Faculty, Staff and Student Publications

UNLABELLED: Clinical studies have shown that subsets of patients with cancer achieve a significant benefit from Aurora kinase inhibitors, suggesting an urgent need to identify biomarkers for predicting drug response. Chromodomain helicase DNA binding protein 1 (CHD1) is involved in chromatin remodeling, DNA repair, and transcriptional plasticity. Prior studies have demonstrated that CHD1 has distinct expression patterns in cancers with different molecular features, but its impact on drug responsiveness remains understudied. Here, we show that CHD1 promotes the susceptibility of prostate cancer cells to inhibitors targeting Aurora kinases, while depletion of CHD1 impairs their efficacy in vitro and in vivo. …

Association Study Between Polymorphisms In Dna Methylation-Related Genes And Testicular Germ Cell Tumor Risk, Chiara Grasso, Maja Popovic, Elena Isaevska, Fulvio Lazzarato, Valentina Fiano, Daniela Zugna, John Pluta, Benita Weathers, Kurt D'Andrea, Kristian Almstrup, Lynn Anson-Cartwright, D Timothy Bishop, Stephen J Chanock, Chu Chen, Victoria K Cortessis, Marlene D Dalgaard, Siamak Daneshmand, Alberto Ferlin, Carlo Foresta, Megan N Frone, Marija Gamulin, Jourik A Gietema, Mark H Greene, Tom Grotmol, Robert J Hamilton, Trine B Haugen, Russ Hauser, Robert Karlsson, Lambertus A Kiemeney, Davor Lessel, Patrizia Lista, Ragnhild A Lothe, Chey Loveday, Coby Meijer, Kevin T Nead, Jérémie Nsengimana, Rolf I Skotheim, Clare Turnbull, David J Vaughn, Fredrik Wiklund, Tongzhang Zheng, Andrea Zitella, Stephen M Schwartz, Katherine A Mcglynn, Peter A Kanetsky, Katherine L Nathanson, Lorenzo Richiardi

Faculty, Staff and Student Publications

Background: Testicular germ cell tumors (TGCT), histologically classified as seminomas and nonseminomas, are believed to arise from primordial gonocytes, with the maturation process blocked when they are subjected to DNA methylation reprogramming. SNPs in DNA methylation machinery and folate-dependent one-carbon metabolism genes have been postulated to influence the proper establishment of DNA methylation.

Methods: In this pathway-focused investigation, we evaluated the association between 273 selected tag SNPs from 28 DNA methylation-related genes and TGCT risk. We carried out association analysis at individual SNP and gene-based level using summary statistics from the Genome Wide Association Study meta-analysis recently conducted by the …

Does A Multiple Myeloma Polygenic Risk Score Predict Overall Survival Of Patients With Myeloma?, Angelica Macauda, Alyssa Clay-Gilmour, Thomas Hielscher, Michelle A T Hildebrandt, Marcin Kruszewski, Robert Z Orlowski, Shaji K Kumar, Elad Ziv, Enrico Orciuolo, Elizabeth E Brown, Asta Försti, Rosalie G Waller, Mitchell J Machiela, Stephen J Chanock, Nicola J Camp, Marcin Rymko, Małgorzata Raźny, Wendy Cozen, Judit Várkonyi, Chiara Piredda, Matteo Pelosini, Alem A Belachew, Edyta Subocz, Kari Hemminki, Malwina Rybicka-Ramos, Graham G Giles, Roger L Milne, Jonathan N Hofmann, Jan Maciej Zaucha, Annette Juul Vangsted, Hartmut Goldschmidt, S Vincent Rajkumar, Waldemar Tomczak, Juan Sainz, Aleksandra Butrym, Marzena Watek, Elżbieta Iskierka-Jazdzewska, Gabriele Buda, Dennis P Robinson, Artur Jurczyszyn, Marek Dudziński, Joaquin Martinez-Lopez, Jason P Sinnwell, Susan L Slager, Krzysztof Jamroziak, Rui Manuel Vieira Reis, Niels Weinhold, Parveen Bhatti, Luis G Carvajal-Carmona, Daria Zawirska, Aaron D Norman, Grzegorz Mazur, Sonja I Berndt, Daniele Campa, Celine M Vachon, Federico Canzian

Faculty, Staff and Student Publications

Background: Genome-wide association studies (GWAS) of multiple myeloma in populations of European ancestry (EA) identified and confirmed 24 susceptibility loci. For other cancers (e.g., colorectum and melanoma), risk loci have also been associated with patient survival.

Methods: We explored the possible association of all the known risk variants and their polygenic risk score (PRS) with multiple myeloma overall survival (OS) in multiple populations of EA [the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the International Lymphoma Epidemiology consortium, CoMMpass, and the German GWAS] for a total of 3,748 multiple myeloma cases. Cox proportional hazards regression was used to assess the association …

Exercise Promotes Pro-Apoptotic Ceramide Signaling In A Mouse Melanoma Model, Jonghae Lee, Hannah Savage, Shinji Maegawa, Riccardo Ballarò, Sumedha Pareek, Bella Samia Guerrouahen, Vidya Gopalakrishnan, Keri Schadler

Faculty, Staff and Student Publications

Ceramides are essential sphingolipids that mediate cell death and survival. Low ceramide content in melanoma is one mechanism of drug resistance. Thus, increasing the ceramide content in tumor cells is likely to increase their sensitivity to cytotoxic therapy. Aerobic exercise has been shown to modulate ceramide metabolism in healthy tissue, but the relationship between exercise and ceramide in tumors has not been evaluated. Here, we demonstrate that aerobic exercise causes tumor cell apoptosis and accumulation of pro-apoptotic ceramides in B16F10 but not BP melanoma models using mice. B16F10 tumor-bearing mice were treated with two weeks of moderate treadmill exercise, or …

Pramlintide: A Novel Therapeutic Approach For Osteosarcoma Through Metabolic Reprogramming, Yuanzheng Yang, Zhanglong Peng, Elsa R Flores, Eugenie S Kleinerman

Faculty, Staff and Student Publications

Despite aggressive combination chemotherapy and surgery, outcomes for patients with osteosarcoma have remained stagnant for more than 25 years, and numerous clinical trials have identified no new therapies. p53 deletion or mutation is found in more than 80% of osteosarcoma tumors. In p53-deficient cancers with structurally altered p63 and p73, interfering with tumor cell metabolism using Pramlintide (an FDA-approved drug for type 2 diabetes) results in tumor regression. Pramlintide response is mediated through upregulation of islet amyloid polypeptide (IAPP). Here, we showed that osteosarcoma cells have altered p63, p73, and p53, and decreased IAPP expression but have the two main …

Smyd3 Impedes Small Cell Lung Cancer Sensitivity To Alkylation Damage Through Rnf113a Methylation-Phosphorylation Cross-Talk, Valentina Lukinović, Simone Hausmann, Gael S Roth, Clement Oyeniran, Tanveer Ahmad, Ning Tsao, Joshua R Brickner, Alexandre G Casanova, Florent Chuffart, Ana Morales Benitez, Jessica Vayr, Rebecca Rodell, Marianne Tardif, Pascal W T C Jansen, Yohann Couté, Michiel Vermeulen, Pierre Hainaut, Pawel K Mazur, Nima Mosammaparast, Nicolas Reynoird

Faculty, Staff and Student Publications

Small cell lung cancer (SCLC) is the most fatal form of lung cancer, with dismal survival, limited therapeutic options, and rapid development of chemoresistance. We identified the lysine methyltransferase SMYD3 as a major regulator of SCLC sensitivity to alkylation-based chemotherapy. RNF113A methylation by SMYD3 impairs its interaction with the phosphatase PP4, controlling its phosphorylation levels. This cross-talk between posttranslational modifications acts as a key switch in promoting and maintaining RNF113A E3 ligase activity, essential for its role in alkylation damage response. In turn, SMYD3 inhibition restores SCLC vulnerability to alkylating chemotherapy. Our study sheds light on a novel role of …

Usp7 Substrates Identified By Proteomics Analysis Reveal The Specificity Of Usp7, Litong Nie, Chao Wang, Xiaoguang Liu, Hongqi Teng, Siting Li, Min Huang, Xu Feng, Guangsheng Pei, Qinglei Hang, Zhongming Zhao, Boyi Gan, Li Ma, Junjie Chen

Faculty, Staff and Student Publications

Deubiquitylating enzymes (DUBs) remove ubiquitin chains from proteins and regulate protein stability and function. USP7 is one of the most extensively studied DUBs, since USP7 has several well-known substrates important for cancer progression, such as MDM2, N-MYC, and PTEN. Thus, USP7 is a promising drug target. However, systematic identification of USP7 substrates has not yet been performed. In this study, we carried out proteome profiling with label-free quantification in control and single/double-KO cells of

Genetic Loci And Prioritization Of Genes For Kidney Function Decline Derived From A Meta-Analysis Of 62 Longitudinal Genome-Wide Association Studies, Mathias Gorski, Humaira Rasheed, Alexander Teumer, Laurent F Thomas, Sarah E Graham, Gardar Sveinbjornsson, Thomas W Winkler, Felix Günther, Klaus J Stark, Jin-Fang Chai, Bamidele O Tayo, Matthias Wuttke, Yong Li, Adrienne Tin, Tarunveer S Ahluwalia, Johan Ärnlöv, Bjørn Olav Åsvold, Stephan J L Bakker, Bernhard Banas, Nisha Bansal, Mary L Biggs, Ginevra Biino, Michael Böhnke, Eric Boerwinkle, Erwin P Bottinger, Hermann Brenner, Ben Brumpton, Robert J Carroll, Layal Chaker, John Chalmers, Miao-Li Chee, Miao-Ling Chee, Ching-Yu Cheng, Audrey Y Chu, Marina Ciullo, Massimiliano Cocca, James P Cook, Josef Coresh, Daniele Cusi, Martin H De Borst, Frauke Degenhardt, Kai-Uwe Eckardt, Karlhans Endlich, Michele K Evans, Mary F Feitosa, Andre Franke, Sandra Freitag-Wolf, Christian Fuchsberger, Piyush Gampawar, Ron T Gansevoort, Mohsen Ghanbari, Sahar Ghasemi, Vilmantas Giedraitis, Christian Gieger, Daniel F Gudbjartsson, Stein Hallan, Pavel Hamet, Asahi Hishida, Kevin Ho, Edith Hofer, Bernd Holleczek, Hilma Holm, Anselm Hoppmann, Katrin Horn, Nina Hutri-Kähönen, Kristian Hveem, Shih-Jen Hwang, M Arfan Ikram, Navya Shilpa Josyula, Bettina Jung, Mika Kähönen, Irma Karabegović, Chiea-Chuen Khor, Wolfgang Koenig, Holly Kramer, Bernhard K Krämer, Brigitte Kühnel, Johanna Kuusisto, Markku Laakso, Leslie A Lange, Terho Lehtimäki, Man Li, Wolfgang Lieb, Lifelines Cohort Study, Lars Lind, Cecilia M Lindgren, Ruth J F Loos, Mary Ann Lukas, Leo-Pekka Lyytikäinen, Anubha Mahajan, Pamela R Matias-Garcia, Christa Meisinger, Thomas Meitinger, Olle Melander, Yuri Milaneschi, Pashupati P Mishra, Nina Mononen, Andrew P Morris, Josyf C Mychaleckyj, Girish N Nadkarni, Mariko Naito, Masahiro Nakatochi, Mike A Nalls, Matthias Nauck, Kjell Nikus, Boting Ning, Ilja M Nolte, Teresa Nutile, Michelle L O'Donoghue, Jeffrey O'Connell, Isleifur Olafsson, Marju Orho-Melander, Afshin Parsa, Sarah A Pendergrass, Brenda W J H Penninx, Mario Pirastu, Michael H Preuss, Bruce M Psaty, Laura M Raffield, Olli T Raitakari, Myriam Rheinberger, Kenneth M Rice, Federica Rizzi, Alexander R Rosenkranz, Peter Rossing, Jerome I Rotter, Daniela Ruggiero, Kathleen A Ryan, Charumathi Sabanayagam, Erika Salvi, Helena Schmidt, Reinhold Schmidt, Markus Scholz, Ben Schöttker, Christina-Alexandra Schulz, Sanaz Sedaghat, Christian M Shaffer, Karsten B Sieber, Xueling Sim, Mario Sims, Harold Snieder, Kira J Stanzick, Unnur Thorsteinsdottir, Hannah Stocker, Konstantin Strauch, Heather M Stringham, Patrick Sulem, Silke Szymczak, Kent D Taylor, Chris H L Thio, Johanne Tremblay, Simona Vaccargiu, Pim Van Der Harst, Peter J Van Der Most, Niek Verweij, Uwe Völker, Kenji Wakai, Melanie Waldenberger, Lars Wallentin, Stefan Wallner, Judy Wang, Dawn M Waterworth, Harvey D White, Cristen J Willer, Tien-Yin Wong, Mark Woodward, Qiong Yang, Laura M Yerges-Armstrong, Martina Zimmermann, Alan B Zonderman, Tobias Bergler, Kari Stefansson, Carsten A Böger, Cristian Pattaro, Anna Köttgen, Florian Kronenberg, Iris M Heid

Faculty, Staff and Student Publications

Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine …

Major Pathologic Response And Prognostic Score Predict Survival In Patients With Lung Cancer Receiving Neoadjuvant Chemotherapy, Apar Pataer, Annikka Weissferdt, Arlene M Correa, Ara A Vaporciyan, Boris Sepesi, John V Heymach, Sabina Berezowska, Tina Cascone, Stephen G Swisher

Faculty, Staff and Student Publications

INTRODUCTION: Complete pathologic response (CPR) is an acceptable surrogate for survival in clinical trials but it occurs infrequently in patients with NSCLC receiving neoadjuvant chemotherapy (NCT). Therefore, we studied the impact of major pathologic response (MPR) for predicting survival of patients with NSCLC receiving NCT. We also tested a newly reported scoring system-the prognostic score (PRSC)-which combines T category, lymph node status, and MPR status.

METHODS: We analyzed CPR and MPR, defined as 0% and less than or equal to 10% viable tumor cells, respectively, in 339 patients with NSCLC with various histologic types who had been treated with NCT …

Tumor Immune Microenvironment Changes By Multiplex Immunofluorescence Staining In A Pilot Study Of Neoadjuvant Talazoparib For Early-Stage Breast Cancer Patients With A Hereditary Brca Mutation, Tapsi Kumar, Evie Hobbs, Fei Yang, Jeffrey T Chang, Alejandro Contreras, Edwin Roger Parra Cuentas, Haven Garber, Sanghoon Lee, Yiling Lu, Marion E Scoggins, Beatriz E Adrada, Gary J Whitman, Banu K Arun, Elizabeth A Mittendorf, Jennifer K Litton

Faculty, Staff and Student Publications

PURPOSE: The immunological profile of early-stage breast cancer treated with neoadjuvant PARP inhibitors has not been described. The aim of this study was to delineate the changes in the tumor immune microenvironment (TiME) induced by talazoparib.

PATIENTS AND METHODS: Patients with operable germline BRCA1/2 pathogenic variant (gBRCA1/2+) breast cancer were enrolled in a feasibility study of neoadjuvant talazoparib. Thirteen patients who received 8 weeks of neoadjuvant talazoparib were available for analysis, including 11 paired pre- and post-talazoparib core biopsies. Treatment-related changes in tumor-infiltrating lymphocytes were examined and immune cell phenotypes and their spatial distribution in the TiME were identified and …

Confirming Subarachnoid Hemorrhage Induction In The Endovascular Puncture Mouse Model, Ari Dienel, Sung-Ha Hong, Jose Guzman, Kumar T Peeyush, Spiros L Blackburn, Devin W Mcbride

Faculty, Staff and Student Publications

Background and purpose: Experimental studies of subarachnoid hemorrhage (SAH) using the endovascular perforation model routinely use either cerebral blood flow (CBF) or intracranial pressure (ICP) monitoring to confirm SAH induction. We designed this study to test the hypothesis that contralateral CBF is a better marker of SAH induction than ipsilateral CBF.

Methods: Sixty-eight adult C57BL/6J mice were subjected to endovascular perforation. Mice were monitored using laser Doppler (for relative CBF) or ICP probes.

Results: The ipsilateral CBF significantly decreased prior to ICP rising. However, reduction of the CBF in the contralateral hemisphere occurred at the same time as the rise …

Idh1 Prr32h Ctdna And D-2-Hydroxyglutarate As Csf Biomarkers In Patients With Idh-Mutant Gliomas, Yoko Fujita, Luis Nunez-Rubiano, Antonio Dono, Allison Bellman, Mauli Shah, Juan C Rodriguez, Vasanta Putluri, Abu Hena Mostafa Kamal, Nagireddy Putluri, Roy F Riascos, Jay-Jiguang Zhu, Yoshua Esquenazi, Leomar Y Ballester

Faculty, Staff and Student Publications

INTRODUCTION: We aimed to evaluate IDH1 p.R132H mutation and 2-hydroxyglutarate (2HG) in cerebrospinal fluid (CSF) as biomarkers for patients with IDH-mutant gliomas.

METHODS: CSF was collected from patients with infiltrating glioma, and 2HG levels were measured by liquid chromatography-mass spectrometry. IDH1 p.R132H mutant allele frequency (MAF) in CSF-ctDNA was measured by digital droplet PCR (ddPCR). Tumor volume was measured from standard-of-care magnetic resonance images.

RESULTS: The study included 48 patients, 6 with IDH-mutant and 42 with IDH-wildtype gliomas, and 57 samples, 9 from the patients with IDH-mutant and 48 from the patients with IDH-wildtype gliomas. ctDNA was detected in 7 …

Plasmonic Gadolinium Oxide Nanomatryoshkas: Bifunctional Magnetic Resonance Imaging Enhancers For Photothermal Cancer Therapy, Luke Henderson, Oara Neumann, Yara Kadria-Vili, Burak Gerislioglu, James Bankson, Peter Nordlander, Naomi J Halas

Faculty, Staff and Student Publications

Nanoparticle-assisted laser-induced photothermal therapy (PTT) is a promising method for cancer treatment; yet, visualization of nanoparticle uptake and photothermal response remain a critical challenge. Here, we report a magnetic resonance imaging-active nanomatryoshka (Gd2O3-NM), a multilayered (Au core/Gd2O3 shell/Au shell) sub-100 nm nanoparticle capable of combining T1 MRI contrast with PTT. This bifunctional nanoparticle demonstrates an r1 of 1.28 × 108 mM-1 s-1, an MRI contrast enhancement per nanoparticle sufficient for T1 imaging in addition to tumor ablation. Gd2O3-NM also shows excellent stability in an acidic environment, retaining 99% of the internal Gd(3). This report details the synthesis and characterization of …

Automation Of Radiation Treatment Planning For Rectal Cancer, Kai Huang, Prajnan Das, Adenike M Olanrewaju, Carlos Cardenas, David Fuentes, Lifei Zhang, Donald Hancock, Hannah Simonds, Dong Joo Rhee, Sam Beddar, Tina M Briere, Laurence Court

Faculty, Staff and Student Publications

PURPOSE: To develop an automated workflow for rectal cancer three-dimensional conformal radiotherapy (3DCRT) treatment planning that combines deep learning (DL) aperture predictions and forward-planning algorithms.

METHODS: We designed an algorithm to automate the clinical workflow for 3DCRT planning with field aperture creations and field-in-field (FIF) planning. DL models (DeepLabV3+ architecture) were trained, validated, and tested on 555 patients to automatically generate aperture shapes for primary (posterior-anterior [PA] and opposed laterals) and boost fields. Network inputs were digitally reconstructed radiographs, gross tumor volume (GTV), and nodal GTV. A physician scored each aperture for 20 patients on a 5-point scale (>3 …

Fusobacterium Is Enriched In Oral Cancer And Promotes Induction Of Programmed Death-Ligand 1 (Pd-L1), Chieko Michikawa, Vancheswaran Gopalakrishnan, Amani M Harrandah, Tatiana V Karpinets, Rekha Rani Garg, Randy A Chu, Yuk Pheel Park, Sasanka S Chukkapallia, Nikhita Yadlapalli, Kelly C Erikson-Carter, Frederico Omar Gleber-Netto, Elias Sayour, Ann Progulske-Fox, Edward K L Chan, Xiaogang Wu, Jianhua Zhang, Christian Jobin, Jennifer A Wargo, Curtis R Pickering, Jeffrey N Myers, Natalie Silver

Faculty, Staff and Student Publications

Recently, increased number of studies have demonstrated a relationship between the oral microbiome and development of head and neck cancer, however, there are few studies to investigate the role of oral bacteria in the context of the tumor microenvironment in a single head and neck subsite. Here, paired tumor and adjacent normal tissues from thirty-seven oral tongue squamous cell carcinoma (SCC) patients were subjected to 16S rRNA gene sequencing and whole exome sequencing (WES), in addition to RNA sequencing for tumor samples. We observed that Fusobacterium was significantly enriched in oral tongue cancer and that Rothia and Streptococcus were enriched …

Spatially Restricted Drivers And Transitional Cell Populations Cooperate With The Microenvironment In Untreated And Chemo-Resistant Pancreatic Cancer, Daniel Cui Zhou, Reyka G Jayasinghe, Siqi Chen, John M Herndon, Michael D Iglesia, Pooja Navale, Michael C Wendl, Wagma Caravan, Kazuhito Sato, Erik Storrs, Chia-Kuei Mo, Jingxian Liu, Austin N Southard-Smith, Yige Wu, Nataly Naser Al Deen, John M Baer, Robert S Fulton, Matthew A Wyczalkowski, Ruiyang Liu, Catrina C Fronick, Lucinda A Fulton, Andrew Shinkle, Lisa Thammavong, Houxiang Zhu, Hua Sun, Liang-Bo Wang, Yize Li, Chong Zuo, Joshua F Mcmichael, Sherri R Davies, Elizabeth L Appelbaum, Keenan J Robbins, Sara E Chasnoff, Xiaolu Yang, Ashley N Reeb, Clara Oh, Mamatha Serasanambati, Preet Lal, Rajees Varghese, Jay R Mashl, Jennifer Ponce, Nadezhda V Terekhanova, Lijun Yao, Fang Wang, Lijun Chen, Michael Schnaubelt, Rita Jui-Hsien Lu, Julie K Schwarz, Sidharth V Puram, Albert H Kim, Sheng-Kwei Song, Kooresh I Shoghi, Ken S Lau, Tao Ju, Ken Chen, Deyali Chatterjee, William G Hawkins, Hui Zhang, Samuel Achilefu, Milan G Chheda, Stephen T Oh, William E Gillanders, Feng Chen, David G Denardo, Ryan C Fields, Li Ding

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma is a lethal disease with limited treatment options and poor survival. We studied 83 spatial samples from 31 patients (11 treatment-naïve and 20 treated) using single-cell/nucleus RNA sequencing, bulk-proteogenomics, spatial transcriptomics and cellular imaging. Subpopulations of tumor cells exhibited signatures of proliferation, KRAS signaling, cell stress and epithelial-to-mesenchymal transition. Mapping mutations and copy number events distinguished tumor populations from normal and transitional cells, including acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasia. Pathology-assisted deconvolution of spatial transcriptomic data identified tumor and transitional subpopulations with distinct histological features. We showed coordinated expression of TIGIT in exhausted and regulatory T cells …

Repurposing Epigenetic Inhibitors To Target The Clostridioides Difficile-Specific Dna Adenine Methyltransferase And Sporulation Regulator Cama, Jujun Zhou, John R Horton, Dan Yu, Ren Ren, Robert M Blumenthal, Xing Zhang, Xiaodong Cheng

Faculty, Staff and Student Publications

Epigenetically targeted therapeutic development, particularly for SAM-dependent methylations of DNA, mRNA and histones has been proceeding rapidly for cancer treatments over the past few years. However, this approach has barely begun to be exploited for developing new antibiotics, despite an overwhelming global need to counter antimicrobial resistance. Here, we explore whether SAM analogues, some of which are in (pre)clinical studies as inhibitors of human epigenetic enzymes, can also inhibit Clostridioides difficile-specific DNA adenine methyltransferase (CamA), a sporulation regulator present in all C. difficile genomes sequenced to date, but found in almost no other bacteria. We found that SGC0946 (an …

Hic2 Controls Developmental Hemoglobin Switching By Repressing Bcl11a Transcription, Peng Huang, Scott A Peslak, Ren Ren, Eugene Khandros, Kunhua Qin, Cheryl A Keller, Belinda Giardine, Henry W Bell, Xianjiang Lan, Malini Sharma, John R Horton, Osheiza Abdulmalik, Stella T Chou, Junwei Shi, Merlin Crossley, Ross C Hardison, Xiaodong Cheng, Gerd A Blobel

Faculty, Staff and Student Publications

The fetal-to-adult switch in hemoglobin production is a model of developmental gene control with relevance to the treatment of hemoglobinopathies. The expression of transcription factor BCL11A, which represses fetal β-type globin (HBG) genes in adult erythroid cells, is predominantly controlled at the transcriptional level but the underlying mechanism is unclear. We identify HIC2 as a repressor of BCL11A transcription. HIC2 and BCL11A are reciprocally expressed during development. Forced expression of HIC2 in adult erythroid cells inhibits BCL11A transcription and induces HBG expression. HIC2 binds to erythroid BCL11A enhancers to reduce chromatin accessibility and binding of transcription factor GATA1, …

Clinical Acceptability Of Fully Automated External Beam Radiotherapy For Cervical Cancer With Three Different Beam Delivery Techniques, Dong Joo Rhee, Anuja Jhingran, Kai Huang, Tucker J Netherton, Nazia Fakie, Ingrid White, Alicia Sherriff, Carlos E Cardenas, Lifei Zhang, Surendra Prajapati, Stephen F Kry, Beth M Beadle, William Shaw, Frederika O'Reilly, Jeannette Parkes, Hester Burger, Chris Trauernicht, Hannah Simonds, Laurence E Court

Faculty, Staff and Student Publications

Purpose: To fully automate CT-based cervical cancer radiotherapy by automating contouring and planning for three different treatment techniques.

Methods: We automated three different radiotherapy planning techniques for locally advanced cervical cancer: 2D 4-field-box (4-field-box), 3D conformal radiotherapy (3D-CRT), and volumetric modulated arc therapy (VMAT). These auto-planning algorithms were combined with a previously developed auto-contouring system. To improve the quality of the 4-field-box and 3D-CRT plans, we used an in-house, field-in-field (FIF) automation program. Thirty-five plans were generated for each technique on CT scans from multiple institutions and evaluated by five experienced radiation oncologists from three different countries. Every plan was …

Development And Validation Of A Checklist For Use With Automatically Generated Radiotherapy Plans, Kelly A Nealon, Laurence E Court, Raphael J Douglas, Lifei Zhang, Eun Young Han

Faculty, Staff and Student Publications

Purpose: To develop a checklist that improves the rate of error detection during the plan review of automatically generated radiotherapy plans.

Methods: A custom checklist was developed using guidance from American Association of Physicists in Medicine task groups 275 and 315 and the results of a failure modes and effects analysis of the Radiation Planning Assistant (RPA), an automated contouring and treatment planning tool. The preliminary checklist contained 90 review items for each automatically generated plan. In the first study, eight physicists were recruited from our institution who were familiar with the RPA. Each physicist reviewed 10 artificial intelligence-generated resident …

Multidimensional Single-Cell Analysis Identifies A Role For Cd2-Cd58 Interactions In Clinical Antitumor T Cell Responses, Gabrielle Romain, Paolo Strati, Ali Rezvan, Mohsen Fathi, Irfan N Bandey, Jay R T Adolacion, Darren Heeke, Ivan Liadi, Mario L Marques-Piubelli, Luisa M Solis, Ankit Mahendra, Francisco Vega, Laurence Jn Cooper, Harjeet Singh, Mike Mattie, Adrian Bot, Sattva S Neelapu, Navin Varadarajan

Faculty, Staff and Student Publications

The in vivo persistence of adoptively transferred T cells is predictive of antitumor response. Identifying functional properties of infused T cells that lead to in vivo persistence and tumor eradication has remained elusive. We profiled CD19-specific chimeric antigen receptor (CAR) T cells as the infusion products used to treat large B cell lymphomas using high-throughput single-cell technologies based on time-lapse imaging microscopy in nanowell grids (TIMING), which integrates killing, cytokine secretion, and transcriptional profiling. Our results show that the directional migration of CD19-specific CAR T cells is correlated with multifunctionality. We showed that CD2 on T cells is associated with …

Targeting The Dna Damage Response Beyond Poly(Adp-Ribose) Polymerase Inhibitors: Novel Agents And Rational Combinations, Natalie Y L Ngoi, Shannon N Westin, Timothy A Yap

Faculty, Staff and Student Publications

Purpose of review: Poly(ADP-ribose) polymerase (PARP) inhibitors have transformed treatment paradigms in multiple cancer types defined by homologous recombination deficiency (HRD) and have become the archetypal example of synthetic lethal targeting within the DNA damage response (DDR). Despite this success, primary and acquired resistance to PARP inhibition inevitability threaten the efficacy and durability of response to these drugs. Beyond PARP inhibitors, recent advances in large-scale functional genomic screens have led to the identification of a steadily growing list of genetic dependencies across the DDR landscape. This has led to a wide array of novel synthetic lethal targets and corresponding inhibitors, …

The Microbiome In Gastrointestinal Cancers, Michael G White, Jennifer A Wargo

Faculty, Staff and Student Publications

The human microbiome has been recognized as increasingly important to health and disease. This is especially prescient in the development of various cancers, their progression, and the microbiome's modulation of various anticancer therapeutics. Mechanisms behind these interactions have been increasingly well described through modulation of the host immune system as well as induction of genetic changes and local inactivation of cancer therapeutics. Here, we review these associations for a variety of gastrointestinal malignancies as well as contemporary strategies proposed to leverage these associations to improve cancer treatment outcomes.

Game Of Clones: Battles In The Field Of Carcinogenesis, Zahraa Rahal, Ansam Sinjab, Ignacio I Wistuba, Humam Kadara

Faculty, Staff and Student Publications

Recent advances in bulk sequencing approaches as well as genomic decoding at the single-cell level have revealed surprisingly high somatic mutational burdens in normal tissues, as well as increased our understanding of the landscape of "field cancerization", that is, molecular and immune alterations in mutagen-exposed normal-appearing tissues that recapitulated those present in tumors. Charting the somatic mutational landscapes in normal tissues can have strong implications on our understanding of how tumors arise from mutagenized epithelium. Making sense of those mutations to understand the progression along the pathologic continuum of normal epithelia, preneoplasias, up to malignant tissues will help pave way …

Integrated Imaging And Molecular Analysis To Decipher Tumor Microenvironment In The Era Of Immunotherapy, Jia Wu, Aaron T Mayer, Ruijiang Li

Faculty, Staff and Student Publications

Radiological imaging is an integral component of cancer care, including diagnosis, staging, and treatment response monitoring. It contains rich information about tumor phenotypes that are governed not only by cancer cellintrinsic biological processes but also by the tumor microenvironment, such as the composition and function of tumor-infiltrating immune cells. By analyzing the radiological scans using a quantitative radiomics approach, robust relations between specific imaging and molecular phenotypes can be established. Indeed, a number of studies have demonstrated the feasibility of radiogenomics for predicting intrinsic molecular subtypes and gene expression signatures in breast cancer based on MRI. In parallel, promising results …

Imaging Characteristics Of 4th Ventricle Subependymoma, Ali S Haider, Tarek Y El Ahmadieh, Maryam Haider, Kimmo J Hatanpaa, Marco C Pinho, Bruce E Mickey, Raymond Sawaya, Gregory N Fuller, Donald F Schomer, Maria Gule-Monroe

Faculty, Staff and Student Publications

Purpose: Subependymomas located within the 4th ventricle are rare, and the literature describing imaging characteristics is sparse. Here, we describe the clinical and radiological characteristics of 29 patients with 4th ventricle subependymoma.

Methods: This is a retrospective multi-center study performed after Institutional Review Board (IRB) approval. Patients diagnosed with suspected 4th ventricle subependymoma were identified. A review of clinical, radiology, and pathology reports along with magnetic resonance imaging (MRI) images was performed.

Results: Twenty-nine patients, including 6 females, were identified. Eighteen patients underwent surgery with histopathological confirmation of subependymoma. The median age at diagnosis was 52 years. Median tumor volume …

The Insulin Receptor Regulates The Persistence Of Mechanical Nociceptive Sensitization In Flies And Mice, Tatiana V Karpinets, Xiaogang Wu, Travis Solley, Molly B El Alam, Travis T Sims, Kyoko Yoshida-Court, Erica Lynn, Mustapha Ahmed-Kaddar, Greyson Biegert, Jingyan Yue, Xingzhi Song, Huandong Sun, Joseph F Petrosino, Melissa P Mezzari, Pablo Okhuysen, Patricia J Eifel, Anuja Jhingran, Lilie L Lin, Kathleen M Schmeler, Lois Ramondetta, Nadim Ajami, Robert R Jenq, Andrew Futreal, Jianhua Zhang, Ann H Klopp, Lauren E Colbert

Faculty, Staff and Student Publications

Early phase diabetes is often accompanied by pain sensitization. In Drosophila, the insulin receptor (InR) regulates the persistence of injury-induced thermal nociceptive sensitization. Whether Drosophila InR also regulates the persistence of mechanical nociceptive sensitization remains unclear. Mice with a sensory neuron deletion of the insulin receptor (Insr) show normal nociceptive baselines; however, it is uncertain whether deletion of Insr in nociceptive sensory neurons leads to persistent nociceptive hypersensitivity. In this study, we used fly and mouse nociceptive sensitization models to address these questions. In flies, InR mutants and larvae with sensory neuron-specific expression of RNAi …

Efficacy And Safety Of Topical Hypericin Photodynamic Therapy For Early-Stage Cutaneous T-Cell Lymphoma (Mycosis Fungoides): The Flash Phase 3 Randomized Clinical Trial, Ellen J Kim, Aaron R Mangold, Jennifer A Desimone, Henry K Wong, Lucia Seminario-Vidal, Joan Guitart, James Appel, Larisa Geskin, Edward Lain, Neil J Korman, Nathalie Zeitouni, Neda Nikbakht, Kenneth Dawes, Oleg Akilov, Joi Carter, Michi Shinohara, Timothy M Kuzel, Warren Piette, Neal Bhatia, Amy Musiek, David Pariser, Youn H Kim, Dirk Elston, Erin Boh, Madeleine Duvic, Auris Huen, Theresa Pacheco, Jeffrey P Zwerner, Seung Tae Lee, Michael Girardi, Christiane Querfeld, Kimberly Bohjanen, Elise Olsen, Gary S Wood, Adam Rumage, Oreola Donini, Andrea Haulenbeek, Christopher J Schaber, Richard Straube, Christopher Pullion, Alain H Rook, Brian Poligone

Faculty, Staff and Student Publications

IMPORTANCE: Given that mycosis fungoides-cutaneous T-cell lymphoma (MF/CTCL) is chronic, there is a need for additional therapies with minimal short- and long-term adverse effects. Topical synthetic hypericin ointment, 0.25%, activated with visible light is a novel, nonmutagenic photodynamic therapy (PDT).

OBJECTIVES: To determine the efficacy and safety of topical synthetic hypericin ointment, 0.25%, activated with visible light as a nonmutagenic PDT in early-stage MF/CTCL.

DESIGN, SETTINGS, AND PARTICIPANTS: This was a multicenter, placebo-controlled, double-blinded, phase 3 randomized clinical trial (FLASH study) conducted from December 2015 to November 2020 at 39 academic and community-based US medical centers. Participants were adults (≥18 …

Mass Transport Model Of Radiation Response: Calibration And Application To Chemoradiation For Pancreatic Cancer, Charles X Wang, Dalia Elganainy, Mohamed M Zaid, Joseph D Butner, Anshuman Agrawal, Sara Nizzero, Bruce D Minsky, Emma B Holliday, Cullen M Taniguchi, Grace L Smith, Albert C Koong, Joseph M Herman, Prajnan Das, Anirban Maitra, Huamin Wang, Robert A Wolff, Matthew H G Katz, Christopher H Crane, Vittorio Cristini, Eugene J Koay

Faculty, Staff and Student Publications

PURPOSE: The benefit of radiation therapy for pancreatic ductal adenocarcinoma (PDAC) remains unclear. We hypothesized that a new mechanistic mathematical model of chemotherapy and radiation response could predict clinical outcomes a priori, using a previously described baseline measurement of perfusion from computed tomography scans, normalized area under the enhancement curve (nAUC).

METHODS AND MATERIALS: We simplified an existing mass transport model that predicted cancer cell death by replacing previously unknown variables with averaged direct measurements from randomly selected pathologic sections of untreated PDAC. This allowed using nAUC as the sole model input to approximate tumor perfusion. We then compared the …