Medical Specialties Commons^™

Outcomes Of Patients With Treated Secondary Acute Myeloid Leukemia: A High-Risk Subtype That Warrants An Independent Prognostic Designation, Jayastu Senapati, Hagop M Kantarjian, Fadi G Haddad, Nicholas J Short, Gautam Borthakur, Rashmi Kanagal-Shamanna, Guilin Tang, Elias Jabbour, Courtney D Dinardo, Naval Daver, Guillermo Montalban-Bravo, Vishrut Shah, Amin Alousi, Elizabeth Shpall, Uday Popat, Guillermo Garcia-Manero, Farhad Ravandi, Tapan M Kadia

Faculty, Staff and Student Publications

Patients who develop acute myeloid leukemia (AML) after having received treatment for myelodysplastic syndrome (MDS) or related conditions have particularly poor outcomes. This study analyzed adult patients with newly diagnosed AML who previously had MDS, chronic myelomonocytic leukemia (CMML), or MDS/myeloproliferative neoplasm (MPN) overlap syndrome, and who had received hypomethylating agents, chemotherapy, and/or allogeneic stem cell transplantation (HSCT) for these antecedent disorders. From January 2012 to August 2023, we included 673 patients with a median age of 70 years (range, 19-94); 536 (80%) had transformed from MDS, and the remainder from CMML or MDS-MPN. Additionally, 149 patients (22%) had prior …

Frailty And Sleep In Adult Survivors Of Childhood Cancer: A Childhood Cancer Survivor Study Report, Lauren C Daniel, Margaret M Lubas, Huiqi Wang, Mariana Szklo-Coxe, Kirsten K Ness, Annalynn M Williams, Daniel A Mulrooney, Rebecca Howell, Wendy Leisenring, Yutaka Yasui, Leslie L Robison, Gregory T Armstrong, Eric J Chow, Kevin R Krull, Tara M Brinkman

Faculty, Staff and Student Publications

Background: Young adult survivors of childhood cancer exhibit rates of frailty similar to adults several decades older without a cancer history. Frailty has been associated with sleep disturbances in non-cancer populations, but the relationship has not been examined in childhood cancer survivors who are known to exhibit elevated rates of sleep problems.

Aims: Examine associations between frailty and poor sleep quality in long-term survivors of childhood cancer.

Methods: This study utilized data from 9044 participants (> 5 years from diagnosis, Mage = 40.8 years [SD = 9.5]) in the Childhood Cancer Survivor Study. Survivors' frailty status, chronic health conditions (CHC), …

Mutational And Co-Mutational Landscape Of Early Onset Colorectal Cancer, Jumanah Yousef Alshenaifi, Guglielmo Vetere, Giulia Maddalena, Mahmoud Yousef, Michael G White, John Paul Shen, Eduardo Vilar, Christine Parseghian, Arvind Dasari, Van Karlyle Morris, Ryan Huey, Michael J Overman, Robert Wolff, Kanwal P Raghav, Jason Willis, Kristin Alfaro, Andy Futreal, Y Nancy You, Scott Kopetz

Faculty, Staff and Student Publications

Introduction: Colorectal cancer (CRC) incidence and mortality before 50 have been rising alarmingly in the recent decades.

Methods: Using a cohort of 10,000 patients, this study investigates the clinical, mutational, and co-mutational features of CRC in early-onset (EOCRC, < 50 years) compared to late-onset (LOCRC, ≥ 50 years).

Results: EOCRC was associated with a higher prevalence of Asian and Hispanic patients, rectal or left-sided tumors (72% vs. 59%), and advanced-stage disease. Molecular analyses revealed differences in mutation patterns, with EOCRC having higher frequencies of TP53 (74% vs. 68%, p < 0.01) and SMAD4 (17% vs. 14%, p = 0.015), while BRAF (5% vs. 11%, p < 0.001) and NOTCH1 (2.7% vs. 4.1%, p = 0.01) mutations …

Rapid Whole Genome Sequencing Uncovers A Triple Diagnosis: X-Linked Chondrodysplasia Punctata, Mecp2-Related Disorder, And Mosaic Jacobs Syndrome, Megan Samuels, Kathleen Shields, Paul Hillman, Laura Farach

Faculty, Staff and Student Publications

Background: Rapid Whole Genome Sequencing (rWGS) is increasingly being used in neonatal intensive care units, as there is growing evidence that rare singe gene disorders present in the neonatal period and early identification can change management. While the diagnostic utility is increased with this broad testing, the possibility of unexpected findings also increases significantly. Here, we present a patient found to have three distinct genetic conditions through rWGS testing, with significant psychosocial and health consequences.

Methods and results: This case report describes a patient who was identified with a form of chondrodysplasia punctata, as well as incidental findings of MECP2-related …

Association Of Serum Endocannabinoid Levels With Pancreatitis And Pancreatitis-Related Pain, Marc T Goodman, Christina Lombardi, Alexa Torrens, Catherine Bresee, Jami L Saloman, Liang Li, Yunlong Yang, William E Fisher, Evan L Fogel, Christopher E Forsmark, Darwin L Conwell, Phil A Hart, Walter G Park, Mark Topazian, Santhi S Vege, Stephen K Van Den Eeden, Melena D Bellin, Dana K Andersen, Jose Serrano, Dhiraj Yadav, Stephen J Pandol, Daniele Piomelli

Faculty, Staff and Student Publications

No abstract provided.

Preclinical And Clinical-Scale Magnetic Particle Imaging Of Natural Killer Cells: In Vitro And Ex Vivo Demonstration Of Cellular Sensitivity, Resolution, And Quantification, Olivia C Sehl, Yanwen Yang, Ariana R Anjier, Dmitry Nevozhay, Donghang Cheng, Kelvin Guo, Benjamin Fellows, Abdul Rahman Mohtasebzadeh, Erica E Mason, Toby Sanders, Petrina Kim, David Trease, Dimpy Koul, Patrick W Goodwill, Konstantin Sokolov, Max Wintermark, Nancy Gordon, Joan M Greve, Vidya Gopalakrishnan

Faculty, Staff and Student Publications

Purpose: Clinical adoption of NK cell immunotherapy is underway for medulloblastoma and osteosarcoma, however there is currently little feedback on cell fate after administration. We propose magnetic particle imaging (MPI) may have applications for the quantitative detection of NK cells.

Procedures: Human-derived NK-92 cells were labeled by co-incubation with iron oxide nanoparticles (VivoTrax™) for 24 h then excess nanoparticles were washed with centrifugation. Cytolytic activity of labeled versus unlabeled NK-92 cells was assessed after 4 h of co-incubation with medulloblastoma cells (DAOY) or osteosarcoma cells (LM7 or OS17). Labeled NK-92 cells at two different doses (0.5 or 1 × 106) …

Toward A Biological Definition Of Neuronal And Glial Synucleinopathies, Claudio Soto, Brit Mollenhauer, Oskar Hansson, Un Jung Kang, Roy N Alcalay, David Standaert, Claudia Trenkwalder, Kenneth Marek, Douglas Galasko, Kathleen Poston

Faculty, Staff and Student Publications

Cerebral accumulation of alpha-synuclein (αSyn) aggregates is the hallmark event in a group of neurodegenerative diseases-collectively called synucleinopathies-which include Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Currently, these are diagnosed by their clinical symptoms and definitively confirmed postmortem by the presence of αSyn deposits in the brain. Here, we summarize the drawbacks of the current clinical definition of synucleinopathies and outline the rationale for moving toward an earlier, biology-anchored definition of these disorders, with or without the presence of clinical symptoms. We underscore the utility of the αSyn seed amplification assay to detect aggregated αSyn in living …

Refining Diagnostic Subtypes Of Peripheral T-Cell Lymphoma Using A Multiparameter Approach, Catalina Amador, Dennis D Weisenburger, Ana Gomez, Alyssa Bouska, Ahmad Alshomrani, Sunandini Sharma, Ab Rauf Shah, Timothy C Greiner, Francisco Vega, Andreas Rosenwald, German Ott, Andrew L Feldman, Elaine S Jaffe, Neval Ozkaya, Sarah L Ondrejka, James R Cook, Philipp W Raess, Kerry J Savage, Graham W Slack, Joo Y Song, David W Scott, Elias Campo, Lisa M Rimsza, Joseph D Khoury, Louis M Staudt, Wing C Chan, Javeed Iqbal

Faculty, Staff and Student Publications

Peripheral T-cell lymphoma (PTCL) is a heterogeneous category, and many cases are unclassifiable and designated as PTCL-not otherwise specified (PTCL-NOS). Gene expression profiling (GEP) has delineated two prognostic subtypes within PTCL-NOS, PTCL-TBX21, and PTCL-GATA3, characterized by distinctive transcriptomes and a different prognosis. To further evaluate the pathologic features of these subgroups, 101 PTCL cases that did not meet specific criteria for well-defined T-cell lymphoma entities underwent detailed pathologic, immunophenotypic (including TFH biomarkers) and GEP analyses, separating them into PTCL-NOS (n=63) and PTCL-TFH (a.k.a. nodal PTCL-TFH, NOS, and TFH lymphoma, NOS) (n=38). PTCL-NOS cases were further categorized into PTCL-GATA3 (n=22; 34%) …

Performance Comparison Of 10 State-Of-The-Art Machine Learning Algorithms For Outcome Prediction Modeling Of Radiation-Induced Toxicity, Ramon M Salazar, Saurabh S Nair, Alexandra O Leone, Ting Xu, Raymond P Mumme, Jack D Duryea, Brian De, Kelsey L Corrigan, Michael K Rooney, Matthew S Ning, Prajnan Das, Emma B Holliday, Zhongxing Liao, Laurence E Court, Joshua S Niedzielski

Faculty, Staff and Student Publications

Purpose: To evaluate the efficacy of prominent machine learning algorithms in predicting normal tissue complication probability using clinical data obtained from 2 distinct disease sites and to create a software tool that facilitates the automatic determination of the optimal algorithm to model any given labeled data set.

Methods and materials: We obtained 3 sets of radiation toxicity data (478 patients) from our clinic: gastrointestinal toxicity, radiation pneumonitis, and radiation esophagitis. These data comprised clinicopathological and dosimetric information for patients diagnosed with non-small cell lung cancer and anal squamous cell carcinoma. Each data set was modeled using 11 commonly employed machine …

Forecasting Intraoperative Hypotension During Hepatobiliary Surgery, Juan P Cata, Bhavin Soni, Shreyas Bhavsar, Parvathy Sudhir Pillai, Tatiana A Rypinski, Anshuj Deva, Jeffrey H Siewerdsen, Jose M Soliz

Faculty, Staff and Student Publications

Prediction and avoidance of intraoperative hypotension (IOH) can lead to less postoperative morbidity. Machine learning (ML) is increasingly being applied to predict IOH. We hypothesize that incorporating demographic and physiological features in an ML model will improve the performance of IOH prediction. In addition, we added a "dial" feature to alter prediction performance. An ML prediction model was built based on a multivariate random forest (RF) trained algorithm using 13 physiologic time series and patient demographic data (age, sex, and BMI) for adult patients undergoing hepatobiliary surgery. A novel implementation was developed with an adjustable, multi-model voting (MMV) approach to …

Status Of Abortion Curriculum In Genetic Counseling: Survey Of Graduate Programs And Recent Graduates In The United States, Gina Sanchez, S Shahrukh Hashmi, Erica Bednar, Sarah Horvath, Bhavik Kumar, Katelynn Sagaser, Claire N Singletary, Aarti Ramdaney

Faculty, Staff and Student Publications

Genetic counselors (GCs) are trained to help individuals navigate the medical and psychological implications of genetic test results, familial conditions, and ultrasound anomalies. Therefore, familiarity with reproductive options, including abortion, is vital. However, previous studies have found gaps in GCs' knowledge regarding abortion care and there are currently no recommendations regarding abortion curriculum. This study aimed to assess the state of abortion curriculum in genetic counseling graduate programs in the United States and to examine and compare the satisfaction levels of program representatives and recent graduates. Program representatives and recent graduates were invited to complete an anonymous survey evaluating the …

A Statistical Framework For Multi-Trait Rare Variant Analysis In Large-Scale Whole-Genome Sequencing Studies, Xihao Li, Han Chen, Margaret Sunitha Selvaraj, Eric Van Buren, Hufeng Zhou, Yuxuan Wang, Ryan Sun, Zachary R Mccaw, Zhi Yu, Min-Zhi Jiang, Daniel Dicorpo, Sheila M Gaynor, Rounak Dey, Donna K Arnett, Emelia J Benjamin, Joshua C Bis, John Blangero, Eric Boerwinkle, Donald W Bowden, Jennifer A Brody, Brian E Cade, April P Carson, Jenna C Carlson, Nathalie Chami, Yii-Der Ida Chen, Joanne E Curran, Paul S De Vries, Myriam Fornage, Nora Franceschini, Barry I Freedman, Charles Gu, Nancy L Heard-Costa, Jiang He, Lifang Hou, Yi-Jen Hung, Marguerite R Irvin, Robert C Kaplan, Sharon L R Kardia, Tanika N Kelly, Iain Konigsberg, Charles Kooperberg, Brian G Kral, Changwei Li, Yun Li, Honghuang Lin, Ching-Ti Liu, Ruth J F Loos, Michael C Mahaney, Lisa W Martin, Rasika A Mathias, Braxton D Mitchell, May E Montasser, Alanna C Morrison, Take Naseri, Kari E North, Nicholette D Palmer, Patricia A Peyser, Bruce M Psaty, Susan Redline, Alexander P Reiner, Stephen S Rich, Colleen M Sitlani, Jennifer A Smith, Kent D Taylor, Hemant K Tiwari, Ramachandran S Vasan, Satupa'itea Viali, Zhe Wang, Jennifer Wessel, Lisa R Yanek, Bing Yu, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Josée Dupuis, James B Meigs, Paul L Auer, Laura M Raffield, Alisa K Manning, Kenneth M Rice, Jerome I Rotter, Gina M Peloso, Pradeep Natarajan, Zilin Li, Zhonghua Liu, Xihong Lin

Faculty, Staff and Student Publications

Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally scalable analytical pipeline for functionally informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple …

Unprecedented Female Mutation Bias In The Aye-Aye, A Highly Unusual Lemur From Madagascar, Richard J Wang, Yadira Peña-García, Muthuswamy Raveendran, R Alan Harris, Thuy-Trang Nguyen, Marie-Claude Gingras, Yifan Wu, Lesette Perez, Anne D Yoder, Joe H Simmons, Jeffrey Rogers, Matthew W Hahn

Faculty, Staff and Students Publications

Every mammal studied to date has been found to have a male mutation bias: male parents transmit more de novo mutations to offspring than female parents, contributing increasingly more mutations with age. Although male-biased mutation has been studied for more than 75 years, its causes are still debated. One obstacle to understanding this pattern is its near universality-without variation in mutation bias, it is difficult to find an underlying cause. Here, we present new data on multiple pedigrees from two primate species: aye-ayes (Daubentonia madagascariensis), a member of the strepsirrhine primates, and olive baboons (Papio anubis). In stark contrast to …

Historical Demography And Species Distribution Models Shed Light On Speciation In Primates Of Northeast India, Mihir Trivedi, Kunal Arekar, Shivakumara Manu, Lukas F K Kuderna, Jeffrey Rogers, Kyle Kai-How Farh, Tomas Marques Bonet, Govindhaswamy Umapathy

Faculty, Staff and Students Publications

Past climate change is one of the important factors influencing primate speciation. Populations of various species could have risen or declined in response to these climatic fluctuations. Northeast India harbors a rich diversity of primates, where such fluctuations can be implicated. Recent advances in climate modeling as well as genomic data analysis has paved the way for understanding how species accumulate at a particular geographic region. We utilized these methods to explore the primate diversity in this unique region in relation to past climate change. To ascertain the population level changes, we inferred the demographic history of nine species of …

Exome Sequencing In Asian Populations Identifies Low-Frequency And Rare Coding Variation Influencing Parkinson’S Disease Risk, Elaine Gy Chew, Zhehao Liu, Zheng Li, Sun Ju Chung, Michelle M Lian, Moses Tandiono, Yue Jing Heng, Ebonne Y Ng, Louis Cs Tan, Wee Ling Chng, Tiak Ju Tan, Esther Kl Peh, Ying Swan Ho, Xiao Yin Chen, Erin Yt Lim, Chu Hua Chang, Jonavan J Leong, Ting Xuan Peh, Ling Ling Chan, Yinxia Chao, Wing-Lok Au, Kumar M Prakash, Jia Lun Lim, Yi Wen Tay, Vincent Mok, Anne Yy Chan, Juei-Jueng Lin, Beom S Jeon, Kyuyoung Song, Clement C Tham, Chi Pui Pang, Jeeyun Ahn, Kyu Hyung Park, Janey L Wiggs, Tin Aung, Ai Huey Tan, Azlina Ahmad Annuar, Mary B Makarious, Cornelis Blauwendraat, Mike A Nalls, Laurie A Robak, Roy N Alcalay, Ziv Gan-Or, Richard Reynolds, Shen-Yang Lim, Yun Xia, Chiea Chuen Khor, Eng-King Tan, Zhenxun Wang, Jia Nee Foo

Faculty, Staff and Students Publications

Parkinson’s disease (PD) is an incurable, progressive and common movement disorder that is increasing in incidence globally because of population aging. We hypothesized that the landscape of rare, protein-altering variants could provide further insights into disease pathogenesis. Here we performed whole-exome sequencing followed by gene-based tests on 4,298 PD cases and 5,512 controls of Asian ancestry. We showed that GBA1 and SMPD1 were significantly associated with PD risk, with replication in a further 5,585 PD cases and 5,642 controls. We further refined variant classification using in vitro assays and showed that SMPD1 variants with reduced enzymatic activity display the strongest …

Enhancing Immunotherapy Efficacy With Synergistic Low-Dose Radiation In Metastatic Melanoma: Current Insights And Prospects, Zahid Rafiq, Mingyo Kang, Hampartsoum B Barsoumian, Gohar S Manzar, Yun Hu, Carola Leuschner, Ailing Huang, Fatemeh Masrorpour, Weiqin Lu, Nahum Puebla-Osorio, James W Welsh

Faculty, Staff and Student Publications

Recent advances in oncology research have highlighted the promising synergy between low-dose radiation therapy (LDRT) and immunotherapies, with growing evidence highlighting the unique benefits of the combination. LDRT has emerged as a potent tool for stimulating the immune system, triggering systemic antitumor effects by remodeling the tumor microenvironment. Notably, LDRT demonstrates remarkable efficacy even in challenging metastatic sites such as the liver (uveal) and brain (cutaneous), particularly in advanced melanoma stages. The increasing interest in utilizing LDRT for secondary metastatic sites of uveal, mucosal, or cutaneous melanomas underscores its potential efficacy in combination with various immunotherapies. This comprehensive review traverses …

Genetic Ancestry Concordant Rna Splicing In Prostate Cancer Involves Oncogenic Genes And Associates With Recurrence, Muthana Al Abo, Wen-Chi Foo, Lauren Howard, Shannon Mcgue, Bonnie Lacroix, Julie Kephart, Angela Clayton, Blair Thornburg, Monika Anand, Michael Rothberg, Shannon Mccall, Jiaoti Huang, Thomas Esther, Judd Moul, Michael Ferrandino, Thomas Polascik, Cary Robertson, Brant Inman, Andrew Armstrong, Yuan Wu, Terry Hyslop, Daniel George, Steven Patierno, Jennifer Freedman

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Black men suffer disproportionately from prostate cancer (PCa) compared to men of other races and ethnicities. Comparing the molecular landscape of PCa among Black and White patients has the potential to identify targets for development of new precision medicine interventions. Herein, we conducted transcriptomic analysis of prostate tumors and paired tumor-adjacent normals from self-reported Black and White PCa patients and estimated patient genetic ancestry. Clinical follow-up revealed increased biochemical recurrence (BCR) among Black patients compared to White patients with high-grade PCa. Transcriptomic analysis identified differential alternative RNA splicing events (ARSs) between Black and White PCa patients. Genes undergoing genetic ancestry-concordant …

Diverse Roles Of Antibodies In Antibody-Drug Conjugates, Aiko Yamaguchi, H Charles Manning

Faculty, Staff and Student Publications

The emergence of antibody-drug conjugates (ADCs) has transformed the treatment landscape of a variety of cancers. ADCs typically consist of three main components: monoclonal antibody, chemical linker, and cytotoxic payload. These integrated therapeutic modalities harness the benefits of each component to provide a therapeutic response that cannot be achieved by conventional chemotherapy. Antibodies play roles in determining tumor specificity through target-mediated uptake, prolonging the circulation half-life of cytotoxic payloads, and providing additional mechanisms of action inherent to the original antibody, thus significantly contributing to the overall performance of ADCs. However, ADCs have unique safety concerns, such as drug-induced adverse events …

A Morphometric Signature To Identify Ductal Carcinoma In Situ With A Low Risk Of Progression, Marcelo Sobral-Leite, Simon P Castillo, Shiva Vonk, Hendrik A Messal, Xenia Melillo, Noomie Lam, Brandi De Bruijn, Yeman B Hagos, Myrna Van Den Bos, Joyce Sanders, Mathilde Almekinders, Lindy L Visser, Emma J Groen, Petra Kristel, Caner Ercan, Leyla Azarang, Jacco Van Rheenen, E Shelley Hwang, Yinyin Yuan, Renee Menezes, Esther H Lips, Jelle Wesseling

Faculty, Staff and Student Publications

Ductal carcinoma in situ (DCIS) may progress to ipsilateral invasive breast cancer (iIBC), but often never will. Because DCIS is treated as early breast cancer, many women with harmless DCIS face overtreatment. To identify features associated with progression, we developed an artificial intelligence-based DCIS morphometric analysis pipeline (AIDmap) on hematoxylin-eosin-stained (H&E) tissue sections. We analyzed 689 digitized H&Es of pure primary DCIS of which 226 were diagnosed with subsequent iIBC and 463 were not. The distribution of 15 duct morphological measurements was summarized in 55 morphometric variables. A ridge regression classifier with cross validation predicted 5-years-free of iIBC with an …

Optimal Size And Peg Coating Of Gold Nanoparticles For Prolonged Blood Circulation: A Statistical Analysis Of Published Data, Dmitry Nevozhay, Ronald Rauch, Zhongya Wang, Konstantin V Sokolov

Faculty, Staff and Student Publications

This study presents a statistical analysis of how gold nanoparticle (GNP) size and polyethylene glycol (PEG) coating molecular weight (MW) affect the circulation of nanoparticles in blood. We showed a non-linear relationship with interaction between GNP size and PEG MW. The findings revealed a threshold effect, and recommendations for GNP coating are discussed.

Trmt1l-Catalyzed M22g27 On Tyrosine Trna Is Required For Efficient Mrna Translation And Cell Survival Under Oxidative Stress, Sseu-Pei Hwang, Han Liao, Katherine Barondeau, Xinyi Han, Cassandra Herbert, Hunter Mcconie, Amirtha Shekar, Dimitri G Pestov, Patrick A Limbach, Jeffrey T Chang, Catherine Denicourt

Faculty, Staff and Student Publications

tRNA modifications are critical for several aspects of their functions, including decoding, folding, and stability. Using a multifaceted approach encompassing eCLIP-seq and nanopore tRNA-seq, we show that the human tRNA methyltransferase TRMT1L interacts with the component of the Rix1 ribosome biogenesis complex and binds to the 28S rRNA as well as to a subset of tRNAs. Mechanistically, we demonstrate that TRMT1L is responsible for catalyzing N2,N2-dimethylguanosine (m22G) solely at position 27 of tRNA-Tyr-GUA. Surprisingly, TRMT1L depletion also impaired the deposition of 3-(3-amino-3-carboxypropyl) uridine (acp3U) and dihydrouridine on tRNA-Tyr-GUA, Cys-GCA, and Ala-CGC. TRMT1L knockout cells have a marked decrease in tRNA-Tyr-GUA …

Overcoming Cd226-Related Immune Evasion In Acute Myeloid Leukemia With Cd38 Car-Engineered Nk Cells, Luciana Melo Garcia, Achintyan Gangadharan, Pinaki Banerjee, Ye Li, Andy G X Zeng, Hind Rafei, Paul Lin, Bijender Kumar, Sunil Acharya, May Daher, Luis Muniz-Feliciano, Gary M Deyter, Gabriel Dominguez, Jeong Min Park, Francia Reyes Silva, Ana Karen Nunez Cortes, Rafet Basar, Nadima Uprety, Mayra Shanley, Mecit Kaplan, Enli Liu, Elizabeth J Shpall, Katayoun Rezvani

Faculty, Staff and Student Publications

CD226 plays a vital role in natural killer (NK) cell cytotoxicity, interacting with its ligands CD112 and CD155 to initiate immune synapse formation, primarily through leukocyte function-associated-1 (LFA-1). Our study examined the role of CD226 in NK cell surveillance of acute myeloid leukemia (AML). NK cells in patients with AML had lower expression of CD226. CRISPR-Cas9 deletion of CD226 led to reduced LFA-1 recruitment, poor synapse formation, and decreased NK cell anti-leukemic activity. Engineering NK cells to express a chimeric antigen receptor targeting the AML antigen CD38 (CAR38) could overcome the need for CD226 to establish strong immune synapses. LFA-1 …

The Golgi Complex Governs Natural Killer Cell Lytic Granule Positioning To Promote Directionality In Cytotoxicity, Luis A Pedroza, Frederique Van Den Haak, Alexander Frumovitz, Evelyn Hernandez, Everardo Hegewisch-Solloa, Tabitha K Orange, Keri B Sheehan, Susan Prockop, Aaron Bodansky, Ivan K Chinn, James R Lupski, Jennifer E Posey, Emily M Mace, Yu Li, Jordan S Orange

Faculty, Staff and Students Publications

Cytotoxic immune cells mediate precise attacks against diseased cells to maintain organismal health. Their operational unit of killing and host defense is lytic granules (LGs), which are specialized lysosomal-related organelles. Precision in cytotoxicity is achieved by converging the many LGs to the microtubule-organizing center (MTOC) and polarizing these to the diseased cell for secretion. We identify unappreciated intimate relationships between the Golgi, MTOC, and LGs after cytotoxic cell activation, as well as the trans-Golgin protein GCC2 on the LG surface. GCC2 serves to tether LGs to the Golgi following convergence, and both GCC2 and the Golgi are required for the …

Chemotherapy In Synergy With Innate Immune Agonists Enhances T Cell Priming For Checkpoint Inhibitor Treatment In Pancreatic Cancer, Nan Niu, Keyu Li, Junke Wang, Vanessa Funes, Birginia Espinoza, Pan Li, Jianxin Wang, Melissa Lyman, Mengni He, Brian Herbst, Michael Wichroski, Ruslan Novosiadly, Sami Shoucair, Yiping Mou, Lei Zheng

Faculty, Staff and Student Publications

Background: The combination of conventional chemotherapy and immune checkpoint inhibitors (ICIs) has been unsuccessful for pancreatic ductal adenocarcinoma (PDAC). Administration of maximum tolerated dose of chemotherapy drugs may have immunosuppressive effects.

Methods: We thus tested, by using the preclinical model of PDACs including the genetically engineered mouse KPC spontaneous pancreatic tumor model and the pancreatic KPC tumor orthotopic implant model, the combinations of synthetic innate immune agonists including STING and NLRP3 agonist, respectively, and ICIs with or without chemotherapy.

Results: We found that innate agonists potentiate the role of chemotherapy in inducing effector T cells and subsequently to prime the …

Tfap2e Is Implicated In Central Nervous System, Orofacial And Maxillofacial Anomalies, Jeshurun C Kalanithy, Enrico Mingardo, Jil D Stegmann, Ramgopal Dhakar, Tikam Chand Dakal, Jill A Rosenfeld, Wen-Hann Tan, Stephanie A Coury, Audrey C Woerner, Jessica Sebastian, Paul A Levy, Leah R Fleming, Lea Waffenschmidt, Tobias T Lindenberg, Öznur Yilmaz, Khadija Channab, Bimaljeet K Babra, Andrea Christ, Britta Eiberger, Selina Hölzel, Clara Vidic, Felix Häberlein, Nina Ishorst, Juan E Rodriguez-Gatica, Behnaz Pezeshkpoor, Patrick A Kupczyk, Olivier M Vanakker, Sara Loddo, Antonio Novelli, Maria L Dentici, Albert Becker, Holger Thiele, Jennifer E Posey, James R Lupski, Alina C Hilger, Heiko M Reutter, Waltraut M Merz, Gabriel C Dworschak, Benjamin Odermatt

Faculty, Staff and Students Publications

Background: Previous studies in mouse, Xenopus and zebrafish embryos show strong tfap2e expression in progenitor cells of neuronal and neural crest tissues suggesting its involvement in neural crest specification. However, the role of human transcription factor activator protein 2 (TFAP2E) in human embryonic central nervous system (CNS), orofacial and maxillofacial development is unknown.

Methods: Through a collaborative work, exome survey was performed in families with congenital CNS, orofacial and maxillofacial anomalies. Exome variant prioritisation prompted TFAP2E gene for functional analysis in zebrafish embryos. Embryonic morphology and development were assessed after antisense morpholino (MO) knockdown (KD), CRISPR/Cas9 knockout and overexpression …

Phase I Trial Of Hydroxychloroquine To Enhance Palbociclib And Letrozole Efficacy In Er+/Her2- Breast Cancer, Akshara Singareeka Raghavendra, Nicole M Kettner, Danielle Kwiatkowski, Senthil Damodaran, Yan Wang, David Ramirez, Dan S Gombos, Kelly K Hunt, Yu Shen, Khandan Keyomarsi, Debu Tripathy

Faculty, Staff and Student Publications

Endocrine therapy with CDK4/6 inhibitors is standard for estrogen receptor-positive, HER2-negative metastatic breast cancer (ER+/HER2- MBC), yet clinical resistance develops. Previously, we demonstrated that low doses of palbociclib activate autophagy, reversing initial G1 cell cycle arrest, while high concentrations induce off-target senescence. The autophagy inhibitor hydroxychloroquine (HCQ) induced on-target senescence at lower palbociclib doses. We conducted a phase I trial (NCT03774472 registered in ClinicalTrials.gov on 8/20/2018) of HCQ (400, 600, 800 mg/day) with palbociclib (75 mg/day continuous) and letrozole, using a 3 + 3 design. Primary objectives included safety, tolerability, and determining the recommended phase 2 dose (RP2D) of HCQ. …

Statistical Identification Of Cell Type-Specific Spatially Variable Genes In Spatial Transcriptomics, Lulu Shang, Peijun Wu, Xiang Zhou

Faculty, Staff and Student Publications

An essential task in spatial transcriptomics is identifying spatially variable genes (SVGs). Here, we present Celina, a statistical method for systematically detecting cell type-specific SVGs (ct-SVGs)-a subset of SVGs exhibiting distinct spatial expression patterns within specific cell types. Celina utilizes a spatially varying coefficient model to accurately capture each gene's spatial expression pattern in relation to the distribution of cell types across tissue locations, ensuring effective type I error control and high power. Celina proves powerful compared to existing methods in single-cell resolution spatial transcriptomics and stands as the only effective solution for spot-resolution spatial transcriptomics. Applied to five real …

Urine Proteomics Defines An Immune Checkpoint-Associated Nephritis Signature, James P Long, Shailbala Singh, Yanlan Dong, Cassian Yee, Jamie S Lin

Faculty, Staff and Student Publications

Immune checkpoint inhibitor (ICI) therapy is a cornerstone treatment for many cancers, but it can induce severe immunotoxicity, including acute interstitial nephritis (AIN). Currently, kidney biopsy is required to differentiate ICI-AIN from other causes of acute kidney injury (AKI). However, this invasive approach can lead to morbidity, delayed glucocorticoid treatment for patients with AIN, and unnecessarily prolonged suspension of ICI therapy in non-AIN patients. Delayed or incorrect diagnosis of ICI-AIN is particularly detrimental, as over 50% of patients are at risk of permanent renal damage. Thus, there is an urgent need for non-invasive biomarkers that can rapidly and accurately distinguish …

Joint Fluid Multi-Omics Improves Diagnostic Confidence During Evaluation Of Children With Presumed Septic Arthritis, Yolanda Peña-López, Naureen G Tareen, Bo Zhang, Indu Raman, Carlos A Arana, Chengsong Zhu, Yang Liu, Pratibha Selvakumar, Nicolai S C Van Oers, Simrat Morris, Lora V Hooper, Lawson A B Copley, Prithvi Raj

Faculty, Staff and Student Publications

Background: An accurate diagnosis of septic versus reactive or autoimmune arthritis remains clinically challenging. A multi-omics strategy comprising metagenomic and proteomic technologies were undertaken for children diagnosed with presumed septic arthritis to advance clinical diagnoses and care for affected individuals.

Methods: Twelve children with suspected septic arthritis were prospectively enrolled to compare standard of care tests with a rapid multi-omics approach. The multi-omics combined bacterial 16S rRNA metagenomics, single cell transcriptomics, and proteomics on knee joint fluid specimens. The diagnostic value of the multi-omics was ascertained relative to standard of care culture and PCR-negative results.

Results: Ten children with suspected …

Spatial Transcriptome Reveals Histology-Correlated Immune Signature Learnt By Deep Learning Attention Mechanism On H&E-Stained Images For Ovarian Cancer Prognosis, Chun Wai Ng, Kwong-Kwok Wong, Barrett C Lawson, Sammy Ferri-Borgogno, Samuel C Mok

Faculty, Staff and Student Publications

Background: The ability to predict the prognosis of patients with ovarian cancer can greatly improve disease management. However, the knowledge on the mechanism of the prediction is limited. We sought to deconvolute the attention feature learnt by a deep learning convolutional neural networks trained with whole-slide images (WSIs) of hematoxylin-and-eosin (H&E)-stained tumor samples using spatial transcriptomic data.

Methods: In this study, 773 WSIs of H&E-stained tumor sections from 335 patients with treatment naïve high-grade serous ovarian cancer who were included in The Cancer Genome Atlas (TCGA) Pan-Cancer study were used to train, and validate, and to test a ResNet101 CNN …