Medical Specialties Commons^™

Leveraging Artificial Intelligence And Machine Learning To Accelerate Discovery Of Disease-Modifying Therapies In Type 1 Diabetes., Melanie R. Shapiro, Erin M. Tallon, Matthew E. Brown, Amanda L. Posgai, Mark A. Clements, Todd M. Brusko

Manuscripts, Articles, Book Chapters and Other Papers

Progress in developing therapies for the maintenance of endogenous insulin secretion in, or the prevention of, type 1 diabetes has been hindered by limited animal models, the length and cost of clinical trials, difficulties in identifying individuals who will progress faster to a clinical diagnosis of type 1 diabetes, and heterogeneous clinical responses in intervention trials. Classic placebo-controlled intervention trials often include monotherapies, broad participant populations and extended follow-up periods focused on clinical endpoints. While this approach remains the 'gold standard' of clinical research, efforts are underway to implement new approaches harnessing the power of artificial intelligence and machine learning …

Diet-Enhanced Lrg1 Expression Promotes Insulin Hypersecretion And Er Stress In Pancreatic Beta Cells, Desirae D Morales, Jiyoon Ryu, Cong Wei, Jason T Hadley, Maia R Smith, Juli Bai, Juan C Lopez-Alvarenga, Srinivas Mummidi, Ravindranath Duggirala, Jane L Lynch, Feng Liu, Lily Q Dong

Faculty, Staff and Student Publications

Aims/hypothesis: Upregulation of serum leucine-rich α-2-glycoprotein 1 (LRG1) has been implicated in diet-induced obesity and metabolic disorders. However, its specific hormonal actions remain unclear. This study aimed to determine whether diet-enhanced serum LRG1 levels promote hyperinsulinaemia by directly stimulating insulin secretion from pancreatic beta cells.

Methods: Human serum samples were obtained from individuals (both male and female) undergoing plastic surgery. Male C57BL/6 wild-type and Lrg1 whole-body knockout (Lrg1KO) mice were fed a 45% high-fat diet, with serum samples collected every 2 weeks to monitor LRG1 and insulin levels throughout diet-induced obesity. MIN6 beta cells were used to investigate the effects …

Predicting Chemotherapy Responsiveness In Gastric Cancer Through Machine Learning Analysis Of Genome, Immune, And Neutrophil Signatures, Shota Sasagawa, Yoshitaka Honma, Xinxin Peng, Kazuhiro Maejima, Koji Nagaoka, Yukari Kobayashi, Ayako Oosawa, Todd A Johnson, Yuki Okawa, Han Liang, Kazuhiro Kakimi, Yasuhide Yamada, Hidewaki Nakagawa

Faculty, Staff and Student Publications

Background: Gastric cancer is a major oncological challenge, ranking highly among causes of cancer-related mortality worldwide. This study was initiated to address the variability in patient responses to combination chemotherapy, highlighting the need for personalized treatment strategies based on genomic data.

Methods: We analyzed whole-genome and RNA sequences from biopsy specimens of 65 advanced gastric cancer patients before their chemotherapy treatment. Using machine learning techniques, we developed a model with 123 omics features, such as immune signatures and copy number variations, to predict their chemotherapy outcomes.

Results: The model demonstrated a prediction accuracy of 70-80% in forecasting chemotherapy responses in …

Guidelines For Minimal Reporting Requirements, Design And Interpretation Of Experiments Involving The Use Of Eukaryotic Dual Gene Expression Reporters (Mindr), Gary Loughran, Dmitry E Andreev, Ilya M Terenin, Olivier Namy, Martin Mikl, Martina M Yordanova, C Joel Mcmanus, Andrew E Firth, John F Atkins, Christopher S Fraser, Zoya Ignatova, Shintaro Iwasaki, Joanna Kufel, Ola Larsson, Sebastian A Leidel, Alexander S Mankin, Marco Mariotti, Marvin E Tanenbaum, Ivan Topisirovic, Nora Vázquez-Laslop, Gabriela Viero, Neva Caliskan, Yiwen Chen, Patricia L Clark, Jonathan D Dinman, Philip J Farabaugh, Wendy V Gilbert, Pavel Ivanov, Jeffrey S Kieft, Oliver Mühlemann, Matthew S Sachs, Ivan N Shatsky, Nahum Sonenberg, Anna-Lena Steckelberg, Anne E Willis, Michael T Woodside, Leos Shivaya Valasek, Sergey E Dmitriev, Pavel V Baranov

Faculty, Staff and Student Publications

Dual reporters encoding two distinct proteins within the same mRNA have had a crucial role in identifying and characterizing unconventional mechanisms of eukaryotic translation. These mechanisms include initiation via internal ribosomal entry sites (IRESs), ribosomal frameshifting, stop codon readthrough and reinitiation. This design enables the expression of one reporter to be influenced by the specific mechanism under investigation, while the other reporter serves as an internal control. However, challenges arise when intervening test sequences are placed between these two reporters. Such sequences can inadvertently impact the expression or function of either reporter, independent of translation-related changes, potentially biasing the results. …

Prevention And Management Of Infectious Complications In Pediatric Patients With Cancer: A Survey Assessment Of Current Practices Across Children's Oncology Group Institutions., Leonora R. Slatnick, David Hoogstra, Brian T. Fisher, Joshua Wolf, Etan Orgel, C Nathan Nessle, Pratik A. Patel, Tamara P. Miller, Jennifer Wilkes, L Lee Dupuis, Erin Goode, Kasey Jackson, Daniel N. Willis, Caitlin Elgarten, Catherine Aftandilian, Joel Thompson, Sarah Alexander, Melissa P. Beauchemin, Jennifer A. Belsky, Jennifer Hess, Zachary D. Prudowsky, Terri Guinipero, Jenna Rossoff, Jenna Demedis, Alexandra M. Walsh, Rebecca Richards, Daniel K. Choi, Christopher C. Dvorak, Adam J. Esbenshade

Manuscripts, Articles, Book Chapters and Other Papers

INTRODUCTION: While clinical practice guidelines (CPGs) for pediatric oncology infection prophylaxis and management exist, few data describe actual management occurring at pediatric oncology centers.

METHODS: An electronic survey querying infection management practices in nontransplant pediatric oncology patients was iteratively created by the Children's Oncology Group (COG) Cancer Control and Supportive Care Infectious Diseases Subcommittee and sent to leaders at all COG institutions, limiting each site to one response to represent their institution.

RESULTS: The response rate was 57% (129/227 institutions). Many sites reported utilizing COG-endorsed CPGs for antibacterial (76%) and antifungal prophylaxis (74%), and fever and neutropenia (FN, 64%). Most …

Proceedings Of The National Cancer Institute Workshop On Combining Immunotherapy With Radiotherapy: Challenges And Opportunities For Clinical Translation, Zachary S Morris, Sandra Demaria, Arta M Monjazeb, Silvia C Formenti, Ralph R Weichselbaum, James Welsh, Heiko Enderling, Jonathan D Schoenfeld, Joshua D Brody, Heather M Mcgee, Michele Mondini, Michael S Kent, Kristina H Young, Lorenzo Galluzzi, Sana D Karam, Willemijn S M E Theelen, Joe Y Chang, Mai Anh Huynh, Adi Daib, Sean Pitroda, Caroline Chung, Raphael Serre, Clemens Grassberger, Jie Deng, Quaovi H Sodji, Anthony T Nguyen, Ravi B Patel, Simone Krebs, Anusha Kalbasi, Caroline Kerr, Claire Vanpouille-Box, Logan Vick, Todd A Aguilera, Irene M Ong, Fernanda Herrera, Hari Menon, Deedee Smart, Jalal Ahmed, Robyn D Gartrell, Christina L Roland, Fatemeh Fekrmandi, Binita Chakraborty, Eric H Bent, Tracy J Berg, Alan Hutson, Samir Khleif, Andrew G Sikora, Lawrence Fong

Faculty, Staff and Student Publications

Radiotherapy both promotes and antagonises tumour immune recognition. Some clinical studies show improved patient outcomes when immunotherapies are integrated with radiotherapy. Safe, greater than additive, clinical response to the combination is limited to a subset of patients, however, and how radiotherapy can best be combined with immunotherapies remains unclear. The National Cancer Institute-Immuno-Oncology Translational Network-Society for Immunotherapy of Cancer-American Association of Immunology Workshop on Combining Immunotherapy with Radiotherapy was convened to identify and prioritise opportunities and challenges for radiotherapy and immunotherapy combinations. Sessions examined the immune effects of radiation, barriers to anti-tumour immune response, previous clinical trial data, immunological and …

Temperature-Controlled Radiofrequency Treatment Of The Nasal Valve In Nasal Airway Obstruction Patients With Septal Deviation, Dennis M Tang, Philip G Chen, Arthur W Wu, William C Yao

Faculty, Staff and Student Publications

Nasal valve treatment with TCRF results in NAO symptom improvement in the presence of septal deviation. Severe septal deviation does not impact the beneficial effect of TCRF nasal valve treatment. Symptoms improve with TCRF nasal valve treatment even if septal deviations involve the nasal valve.

Outcomes Of Standard-Risk Multiple Myeloma Patients Who Undergo Upfront Autologous Hematopoietic Stem Cell Transplantation, Oren Pasvolsky, Curtis Marcoux, Zhongya Wang, Denái R Milton, Babar Pal, Mark R Tanner, Qaiser Bashir, Samer Srour, Neeraj Saini, Paul Lin, Jeremy Ramdial, Yago Nieto, Guilin Tang, Naureen Syed, Yosra Aljawai, Hans C Lee, Krina K Patel, Melody R Becnel, Christine Ye, Partow Kebriaei, Sheeba K Thomas, Robert Z Orlowski, Richard E Champlin, Elizabeth J Shpall, Muzaffar H Qazilbash

Faculty, Staff and Student Publications

Patients with multiple myeloma (MM) without high-risk cytogenetic abnormalities are classified as having standard-risk MM (SRMM), and data focusing on their outcomes after autologous hematopoietic stem cell transplantation (autoHCT) are limited. We sought to evaluate survival outcomes for patients with SRMM receiving autoHCT, and to elucidate factors that impact these outcomes. This was a single-center retrospective analysis that included consecutive MM patients who received upfront autoHCT between 2013 and 2021, had available cytogenetic information and had no high-risk chromosomal abnormalities on fluorescence in situ hybridization, defined as t(4;14), t(14;16), del(17p) or 1q21 gain or amplification. A total of 1000 SRMM …

In Pursuit Of Ki-Rads: Toward A Single, Evidence-Based Imaging Classification Of Renal Masses, Stuart G Silverman, Ivan Pedrosa, Nicola Schieda, Vitaly Margulis, Payal Kapur, Matthew S Davenport

Faculty, Staff and Student Publications

Despite the successful application of Imaging Reporting and Data Systems to improve the radiologic description and management of disease in many organs, one does not yet exist for the kidney. Instead, the radiologic approach to the kidney has focused on the Bosniak classification system, which is based on imaging characteristics for cystic renal masses, and detecting macroscopic fat within solid renal masses. Radiologically, cystic and solid renal masses are categorized and evaluated separately because of historical precedent, differences in appearance at imaging, and differences in biologic behavior. However, the World Health Organization classification of renal neoplasms does not support such …

The Associations Of Sensory Impairment With 10-Year Risk Of Dementia And Alzheimer's Disease: The Health And Retirement Study, 2010-2020, Kun Li, Rahul Ghosal, Donglan Zhang, Yike Li, Matthew C Lohman, Monique J Brown, Anwar T Merchant, Chih-Hsiang Yang, Jean Neils-Strunjas, Daniela B Friedman, Jingkai Wei

Faculty, Staff and Student Publications

Background: Studies have examined the association between dual sensory impairment and late-life cognitive outcomes in the U.S with inconsistent findings.

Objective: To examine the associations between sensory impairment and 10-year risk of dementia or Alzheimer's disease among U.S. adults aged ≥ 50.

Methods: A prospective cohort study based on the Health and Retirement Study from 2010 to 2020. Individuals aged ≥ 50 years without self-reported dementia and Alzheimer's disease in 2010 were included in the analysis. Self-reported visual and hearing impairments were measures in 2010. Main failure events included self-reported incident dementia and Alzheimer's disease over a 10-year follow-up period. …

Elder Mistreatment Within Stroke Family Caregiving, Carina Katigbak, Wesley R Browning, Sean Savitz, Carolyn E Z Pickering

Faculty, Staff and Student Publications

This secondary data analysis sought to identify characteristics associated with mistreatment among chronic stroke survivors who transition to dementia. We examined baseline data from a multi-time series survey study (n = 453; where caregivers of those with stroke n = 107, and those without stroke, n = 346) on caregiving experiences influencing dementia family caregivers’ abusive or neglectful behaviors. Inferential statistical analysis indicated that baseline mistreatment rates were similar across stroke and non-stroke subgroups, though this finding was not significant. Caregiver depression was significantly associated with mistreatment. Multi-morbidity, prescription medication use, and limited mobility were more common among stroke …

Difference-Makers For Collecting Sexual Orientation And Gender Identity Data In Oncology Settings, Mandi L Pratt-Chapman, Edward J Miech, Megan A Mullins, Shine Chang, Gwendolyn P Quinn, Shail Maingi, Matthew B Schabath, Charles Kamen

Faculty, Staff and Student Publications

Purpose: The purpose of this analysis was to identify key difference-making conditions that distinguish oncology institutions that collect sexual orientation and gender identity (SOGI) data across a sample of American Society of Clinical Oncology (ASCO) members.

Methods: From October to November 2020, an anonymous 54-item web-based survey was distributed to ASCO members. Coincidence analysis was used to identify difference-making conditions for the collection of SOGI data.

Results: ASCO members' responses to just three items consistently distinguished practices that reported collecting both SO and GI data (n = 25) from those who did not (n = 20): (1)."Do you ask your …

An Automated Treatment Planning Portfolio For Whole Breast Radiotherapy, Hana Baroudi, Leonard Che Fru, Deborah Schofield, Dominique L Roniger, Callistus Nguyen, Donald Hancock, Christine Chung, Beth M Beadle, Kent A Gifford, Tucker Netherton, Joshua S Niedzielski, Adam Melancon, Manickam Muruganandham, Meena Khan, Simona F Shaitelman, Sanjay Shete, Patricia Murina, Daniel Venencia, Sheeba Thengumpallil, Conny Vrieling, Joy Zhang, Melissa P Mitchell, Laurence E Court

Faculty, Staff and Student Publications

Background: Automation in radiotherapy presents a promising solution to the increasing cancer burden and workforce shortages. However, existing automated methods for breast radiotherapy lack a comprehensive, end-to-end solution that meets varying standards of care.

Purpose: This study aims to develop a complete portfolio of automated radiotherapy treatment planning for intact breasts, tailored to individual patient factors, clinical approaches, and available resources.

Methods: We developed five automated conventional treatment approaches and utilized an established RapidPlan model for volumetric arc therapy. These approaches include conventional tangents for whole breast treatment, two variants for supraclavicular nodes (SCLV) treatment with/without axillary nodes, and two …

Combining Radioembolization And Immune Checkpoint Inhibitors For The Treatment Of Hepatocellular Carcinoma: The Quest For Synergy, Christopher D Malone, Suryansh Bajaj, Aiwu He, Kabir Mody, Ryan M Hickey, Ammar Sarwar, Sunil Krishnan, Tushar C Patel, Beau B Toskich

Faculty, Staff and Student Publications

Hepatocellular carcinoma is a leading and increasing contributor to cancer-related death worldwide. Recent advancements in both liver-directed therapies in the form of yttrium-90 (90Y) radioembolization (RE) and systemic therapy in the form of immune checkpoint inhibitors (ICI) have expanded treatment options for patients with an otherwise poor prognosis. Despite these gains, ICIs and 90Y-RE each have key limitations with low objective response rates and persistent hazard of out-of-field recurrence, respectively, and overall survival remains low. However, each therapy's strength may mitigate the other's weakness, making them potentially ideal partners for combination treatment strategies. This review discusses the scientific and clinical …

Qsp Modeling Shows Pathological Synergism Between Insulin Resistance And Amyloid-Beta Exposure In Upregulating Vcam1 Expression At The Bbb Endothelium, Zengtao Wang, Vaishnavi Veerareddy, Xiaojiao Tang, Kevin J Thompson, Sunil Krishnan, Krishna R Kalari, Karunya K Kandimalla

Faculty, Staff and Student Publications

Type 2 diabetes mellitus (T2DM), characterized by insulin resistance, is closely associated with Alzheimer's disease (AD). Cerebrovascular dysfunction is manifested in both T2DM and AD, and is often considered as a pathological link between the two diseases. Insulin signaling regulates critical functions of the blood-brain barrier (BBB), and endothelial insulin resistance could lead to BBB dysfunction, aggravating AD pathology. However, insulin signaling is intrinsically dynamic and involves interactions among numerous molecular mediators. Hence, a mechanistic systems biology model is needed to understand how insulin regulates BBB physiology and the consequences of its impairment in T2DM and AD. In this study, …

Rhabdoid Tumor Of The Kidney And Soft Tissues: Results From National Wilms Tumor Study-5 And Children's Oncology Group Study Aren0321, James I Geller, Lindsay A Renfro, Paul E Grundy, Elizabeth J Perlman, John A Kalapurakal, Peter F Ehrlich, Jackie Biegel, Vicki Huff, Anne B Warwick, Arnold Paulino, Elizabeth A Mullen, Najat C Daw, Fredric A Hoffer, Zelig Tochner, Kenneth Gow, Eric Gratias, Deborah A Ward, James R Anderson, Conrad V Fernandez, Jeffrey S Dome

Faculty, Staff and Student Publications

Purpose: National Wilms Tumor Study-5 (NWTS-5) and AREN0321 evaluated the outcomes of children with rhabdoid tumor of the kidney (RTK) and malignant rhabdoid tumor of soft tissues (MRT).

Patients and methods: Eligible patients with RTK were enrolled prospectively on NWTS-5 (1995-2002) and treated with carboplatin and etoposide alternating with cyclophosphamide (Regimen RTK). Patients with RTK or MRT were enrolled on AREN0321 (2005-2012) and received vincristine, doxorubicin, and cyclophosphamide alternating with carboplatin, cyclophosphamide, and etoposide (Regimens UH-1 or dose-reduced Revised UH-1). We report event-free survival (EFS) and overall survival (OS) from each study.

Results: Thirty patients received Regimen RTK on NWTS-5; …

An Antibody-Toxin Conjugate Targeting Cd47 Linked To The Bacterial Toxin Listeriolysin O For Cancer Immunotherapy, Benjamin R Schrank, Yifan Wang, Annette Wu, Nhat Tran, Daeyong Lee, Jared Edwards, Kristin Huntoon, Shiyan Dong, Jonghoon Ha, Yifan Ma, Adam J Grippin, Seong Dong Jeong, Abin Antony, Mengyu Chang, Minjeong Kang, Thomas D Gallup, Albert C Koong, Jing Li, Kyuson Yun, Betty Y S Kim, Wen Jiang

Faculty, Staff and Student Publications

Antigen-presenting cells phagocytose tumor cells and subsequently cross-present tumor-derived antigens. However, these processes are impeded by phagocytosis checkpoints and inefficient cytosolic transport of antigenic peptides from phagolysosomes. Here, using a microbial-inspired strategy, we engineered an antibody-toxin conjugate (ATC) that targets the 'don't eat me' signal CD47 linked to the bacterial toxin listeriolysin O from the intracellular bacterium Listeria monocytogenes via a cleavable linker (CD47-LLO). CD47-LLO promotes cancer cell phagocytosis by macrophages followed by LLO release and activation to form pores on phagolysosomal membranes that enhance antigen cross-presentation of tumor-derived peptides and activate cytosolic immune sensors. CD47-LLO treatment in vivo significantly …

Wmh Contributions To Cognitive Impairment: Rationale And Design Of The Diverse Vcid Study, Charles Decarli, Kumar B Rajan, Lee-Way Jin, Jason Hinman, David K Johnson, Danielle Harvey, Myriam Fornage

Faculty, Staff and Student Publications

As awareness of dementia increases, more individuals with minor cognitive complaints are requesting clinical assessment. Neuroimaging studies frequently identify incidental white matter hyperintensities, raising patient concerns about their brain health and future risk for dementia. Moreover, current US demographics indicate that ≈50% of these individuals will be from diverse backgrounds by 2060. Racial and ethnic minority populations bear a disproportionate burden of vascular risk factors magnifying dementia risk. Despite established associations between white matter hyperintensities and cognitive impairment, including dementia, no study has comprehensively and prospectively examined the impact of individual and combined magnetic resonance imaging measures of white matter …

Seq-Scope: Repurposing Illumina Sequencing Flow Cells For High-Resolution Spatial Transcriptomics, Yongsung Kim, Weiqiu Cheng, Chun-Seok Cho, Yongha Hwang, Yichen Si, Anna Park, Mitchell Schrank, Jer-En Hsu, Angelo Anacleto, Jingyue Xi, Myungjin Kim, Ellen Pedersen, Olivia I Koues, Thomas Wilson, Changhee Lee, Goo Jun, Hyun Min Kang, Jun Hee Lee

Faculty, Staff and Student Publications

Spatial transcriptomics technologies aim to advance gene expression studies by profiling the entire transcriptome with intact spatial information from a single histological slide. However, the application of spatial transcriptomics is limited by low resolution, limited transcript coverage, complex procedures, poor scalability and high costs of initial setup and/or individual experiments. Seq-Scope repurposes the Illumina sequencing platform for high-resolution, high-content spatial transcriptome analysis, overcoming these limitations. It offers submicrometer resolution, high capture efficiency, rapid turnaround time and precise annotation of histopathology at a much lower cost than commercial alternatives. This protocol details the implementation of Seq-Scope with an Illumina NovaSeq 6000 …

American Association Of Physicists In Medicine (Aapm) Chapter Climate Check: Mixed Methods Analysis Of Survey Responses, Ashley J Cetnar, Ghada Aldosary, Meghan C Koo, Holly Lincoln, Angélica Pérez-Andújar, Surendra Prajapati, Samantha J Simiele, Kristi R G Hendrickson

Faculty, Staff and Student Publications

Introduction: The American Association of Physicists in Medicine (AAPM) recently shared results and recommendations from its first Equity, Diversity, and Inclusion (EDI) Climate Survey, which was designed to assess the climate at the workplace, the AAPM organization, and the AAPM regional chapter level. This work further explores the status of EDI at the regional chapter level.

Methods: AAPM's EDI Survey was distributed to 5500 members and had a response rate of 25%. In the survey, three open-ended comment boxes were provided for feedback, including one for regional AAPM members. Sixty-four percent of respondents indicated they were part of a regional …

Psychometric Evaluation Of The Scleroderma Skin Questionnaire: A Novel Patient-Reported Outcome For Skin Disease In Patients With Systemic Sclerosis, Jeong Min Yu, John M Vanburen, Angela Child, Jessica S Alvey, Lisa A Mandl, Laura C Pinheiro, Shervin Assassi, Elana J Bernstein, Flavia V Castelino, Lorinda Chung, Luke Evnin, Tracy M Frech, Faye N Hant, Laura K Hummers, Dinesh Khanna, Kimberly S Lakin, Dorota Lebiedz-Odrobina, Yiming Luo, Ashima Makol, Jerry A Molitor, Duncan F Moore, Carrie Richardson, Nora Sandorfi, Ami A Shah, Ankoor Shah, Victoria K Shanmugam, Brian Skaug, Virginia D Steen, Elizabeth R Volkmann, Jessica K Gordon

Faculty, Staff and Student Publications

Objective: We aimed to evaluate the psychometric properties of the Scleroderma Skin Questionnaire (SSQ), a novel patient-reported outcome (PRO) to assess systemic sclerosis (SSc)-related skin symptoms.

Methods: Participants were recruited from the SSc Collaborative National Quality and Efficacy Registry (CONQUER). Internal consistency was determined using Cronbach α and McDonald ω total (ωt). The correlation of the SSQ was assessed with the modified Rodnan skin score (mRSS), physician global assessment (PGA), Scleroderma Health Assessment Questionnaire, 29-item Patient-Reported Outcomes Measurement Information System (PROMIS-29), and patient global assessment to assess criterion, convergent, and divergent validity. Correlations were also assessed between patients' self-reported recall …

Resolving Tissue Complexity By Multimodal Spatial Omics Modeling With Miso, Kyle Coleman, Amelia Schroeder, Melanie Loth, Daiwei Zhang, Jeong Hwan Park, Ji-Youn Sung, Niklas Blank, Alexis J Cowan, Xuyu Qian, Jianfeng Chen, Jiahui Jiang, Hanying Yan, Laith Z Samarah, Jean R Clemenceau, Inyeop Jang, Minji Kim, Isabel Barnfather, Joshua D Rabinowitz, Yanxiang Deng, Edward B Lee, Alexander Lazar, Jianjun Gao, Emma E Furth, Tae Hyun Hwang, Linghua Wang, Christoph A Thaiss, Jian Hu, Mingyao Li

Faculty, Staff and Student Publications

Spatial molecular profiling has provided biomedical researchers valuable opportunities to better understand the relationship between cellular localization and tissue function. Effectively modeling multi-modal spatial omics data is crucial for understanding tissue complexity and underlying biology. Furthermore, improvements in spatial resolution have led to the advent of technologies that can generate spatial molecular data with sub-cellular resolution, requiring the development of computationally efficient methods that can handle the resulting large-scale datasets. MISO (MultI-modal Spatial Omics) is a versatile algorithm for feature extraction and clustering, capable of integrating multiple modalities from diverse spatial omics experiments with high spatial resolution. Its effectiveness is …

Impact Of Postprogression Therapies On Overall Survival: Recommendations From The 2023 Kidney Cancer Association Think Tank Meeting, Stephanie A Berg, Salvatore La Rosa, Tian Zhang, Phillip M Pierorazio, Laurence Albiges, Kathryn E Beckermann, Matthew T Campbell, Maria I Carlo, Katie Coleman, Daniel J George, Daniel M Geynisman, Ritchie Johnson, Eric Jonasch, Jodi K Maranchie, Bradley A Mcgregor, Daniel D Shapiro, Eric A Singer, Brian M Shuch, Walter M Stadler, Nizar M Tannir, Yousef Zakharia, Ulka N Vaishampayan, Peter F Thall, Pavlos Msaouel

Faculty, Staff and Student Publications

Modern advances in systemic and localized therapies for patients with renal cell carcinoma (RCC) have significantly improved patients' outcomes. If disease progression occurs after initial treatment, clinicians often have multiple options for a first salvage therapy. Because salvage and initial treatments both may affect overall survival time, and they may interact in unanticipated ways, there is a growing need to determine sequences of initial therapy and first salvage therapy that maximize overall survival while maintaining quality of life. The complexity of this problem grows if a second salvage therapy must be chosen for patients with treatment-resistant disease or a second …

An Inducible Foxl2-Dependent Mouse Model Of Ovarian Adult Type Granulosa Cell Tumor, Jian Li, Thomas Welte, Katherine Calzoncinth, Veena K Vuttaradhi, Allison L Brodsky, Kwong-Kwok Wong, Manu M Sebastian, Barrett Lawson, Charles V Kingsley, R Tyler Hillman

Faculty, Staff and Student Publications

Background: Adult-type granulosa cell tumors (AGCTs) are rare ovarian sex cord/stromal tumors with near-universal hotspot mutations in FOXL2 (c.C402G; p.Cys134Trp). Progress in the treatment of relapsed AGCT has been hindered by the lack of high-fidelity FOXL2-based mouse models. To address this critical unmet need, we created and validated a genetically engineered inducible mouse model of the human FOXL2 mutation that recapitulates the key features of the human disease.

Methods: Gene targeting in embryonic stem cells was used to introduce a Cre-inducible Foxl2C130W allele (mouse equivalent of the human oncogenic mutation) into the endogenous mouse Foxl2 locus. Animals with the Foxl2C130W-FLEx …

Loncastuximab In High-Risk And Heavily Pretreated Relapsed/Refractory Diffuse Large B-Cell Lymphoma: A Realworld Analysis From 21 Us Centers, Viktoriya Zelikson, Ashwath Gurumurthi, Yazeed Sawalha, Kaitlin Annunzio, Aditi Saha, Ning Dong, David Qualls, Behzad Amoozgar, Brad Kahl, John Baird, Pavan Challa, Scott F Huntington, Jennifer Santos, Steven Bair, Mayur Narkhede, Shuning Li, Zachary Frosch, Carrie Ho, Stephen D Smith, Allison Winter, Daniel Landsburg, Fateeha Furqan, Mehdi Hamadani, Katelin Baird, Jason Romancik, Hanan Alharthy, Jennie Law, Leyla Bojanini, Ranjana Advani, Boyu Hu, Patrick Connor Johnson, Natalie S Grover, Mwanasha Merril, Jennifer L Crombie, Nazila Shafagati, Cole Sterling, Loretta J Nastoupil, Narendranath Epperla, Emily C Ayers

Faculty, Staff and Student Publications

Outcomes in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) are poor. Loncastuximab- teserine (Lonca) is an antibody-drug conjugate which was approved by the Food and Drug Administration for the treatment of patients with R/R DLBCL who have received at least two prior lines of therapy, based on the results of the LOTIS-2 trial. However, there are limited data regarding its efficacy in the real-world setting. This retrospective study included 21 US centers and evaluated outcomes of patients with R/R DLBCL treated with Lonca. Our analysis comprises 187 patients with notably higher-risk baseline features compared to those of the …

A Phase 1 Study Of Durvalumab As Monotherapy Or Combined With Tremelimumab With Or Without Azacitidine In Patients With Myelodysplastic Syndrome, Guillermo Garcia-Manero, Manila Gaddh, Uwe Platzbecker, R Coleman Lindsley, Sarah M Larson, Timothy Chevassut, Pierre Fenaux, Rami Komrokji, Roger Lyons, Aref Al-Kali, Yu Jiang, John Bothos, Danielle M Townsley, Amer M Zeidan

Faculty, Staff and Student Publications

Upregulation of programmed death ligand-1 (PD-L1) has been observed in patients with MDS, and its expression on myeloblasts is associated with progression to AML. This open-label, phase 1 study evaluated the safety and tolerability of the PD-L1 antibody durvalumab as monotherapy (part 1) and in combination with tremelimumab, with or without azacitidine (part 2), in patients with MDS who progressed following hypomethylating agent treatment. Sixty-seven adults with MDS were enrolled (part 1, 40 with low/intermediate-1 or intermediate-2/high IPSS risk status; part 2, 27 with intermediate-2/high IPSS risk status). Primary safety endpoints included dose-limiting toxicities (DLTs) and treatment-emergent adverse events (TEAEs). …

A Predictive Chromatin Architecture Nexus Regulates Transcription And Dna Damage Repair, Audesh Bhat, Sonali Bhan, Aindrila Kabiraj, Raj K Pandita, Keneth S Ramos, Sandhik Nandi, Shreya Sopori, Parthas S Sarkar, Arti Dhar, Shruti Pandita, Rakesh Kumar, Chandrima Das, John A Tainer, Tej K Pandita

Faculty, Staff and Student Publications

Genomes are blueprints of life essential for an organism's survival, propagation, and evolutionary adaptation. Eukaryotic genomes comprise of DNA, core histones, and several other nonhistone proteins, packaged into chromatin in the tiny confines of nucleus. Chromatin structural organization restricts transcription factors to access DNA, permitting binding only after specific chromatin remodeling events. The fundamental processes in living cells, including transcription, replication, repair, and recombination, are thus regulated by chromatin structure through ATP-dependent remodeling, histone variant incorporation, and various covalent histone modifications including phosphorylation, acetylation, and ubiquitination. These modifications, particularly involving histone variant H2AX, furthermore play crucial roles in DNA damage …

Encorafenib, Cetuximab And Chemotherapy In Braf-Mutant Colorectal Cancer: A Randomized Phase 3 Trial, Scott Kopetz, Takayuki Yoshino, Eric Van Cutsem, Cathy Eng, Tae Won Kim, Harpreet Singh Wasan, Jayesh Desai, Fortunato Ciardiello, Rona Yaeger, Timothy S Maughan, Elena Beyzarov, Xiaoxi Zhang, Graham Ferrier, Xiaosong Zhang, Josep Tabernero

Faculty, Staff and Student Publications

Encorafenib + cetuximab (EC) is approved for previously treated BRAF V600E-mutant metastatic colorectal cancer (mCRC) based on the BEACON phase 3 study. Historically, first-line treatment of BRAF V600E-mutant mCRC with chemotherapy regimens has had limited efficacy. The phase 3 BREAKWATER study investigated EC+mFOLFOX6 versus standard of care (SOC) in patients with previously untreated BRAF V600E mCRC. The dual primary endpoint of progression-free survival is event driven; data were not mature at data cutoff. BREAKWATER met the other dual primary endpoint of objective response rate, demonstrating significant and clinically relevant improvement in objective response rate (EC+mFOLFOX6: 60.9%; SOC: 40.0%; odds ratio, …

Detection Of Alteration In Carotid Artery Volumetry Using Standard-Of-Care Computed Tomography Surveillance Scans Following Unilateral Radiation Therapy For Early-Stage Tonsillar Squamous Cell Carcinoma Survivors: A Cross-Sectional Internally-Matched Carotid Isodose Analysis, Efstratios Koutroumpakis, Mohamed A Naser, Abdallah Sherif Radwan Mohamed, Salman A Eraj, Andrea Jarre, Jay C Shiao, Mona Kamal, Subha Perni, Jack P Phan, William H Morrison, Steven J Frank, G Brandon Gunn, Adam S Garden, Anita Deswal, Jun-Ichi Abe, David I Rosenthal, Elie Mouhayar, Clifton D Fuller

Faculty, Staff and Student Publications

Aim: This study leveraged standard-of-care CT scans of patients receiving unilateral radiotherapy (RT) for early tonsillar cancer to detect volumetric changes in the carotid arteries, and determine whether there is a dose-response relationship.

Methods: Disease-free cancer survivors (>3 months since therapy and age > 18 years) treated with intensity modulated RT for early (T1-2, N0-2b) tonsillar cancer with pre- and post-therapy contrast-enhanced CT scans available were included. Patients treated with definitive surgery, bilateral RT, or additional RT before the post-RT CT scan were excluded. Isodose lines from treatment plans were projected onto both scans, facilitating the delineation of carotid artery …

Imgn853 Induces Autophagic Cell Death In Combination Therapy For Ovarian Cancer, Anca Chelariu-Raicu, Thanh Chung Vu, Sujanitha Umamaheswaran, Elaine Stur, Pahul Hanjra, Yunah Han, Min Hu, Jerome Lin, Barrett C Lawson, Jinsong Liu, Anil K Sood, Yunfei Wen

Faculty, Staff and Student Publications

FOLR1 is heterogeneously overexpressed in epithelial ovarian cancer. We examined the combined effects of the anti-FOLR1 antibody-drug conjugate (IMGN853) with other drugs, including topotecan, anti-VEGF-A antibody, and olaparib. These findings could contribute to the continued development of IMGN853 in the treatment of ovarian cancer.