Genetic Phenomena Commons^™

Cryptic Kmt2a::Afdn Fusion Due To Afdn Insertion Into Kmt2a In A Patient With Acute Monoblastic Leukemia, Qing Wei, Gokce A Toruner, Beenu Thakral, Keyur P Patel, Naveen Pemmaraju, Sa A Wang, Rashmi Kanagal-Shamanna, Guilin Tang, Ghayas C Issa, Sanam Loghavi, L Jeffrey Medeiros, Courtney Dinardo

Faculty, Staff and Student Publications

Background: KMT2A rearrangements occur in ~10% of acute myeloid leukemia (AML) cases and are critical for classification, risk stratification, and use of targeted therapy. However, insertions involving the KMT2A gene can evade detection using chromosomal analysis and/or fluorescence in situ hybridization (FISH).

Methods: We present a case of a 22-year-old woman with acute monoblastic leukemia harboring a cryptic KMT2A::AFDN fusion identified by RNA sequencing. Initial FISH showed a 3' KMT2A deletion, while conventional karyotyping and the automated bioinformatic pipeline for optical genome mapping (OGM) did not identify the canonical translocation.

Results: To resolve these discrepancies, metaphase KMT2A FISH (break-apart fusion …

Cryptic Kmt2a::Afdn Fusion Due To Afdn Insertion Into Kmt2a In A Patient With Acute Monoblastic Leukemia, Qing Wei, Gokce A Toruner, Beenu Thakral, Keyur P Patel, Naveen Pemmaraju, Sa A Wang, Rashmi Kanagal-Shamanna, Guilin Tang, Ghayas C Issa, Sanam Loghavi, L Jeffrey Medeiros, Courtney Dinardo

Faculty, Staff and Student Publications

Background: KMT2A rearrangements occur in ~10% of acute myeloid leukemia (AML) cases and are critical for classification, risk stratification, and use of targeted therapy. However, insertions involving the KMT2A gene can evade detection using chromosomal analysis and/or fluorescence in situ hybridization (FISH).

Methods: We present a case of a 22-year-old woman with acute monoblastic leukemia harboring a cryptic KMT2A::AFDN fusion identified by RNA sequencing. Initial FISH showed a 3' KMT2A deletion, while conventional karyotyping and the automated bioinformatic pipeline for optical genome mapping (OGM) did not identify the canonical translocation.

Results: To resolve these discrepancies, metaphase KMT2A FISH (break-apart fusion …

Drbioright 20: An Llm-Powered Bioinformatics Chatbot For Large-Scale Cancer Functional Proteomics Analysis, Wei Liu, Jun Li, Yitao Tang, Yining Zhao, Chaozhong Liu, Meiyi Song, Zhenlin Ju, Shwetha V Kumar, Yiling Lu, Rehan Akbani, Gordon B Mills, Han Liang

Faculty, Staff and Student Publications

Functional proteomics provides critical insights into cancer mechanisms, facilitating the discovery of novel biomarkers and therapeutic targets. We have developed a comprehensive cancer functional proteomics resource using reverse phase protein arrays, incorporating data from nearly 8000 patient samples from The Cancer Genome Atlas and approximately 900 samples from the Cancer Cell Line Encyclopedia. Our dataset includes a curated panel of nearly 500 high-quality antibodies, covering all major cancer hallmark pathways. To enhance the accessibility and analytic power of this resource, we introduce DrBioRight 2.0 ( https://drbioright.org ), an intuitive bioinformatic platform powered by state-of-the-art large language models. DrBioRight enables researchers …

Structure-Function Relationship Of Ash1l And Histone H3k36 And H3k4 Methylation, Kendra R Vann, Rajal Sharma, Chih-Chao Hsu, Maeva Devoucoux, Adam H Tencer, Lei Zeng, Kevin Lin, Li Zhu, Qin Li, Catherine Lachance, Ruben Rosas Ospina, Qiong Tong, Ka Lung Cheung, Shuai Yang, Soumi Biswas, Hongwen Xuan, Jovylyn Gatchalian, Lorena Alamillo, Jianlong Wang, Suk Min Jang, Brianna J Klein, Yue Lu, Patricia Ernst, Brian D Strahl, Scott B Rothbart, Martin J Walsh, Michael L Cleary, Jacques Côté, Xiaobing Shi, Ming-Ming Zhou, Tatiana G Kutateladze

Faculty, Staff and Student Publications

The histone H3K36-specific methyltransferase ASH1L plays a critical role in development and is frequently dysregulated in human diseases, particularly cancer. Here, we report on the biological functions of the C-terminal region of ASH1L encompassing a bromodomain (ASH1LBD), a plant homeodomain (ASH1LPHD) finger, and a bromo-adjacent homology (ASH1LBAH) domain, structurally characterize these domains, describe their mechanisms of action, and explore functional crosstalk between them. We find that ASH1LPHD recognizes H3K4me2/3, whereas the neighboring ASH1LBD and ASH1LBAH have DNA binding activities. The DNA binding function of ASH1LBAH is a driving force for the association of ASH1L with the linker DNA in the …

Pspc1 Exerts An Oncogenic Role In Aml By Regulating A Leukemic Transcription Program In Cooperation With Pu1, Juyeong Hong, Pinpin Sui, Ying Li, Kerryn Y Xu, Ji-Hoon Lee, Juan Wang, Shi Chen, Peng Zhang, Noah Wingate, Asra Noor, Yaxia Yuan, Robert Hromas, Hongwei Zhou, Karina Hamamoto, Rui Su, C Cameron Yin, Fengxi Ye, Andrés E Quesada, Jianjun Chen, Suming Huang, Daohong Zhou, M James You, Feng-Chun Yang, Jianlong Wang, Mingjiang Xu

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy characterized by the blockage of myeloid cell differentiation and uncontrolled proliferation of immature myeloid cells. Here, we show that paraspeckle component 1 (PSPC1) is aberrantly overexpressed and associated with poor survival in AML patients. Using human AML cells and mouse models, we demonstrate that PSPC1 is not required for normal hematopoiesis, but it is critical and essential for AML cells to maintain their leukemic characteristics. PSPC1 loss induces robust differentiation, suppresses proliferation, and abolishes leukemogenesis in diverse AML cells. Mechanistically, PSPC1 exerts a pro-leukemia effect by regulating a unique leukemic transcription …

Identification Of Genes Associated With Testicular Germ Cell Tumor Susceptibility Through A Transcriptome-Wide Association Study, Emilio Ugalde-Morales, Rona Wilf, John Pluta, Alexander Ploner, Mengyao Fan, Mohammad Damra, Katja K Aben, Lynn Anson-Cartwright, Chu Chen, Victoria K Cortessis, Siamak Daneshmand, Alberto Ferlin, Marija Gamulin, Jourik A Gietema, Anna Gonzalez-Niera, Tom Grotmol, Robert J Hamilton, Mark Harland, Trine B Haugen, Russ Hauser, Michelle A T Hildebrandt, Robert Karlsson, Lambertus A Kiemeney, Jung Kim, Davor Lessel, Ragnhild A Lothe, Chey Loveday, Stephen J Chanock, Katherine A Mcglynn, Coby Meijer, Kevin T Nead, Jeremie Nsengimana, Maja Popovic, Thorunn Rafnar, Lorenzo Richiardi, Maria S Rocca, Stephen M Schwartz, Rolf I Skotheim, Kari Stefansson, Douglas R Stewart, Clare Turnbull, David J Vaughn, Sofia B Winge, Tongzhang Zheng, Alvaro N Monteiro, Kristian Almstrup, Peter A Kanetsky, Katherine L Nathanson, Fredrik Wiklund, Testicular Cancer Consortium

Faculty, Staff and Student Publications

Transcriptome-wide association studies (TWASs) have the potential to identify susceptibility genes associated with testicular germ cell tumors (TGCTs). We conducted a comprehensive TGCT TWAS by integrating genome-wide association study (GWAS) summary data with predicted expression models from normal testis, TGCT tissues, and a cross-tissue panel that encompasses shared regulatory features across 22 normal tissues, including the testis. Gene associations were evaluated while accounting for variant-level effects from GWASs, followed by fine-mapping analyses in regions exhibiting multiple TWAS signals, and finally supplemented by colocalization analysis. Expression and protein patterns of identified TWAS genes were further examined in relevant tissues. Our analysis …

Photoacoustic Imaging For Image-Guided Gastric Tube Placement: Ex Vivo Characterization, Samuel John, Yeidi Yuja Vaquiz, Nikhila Nyayapathi, Loay Kabbani, Anoop Nilam, Jonathan F Lovell, Nicole A Wilson, Yan Yan, Mohammad Mehrmohammadi

Faculty, Staff and Student Publications

Over 250,000 gastrostomy tubes (G-tubes) are placed annually in the United States. Percutaneous endoscopic gastrostomy (PEG) is the most widely used clinical method for placing G-tubes within the stomach. However, endoscope detectability is limited due to the scattering of light by tissues. Poor organ visibility and low sensitivity of the palpation techniques cause blind needle insertions, which cause colon/liver perforations, abdominal bleeding, and gastric resections. Additionally, imaging artifacts and the poor distinguishability between water-filled tissues make ultrasound (US) imaging-based techniques incompatible with G-tube placement. The risk of ionizing radiation exposure and the confinement of fluoroscopy to radiology suites limits its …

Addressing Health Disparities In Hematologic Malignancies: From Genes To Outreach, Christopher R Flowers, Rachel W Anantha, Veronica Leautaud, Pinkal Desai, Chancellor E Donald, Michelle A T Hildebrandt, Jean L Koff, Rulla M Tamimi, Wendy Cozen, Chijioke Nze, Ari M Melnick

Faculty, Staff and Student Publications

This review underscores our shared responsibility to champion multidimensional strategies rooted in basic and translational science, community involvement, and societal responsiveness for a meaningful impact. Unifying themes include the need to enhance collaborative infrastructure to engage laboratory researchers, epidemiologists, data scientists, clinicians, patients, community leaders, and policymakers; patient-level support services; outreach, education, and navigation for patients at the community level; recruitment and retention of underrepresented groups in the healthcare and research workforce; and funding for these efforts.

Learning Directed Acyclic Graphs For Ligands And Receptors Based On Spatially Resolved Transcriptomic Data Of Ovarian Cancer, Shrabanti Chowdhury, Sammy Ferri-Borgogno, Peng Yang, Wenyi Wang, Jie Peng, Samuel C Mok, Pei Wang

Faculty, Staff and Student Publications

To unravel the mechanism of immune activation and suppression within tumors, a critical step is to identify transcriptional signals governing cell-cell communication between tumor and immune/stromal cells in the tumor microenvironment. Central to this communication are interactions between secreted ligands and cell-surface receptors, creating a highly connected signaling network among cells. Recent advancements in in situ-omics profiling, particularly spatial transcriptomic (ST) technology, provide unique opportunities to directly characterize ligand-receptor signaling networks that power cell-cell communication. In this paper, we propose a novel statistical method, LRnetST, to characterize the ligand-receptor interaction networks between adjacent tumor and immune/stroma cells based on ST …

Ancestral Differences In Anticancer Treatment Efficacy And Their Underlying Genomic And Molecular Alterations, Mei Luo, Jingwen Yang, Alejandro A Schäffer, Chengxuan Chen, Yuan Liu, Yamei Chen, Chunru Lin, Lixia Diao, Yong Zang, Yanyan Lou, Huda Salman, Gordon B Mills, Eytan Ruppin, Leng Han

Faculty, Staff and Student Publications

Systematic multi-omics analysis revealed ancestry-dependent molecular alterations, but their impact on the efficacy of anti-cancer treatment is yet largely unknown. Here, we analyzed clinical trials from ClinicalTrials.gov and found that only 8,779/102,721 (8.5%) oncology clinical trials posted information on enrollment by race/ethnicity. The underrepresentation of non-White populations suggests that it remains challenging to determine differences in the efficacy of anti-tumor treatments among different racial groups. Through a comprehensive analysis of clinically actionable genes, imputed drug responses, and immune features, we identified potential differences in treatment response to targeted, chemo and immunotherapies between different ancestral populations. Further analysis of multiple independent …

Epigenetic Landscapes Of Aging In Breast Cancer Survivors: Unraveling The Impact Of Therapeutic Interventions-A Scoping Review, Nikita Nikita, Zhengyang Sun, Swapnil Sharma, Amy L Shaver, Victoria Seewaldt, Grace Lu-Yao

Department of Medical Oncology Faculty Papers

Breast cancer therapies have dramatically improved survival rates, but their long-term effects, especially on aging survivors, need careful consideration. This review delves into how breast cancer treatments and aging intersect, focusing on the epigenetic changes triggered by chemotherapy, radiation, hormonal treatments, and targeted therapies. Treatments can speed up biological aging by altering DNA methylation, histone modifications, and chromatin remodeling, affecting gene expression without changing the DNA sequence itself. The review explains the double-edged sword effect of therapy-induced epigenetic modifications, which help fight cancer but also accelerate aging. Chemotherapy and targeted therapies, in particular, impact DNA methylation and histone modifications, promoting …

Gain-Of-Function Chromatin Remodeling Activity Of Oncogenic Foxl2c134w Reprograms Glucocorticoid Receptor Occupancy To Drive Granulosa Cell Tumors, Thomas Welte, Veena K Vuttaradhi, Eleonora Y Khlebus, Allison Brodsky, Alejandra Flores Legarreta, Joseph Celestino, Reid T Powell, Clifford C Stephan, Nghi Nguyen, Jian Li, Shiro Takamatsu, Katherine Calzoncinth, Anil K Sood, David M Gershenson, P Andrew Futreal, Barrett Lawson, R Tyler Hillman

Faculty, Staff and Student Publications

Adult type ovarian granulosa cell tumors (AGCT) are rare malignancies with the near universal c.C402G (p.Cys134Trp) somatic mutation in FOXL2, a forkhead box family transcription factor important for ovarian function. Relapsed AGCT is incurable, but the mechanism of the unique FOXL2 mutation could confer therapeutic vulnerabilities. To identify FOXL2C134W-dependent pharmacologic synergies, we created and characterized endogenous FOXL2 isogenic AGCT cells and an AGCT tumoroid biobank. A drug screen identified that glucocorticoids promote FOXL2C134W-dependent AGCT growth. Epigenetic investigation revealed that the Cys134Trp mutation exposes latent DNA sequence-specific chromatin remodeling activity in FOXL2. FOXL2C134W-dependent chromatin remodeling activity redirected glucocorticoid receptor chromatin occupancy …

First-In-Human Clinical Trial Of A Small-Molecule Ebna1 Inhibitor, Vk-2019, In Patients With Epstein-Barr-Positive Nasopharyngeal Cancer, With Pharmacokinetic And Pharmacodynamic Studies, A Dimitrios Colevas, Zahra Talebi, Elizabeth Winters, Caroline Even, Victor Ho-Fun Lee, Maura L Gillison, Saad A Khan, Rong Lu, Benjamin A Pinsky, Samantha S Soldan, Olga Vladmirova, Paul M Lieberman, Troy E Messick

Faculty, Staff and Student Publications

Purpose: A first-in-human phase I study was conducted in patients with nasopharyngeal carcinoma to assess the safety and tolerability of VK-2019, a small-molecule selective inhibitor of Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1).

Patients and methods: Pharmacokinetic and pharmacodynamic studies were performed, including the measurement of EBV DNA plasma levels. Twenty-three patients received VK-2019 orally once daily at doses ranging from 60 to 1,800 mg using an accelerated titration design, with cohort expansion at 1,800 mg. EBV genome copy number and spatial transcriptomic analyses were conducted on biopsies collected from three patients at baseline and after treatment.

Results: VK-2019 was …

A Novel Sensitivity Maximization At A Given Specificity Method For Binary Classifications, Seyyed Mahmood Ghasemi, Chunhui Gu, Johannes F Fahrmann, Samir Hanash, Kim-Anh Do, James P Long, Ehsan Irajizad

Faculty, Staff and Student Publications

In the cancer early detection field, logistic regression (LR) is a frequently used approach to establish a combination rule that differentiates cancer from noncancer. However, the application of LR relies on a maximum likelihood approach, which may not yield optimal combination rules for maximizing sensitivity at a clinically desirable specificity and vice versa. In this article, we have developed an improved regression framework, sensitivity maximization at a given specificity (SMAGS), for binary classification that finds the linear decision rule, yielding the maximum sensitivity for a given specificity or the maximum specificity for a given sensitivity. We additionally expand the framework …

A Sample Size Analysis Of A Mathematical Model Of Longitudinal Tumor Volume And Progression-Free Survival For Bayesian Individual Dynamic Predictions In Recurrent High-Grade Glioma, Daniel J Glazar, Solmaz Sahebjam, Hsiang-Husan M Yu, Dung-Tsa Chen, Menal Bhandari, Heiko Enderling

Faculty, Staff and Student Publications

Patients with recurrent high-grade glioma (rHGG) have a poor prognosis with median progression-free survival (PFS) ofheterogenous, suggesting a clinical need for prognostic models. Bayesian data analysis can exploit individual patient follow-up imaging studies to adaptively predict the risk of progression. We propose a novel sample size analysis for Bayesian individual dynamic predictions and demonstrate proof of principle. We coupled a nonlinear mixed effects tumor growth inhibition model with a survival model. Longitudinal tumor volumes and time-to-progression were simulated for 2000 in silico rHGG patients. Bayesian individual dynamic predictions of PFS curves were evaluated using area under the receiver operating characteristic …

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). …

Cd147 Mediates The Metabolic Reprogramming Of Cancer Associated Fibroblasts Induced By Evs Released By Differentiating Cancer Stem Cells, Filomena Colella, Federica Calapà, Giulia Artemi, Erica Pazzaglia, Rita Colonna, Sara Vitale, Giacomo Lazzarino, Federica Vincenzoni, Micol Eleonora Fiori, Ruggero De Maria, Sara Lucchisani, Giannicola Genovese, Luigi Perelli, Barbara Tavazzi, Alessandro Sgambato, Donatella Lucchetti

Faculty, Staff and Student Publications

Several reports have demonstrated that CD147, an N-glycosylated protein that is exchanged by cells in soluble form or through small extracellular vesicles (sEVs), can promote cancer progression. However, its activity related to EVs in colorectal cancer (CRC) is still not fully understood. Previously, we showed that sEV secretion during CRC stem cell (CR-CSCs) differentiation is partially controlled by CD147, and that CD147-expressing sEVs (sEVs-CD147) activate a signalling cascade in recipient cells, inducing molecular invasive features in CR-CSCs. In the present study, we demonstrated that sEVs-CD147 increase the expression of myofibroblast and activation markers in cancer-associated fibroblasts (CAF). In sEVs-CD147-activated CAF, …

Systems Neuroimmunology: Current Bottlenecks, Research Priorities And Future Directions, Harini Iyer, Christophe Benoist, Staci D Bilbo, Lisa M Boulanger, Michael D Burton, Brian P Daniels, Aleksandra Deczkowska, Martin F Flajnik, Mélanie G Gareau, Peter M Grace, Javier E Irazoqui, Susanna Rosi, Irene Salinas, Anne Schaefer, Caroline L Sokol, Dionna W Williams, Robyn S Klein

Faculty, Staff and Student Publications

Strategies to advance the field of neuroimmunology by embracing its complexity via inclusion of its multidisciplinary properties were discussed at a meeting in Cold Spring Harbor. Attendees proposed fostering of open communications and funding of collaborations across disciplines, and the recognition that our understanding of the neuroimmune system requires interdisciplinary science.

Reducing Igg Accumulation Via Neonatal Fc Receptor (Fcrn) Blockade Relieves Neuropathic Pain, Nathan T Fiore, Kendal F Willcox, Dorsa Dayani, Younus A Zuberi, Cobi J Heijnen, Peter M Grace

Faculty, Staff and Student Publications

Preclinical and clinical studies have established that autoreactive immunoglobulin G (IgG) can drive neuropathic pain. We recently demonstrated that sciatic nerve chronic constriction injury (CCI) in male and female mice results in the production of pronociceptive IgG, which accumulates around the lumbar region, including within the dorsal root ganglia (DRG) and spinal cord, facilitating the development of neuropathic pain. These data raise the intriguing possibility that neuropathic pain may be alleviated by reducing the accumulation of IgG. To this end, we tested whether biologic inhibition or genetic deletion of the neonatal Fc receptor (FcRn) would attenuate mechanical hypersensitivity (allodynia) and …

Exome Sequencing Identifies Helb As A Novel Susceptibility Gene For Non-Mucinous, Non-High-Grade-Serous Epithelial Ovarian Cancer, Ed M Dicks, Jonthan P Tyrer, Suzana Ezquina, Michelle Jones, John Baierl, Pei-Chen Peng, Michael Diaz, Ellen Goode, Stacey J Winham, Thilo Dörk, Toon Van Gorp, Anna De Fazio, David D L Bowtell, Dale W Garsed, Kunle Odunsi, Kirsten Moysich, Marina Pavanello, Florentia Fostira, Penelope M Webb, Jana Soukupová, Paul A Cohen, Weiva Sieh, Renée Turzanski Fortner, Charite Ricker, Beth Karlan, Ian Campbell, James D Brenton, Susan J Ramus, Simon A Gayther, Paul D P Pharoah

Faculty, Staff and Student Publications

Rare, germline loss-of-function variants in a handful of DNA repair genes are associated with epithelial ovarian cancer. The aim of this study was to evaluate the role of rare, coding, loss-of-function variants across the genome in epithelial ovarian cancer. We carried out a gene-by-gene burden test with various histotypes using data from 2573 non-mucinous cases and 13,923 controls. Twelve genes were associated at a False Discovery Rate of less than 0.1 of which seven were the known ovarian cancer susceptibility genes BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, MSH6 and PALB2. The other five genes were OR2T35, HELB, MYO1A and GABRP which …

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 …

Immunelens Characterizes Systemic Immune Dysregulation In Aging And Cancer, Robert Bentham, Thomas P Jones, James R M Black, Carlos Martinez-Ruiz, Michelle Dietzen, Maria Litovchenko, Kerstin Thol, Thomas B K Watkins, Chris Bailey, Oriol Pich, Zhihui Zhang, Peter Van Loo, Genomics England Consortium, Tracerx Consortium, Charles Swanton, Nicholas Mcgranahan

Faculty, Staff and Student Publications

Recognition and elimination of pathogens and cancer cells depend on the adaptive immune system. Thus, accurate quantification of immune subsets is vital for precision medicine. We present immune lymphocyte estimation from nucleotide sequencing (ImmuneLENS), which estimates T cell and B cell fractions, class switching and clonotype diversity from whole-genome sequencing data at depths as low as 5× coverage. By applying ImmuneLENS to the 100,000 Genomes Project, we identify genes enriched with somatic mutations in T cell-rich tumors, significant sex-based differences in circulating T cell fraction and demonstrated that the circulating T cell fraction in patients with cancer is significantly lower …

Bevacizumab Beyond Progression: Impact Of Subsequent Bevacizumab Re-Treatment In Patients With Ovarian, Fallopian Tube, And Peritoneal Cancer After Progression, Amma Asare, Rebecca Ann Previs, Daniel Spinosa, Bryan Fellman, Amelia L Scott, Isabelle Mulder, May Mahmoud, Ahmed Enbaya, Jean Hansen Siedel, Lauren Cobb, Pamela T Soliman, Anil K Sood, Robert L Coleman, Angeles Alvarez Secord, Shannon N Westin

Faculty, Staff and Student Publications

Background: This study evaluated whether patients with epithelial ovarian, fallopian tube, and primary peritoneal carcinoma (OC) who are immediately re-treated with bevacizumab derive benefit after disease progression on a bevacizumab-containing regimen.

Methods: This multi-institutional, retrospective study compared patients with high grade non-mucinous epithelial OC who received bevacizumab followed directly by another bevacizumab-containing treatment regimen to patients who received bevacizumab followed by a regimen that did not contain bevacizumab (or received no further treatment). Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan Meier product-limit estimator and modeled via Cox proportional hazards regression.

Results: Among 226 patients with OC …

Clinical Use Of Gafchromic Ebt4 Film For In Vivo Dosimetry For Total Body Irradiation, Emily Draeger, Fada Guan, Min-Young Lee, Dae Yup Han, William Donahue, Zhe Jay Chen

Faculty, Staff and Student Publications

Purpose: In vivo dosimetry is a common requirement to validate dose accuracy/uniformity in total body irradiation (TBI). Several detectors can be used for in vivo dosimetry, including thermoluminescent dosimeters (TLDs), diodes, ion chambers, optically stimulated luminescent dosimeters (OSLDs), and film. TLDs are well established for use in vivo but required expertise and clinical system availability may make them impractical for multifractionated TBI. OSLDs offer quick readout, but recalls have restricted their use. The purpose of this work was to validate the newly available Gafchromic EBT4 film for TBI in vivo dosimetry.

Methods: Film calibration curves were created under standard conditions …

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.

Optimal Surveillance For Detecting Sarcoma Lung Metastasis – A Systematic Review, Neha Malik, Kate Krause, Emily Z Keung, Heather G Lyu, Heather Lillemoe, Christopher Scally, Keila Torres, Kelly Hunt, Mary Austin, Christina L Roland

Faculty, Staff and Student Publications

Introduction: Accurate diagnosis of lung metastasis for patients with soft tissue sarcoma (STS) can impact overall survival, but there is considerable variability in imaging utilized to detect metastasis. Chest x-ray (CXR) or computer tomography (CT) scan of the chest are the most common studies in current practice.

Methods: A systematic literature search was performed. Databases were searched from inception to January 3, 2024. Articles were reviewed to determine if CXR or CT chest was associated with improved overall or recurrence-free survival in patients with STS. Articles were also reviewed for data on cost-effectiveness of CXR versus CT chest. The quality …

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 …

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 …

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 …