Biomedical Informatics Commons^™

Tumor-Associated Tractography Derived From High-Angular-Resolution Q-Space Mri May Predict Patterns Of Cellular Invasion In Glioblastoma, Owen P Leary, John P Zepecki, Mattia Pizzagalli, Steven A Toms, David D Liu, Yusuke Suita, Yao Ding, Jihong Wang, Renjie He, Caroline Chung, Clifton D Fuller, Jerrold L Boxerman, Nikos Tapinos, Richard J Gilbert

Faculty, Staff and Student Publications

BACKGROUND: The invasion of glioblastoma cells beyond the visible tumor margin depicted by conventional neuroimaging is believed to mediate recurrence and predict poor survival. Radiomic biomarkers that are associated with the direction and extent of tumor infiltration are, however, non-existent.

METHODS: Patients from a single center with newly diagnosed glioblastoma (

RESULTS: In the principal enrollment cohort of patients with glioblastoma, all cases displayed tractography patterns with tumor-intersecting tract bundles extending into brain parenchyma, a phenotype which was reproduced in PDX mice as well as in a larger comparison cohort of glioblastoma patients (

CONCLUSIONS: QSI discriminates tumor-specific patterns of …

Volumetric Ct Assessment Of In Situ Induced Hepatic Lesions In A Transgenic Swine Model, Derek Smetanick, Danielle Stolley, David Fuentes, Natalie W Fowlkes, Faith Shakoor, Maria Sophia Stenkamp, Samantha Hicks, Steve Parrish, Erik Cressman

Faculty, Staff and Student Publications

The growth rate of in situ-induced hepatic lesions in an Oncopig large animal model is quantitatively assessed. Oncopigs (n = 9) received baseline triple-phase CT scans prior to lesion induction. Lesions were subsequently induced by delivering the Ad-Cre vector to four locations in the liver. Triple-phase CT scans were obtained weekly to track the growth of the lesions. Animals were sacrificed at 14, 21, or 28 days (n = 3 in each group). The overall success rate of lesion generation was ~78%. Histopathology sections consistently revealed lesions that were highly inflammatory and consisted of a large leukocyte population without clear …

Type I Met Inhibitors Cooperate With Pd-1 Blockade To Promote Rejection Of Hepatocellular Carcinoma, Ricardo Deazevedo, Madeline Steiner, Broderick X Turner, Arthur Liu, Sherwin Newton, Joanna Schmidt, Rachel Fleming, Angelica Tolentino, Ahmed O Kaseb, Michael A Curran

Faculty, Staff and Student Publications

Blockade of the immune checkpoints programmed death-1 (PD-1) and cytotoxic lymphocyte antigen 4 has improved outcomes for patients with hepatocellular carcinoma (HCC), yet most still fail to achieve objective clinical benefit. MET plays key roles in both HCC tumorigenesis and immunosuppressive conditioning; however, inhibition of MET causes upregulation of PD-ligand 1 (PD-L1) suggesting the use of these inhibitors in the context of PD-1 blockade. We sought to investigate across the Hepa1-6, HCA-1 and diethylnitrosamine (DEN) models of HCC whether the combination of more specific type I versus more pleiotropic type II MET inhibitors would confer superior outcomes in combination with …

Enhancing Surgical Guidance: Deep Learning-Based Liver Vessel Segmentation In Real-Time Ultrasound Video Frames, Muhammad Awais, Mais Al Taie, Caleb S O'Connor, Austin H Castelo, Belkacem Acidi, Hop S Tran Cao, Kristy K Brock

Faculty, Staff and Student Publications

Background/objectives: In the field of surgical medicine, the planning and execution of liver resection procedures present formidable challenges, primarily attributable to the intricate and highly individualized nature of liver vascular anatomy. In the current surgical milieu, intraoperative ultrasonography (IOUS) has become indispensable; however, traditional 2D ultrasound imaging's interpretability is hindered by noise and speckle artifacts. Accurate identification of critical structures for preservation during hepatectomy requires advanced surgical skills.

Methods: An AI-based model that can help detect and recognize vessels including the inferior vena cava (IVC); the right (RHV), middle (MHV), and left (LVH) hepatic veins; the portal vein (PV) and …

Tumour-Intrinsic Pdl1 Signals Regulate The Chk2 Dna Damage Response In Cancer Cells And Mediate Resistance To Chk1 Inhibitors, Clare E Murray, Anand V R Kornepati, Carlos Ontiveros, Yiji Liao, Bárbara De La Peña Avalos, Cody M Rogers, Zexuan Liu, Yilun Deng, Haiyan Bai, Suresh Kari, Alvaro S Padron, Jacob T Boyd, Ryan Reyes, Curtis A Clark, Robert S Svatek, Rong Li, Yanfen Hu, Meiling Wang, José R Conejo-Garcia, Lauren A Byers, Kavya Ramkumar, Anil K Sood, Jung-Min Lee, Christin E Burd, Ratna K Vadlamudi, Harshita B Gupta, Weixing Zhao, Eloïse Dray, Patrick Sung, Tyler J Curiel

Faculty, Staff and Student Publications

Background: Aside from the canonical role of PDL1 as a tumour surface-expressed immune checkpoint molecule, tumour-intrinsic PDL1 signals regulate non-canonical immunopathological pathways mediating treatment resistance whose significance, mechanisms, and therapeutic targeting remain incompletely understood. Recent reports implicate tumour-intrinsic PDL1 signals in the DNA damage response (DDR), including promoting homologous recombination DNA damage repair and mRNA stability of DDR proteins, but many mechanistic details remain undefined.

Methods: We genetically depleted PDL1 from transplantable mouse and human cancer cell lines to understand consequences of tumour-intrinsic PDL1 signals in the DNA damage response. We complemented this work with studies of primary human tumours …

Targeting A Chemo-Induced Adaptive Signaling Circuit Confers Therapeutic Vulnerabilities In Pancreatic Cancer, Yohei Saito, Yi Xiao, Jun Yao, Yunhai Li, Wendao Liu, Arseniy E Yuzhalin, Yueh-Ming Shyu, Hongzhong Li, Xiangliang Yuan, Ping Li, Qingling Zhang, Ziyi Li, Yongkun Wei, Xuedong Yin, Jun Zhao, Seyed M Kariminia, Yao-Chung Wu, Jinyang Wang, Jun Yang, Weiya Xia, Yutong Sun, Eek-Hoon Jho, Paul J Chiao, Rosa F Hwang, Haoqiang Ying, Huamin Wang, Zhongming Zhao, Anirban Maitra, Mien-Chie Hung, Ronald A Depinho, Dihua Yu

Faculty, Staff and Student Publications

Advanced pancreatic ductal adenocarcinomas (PDACs) respond poorly to all therapies, including the first-line treatment, chemotherapy, the latest immunotherapies, and KRAS-targeting therapies. Despite an enormous effort to improve therapeutic efficacy in late-stage PDAC patients, effective treatment modalities remain an unmet medical challenge. To change the status quo, we explored the key signaling networks underlying the universally poor response of PDAC to therapy. Here, we report a previously unknown chemo-induced symbiotic signaling circuit that adaptively confers chemoresistance in patients and mice with advanced PDAC. By integrating single-cell transcriptomic data from PDAC mouse models and clinical pathological information from PDAC patients, we identified …

Dynamic Dysregulation Of Retrotransposons In Neurodegenerative Diseases At The Single-Cell Level\, Wankun Deng, Citu Citu, Andi Liu, Zhongming Zhao

Faculty, Staff and Student Publications

Retrotransposable elements (RTEs) are common mobile genetic elements comprising ∼42% of the human genome. RTEs play critical roles in gene regulation and function, but how they are specifically involved in complex diseases is largely unknown. Here, we investigate the cellular heterogeneity of RTEs using 12 single-cell transcriptome profiles covering three neurodegenerative diseases, Alzheimer's disease (AD), Parkinson's disease, and multiple sclerosis. We identify cell type marker RTEs in neurons, astrocytes, oligodendrocytes, and oligodendrocyte precursor cells that are related to these diseases. The differential expression analysis reveals the landscape of dysregulated RTE expression, especially L1s, in excitatory neurons of multiple neurodegenerative diseases. …

Dna-Binding Proteins From Mbd Through Zf To Ben: Recognition Of Cytosine Methylation Status By One Arginine With Two Conformations, Xing Zhang, Robert M Blumenthal, Xiaodong Cheng

Faculty, Staff and Student Publications

Maintenance methylation, of palindromic CpG dinucleotides at DNA replication forks, is crucial for the faithful mitotic inheritance of genomic 5-methylcytosine (5mC) methylation patterns. MBD proteins use two arginine residues to recognize symmetrically-positioned methyl groups in fully-methylated 5mCpG/5mCpG and 5mCpA/TpG dinucleotides. In contrast, C2H2 zinc finger (ZF) proteins recognize CpG and CpA, whether methylated or not, within longer specific sequences in a site- and strand-specific manner. Unmethylated CpG sites, often within CpG island (CGI) promoters, need protection by protein factors to maintain their hypomethylated status. Members of the BEN domain proteins bind CGCG or CACG elements within CGIs to regulate gene …

Developmental-Status-Aware Transcriptional Decomposition Establishes A Cell State Panorama Of Human Cancers, Yikai Luo, Han Liang

Faculty, Staff and Student Publications

Background: Cancer cells evolve under unique functional adaptations that unlock transcriptional programs embedded in adult stem and progenitor-like cells for progression, metastasis, and therapeutic resistance. However, it remains challenging to quantify the stemness-aware cell state of a tumor based on its gene expression profile.

Methods: We develop a developmental-status-aware transcriptional decomposition strategy using single-cell RNA-sequencing-derived tissue-specific fetal and adult cell signatures as anchors. We apply our method to various biological contexts, including developing human organs, adult human tissues, experimentally induced differentiation cultures, and bulk human tumors, to benchmark its performance and to reveal novel biology of entangled developmental signaling in …

Ten Challenges And Opportunities In Computational Immuno-Oncology, Riyue Bao, Alan Hutson, Anant Madabhushi, Vanessa D Jonsson, Spencer R Rosario, Jill S Barnholtz-Sloan, Elana J Fertig, Himangi Marathe, Lyndsay Harris, Jennifer Altreuter, Qingrong Chen, James Dignam, Andrew J Gentles, Edgar Gonzalez-Kozlova, Sacha Gnjatic, Erika Kim, Mark Long, Martin Morgan, Eytan Ruppin, David Van Valen, Hong Zhang, Natalie Vokes, Daoud Meerzaman, Song Liu, Eliezer M Van Allen, Yi Xing

Faculty, Staff and Student Publications

Immuno-oncology has transformed the treatment of cancer, with several immunotherapies becoming the standard treatment across histologies. Despite these advancements, the majority of patients do not experience durable clinical benefits, highlighting the imperative for ongoing advancement in immuno-oncology. Computational immuno-oncology emerges as a forefront discipline that draws on biomedical data science and intersects with oncology, immunology, and clinical research, with the overarching goal to accelerate the development of effective and safe immuno-oncology treatments from the laboratory to the clinic. In this review, we outline 10 critical challenges and opportunities in computational immuno-oncology, emphasizing the importance of robust computational strategies and interdisciplinary …

Interpreting The Biological Effects Of Protons As A Function Of Physical Quantity: Linear Energy Transfer Or Microdosimetric Lineal Energy Spectrum?, Fada Guan, Lawrence Bronk, Matthew Kerr, Yuting Li, Leslie A Braby, Mary Sobieski, Xiaochun Wang, Xiaodong Zhang, Clifford Stephan, David R Grosshans, Radhe Mohan

Faculty, Staff and Student Publications

The choice of appropriate physical quantities to characterize the biological effects of ionizing radiation has evolved over time coupled with advances in scientific understanding. The basic hypothesis in radiation dosimetry is that the energy deposited by ionizing radiation initiates all the consequences of exposure in a biological sample (e.g., DNA damage, reproductive cell death). Physical quantities defined to characterize energy deposition have included dose, a measure of the mean energy imparted per unit mass of the target, and linear energy transfer (LET), a measure of the mean energy deposition per unit distance that charged particles traverse in a medium. The …

Interpreting The Biological Effects Of Protons As A Function Of Physical Quantity: Linear Energy Transfer Or Microdosimetric Lineal Energy Spectrum?, Fada Guan, Lawrence Bronk, Matthew Kerr, Yuting Li, Leslie A Braby, Mary Sobieski, Xiaochun Wang, Xiaodong Zhang, Clifford Stephan, David R Grosshans, Radhe Mohan

Faculty, Staff and Student Publications

The choice of appropriate physical quantities to characterize the biological effects of ionizing radiation has evolved over time coupled with advances in scientific understanding. The basic hypothesis in radiation dosimetry is that the energy deposited by ionizing radiation initiates all the consequences of exposure in a biological sample (e.g., DNA damage, reproductive cell death). Physical quantities defined to characterize energy deposition have included dose, a measure of the mean energy imparted per unit mass of the target, and linear energy transfer (LET), a measure of the mean energy deposition per unit distance that charged particles traverse in a medium. The …

Pclaf-Dream Drives Alveolar Cell Plasticity For Lung Regeneration, Bongjun Kim, Yuanjian Huang, Kyung-Pil Ko, Shengzhe Zhang, Gengyi Zou, Jie Zhang, Moon Jong Kim, Danielle Little, Lisandra Vila Ellis, Margherita Paschini, Sohee Jun, Kwon-Sik Park, Jichao Chen, Carla Kim, Jae-Il Park

Faculty, Staff and Student Publications

Cell plasticity, changes in cell fate, is crucial for tissue regeneration. In the lung, failure of regeneration leads to diseases, including fibrosis. However, the mechanisms governing alveolar cell plasticity during lung repair remain elusive. We previously showed that PCLAF remodels the DREAM complex, shifting the balance from cell quiescence towards cell proliferation. Here, we find that PCLAF expression is specific to proliferating lung progenitor cells, along with the DREAM target genes transactivated by lung injury. Genetic ablation of Pclaf impairs AT1 cell repopulation from AT2 cells, leading to lung fibrosis. Mechanistically, the PCLAF-DREAM complex transactivates CLIC4, triggering TGF-β signaling activation, …

Salvage Reirradiation With Proton Beam Therapy For Locoregionally Recurrent Non-Small Cell Lung Cancer, Matthew S Ning, Abigael Odwuor, Joe Y Chang, Saumil Gandhi, Zhongxing Liao, Steven H Lin, Aileen Chen, James W Welsh, Quynh-Nhu Nguyen, Michael S O'Reilly, Stephen G Chun, Julianna Bronk, David Qian, Percy Lee

Faculty, Staff and Student Publications

Background/objectives: This retrospective study evaluates outcomes of 66 patients who underwent reirradiation (re-RT) with proton beam therapy (PBT) for recurrent non-small cell lung cancer.

Methods: Toxicity was scored via the CTCAE v5.0, and outcomes estimated using the Kaplan-Meier method, with associations evaluated via Cox proportional hazards and logistic regression analyses.

Results: Patients were treated to a median re-RT prescription of 66 Gy/33 fxs (BED10 = 79 Gy; IQR: 71-84 Gy) at an interval of 1.4 years from prior RT. Half (50%) received concurrent chemotherapy. At 14 months follow-up, the median OS and PFS were 5 months (95%CI: 13-17) and 12.5 …

Interpreting The Biological Effects Of Protons As A Function Of Physical Quantity: Linear Energy Transfer Or Microdosimetric Lineal Energy Spectrum?, Fada Guan, Lawrence Bronk, Matthew Kerr, Yuting Li, Leslie A Braby, Mary Sobieski, Xiaochun Wang, Xiaodong Zhang, Clifford Stephan, David R Grosshans, Radhe Mohan

Faculty, Staff and Student Publications

The choice of appropriate physical quantities to characterize the biological effects of ionizing radiation has evolved over time coupled with advances in scientific understanding. The basic hypothesis in radiation dosimetry is that the energy deposited by ionizing radiation initiates all the consequences of exposure in a biological sample (e.g., DNA damage, reproductive cell death). Physical quantities defined to characterize energy deposition have included dose, a measure of the mean energy imparted per unit mass of the target, and linear energy transfer (LET), a measure of the mean energy deposition per unit distance that charged particles traverse in a medium. The …

Childhood Neglect Is Associated With Alterations In Neural Prediction Error Signaling And The Response To Novelty, Joseph Aloi, Kathleen I Crum, Karina S Blair, Ru Zhang, Johannah Bashford-Largo, Sahil Bajaj, Soonjo Hwang, Bruno B Averbeck, Nim Tottenham, Matthew Dobbertin, R James R Blair

Faculty, Staff and Student Publications

Background: One in eight children experience early life stress (ELS), which increases risk for psychopathology. ELS, particularly neglect, has been associated with reduced responsivity to reward. However, little work has investigated the computational specifics of this disrupted reward response - particularly with respect to the neural response to Reward Prediction Errors (RPE) - a critical signal for successful instrumental learning - and the extent to which they are augmented to novel stimuli. The goal of the current study was to investigate the associations of abuse and neglect, and neural representation of RPE to novel and non-novel stimuli.

Methods: One hundred …

Interpreting The Biological Effects Of Protons As A Function Of Physical Quantity: Linear Energy Transfer Or Microdosimetric Lineal Energy Spectrum?, Fada Guan, Lawrence Bronk, Matthew Kerr, Yuting Li, Leslie A Braby, Mary Sobieski, Xiaochun Wang, Xiaodong Zhang, Clifford Stephan, David R Grosshans, Radhe Mohan

Faculty, Staff and Student Publications

The choice of appropriate physical quantities to characterize the biological effects of ionizing radiation has evolved over time coupled with advances in scientific understanding. The basic hypothesis in radiation dosimetry is that the energy deposited by ionizing radiation initiates all the consequences of exposure in a biological sample (e.g., DNA damage, reproductive cell death). Physical quantities defined to characterize energy deposition have included dose, a measure of the mean energy imparted per unit mass of the target, and linear energy transfer (LET), a measure of the mean energy deposition per unit distance that charged particles traverse in a medium. The …

Interpreting The Biological Effects Of Protons As A Function Of Physical Quantity: Linear Energy Transfer Or Microdosimetric Lineal Energy Spectrum?, Fada Guan, Lawrence Bronk, Matthew Kerr, Yuting Li, Leslie A Braby, Mary Sobieski, Xiaochun Wang, Xiaodong Zhang, Clifford Stephan, David R Grosshans, Radhe Mohan

Faculty, Staff and Student Publications

The choice of appropriate physical quantities to characterize the biological effects of ionizing radiation has evolved over time coupled with advances in scientific understanding. The basic hypothesis in radiation dosimetry is that the energy deposited by ionizing radiation initiates all the consequences of exposure in a biological sample (e.g., DNA damage, reproductive cell death). Physical quantities defined to characterize energy deposition have included dose, a measure of the mean energy imparted per unit mass of the target, and linear energy transfer (LET), a measure of the mean energy deposition per unit distance that charged particles traverse in a medium. The …

Interpreting The Biological Effects Of Protons As A Function Of Physical Quantity: Linear Energy Transfer Or Microdosimetric Lineal Energy Spectrum?, Fada Guan, Lawrence Bronk, Matthew Kerr, Yuting Li, Leslie A Braby, Mary Sobieski, Xiaochun Wang, Xiaodong Zhang, Clifford Stephan, David R Grosshans, Radhe Mohan

Faculty, Staff and Student Publications

The choice of appropriate physical quantities to characterize the biological effects of ionizing radiation has evolved over time coupled with advances in scientific understanding. The basic hypothesis in radiation dosimetry is that the energy deposited by ionizing radiation initiates all the consequences of exposure in a biological sample (e.g., DNA damage, reproductive cell death). Physical quantities defined to characterize energy deposition have included dose, a measure of the mean energy imparted per unit mass of the target, and linear energy transfer (LET), a measure of the mean energy deposition per unit distance that charged particles traverse in a medium. The …

Interpreting The Biological Effects Of Protons As A Function Of Physical Quantity: Linear Energy Transfer Or Microdosimetric Lineal Energy Spectrum?, Fada Guan, Lawrence Bronk, Matthew Kerr, Yuting Li, Leslie A Braby, Mary Sobieski, Xiaochun Wang, Xiaodong Zhang, Clifford Stephan, David R Grosshans, Radhe Mohan

Faculty, Staff and Student Publications

The choice of appropriate physical quantities to characterize the biological effects of ionizing radiation has evolved over time coupled with advances in scientific understanding. The basic hypothesis in radiation dosimetry is that the energy deposited by ionizing radiation initiates all the consequences of exposure in a biological sample (e.g., DNA damage, reproductive cell death). Physical quantities defined to characterize energy deposition have included dose, a measure of the mean energy imparted per unit mass of the target, and linear energy transfer (LET), a measure of the mean energy deposition per unit distance that charged particles traverse in a medium. The …

Phenormgpt: A Framework For Extraction And Normalization Of Key Medical Findings, Ekin Soysal, Kirk Roberts

Faculty, Staff and Student Publications

This manuscript presents PheNormGPT, a framework for extraction and normalization of key findings in clinical text. PheNormGPT relies on an innovative approach, leveraging large language models to extract key findings and phenotypic data in unstructured clinical text and map them to Human Phenotype Ontology concepts. It utilizes OpenAI's GPT-3.5 Turbo and GPT-4 models with fine-tuning and few-shot learning strategies, including a novel few-shot learning strategy for custom-tailored few-shot example selection per request. PheNormGPT was evaluated in the BioCreative VIII Track 3: Genetic Phenotype Extraction from Dysmorphology Physical Examination Entries shared task. PheNormGPT achieved an F1 score of 0.82 for standard …

Neuregulin1 Nuclear Signaling Influences Adult Neurogenesis And Regulates A Schizophrenia Susceptibility Gene Network Within The Mouse Dentate Gyrus, Prithviraj Rajebhosale, Alice Jone, Kory R Johnson, Rohan Hofland, Camille Palarpalar, Samara Khan, Lorna W Role, David A Talmage

Faculty, Staff and Student Publications

Neuregulin1 (Nrg1) signaling is critical for neuronal development and function from fate specification to synaptic plasticity. Type III Nrg1 is a synaptic protein which engages in bidirectional signaling with its receptor ErbB4. Forward signaling engages ErbB4 phosphorylation, whereas back signaling engages two known mechanisms: (1) local axonal PI3K-AKT signaling and (2) cleavage by γ-secretase resulting in cytosolic release of the intracellular domain (ICD), which can traffic to the nucleus (Bao et al., 2003; Hancock et al., 2008). To dissect the contribution of these alternate signaling strategies to neuronal development, we generated a transgenic mouse with a missense mutation (V

Therapeutic Approaches To Modulate The Immune Microenvironment In Gliomas, Andreas Sarantopoulos, Chibawanye Ene, Elisa Aquilanti

Faculty, Staff and Student Publications

Immunomodulatory therapies, including immune checkpoint inhibitors, have drastically changed outcomes for certain cancer types over the last decade. Gliomas are among the cancers that have seem limited benefit from these agents, with most trials yielding negative results. The unique composition of the glioma immune microenvironment is among the culprits for this lack of efficacy. In recent years, several efforts have been made to improve understanding of the glioma immune microenvironment, aiming to pave the way for novel therapeutic interventions. In this review, we discuss some of the main components of the glioma immune microenvironment, including macrophages, myeloid-derived suppressor cells, neutrophils …

Impact Of Select Actionable Genomic Alterations On Efficacy Of Neoadjuvant Immunotherapy In Resectable Non-Small Cell Lung Cancer, Nicolas Zhou, Cheuk H Leung, William N William, Annikka Weissferdt, Apar Pataer, Myrna C B Godoy, Brett W Carter, Frank V Fossella, Anne S Tsao, George R Blumenschein, Xiuning Le, Jianjun Zhang, Ferdinandos Skoulidis, Jonathan M Kurie, Mehmet Altan, Charles Lu, Bonnie S Glisson, Lauren A Byers, Yasir Y Elamin, Reza J Mehran, David C Rice, Garrett L Walsh, Wayne L Hofstetter, Jack A Roth, Hai T Tran, Jia Wu, Luisa M Solis Soto, Humam Kadara, Stephen G Swisher, Ara A Vaporciyan, Don L Gibbons, Heather Y Lin, J Jack Lee, John V Heymach, Marcelo V Negrao, Boris Sepesi, Tina Cascone

Faculty, Staff and Student Publications

Background: Neoadjuvant immune checkpoint inhibitors (ICIs) have improved survival outcomes compared with chemotherapy in resectable non-small cell lung cancer (NSCLC). However, the impact of actionable genomic alterations (AGAs) on the efficacy of neoadjuvant ICIs remains unclear. We report the influence of AGAs on treatment failure (TF) in patients with resectable NSCLC treated with neoadjuvant ICIs.

Methods: Tumor molecular profiles were obtained from patients with stage I-IIIA resectable NSCLC (American Joint Committee on Cancer seventh edition) treated with either neoadjuvant nivolumab (N, n=23) or nivolumab+ipilimumab (NI, n=21) followed by surgery in a previously reported phase-2 randomized study (NCT03158129). TF …

The Dleu2/Mir-15a/Mir-16-1 Cluster Shapes The Immune Microenvironment Of Chronic Lymphocytic Leukemia, Ronghua Zhang, Priyanka Khare, Priyanka Banerjee, Cristina Ivan, Sarah Schneider, Federica Barbaglio, Karen Clise-Dwyer, Vanessa Behrana Jensen, Erika Thompson, Marisela Mendoza, Nicholas Chiorazzi, Shih-Shih Chen, Xiao-Jie Joy Yan, Nitin Jain, Paolo Ghia, Federico Caligaris-Cappio, Rima Mendonsa, Sashi Kasimsetty, Ryan Swoboda, Recep Bayraktar, William Wierda, Varsha Gandhi, George A Calin, Michael J Keating, Maria Teresa Sabrina Bertilaccio

Faculty, Staff and Student Publications

The development and progression of chronic lymphocytic leukemia (CLL) depend on genetic abnormalities and on the immunosuppressive microenvironment. We have explored the possibility that genetic drivers might be responsible for the immune cell dysregulation that shapes the protumor microenvironment. We performed a transcriptome analysis of coding and non-coding RNAs (ncRNAs) during leukemia progression in the Rag2-/-γc-/- MEC1-based xenotransplantation model. The DLEU2/miR-16 locus was found downmodulated in monocytes/macrophages of leukemic mice. To validate the role of this cluster in the tumor immune microenvironment, we generated a mouse model that simultaneously mimics the overexpression of hTCL1 and the germline deletion of the …

Optical Genome Mapping For Detection Of Bcr::Abl1-Another Tool In Our Toolbox, Zhenya Tang, Wei Wang, Gokce A Toruner, Shimin Hu, Hong Fang, Jie Xu, M James You, L Jeffrey Medeiros, Joseph D Khoury, Guilin Tang

Faculty, Staff and Student Publications

Background:BCR::ABL1 fusion is mostly derived from a reciprocal translocation t(9;22)(q34.1;q11.2) and is rarely caused by insertion. Various methods have been used for the detection of t(9;22)/BCR::ABL1, such as G-banded chromosomal analysis, fluorescence in situ hybridization (FISH), quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) and optical genome mapping (OGM). Understanding the strengths and limitations of each method is essential for the selection of appropriate method(s) of disease diagnosis and/or during the follow-up.

Methods: We compared the results of OGM, chromosomal analysis, FISH, and/or RT-PCR in 12 cases with BCR::ABL1.

Results:BCR:ABL1 was detected by FISH and RT-PCR …

Unmasking Neuroendocrine Prostate Cancer With A Machine Learning-Driven Seven-Gene Stemness Signature That Predicts Progression, Agustina Sabater, Pablo Sanchis, Rocio Seniuk, Gaston Pascual, Nicolas Anselmino, Daniel F Alonso, Federico Cayol, Elba Vazquez, Marcelo Marti, Javier Cotignola, Ayelen Toro, Estefania Labanca, Juan Bizzotto, Geraldine Gueron

Faculty, Staff and Student Publications

Prostate cancer (PCa) poses a significant global health challenge, particularly due to its progression into aggressive forms like neuroendocrine prostate cancer (NEPC). This study developed and validated a stemness-associated gene signature using advanced machine learning techniques, including Random Forest and Lasso regression, applied to large-scale transcriptomic datasets. The resulting seven-gene signature (KMT5C, DPP4, TYMS, CDC25B, IRF5, MEN1, and DNMT3B) was validated across independent cohorts and patient-derived xenograft (PDX) models. This signature demonstrated strong prognostic value for progression-free, disease-free, relapse-free, metastasis-free, and overall survival. Importantly, the signature not only identified specific NEPC subtypes, …

Nutritional Intervention As Adjuvant Therapy For T-Cell Acute Lymphoblastic Leukemia, Miriam B Garcia, Palaniraja Thandapani

Faculty, Staff and Student Publications

No abstract provided.

Impact Of Pik3ca Gain And Pten Loss On Mantle Cell Lymphoma Biology And Sensitivity To Targeted Therapies, Nardjas Bettazova, Jana Senavova, Kristyna Kupcova, Dana Sovilj, Anezka Rajmonova, Ladislav Andera, Karla Svobodova, Adela Berkova, Zuzana Zemanova, Lenka Daumova, Vaclav Herman, Alexandra Dolníkova, R Eric Davis, Marek Trneny, Pavel Klener, Ondrej Havranek

Faculty, Staff and Student Publications

Besides many other mutations in known cancer driver genes, mantle cell lymphoma (MCL) is characterized by recurrent genetic alterations of important regulators of the phosphoinositol-3-kinase (PI3K) cascade including PIK3CA gains and PTEN losses. To evaluate the biological and functional consequences of these aberrations in MCL, we have introduced transgenic expression of PIK3CA (PIK3CA UP) and performed knockout/knockdown of PTEN gene (PTEN KO/KD) in 5 MCL cell lines. The modified cell lines were tested for associated phenotypes including dependence on upstream B-cell receptor (BCR) signaling (by an additional BCR knockout). PIK3CA overexpression decreased the dependence of the tested MCL on prosurvival …

Comments On The Paper “Data-Driven Gating (Ddg)-Based Motion Match For Improved Ctac Registration Ejnmmi Physics 2024; 11(1):42”, Tinsu Pan

Faculty, Staff and Student Publications

Misregistration between CT and PET in PET/CT is mainly caused by respiratory motion or irregular respiration during the CT scan in PET/CT. Other than repeat CT, repeat PET/CT, or data-driven gated (DDG) CT, there is no practical approach to mitigate the misregistration artifacts and subsequent CT attenuation correction (CTAC) of the PET data. DDG PET derives a respiratory motion model based on the multiple phases of PET images without hardware gating and it allows for a potential correction of the misregistration artifacts based on the respiratory motion model. The purpose of this commentary was to compare the recent two publications …