Medical Specialties Commons^™

Pbi-05204, A Supercritical Co2 Extract Of Nerium Oleander, Suppresses Glioblastoma Stem Cells By Inhibiting Grp78 And Inducing Programmed Necroptotic Cell, Sharmistha Chakraborty, Daoyan Wei, Megan Tran, Frederick F Lang, Robert A Newman, Peiying Yang

Faculty, Staff and Student Publications

Successful treatment of glioblastoma multiforme (GBM), an aggressive form of primary brain neoplasm, mandates the need to develop new therapeutic strategies. In this study, we investigated the potential of PBI-05204 in targeting GBM stem cells (GSCs) and the underlying mechanisms. Treatment with PBI-05204 significantly reduced both the number and size of tumor spheres derived from patient-derived GSCs (GBM9, GSC28 and TS543), and suppressed the tumorigenesis of GBM9 xenografts. Moreover, PBI-05204 treatment led to a significant decrease in the expression of CD44 and NANOG, crucial markers of progenitor stem cells, in GBM9 and GSC28 GSCs. This treatment also down-regulated GRP78 expression …

Inhibition Of Lysine Acetyltransferase Kat6 In Er+Her2− Metastatic Breast Cancer: A Phase 1 Trial, Toru Mukohara, Yeon Hee Park, David Sommerhalder, Kan Yonemori, Erika Hamilton, Sung-Bae Kim, Jee Hyun Kim, Hiroji Iwata, Toshinari Yamashita, Rachel M Layman, Monica Mita, Timothy Clay, Yee Soo Chae, Catherine Oakman, Fengting Yan, Gun Min Kim, Seock-Ah Im, Geoffrey J Lindeman, Hope S Rugo, Marlon Liyanage, Michelle Saul, Christophe Le Corre, Athanasia Skoura, Li Liu, Meng Li, Patricia M Lorusso

Faculty, Staff and Student Publications

Inhibition of histone lysine acetyltransferases (KATs) KAT6A and KAT6B has shown antitumor activity in estrogen receptor-positive (ER+) breast cancer preclinical models. PF-07248144 is a selective catalytic inhibitor of KAT6A and KAT6B. In the present study, we report the safety, pharmacokinetics (PK), pharmacodynamics, efficacy and biomarker results from the first-in-human, phase 1 dose escalation and dose expansion study (n = 107) of PF-07248144 monotherapy and fulvestrant combination in heavily pretreated ER+ human epidermal growth factor receptor-negative (HER2−) metastatic breast cancer (mBC). The primary objectives of assessing the safety and tolerability and determining the recommended dose for expansion of PF-07248144, as …

Metronidazole May Display Anti-Inflammatory Features In Periodontitis Treatment: A Scoping Review, Lina J Suárez, Roger M Arce, Cristiane Gonçalves, Camila Pinheiro Furquim, Nidia Castro Dos Santos, Belén Retamal-Valdes, Magda Feres

Faculty, Staff and Student Publications

Aim: Metronidazole (MTZ) is an antimicrobial agent used to treat anaerobic infections. It has been hypothesized that MTZ may also have anti-inflammatory properties, but the evidence is limited and has not been previously reviewed. Thus, this scoping review aimed to answer the following question: "What is the evidence supporting anti-inflammatory properties of metronidazole that are not mediated by its antimicrobial effects?"

Methods: A scoping review was conducted according to the PRISMA-ScR statement. Five databases were searched up to January 2023 for studies evaluating the anti-inflammatory properties of MTZ used as monotherapy for treating infectious and inflammatory diseases.

Results: A total …

Estimating The Direct Effects Of The Genetic Liabilities To Bipolar Disorder, Schizophrenia, And Behavioral Traits On Suicide Attempt Using A Multivariable Mendelian Randomization Approach, Brenda Cabrera-Mendoza, Necla Aydin, Gabriel R Fries, Anna R Docherty, Consuelo Walss-Bass, Renato Polimanti

Faculty, Staff and Student Publications

Bipolar disorder (BD) and schizophrenia (SZ) are associated with higher odds of suicide attempt (SA). In this study, we aimed to explore the effect of BD and SZ genetic liabilities on SA, also considering the contribution of behavioral traits, socioeconomic factors, and substance use disorders. Leveraging large-scale genome-wide association data from the Psychiatric Genomics Consortium (PGC) and the UK Biobank (UKB), we conducted a two-sample Mendelian randomization (MR) analysis to evaluate the putative causal effect of BD (41,917 cases, 371,549 controls) and SZ (53,386 cases, 77,258 controls) on SA (26,590 cases, 492,022 controls). Then, we assessed the putative causal effect …

Markov Models For Clinical Decision-Making In Radiation Oncology: A Systematic Review, Lucas B Mccullum, Aysenur Karagoz, Cem Dede, Raul Garcia, Fatemeh Nosrat, Mehdi Hemmati, Seyedmohammadhossein Hosseinian, Andrew J Schaefer, Clifton D Fuller

Faculty, Staff and Student Publications

The intrinsic stochasticity of patients' response to treatment is a major consideration for clinical decision-making in radiation therapy. Markov models are powerful tools to capture this stochasticity and render effective treatment decisions. This paper provides an overview of the Markov models for clinical decision analysis in radiation oncology. A comprehensive literature search was conducted within MEDLINE using PubMed, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Only studies published from 2000 to 2023 were considered. Selected publications were summarized in two categories: (i) studies that compare two (or more) fixed treatment policies using Monte Carlo simulation …

Pb-05204, A Supercritical Co2 Extract Of Nerium Oleander, Suppresses Glioblastoma Stem Cells By Inhibiting Grp78 And Inducing Programmed Necroptotic Cell Death, Sharmistha Chakraborty, Daoyan Wei, Megan Tran, Frederick F Lang, Robert A Newman, Peiying Yang

Faculty, Staff and Student Publications

Successful treatment of glioblastoma multiforme (GBM), an aggressive form of primary brain neoplasm, mandates the need to develop new therapeutic strategies. In this study, we investigated the potential of PBI-05204 in targeting GBM stem cells (GSCs) and the underlying mechanisms. Treatment with PBI-05204 significantly reduced both the number and size of tumor spheres derived from patient-derived GSCs (GBM9, GSC28 and TS543), and suppressed the tumorigenesis of GBM9 xenografts. Moreover, PBI-05204 treatment led to a significant decrease in the expression of CD44 and NANOG, crucial markers of progenitor stem cells, in GBM9 and GSC28 GSCs. This treatment also down-regulated GRP78 expression …

Pharmacodynamic Activity Of [18f]-Fluorthanatrace Poly(Adp-Ribose) Polymerase Positron Emission Tomography In Patients With Brca1/2-Mutated Breast Cancer Receiving Talazoparib, Lilie L Lin, Franklin Wong, Ruitao Lin, Timothy Yap, Jennifer K Litton

Faculty, Staff and Student Publications

Purpose: We tested the ability of [18F] fluorthanatrace (FTT), a radiolabeled analog of poly(ADP-ribose) polymerase (PARP)-1 inhibitors, to demonstrate target engagement on positron emission tomography (PET) scans from patients with newly diagnosed primary breast cancer receiving the PARP inhibitor (PARPi) talazoparib.

Methods: Seven patients with germline BRCA1/2 pathogenic variants underwent [18F]FTT PET-computed tomography scanning at baseline, and five underwent repeat scanning 14 days after talazoparib initiation. Maximum uptake on PET was quantified in the primary tumor, involved nodes, contralateral pectoralis muscle, and lumbar vertebra body level 3, and compared between the two time points.

Results: Blocking of [18F]FTT was observed …

Patient Education Practices And Preferences Of Radiation Oncologists And Interprofessional Radiation Therapy Care Teams: A Mixed-Methods Study Exploring Strategies For Effective Patient Education Delivery, Jie Jane Chen, Anna M Brown, Allison E Garda, Ellen Kim, Sarah A Mcavoy, Subha Perni, Michael K Rooney, Kevin Shiue, Kristi L Tonning, Laura E Warren, Daniel W Golden, Jennifer M Croke

Faculty, Staff and Student Publications

Purpose: Patients' understanding of radiation therapy (RT) and data regarding optimal approaches to patient education (PE) within radiation oncology (RO) are limited. We aimed to evaluate PE practices of radiation oncologists and interprofessional RT care team members to inform recommendations for delivering inclusive and accessible PE.

Methods and materials: An anonymous survey was administered to all Radiation Oncology Education Collaborative Study Group members (10/5/22-11/23/22). Respondent demographics, individual practices/preferences, and institutional practices were collected. Qualitative items explored strategies, challenges, and desired resources for PE. Descriptive statistics summarized survey responses. The Fisher exact test compared PE practices by respondent role and PE …

Proteomics In Orthopedic Research: Recent Studies And Their Translational Implications, George Li, Argyrios Stampas, Yoshihiro Komatsu, Xueqin Gao, Johnny Huard, Sheng Pan

Faculty, Staff and Student Publications

Proteomics is a growing field that offers insights into various aspects of disease processes and therapy responses. Within the field of orthopedics, there are a variety of diseases that have a poor prognosis due to a lack of targeted curative therapy or disease modifying therapy. Other diseases have been difficult to manage in part due to lack of clinical biomarkers that offer meaningful insight into disease progression or severity. As an emerging technology, proteomics has been increasingly applied in studying bone biology and an assortment of orthopedics related diseases, such as osteoarthritis, osteosarcoma and bone tumors, osteoporosis, traumatic bone injury, …

A First-In-Class Selective Inhibitor Of Egfr And Pi3k Offers A Single-Molecule Approach To Targeting Adaptive Resistance, Christopher E Whitehead, Elizabeth K Ziemke, Christy L Frankowski-Mcgregor, Rachel A Mumby, June Chung, Jinju Li, Nathaniel Osher, Oluwadara Coker, Veerabhadran Baladandayuthapani, Scott Kopetz, Judith S Sebolt-Leopold

Faculty, Staff and Student Publications

Despite tremendous progress in precision oncology, adaptive resistance mechanisms limit the long-term effectiveness of molecularly targeted agents. Here we evaluated the pharmacological profile of MTX-531 that was computationally designed to selectively target two key resistance drivers, epidermal growth factor receptor and phosphatidylinositol 3-OH kinase (PI3K). MTX-531 exhibits low-nanomolar potency against both targets with a high degree of specificity predicted by cocrystal structural analyses. MTX-531 monotherapy uniformly resulted in tumor regressions of squamous head and neck patient-derived xenograft (PDX) models. The combination of MTX-531 with mitogen-activated protein kinase kinase or KRAS-G12C inhibitors led to durable regressions of BRAF-mutant or KRAS-mutant colorectal …

Perioperative Nivolumab Versus Observation In Patients With Renal Cell Carcinoma Undergoing Nephrectomy (Prosper Ecog-Acrin Ea8143): An Open-Label, Randomised, Phase 3 Study, Mohamad E Allaf, Se-Eun Kim, Viraj Master, David F Mcdermott, Lauren C Harshman, Suzanne M Cole, Charles G Drake, Sabina Signoretti, Mahmut Akgul, Nicholas Baniak, Elsa Li-Ning, Matthew B Palmer, Hamid Emamekhoo, Nabil Adra, Hristos Kaimakliotis, Yasser Ged, Phillip M Pierorazio, E Jason Abel, Mehmet A Bilen, Kenneth Ogan, Helen H Moon, Krishna A Ramaswamy, Eric A Singer, Tina M Mayer, Jay Lohrey, Vitaly Margulis, Jessie Gills, Scott E Delacroix, Mark J Waples, Andrew C James, Peng Wang, Toni Choueiri, M Dror Michaelson, Anil Kapoor, Daniel Y Heng, Brian Shuch, Bradley C Leibovich, Primo N Lara, Judith Manola, Deborah Maskens, Dena Battle, Robert Uzzo, Gennady Bratslavsky, Naomi B Haas, Michael A Carducci

Faculty, Staff and Student Publications

Background: The standard of care for patients with intermediate-to-high risk renal cell carcinoma is partial or radical nephrectomy followed by surveillance. We aimed to investigate use of nivolumab before nephrectomy followed by adjuvant nivolumab in patients with high-risk renal cell carcinoma to determine recurrence-free survival compared with surgery only.

Methods: In this open-label, randomised, phase 3 trial (PROSPER EA8143), patients were recruited from 183 community and academic sites across the USA and Canada. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, with previously untreated clinical stage T2 or greater or …

Updated Understanding Of The Protein-Dna Recognition Code Used By C2h2 Zinc Finger Proteins, Xing Zhang, Robert M Blumenthal, Xiaodong Cheng

Faculty, Staff and Student Publications

C2H2 zinc-finger (ZF) proteins form the largest family of DNA-binding transcription factors coded by mammalian genomes. In a typical DNA-binding ZF module, there are twelve residues (numbered from -1 to -12) between the last zinc-coordinating cysteine and the first zinc-coordinating histidine. The established C2H2-ZF "recognition code" suggests that residues at positions -1, -4, and -7 recognize the 5', central, and 3' bases of a DNA base-pair triplet, respectively. Structural studies have highlighted that additional residues at positions -5 and -8 also play roles in specific DNA recognition. The presence of bulky and either charged or polar residues at these five …

P53r172h And P53r245w Hotspot Mutations Drive Distinct Transcriptomes In Mouse Mammary Tumors Through A Convergent Transcriptional Mediator, Joy M Mcdaniel, Rhiannon L Morrissey, Denada Dibra, Lalit R Patel, Shunbin Xiong, Yun Zhang, Gilda P Chau, Xiaoping Su, Yuan Qi, Adel K El-Naggar, Guillermina Lozano

Faculty, Staff and Student Publications

Aggressive breast cancers harbor TP53 missense mutations. Tumor cells with TP53 missense mutations exhibit enhanced growth and survival through transcriptional rewiring. To delineate how TP53 mutations in breast cancer contribute to tumorigenesis and progression in vivo, we created a somatic mouse model driven by mammary epithelial cell-specific expression of Trp53 mutations. Mice developed primary mammary tumors reflecting the human molecular subtypes of luminal A, luminal B, HER2-enriched, and triple-negative breast cancer with metastases. Transcriptomic analyses comparing MaPR172H/− or MaPR245W/− mammary tumors to MaP−/− tumors revealed (1) differences in cancer-associated pathways activated in both p53 …

A Qualitative Exploration To Inform An Oral Health Training For Disability Care Workers In Burkina Faso, Ave Põld, Dan Filwendé Kientega, Jocelyne Valérie Garé, Michael Lorenz

Faculty, Staff and Student Publications

AIM: To explore enablers and barriers to the creation of an oral health training for care workers at specialized centres for children with disabilities in Ouagadougou.

DESIGN: This was a formative study informed by the Theoretical Domains Framework using qualitative methods.

METHODS: Qualitative observations and 14 semi-structured interviews were conducted with care workers from six specialized centres for disability.

RESULTS: Carer workers emphasized that a successful oral health training must account for available resources and competencies in each specific centre. Part of the training must be dedicated to oral hygiene targeted for people with disabilities and provide knowledge about risk …

Sotatercept For Anemia Of Myelofibrosis: A Phase Ii Investigator-Initiated Study, Prithviraj Bose, Lucia Masarova, Naveen Pemmaraju, Sharon D Bledsoe, Naval G Daver, Elias J Jabbour, Tapan M Kadia, Zeev Estrov, Steven M Kornblau, Michael Andreeff, Nitin Jain, Jorge E Cortes, Gautam Borthakur, Yesid Alvarado, Mary Ann Richie, Mackenzie H Dobbins, Selene A Mccrackin, Lingsha Zhou, Sherry A Pierce, Xuemei Wang, Allison M Pike, Guillermo Garcia-Manero, Hagop M Kantarjian, Srdan Verstovsek

Faculty, Staff and Student Publications

No abstract provided.

Structural Dynamics In Α-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionic Acid Receptor Gating, Cuauhtemoc U Gonzalez, Vasanthi Jayaraman

Faculty, Staff and Student Publications

The ionotropic glutamate receptors (iGluRs) are comprised of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), N-methyl-d-aspartate receptor, kainate, and delta subtypes and are pivotal in neuronal plasticity. Recent structural studies on AMPA receptors reveal intricate conformational changes during activation and desensitization elucidating the steps from agonist binding to channel opening and desensitization. Additionally, interactions with auxiliary subunits, including transmembrane AMPA-receptor regulatory proteins, germ-cell-specific gene 1-like protein, and cornichon homologs, intricately modulate AMPA receptors. We discuss the recent high-resolution structures of these complexes that unveil stoichiometry, subunit positioning, and differences in specific side-chain interactions that influence these functional modulations.

Case-Case Genome-Wide Analyses Identify Subtype-Informative Variants That Confer Risk For Breast Cancer, Xiaohui Sun, Shiv P Verma, Guochong Jia, Xinjun Wang, Jie Ping, Xingyi Guo, Xiao-Ou Shu, Jianhong Chen, Andriy Derkach, Qiuyin Cai, Xiaolin Liang, Jirong Long, Kenneth Offit, Jung H Oh, Anne S Reiner, Gordon P Watt, Meghan Woods, Yaohua Yang, Christine B Ambrosone, Stefan Ambs, Yu Chen, Patrick Concannon, Montserrat Garcia-Closas, Jian Gu, Christopher A Haiman, Jennifer J Hu, Dezheng Huo, Esther M John, Julia A Knight, Christopher I Li, Charles F Lynch, Lene Mellemkjær, Katherine L Nathanson, Barbara Nemesure, Olufunmilayo I Olopade, Andrew F Olshan, Tuya Pal, Julie R Palmer, Michael F Press, Maureen Sanderson, Dale P Sandler, Melissa A Troester, Wei Zheng, Jonine L Bernstein, Matthew F Buas, Xiang Shu

Faculty, Staff and Student Publications

Breast cancer includes several subtypes with distinct characteristic biological, pathologic, and clinical features. Elucidating subtype-specific genetic etiology could provide insights into the heterogeneity of breast cancer to facilitate the development of improved prevention and treatment approaches. In this study, we conducted pairwise case-case comparisons among five breast cancer subtypes by applying a case-case genome-wide association study (CC-GWAS) approach to summary statistics data of the Breast Cancer Association Consortium. The approach identified 13 statistically significant loci and eight suggestive loci, the majority of which were identified from comparisons between triple-negative breast cancer (TNBC) and luminal A breast cancer. Associations of lead …

Why Do Patients With Cancer Die?, Adrienne Boire, Katy Burke, Thomas R Cox, Theresa Guise, Mariam Jamal-Hanjani, Tobias Janowitz, Rosandra Kaplan, Rebecca Lee, Charles Swanton, Matthew G Vander Heiden, Erik Sahai

Faculty, Staff and Student Publications

Cancer is a major cause of global mortality, both in affluent countries and increasingly in developing nations. Many patients with cancer experience reduced life expectancy and have metastatic disease at the time of death. However, the more precise causes of mortality and patient deterioration before death remain poorly understood. This scarcity of information, particularly the lack of mechanistic insights, presents a challenge for the development of novel treatment strategies to improve the quality of, and potentially extend, life for patients with late-stage cancer. In addition, earlier deployment of existing strategies to prolong quality of life is highly desirable. In this …

A Comparison Of Available Guidelines For The Detection Of Cauda Equina Syndrome And Assessing The Need For Further Clinical Guidance In Ireland, Lorcan Gavin, Michael G Curran, John P Mccabe

Faculty, Staff and Student Publications

The cauda equina syndrome (CES) is a rare but critical disorder, which can result in devastating motor weakness and sensory deficit, alongside often irreversible bladder, bowel and sexual dysfunction. In addition to the clinical burden of disease, this syndrome results in a disproportionately high medicolegal strain due to missed or delayed diagnoses. Despite being an emergency diagnosis, often necessitating urgent surgical decompression to treat, we believe there is a lack of clarity for clinicians in the current literature, with no published Irish guideline concerning screening or detection. The current study aims to identify and analyse appropriate guidelines in relation to …

T-Bet Suppresses Proliferation Of Malignant B Cells In Chronic Lymphocytic Leukemia, Philipp M Roessner, Isabelle Seufert, Vicente Chapaprieta, Ruparoshni Jayabalan, Hannah Briesch, Ramon Massoni-Badosa, Pavle Boskovic, Julian Benckendorff, Tobias Roider, Lavinia Arseni, Mariana Coelho, Supriya Chakraborty, Alicia M Vaca, Mariela Sivina, Markus Muckenhuber, Sonia Rodriguez-Rodriguez, Alice Bonato, Sophie A Herbst, Marc Zapatka, Clare Sun, Helene Kretzmer, Thomas Naake, Peter-Martin Bruch, Felix Czernilofsky, Elisa Ten Hacken, Martin Schneider, Dominic Helm, Deyan Y Yosifov, Joseph Kauer, Alexey V Danilov, Moritz Bewarder, Kristina Heyne, Christof Schneider, Stephan Stilgenbauer, Adrian Wiestner, Jan-Philipp Mallm, Jan A Burger, Dimitar G Efremov, Peter Lichter, Sascha Dietrich, José I Martin-Subero, Karsten Rippe, Martina Seiffert

Faculty, Staff and Student Publications

The T-box transcription factor T-bet is known as a master regulator of the T-cell response but its role in malignant B cells has not been sufficiently explored. Here, we conducted single-cell resolved multi-omics analyses of malignant B cells from patients with chronic lymphocytic leukemia (CLL) and studied a CLL mouse model with a genetic knockout of Tbx21. We found that T-bet acts as a tumor suppressor in malignant B cells by decreasing their proliferation rate. NF-κB activity, induced by inflammatory signals provided by the microenvironment, triggered T-bet expression, which affected promoter-proximal and distal chromatin coaccessibility and controlled a specific gene …

Outcome Of 3q262/Mecom Rearrangements In Chronic Myeloid Leukemia, Hiroki Akiyama, Hagop Kantarjian, Elias Jabbour, Ghayas Issa, Fadi G Haddad, Nicholas J Short, Shimin Hu, Jo Ishizawa, Michael Andreeff, Koji Sasaki

Faculty, Staff and Student Publications

Study aims: To evaluate the outcomes of patients with 3q26.2/MECOM-rearranged chronic myeloid leukemia (CML).

Methods: We reviewed consecutive adult patients with 3q26.2/MECOM-rearranged CML between January 1, 1998 and February 16, 2023. Rearrangements of 3q26.2/MECOM were confirmed by conventional cytogenetics, and fluorescence in situ hybridization starting in 2015.

Results: We identified 55 patients with MECOM-rearranged CML, including 23 in chronic phase (CP) or accelerated phase (AP) and 32 in blast phase (BP). Nine patients (16%) achieved a major cytogenetic response (MCyR) or deeper. At a median follow-up of 89 months, median survival was 14 months. The 5-year survival rate was 19% …

Safety And Efficacy Of Percutaneous Image-Guided Ablation For Soft Tissue Sarcoma Metastases To The Liver, Ahmed Awad, Koustav Pal, Steven Yevich, Joshua D Kuban, Alda Tam, Bruno C Odisio, Sanjay Gupta, Peiman Habibollahi, Andrew J Bishop, Anthony Paul Conley, Neeta Somaiah, Dejka M Araujo, Maria Alejandra Zarzour, Ravin Ratan, Christina L Roland, Emily Z Keung, Steven Y Huang, Rahul A Sheth

Faculty, Staff and Student Publications

Purpose: To evaluate outcomes following percutaneous image-guided ablation of soft tissue sarcoma metastases to the liver.

Materials and methods: A single-institution retrospective analysis of patients with a diagnosis of metastatic soft tissue sarcoma who underwent percutaneous image-guided ablation of hepatic metastases between January 2011 and December 2021 was performed. Patients with less than 60 days of follow-up after ablation were excluded. The primary outcome was local tumor progression-free survival (LPFS). Secondary outcomes included overall survival, liver-specific progression-free survival. and chemotherapy-free survival.

Results: Fifty-five patients who underwent percutaneous ablation for 84 metastatic liver lesions were included. The most common histopathological subtypes …

Tumoral Interferon Beta Induces An Immune-Stimulatory Phenotype In Tumor-Associated Macrophages In Melanoma Brain Metastases, Julia Gellert, Dennis A Agardy, Swaminathan Kumar, Alexandros Kourtesakis, Tamara Boschert, Kristine Jähne, Michael O Breckwoldt, Lukas Bunse, Wolfgang Wick, Michael A Davies, Michael Platten, Theresa Bunse

Faculty, Staff and Student Publications

Type I interferons (IFN) are immune-stimulatory cytokines involved in antiviral and antitumor immune responses. They enhance the efficacy of immunogenic anticancer therapies such as radiotherapy by activating both innate and adaptive immune cells. Macrophages are one of the most abundant innate immune cells in the immune microenvironment of melanoma brain metastases (MBM) and can exert potent immune-suppressive functions. Here, we investigate the potential of tumoral type I IFNs to repolarize tumor-associated macrophages (TAM) in two murine MBM models and assess the effects of radiotherapy-induced type I IFN on TAMs in a transcriptomic MBM patient dataset. In mice, we describe a …

Auto-Segmentation Of Adult-Type Diffuse Gliomas: Comparison Of Transfer Learning-Based Convolutional Neural Network Model Vs Radiologists, Qi Wan, Jisoo Kim, Clifford Lindsay, Xin Chen, Jing Li, J Bryan Iorgulescu, Raymond Y Huang, Chenxi Zhang, David Reardon, Geoffrey S Young, Lei Qin

Faculty, Staff and Student Publications

Segmentation of glioma is crucial for quantitative brain tumor assessment, to guide therapeutic research and clinical management, but very time-consuming. Fully automated tools for the segmentation of multi-sequence MRI are needed. We developed and pretrained a deep learning (DL) model using publicly available datasets A (n = 210) and B (n = 369) containing FLAIR, T2WI, and contrast-enhanced (CE)-T1WI. This was then fine-tuned with our institutional dataset (n = 197) containing ADC, T2WI, and CE-T1WI, manually annotated by radiologists, and split into training (n = 100) and testing (n = 97) sets. The Dice similarity coefficient (DSC) was used to …

Acute Myeloid Leukemia With Mast Cell Differentiation Is Characterized By Interstitial Mast Cells, Complex Karyotype, Do Hwan Kim, Sa A Wang, Wei Wang, Guilin Tang, Shaoying Li, C Cameron Yin, Pei Lin, Marina Konopleva, M James You, Roberto N Miranda, Xiaoqiong Wang, Qing Wei, L Jeffrey Medeiros, Jie Xu

Faculty, Staff and Student Publications

No abstract provided.

T-Cell-Rich Hodgkin Lymphoma With Features Of Classic Hodgkin Lymphoma And Nodular Lymphocyte-Predominant Hodgkin Lymphoma: A Borderline Category With Overlapping Morphologic And Immunophenotypic Features, Siba El Hussein, Hong Fang, Fatima Zahra Jelloul, Wei Wang, Sanam Loghavi, Roberto N Miranda, Jonathan W Friedberg, W Richard Burack, Andrew G Evans, Jie Xu, L Jeffrey Medeiros

Faculty, Staff and Student Publications

Context.—: It is known that a subset of cases of classic Hodgkin lymphoma (CHL) with B-cell-rich nodules (lymphocyte-rich CHL) exhibits morphologic and immunophenotypic features that overlap with nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), raising diagnostic difficulties that can be resolved in most cases by performing an adequate battery of immunohistochemical studies.

Objective.—: To fully characterize cases of T-cell-rich Hodgkin lymphoma where a specific diagnosis of NLPHL (ie, pattern D) or CHL could not be made even after complete immunophenotypic investigation.

Design.—: The clinical, immunomorphologic, and molecular (when applicable) presentation of 3 cases of T-cell-rich Hodgkin lymphoma was thoroughly investigated.

Results.—: These …

A Joint Estro And Aapm Guideline For Development, Clinical Validation And Reporting Of Artificial Intelligence Models In Radiation Therapy, Coen Hurkmans, Jean-Emmanuel Bibault, Kristy K Brock, Wouter Van Elmpt, Mary Feng, Clifton David Fuller, Barbara A Jereczek-Fossa, Stine Korreman, Guillaume Landry, Frederic Madesta, Chuck Mayo, Alan Mcwilliam, Filipe Moura, Ludvig P Muren, Issam El Naqa, Jan Seuntjens, Vincenzo Valentini, Michael Velec

Faculty, Staff and Student Publications

Background and purpose: Artificial Intelligence (AI) models in radiation therapy are being developed with increasing pace. Despite this, the radiation therapy community has not widely adopted these models in clinical practice. A cohesive guideline on how to develop, report and clinically validate AI algorithms might help bridge this gap.

Methods and materials: A Delphi process with all co-authors was followed to determine which topics should be addressed in this comprehensive guideline. Separate sections of the guideline, including Statements, were written by subgroups of the authors and discussed with the whole group at several meetings. Statements were formulated and scored as …

Cluster-Based Toxicity Estimation Of Osteoradionecrosis Via Unsupervised Machine Learning: Moving Beyond Single Dose-Parameter Normal Tissue Complication Probability By Using Whole Dose-Volume Histograms For Cohort Risk Stratification, Seyedmohammadhossein Hosseinian, Mehdi Hemmati, Cem Dede, Travis C Salzillo, Lisanne V Van Dijk, Abdallah S R Mohamed, Stephen Y Lai, Andrew J Schaefer, Clifton D Fuller

Faculty, Staff and Student Publications

PURPOSE: Given the limitations of extant models for normal tissue complication probability estimation for osteoradionecrosis (ORN) of the mandible, the purpose of this study was to enrich statistical inference by exploiting structural properties of data and provide a clinically reliable model for ORN risk evaluation through an unsupervised-learning analysis that incorporates the whole radiation dose distribution on the mandible.

METHODS AND MATERIALS: The analysis was conducted on retrospective data of 1259 patients with head and neck cancer treated at The University of Texas MD Anderson Cancer Center between 2005 and 2015. During a minimum 12-month posttherapy follow-up period, 173 patients …

Human Platelet Lysate Enhances In Vivo Activity Of Car-Vδ2 T Cells By Reducing Cellular Senescence And Apoptosis, Feiyan Mo, Chiou-Tsun Tsai, Rong Zheng, Chonghui Cheng, Helen E Heslop, Malcolm K Brenner, Maksim Mamonkin, Norihiro Watanabe

Faculty, Staff and Students Publications

BACKGROUND AIMS: Vγ9Vδ2 T cells are an attractive cell platform for the off-the-shelf cancer immunotherapy as the result of their lack of alloreactivity and inherent multi-pronged cytotoxicity, which could be further amplified with chimeric antigen receptors (CARs). In this study, we sought to enhance the in vivo longevity of CAR-Vδ2 T cells by modulating ex vivo manufacturing conditions and selecting an optimal CAR costimulatory domain.

METHODS: Specifically, we compared the anti-tumor activity of Vδ2 T cells expressing anti-CD19 CARs with costimulatory endodomains derived from CD28, 4-1BB or CD27 and generated in either standard fetal bovine serum (FBS)- or human platelet …

Cerebellar Functions Beyond Movement And Learning, Linda H Kim, Detlef H Heck, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

The cerebellum has a well-established role in controlling motor functions, including coordination, posture, and the learning of skilled movements. The mechanisms for how it carries out motor behavior remain under intense investigation. Interestingly though, in recent years the mechanisms of cerebellar function have faced additional scrutiny since nonmotor behaviors may also be controlled by the cerebellum. With such complexity arising, there is now a pressing need to better understand how cerebellar structure, function, and behavior intersect to influence behaviors that are dynamically called upon as an animal experiences its environment. Here, we discuss recent experimental work that frames possible neural …