Medical Genetics Commons^™

How Erastin Assassinates Cells By Ferroptosis Revealed, Boyi Gan

Faculty, Staff and Student Publications

No abstract provided.

The Alpha7 Integrin Subunit In Astrocytes Promotes Endothelial Blood-Brain Barrier Integrity, Zhihua Chen, Jack R Kelly, John E Morales, Raymond C Sun, Arpan De, Joseph H Mccarty

Faculty, Staff and Student Publications

The blood-brain barrier (BBB) is a vascular endothelial cell boundary that partitions the circulation from the central nervous system to promote normal brain health. We have a limited understanding of how the BBB is formed during development and maintained in adulthood. We used quantitative transcriptional profiling to investigate whether specific adhesion molecules are involved in BBB functions, with an emphasis on understanding how astrocytes interact with endothelial cells. Our results reveal a striking enrichment of multiple genes encoding laminin subunits as well as the laminin receptor gene Itga7, which encodes the alpha7 integrin subunit, in astrocytes. Genetic ablation of Itga7 …

Sequential Targeting Of Retinoblastoma And Dna Synthesis Pathways Is A Therapeutic Strategy For Sarcomas That Can Be Monitored In Real Time, Tuyen Duong Thanh Nguyen, Yan Wang, Tuyen N Bui, Rossana Lazcano, Davis R Ingram, Varshini Vakulabharanam, Marc A Pina, Cansu Karakas, Mi Li, Nicole M Kettner, Neeta Somaiah, Peter J Hougton, Osama Mawlawi, Alexander J Lazar, Kelly K Hunt, Khandan Keyomarsi

Faculty, Staff and Student Publications

Treatment strategies with a strong scientific rationale based on specific biomarkers are needed to improve outcomes in patients with advanced sarcomas. Suppression of cell cycle progression through reactivation of the tumor suppressor retinoblastoma (Rb) using CDK4/6 inhibitors is a potential avenue for novel targeted therapies in sarcomas that harbor intact Rb signaling. Here, we evaluated combination treatment strategies (sequential and concomitant) with the CDK4/6 inhibitor abemacicib to identify optimal combination strategies. Expression of Rb was examined in 1043 sarcoma tumor specimens, and 50% were found to be Rb-positive. Using in vitro and in vivo models, an effective 2-step sequential combination …

Etnk1 Mutation Occurs In A Wide Spectrum Of Myeloid Neoplasms And Is Not Specific For Atypical Chronic Myeloid Leukemia, Wen Shuai, Zhuang Zuo, Nianyi Li, Sofia Garces, Fatima Zahra Jelloul, Shaoying Li, M James You, Wei Wang, Catherine Rehder, Elias J Jabbour, Keyur P Patel, L Jeffrey Medeiros, C Cameron Yin

Faculty, Staff and Student Publications

Background: ETNK1 mutation has been suggested as a useful tool to support the diagnosis of atypical chronic myeloid leukemia. ETNK1 mutations, however, occur in other myeloid neoplasms.

Methods: The authors assessed the clinicopathologic and molecular genetic features of 80 ETNK1-mutated myeloid neoplasms.

Results: Thirty-seven neoplasms (46%) were classified as myelodysplastic syndrome, 17 (21%) were classified as myelodysplastic/myeloproliferative neoplasm, 14 (18%) were classified as acute myeloid leukemia, and 12 (15%) were classified as myeloproliferative neoplasm. ETNK1 mutations were detected at the first test in 96% of patients, suggesting that ETNK1 mutation is an early event in pathogenesis. ETNK1 mutations represented the …

Validation Of The Alfa-1200 Model In Older Patients With Aml Treated With Intensive Chemotherapy, Hussein A Abbas, Hanxiao Sun, Sherry Pierce, Rashmi Kanagal-Shamanna, Ziyi Li, Gautam Borthakur, Elias Jabbour, Marina Konopleva, Nicholas J Short, Courtney Dinardo, Naval Daver, Farhad Ravandi, Tapan M Kadia

Faculty, Staff and Student Publications

No abstract provided.

Long-Term Morbidity And Mortality Among Survivors Of Neuroblastoma Diagnosed During Infancy: A Report From The Childhood Cancer Survivor Study, Danielle Novetsky Friedman, Pamela J Goodman, Wendy M Leisenring, Lisa R Diller, Susan L Cohn, Susan A Smith, Suzanne L Wolden, Joseph P Neglia, Kirsten K Ness, Todd M Gibson, Paul C Nathan, Brent R Weil, Leslie L Robison, Kevin C Oeffinger, Gregory T Armstrong, Charles A Sklar, Tara O Henderson

Faculty, Staff and Student Publications

Purpose: To describe the risk of late mortality, subsequent malignant neoplasms (SMNs), and chronic health conditions (CHCs) in survivors of neuroblastoma diagnosed in infancy by treatment era and exposures.

Methods: Among 5-year survivors of neuroblastoma in the Childhood Cancer Survivor Study diagnosed age < 1 year between 1970 and 1999, we examined the cumulative incidence of late (> 5 years from diagnosis) mortality, SMN, and CHCs (grades 2-5 and 3-5). Multivariable Cox regression models estimated hazard ratios (HRs) and 95% CIs by decade and treatment (surgery-alone v chemotherapy with or without surgery [C ± S] v radiation with or without chemotherapy ± surgery [R ± C ± S]) among survivors and between survivors and 5,051 …

Structure-Based Regulatory Role For The 5'Utr Of Rcnmv Rna2, Jennifer S H Im, Jasmine R Sheppard, K Andrew White

Faculty, Staff and Student Publications

Red clover necrotic mosaic virus (RCNMV) is a segmented positive-strand RNA virus consisting of RNA1 and RNA2. Previous studies demonstrated that efficient translation of RCNMV RNA2 requires de novo synthesis of RNA2 during infections, suggesting that RNA2 replication is required for its translation. We explored a potential mechanism underlying the regulation of replication-associated translation of RNA2 by examining RNA elements in its 5' untranslated region (5'UTR). Structural analysis of the 5'UTR suggested that it can form two mutually exclusive configurations: a more thermodynamically stable conformation, termed the 5'-basal stem structure (5'BS), in which 5'-terminal sequences are base paired, and an …

Differential Spatial Gene And Protein Expression Associated With Recurrence Following Chemoradiation For Localized Anal Squamous Cell Cancer, Sharia Hernandez, Prajnan Das, Emma B Holliday, Li Shen, Wei Lu, Craig A Messick, John Skibber, Ethan B Ludmir, Y Nancy You, Grace Li Smith, Brian Bednarski, Larisa Kostousov, Eugene J Koay, Bruce D Minsky, Matthew Tillman, Shaelynn Portier, Cathy Eng, Albert C Koong, George J Chang, Wai Chin Foo, Jing Wang, Luisa Solis Soto, Van K Morris

Faculty, Staff and Student Publications

The identification of transcriptomic and protein biomarkers prognosticating recurrence risk after chemoradiation of localized squamous cell carcinoma of the anus (SCCA) has been limited by a lack of available fresh tissue at initial presentation. We analyzed archival FFPE SCCA specimens from pretreatment biopsies prior to chemoradiation for protein and RNA biomarkers from patients with localized SCCA who recurred (N = 23) and who did not recur (N = 25). Tumor cells and the tumor microenvironment (TME) were analyzed separately to identify biomarkers with significantly different expression between the recurrent and non-recurrent groups. Recurrent patients had higher mean protein expression of …

Overall Survival With Daratumumab, Lenalidomide, And Dexamethasone In Previously Treated Multiple Myeloma (Pollux): A Randomized, Open-Label, Phase Iii Trial, Meletios A Dimopoulos, Albert Oriol, Hareth Nahi, Jesus San-Miguel, Nizar J Bahlis, Neil Rabin, Kenshi Suzuki, Torben Plesner, Sung-Soo Yoon, Dina Ben Yehuda, Paul G Richardson, Hartmut Goldschmidt, Donna Reece, Tahamtan Ahmadi, Xiang Qin, Wendy Garvin Mayo, Xue Gai, Jodi Carey, Robin Carson, Philippe Moreau

Faculty, Staff and Student Publications

Purpose: With the initial analysis of POLLUX at a median follow-up of 13.5 months, daratumumab in combination with lenalidomide and dexamethasone (D-Rd) significantly prolonged progression-free survival versus lenalidomide and dexamethasone (Rd) alone in patients with relapsed or refractory multiple myeloma (RRMM). We report updated efficacy and safety results at the time of final analysis for overall survival (OS).

Methods: POLLUX was a multicenter, randomized, open-label, phase III study during which eligible patients with ≥ 1 line of prior therapy were randomly assigned 1:1 to D-Rd or Rd until disease progression or unacceptable toxicity. After positive primary analysis and protocol amendment, …

Real-Time Liver Tumor Localization Via Combined Surface Imaging And A Single X-Ray Projection, Hua-Chieh Shao, Yunxiang Li, Jing Wang, Steve Jiang, You Zhang

Faculty, Staff and Student Publications

Objective. Real-time imaging, a building block of real-time adaptive radiotherapy, provides instantaneous knowledge of anatomical motion to drive delivery adaptation to improve patient safety and treatment efficacy. The temporal constraint of real-time imaging (< 500 milliseconds) significantly limits the imaging signals that can be acquired, rendering volumetric imaging and 3D tumor localization extremely challenging. Real-time liver imaging is particularly difficult, compounded by the low soft tissue contrast within the liver. We proposed a deep learning (DL)-based framework (Surf-X-Bio), to track 3D liver tumor motion in real-time from combined optical surface image and a single on-board x-ray projection.

Approach. Surf-X-Bio performs mesh-based deformable registration to track/localize liver tumors volumetrically via three steps. First, a DL model was built to estimate liver boundary motion from an optical surface image, using learnt motion correlations between the respiratory-induced external body surface and liver boundary. Second, the residual liver boundary motion estimation error was further corrected by a graph neural network-based DL model, using information extracted from a …

Applications And Clinical Trial Landscape Using Toll-Like Receptor Agonists To Reduce The Toll Of Cancer, Christian Rolfo, Elisa Giovannetti, Pablo Martinez, Shannon Mccue, Aung Naing

Faculty, Staff and Student Publications

Toll-like receptors (TLRs), which serve as a bridge between innate and adaptive immunity, may be viable treatment targets. TLRs are the first line of defense against microbes and activate signaling cascades that induce immune and inflammatory responses. Patients with "hot" versus "cold" tumors may respond more favorably to immune checkpoint inhibition, and through their downstream effects, TLR agonists have the potential to convert "cold tumors" into "hot tumors" making TLRs in combination with immune checkpoint inhibitors, potential targets for cancer therapies. Imiquimod is a topical TLR7 agonist, approved by the FDA for antiviral and skin cancer treatments. Other TLR adjuvants …

Immortalized B Cells Transfected With Mrna Of Antigen Fused To Mitd (Ibmam): An Effective Tool For Antigen-Specific T-Cell Expansion And Tcr Validation, Zhe Wang, Tiantian Zhang, Aaron Anderson, Vincent Lee, Szymon Szymura, Benjamin Kuang, Jingwei Liu, Sattva S Neelapu, Larry Kwak, Soung-Chul Cha

Faculty, Staff and Student Publications

Peripheral mononuclear blood cells (PBMCs) are the most widely used study materials for immunomonitoring and antigen-specific T-cell identification. However, limited patient PBMCs and low-frequency antigen-specific T cells remain as significant technical challenges. To address these limitations, we established a novel platform comprised of optimized HLA-matched immortalized B cells transfected with mRNA of a prototype viral or tumor antigen conjugated to MHC class-I trafficking domain protein (MITD) to increase the efficiency of epitope expression in antigen-presenting cells (APCs) essential to expanding antigen-specific T cells. When applied to CMV as a model, the IBMAM platform could successfully expand CMV-specific T cells from …

Treatment Outcomes For Newly Diagnosed, Treatment-Naïve Tp53-Mutated Acute Myeloid Leukemia: A Systematic Review And Meta-Analysis, Naval G Daver, Shahed Iqbal, Camille Renard, Rebecca J Chan, Ken Hasegawa, Preston Tse, Michael J Zoratti, Feng Xie, Giridharan Ramsingh

Faculty, Staff and Student Publications

Background: TP53 mutations, which are present in 5% to 10% of patients with acute myeloid leukemia (AML), are associated with treatment resistance and poor outcomes. First-line therapies for TP53-mutated (TP53m) AML consist of intensive chemotherapy (IC), hypomethylating agents (HMA), or venetoclax combined with HMA (VEN + HMA).

Methods: We conducted a systematic review and meta-analysis to describe and compare treatment outcomes in newly diagnosed treatment-naïve patients with TP53m AML. Randomized controlled trials, single-arm trials, prospective observational studies, and retrospective studies were included that reported on complete remission (CR), CR with incomplete hematologic recovery (CRi), overall survival (OS), event-free survival (EFS), …

Phenotypic Plasticity In Circulating Tumor Cells Is Associated With Poor Response To Therapy In Metastatic Breast Cancer Patients, Evan N Cohen, Gitanjali Jayachandran, Hui Gao, Phillip Peabody, Heather B Mcbride, Megumi Kai, Yu Shen, Jie S Willey, Bora Lim, Vicente Valero, Naoto T Ueno, James M Reuben

Faculty, Staff and Student Publications

Circulating tumor cells (CTCs) are indicators of metastatic spread and progression. In a longitudinal, single-center trial of patients with metastatic breast cancer starting a new line of treatment, a microcavity array was used to enrich CTCs from 184 patients at up to 9 timepoints at 3-month intervals. CTCs were analyzed in parallel samples from the same blood draw by imaging and by gene expression profiling to capture CTC phenotypic plasticity. Enumeration of CTCs by image analysis relying primarily on epithelial markers from samples obtained before therapy or at 3-month follow-up identified the patients at the highest risk of progression. CTC …

Molecularly Targeted Therapy In Acute Myeloid Leukemia: Current Treatment Landscape And Mechanisms Of Response And Resistance, Curtis A Lachowiez, Courtney D Dinardo, Sanam Loghavi

Faculty, Staff and Student Publications

Treatment for acute myeloid leukemia (AML) has evolved rapidly over the last decade as improved understanding of cytogenetic and molecular drivers of leukemogenesis refined survival prognostication and enabled development of targeted therapeutics. Molecularly targeted therapies are now approved for the treatment of FLT3 and IDH1/2-mutated AML and additional molecularly and cellularly targeted therapeutics are in development for defined patient subgroups. Alongside these welcome therapeutic advancements, increased understanding of leukemic biology and treatment resistance has resulted in clinical trials investigating combinations of cytotoxic, cellular, and molecularly targeted therapeutics resulting in improved response and survival outcomes in patients with AML. Herein, …

Srtsim: Spatial Pattern Preserving Simulations For Spatially Resolved Transcriptomics, Jiaqiang Zhu, Lulu Shang, Xiang Zhou

Faculty, Staff and Student Publications

Spatially resolved transcriptomics (SRT)-specific computational methods are often developed, tested, validated, and evaluated in silico using simulated data. Unfortunately, existing simulated SRT data are often poorly documented, hard to reproduce, or unrealistic. Single-cell simulators are not directly applicable for SRT simulation as they cannot incorporate spatial information. We present SRTsim, an SRT-specific simulator for scalable, reproducible, and realistic SRT simulations. SRTsim not only maintains various expression characteristics of SRT data but also preserves spatial patterns. We illustrate the benefits of SRTsim in benchmarking methods for spatial clustering, spatial expression pattern detection, and cell-cell communication identification.

Epigenetic-Metabolic Interplay In The Dna Damage Response And Therapeutic Resistance Of Breast Cancer, Chandrima Das, Swagata Adhikari, Apoorva Bhattacharya, Sanjukta Chakraborty, Payel Mondal, Santanu Adhikary, Kamlesh K Yadav, Shruti Pandita, Siddhartha Roy, John A Tainer, Zamal Ahmed, Tej K Pandita

Faculty, Staff and Student Publications

Therapy resistance is imposing a daunting challenge on effective clinical management of breast cancer. Although the development of resistance to drugs is multifaceted, reprogramming of energy metabolism pathways is emerging as a central but heterogenous regulator of this therapeutic challenge. Metabolic heterogeneity in cancer cells is intricately associated with alterations of different signaling networks and activation of DNA damage response pathways. Here we consider how the dynamic metabolic milieu of cancer cells regulates their DNA damage repair ability to ultimately contribute to development of therapy resistance. Diverse epigenetic regulators are crucial in remodeling the metabolic landscape of cancer. This epigenetic-metabolic …

Leukemic Phase Follicular Lymphoma In A Young Adult, Daniel Rivera, Wei Wang, Zubaidah Al-Jumaili, Zhihong Hu

Faculty, Staff and Student Publications

Background: Leukemic presentation of follicular lymphoma (FL) is uncommon, with most cases reported in older adults.

Design: This report describes an unusual case of a young adult diagnosed with leukemic phase of FL. We reviewed the existing literature on this rare presentation of the disease and its potential impact on patient outcomes.

Results: Leukemic phase of FL in young adults can be mistaken for other high-grade hematologic malignancies. Morphology assessment and ancillary testing, such as flow cytometry and FISH analysis, can assist in achieving an accurate diagnosis of the leukemic phase of FL. Notably, our young patient responded well to …

Evaluating Bone Marrow Dosimetry With The Addition Of Bone Marrow Structures To The Medical Internal Radiation Dose Phantom, Kristine L Ferrone, Charles E Willis, Fada Guan, Jingfei Ma, Leif E Peterson

Faculty, Staff and Student Publications

Background: Reliable estimates of radiation dose to bone marrow are critical to understanding the risk of radiation-induced cancers. Although the medical internal radiation dose phantom is routinely used for dose estimation, bone marrow is not defined in the phantom. Consequently, methods of indirectly estimating bone marrow dose have been implemented based on dose to surrogate volumes or average dose to soft tissue.

Methods: In this study, new bone marrow structures were implemented and evaluated to the medical internal radiation dose phantom in geant4, offering improved fidelity. The dose equivalent to the bone marrow was calculated across medical, occupational, and space …

Adding The X-Ray Bragg Reflection Physical Process In Crystal To The Geant4 Monte Carlo Simulation Toolkit, Part I: Reflection From A Crystal Slab, Fada Guan, Makoto Asai, Dirk A Bartkoski, Michael Kleckner, Ze'ev Harel

Faculty, Staff and Student Publications

X-ray diffraction from a solid crystal shows the wave nature of photons. It is an important electromagnetic (EM) physics process when X-ray photons interact with a crystal. Bragg diffraction, often called Bragg reflection, is a special case of the general form of X-ray diffraction, known as Laue diffraction. When the Bragg's law is met, the incident photon beam is reflected from the crystal plane behaving as a specular reflection at the Bragg angle. However, the Bragg reflection physical process has not been integrated into the general-purpose Monte Carlo simulation toolkit Geant4 for particle physics. In the current study, we developed …

Customizable Landmark-Based Field Aperture Design For Automated Whole-Brain Radiotherapy Treatment Planning, Yao Xiao, Carlos Cardenas, Dong Joo Rhee, Tucker Netherton, Lifei Zhang, Raphael Douglas, Stephen Skett, Tina Patel, Chris Trauernicht, Caroline Chung, Hannah Simonds, Ajay Aggarwal, Laurence Court

Faculty, Staff and Student Publications

Purpose: To develop and evaluate an automated whole-brain radiotherapy (WBRT) treatment planning pipeline with a deep learning-based auto-contouring and customizable landmark-based field aperture design.

Methods: The pipeline consisted of the following steps: (1) Auto-contour normal structures on computed tomography scans and digitally reconstructed radiographs using deep learning techniques, (2) locate the landmark structures using the beam's-eye-view, (3) generate field apertures based on eight different landmark rules addressing different clinical purposes and physician preferences. Two parallel approaches for generating field apertures were developed for quality control. The performance of the generated field shapes and dose distributions were compared with the original …

Disruption Of Gcn2 Pathway Aggravates Vascular And Parenchymal Remodeling During Pulmonary Fibrosis, Diana Santos-Ribeiro, Marylène Lecocq, Michèle De Beukelaer, Stijn Verleden, Caroline Bouzin, Peter Dorfmuller, François Huaux, Rozenn Quarck, Harry Karmouty-Quintana, Maria-Rosa Ghigna, Juliette Bignard, Sophie Nadaud, Florent Soubrier, Sandrine Horman, Frederic Perros, Laurent Godinas, Charles Pilette

Faculty, Staff and Student Publications

Pulmonary fibrosis (PF) and pulmonary hypertension (PH) are chronic diseases of the pulmonary parenchyma and circulation, respectively, which may coexist, but underlying mechanisms remain elusive. Mutations in the GCN2 (general control nonderepressible 2) gene (EIF2AK4 [eukaryotic translation initiation factor 2 alpha kinase 4]) were recently associated with pulmonary veno-occlusive disease. The aim of this study is to explore the involvement of the GCN2/eIF2α (eukaryotic initiation factor 2α) pathway in the development of PH during PF, in both human disease and in a laboratory animal model. Lung tissue from patients with PF with or without PH was collected at the …

Meniscal And Articular Cartilage Predictors Of Outcome After Revision Acl Reconstruction: A 6-Year Follow-Up Cohort Study, Rick W Wright, Laura J Huston, Amanda K Haas, Jacquelyn S Pennings, Christina R Allen, Thomas M Deberardino, Brett Brick A Lantz, Kurt P Spindler, Michael J Stuart, John P Albright, Annunziato Ned Amendola, Jack T Andrish, Christopher C Annunziata, Robert A Arciero, Bernard R Bach, Champ L Baker, Arthur R Bartolozzi, Keith M Baumgarten, Jeffery R Bechler, Jeffrey H Berg, Geoffrey A Bernas, Stephen F Brockmeier, Robert H Brophy, Charles A Bush-Joseph, J Brad Butler, John D Campbell, James L Carey, James E Carpenter, Brian J Cole, Jonathan M Cooper, Charles L Cox, R Alexander Creighton, Diane L Dahm, Tal S David, David C Flanigan, Robert W Frederick, Theodore J Ganley, Elizabeth A Garofoli, Charles J Gatt, Steven R Gecha, James Robert Giffin, Sharon L Hame, Jo A Hannafin, Christopher D Harner, Norman Lindsay Harris, Keith S Hechtman, Elliott B Hershman, Rudolf G Hoellrich, David C Johnson, Timothy S Johnson, Morgan H Jones, Christopher C Kaeding, Ganesh V Kamath, Thomas E Klootwyk, Bruce A Levy, C Benjamin Ma, G Peter Maiers, Robert G Marx, Matthew J Matava, Gregory M Mathien, David R Mcallister, Eric C Mccarty, Robert G Mccormack, Bruce S Miller, Carl W Nissen, Daniel F O'Neill, Brett D Owens, Richard D Parker, Mark L Purnell, Arun J Ramappa, Michael A Rauh, Arthur C Rettig, Jon K Sekiya, Kevin G Shea, Orrin H Sherman, James R Slauterbeck, Matthew V Smith, Jeffrey T Spang, Ltc Steven J Svoboda, Timothy N Taft, Joachim J Tenuta, Edwin M Tingstad, Armando F Vidal, Darius G Viskontas, Richard A White, James S Williams, Michelle L Wolcott, Brian R Wolf, James J York

Faculty, Staff and Student Publications

Background: Meniscal and chondral damage is common in the patient undergoing revision anterior cruciate ligament (ACL) reconstruction.

Purpose: To determine if meniscal and/or articular cartilage pathology at the time of revision ACL surgery significantly influences a patient's outcome at 6-year follow-up.

Study design: Cohort study; Level of evidence, 3.

Methods: Patients undergoing revision ACL reconstruction were prospectively enrolled between 2006 and 2011. Data collection included baseline demographics, surgical technique, pathology, treatment, and scores from 4 validated patient-reported outcome instruments: International Knee Documentation Committee (IKDC), Knee injury and Osteoarthritis Outcome Score (KOOS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and …

Unique Pathologic Features And Gene Expression Signatures Distinguish Blastoid High-Grade B-Cell Lymphoma From B-Acute Lymphoblastic Leukemia/Lymphoma, Lianqun Qiu, Jie Xu, Pei Lin, Evan N Cohen, Guilin Tang, Mahsa Khanlari, Joseph D Khoury, Sergej Konoplev, C Cameron Yin, Jeffrey L Jorgensen, Francisco Vega, L Jeffrey Medeiros, Shaoying Li

Faculty, Staff and Student Publications

No abstract provided.

A Bidirectional Single-Cell Migration And Retrieval Chip For Quantitative Study Of Dendritic Cell Migration, Ning Shao, Yufu Zhou, Jun Yao, Pengchao Zhang, Yanni Song, Xin Han, Xuewu Liu

Faculty, Staff and Student Publications

Dendritic cell (DC) migration is a fundamental step during execution of its adaptive immunity functions. Studying DC migration characteristics is critical for development of DC-dependent allergy treatments, vaccines, and cancer immunotherapies. Here, a microfluidics-based single-cell migration platform is described that enables high-throughput and precise bidirectional cell migration assays. It also allows selective retrieval of cell subpopulations that have different migratory potentials. Using this microfluidic platform, DC migration is investigated in response to different chemoattractants and inhibitors, quantitatively describe DC migration patterns and retrieve DC subpopulations of different migratory potentials for differential gene expression analysis. This platform opens an avenue for …

A Phase I, Open-Label, Dose Confirmation, Escalation, And Expansion Trial Of Bi 1810631 As Monotherapy In Patients With Advanced Or Metastatic Solid Tumors With Her2 Aberrations, John Heymach, Frans Opdam, Minal Barve, Neil Gibson, Behbood Sadrolhefazi, Noboru Yamamoto

Faculty, Staff and Student Publications

Background: BI 1810631 is a human HER2-selective tyrosine kinase inhibitor that covalently binds to both wild-type and mutated HER2 receptors, including exon 20 insertion mutations, whilst sparing EGFR signaling. This phase Ia/Ib, open-label, non-randomized study will determine the safety, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of BI 1810631 in patients with HER2 aberration-positive solid tumors (NCT04886804).

Patients and methods: In phase Ia, patients with histologically/cytologically confirmed HER2 aberration-positive advanced/metastatic solid tumors will receive BI 1810631 orally twice daily (BID) or once daily (QD) at escalating doses. Starting dose level is 15 mg BID; QD …

What Are Risk Factors For And Outcomes Of Late Amputation After Treatment For Lower Extremity Sarcoma: A Childhood Cancer Survivor Study Report, Erik J Geiger, Wei Liu, Deo Kumar Srivastava, Nicholas M Bernthal, Brent R Weil, Kirsten K Ness, Robert E Goldsby, Kevin C Oeffinger, Leslie L Robison, Bryan V Dieffenbach, Christopher B Weldon, Mark C Gebhardt, Rebecca Howell, Andrew J Murphy, Wendy M Leisenring, Gregory T Armstrong, Eric J Chow, Rosanna L Wustrack

Faculty, Staff and Student Publications

Background: Although pediatric lower extremity sarcoma once was routinely treated with amputation, multiagent chemotherapy as well as the evolution of tumor resection and reconstruction techniques have enabled the wide adoption of limb salvage surgery (LSS). Even though infection and tumor recurrence are established risk factors for early amputation (< 5 years) after LSS, the frequency of and factors associated with late amputation (≥ 5 years from diagnosis) in children with sarcomas are not known. Additionally, the resulting psychosocial and physical outcomes of these patients compared with those treated with primary amputation or LSS that was not complicated by subsequent amputation are not well studied. Studying these outcomes is critical to enhancing the quality of life of patients with sarcomas.

Questions/purposes: (1) How have treatments changed over time in patients with lower extremity sarcoma who are included in the Childhood Cancer Survivor Study (CCSS), and did primary treatment with amputation or LSS affect overall survival at 25 years among patients who had survived at least 5 years from diagnosis? (2) What …

Expansion Of The Genotypic And Phenotypic Spectrum Of Ctcf-Related Disorder Guides Clinical Management: 43 New Subjects And A Comprehensive Literature Review, Hannah Gabriela Valverde De Morales, Hsiao-Lin V Wang, Kathryn Garber, Xiaodong Cheng, Victor G Corces

Faculty, Staff and Student Publications

Monoallelic variants of CTCF cause an autosomal dominant neurodevelopmental disorder with a wide range of features, including impacts on the brain, growth, and craniofacial development. A growing number of subjects with CTCF-related disorder (CRD) have been identified due to the increased application of exome sequencing, and further delineation of the clinical spectrum of CRD is needed. Here, we examined the clinical features, including facial profiles, and genotypic spectrum of 107 subjects with identified CTCF variants, including 43 new and 64 previously described subjects. Among the 43 new subjects, 23 novel variants were reported. The cardinal clinical features in subjects with …

Mitochondrial Structure And Function Adaptation In Residual Triple Negative Breast Cancer Cells Surviving Chemotherapy Treatment, Mokryun L Baek, Junegoo Lee, Katherine E Pendleton, Mariah J Berner, Emily B Goff, Sara A Martinez, Tao Wang, Matthew D Meyer, Bora Lim, James P Barrish, Weston Porter, Philip L Lorenzi, Gloria V Echeverria

Faculty, Staff and Student Publications

Neoadjuvant chemotherapy (NACT) used for triple negative breast cancer (TNBC) eradicates tumors in ~45% of patients. Unfortunately, TNBC patients with substantial residual cancer burden have poor metastasis free and overall survival rates. We previously demonstrated mitochondrial oxidative phosphorylation (OXPHOS) was elevated and was a unique therapeutic dependency of residual TNBC cells surviving NACT. We sought to investigate the mechanism underlying this enhanced reliance on mitochondrial metabolism. Mitochondria are morphologically plastic organelles that cycle between fission and fusion to maintain mitochondrial integrity and metabolic homeostasis. The functional impact of mitochondrial structure on metabolic output is highly context dependent. Several chemotherapy agents …

An Extension Of Estimating Equations To Model Longitudinal Medical Cost Trajectory With Medicare Claims Data Linked To Seer Cancer Registry, Shikun Wang, Jing Ning, Ying Xu, Ya-Chen Tina Shih, Y U Shen

Faculty, Staff and Student Publications

Insurance claims data is an increasingly important health policy research resource, given its longitudinal assessment of cancer care clinical outcomes. Population-level information on medical cost trajectory from disease diagnosis to terminal events, such as death, specifically interests policy makers. Estimating the mean cost trajectory has statistical challenges. The shape of the trajectory is usually highly nonlinear with varying durations, depending on the diagnosis-to-death population time distribution. The terminal event may be right censored, resulting in missing subsequent costs. Medical costs often have skewed distributions with zero-inflation and heteroscedasticity, which may not fit well with the commonly used parametric family of …