Medical Specialties Commons^™

Integration Of Kupffer Cells Into Human Ipsc-Derived Liver Organoids For Modeling Liver Dysfunction In Sepsis, Yang Li, Yunzhong Nie, Xia Yang, Yang Liu, Xiaoshan Deng, Yoshihito Hayashi, Riana Plummer, Qinglin Li, Na Luo, Toshiharu Kasai, Takashi Okumura, Yu Kamishibahara, Takemasa Komoto, Takuya Ohkuma, Satoshi Okamoto, Yumiko Isobe, Kiyoshi Yamaguchi, Yoichi Furukawa, Hideki Taniguchi

Faculty, Staff and Student Publications

Maximizing the potential of human liver organoids (LOs) for modeling human septic liver requires the integration of innate immune cells, particularly resident macrophage Kupffer cells. In this study, we present a strategy to generate LOs containing Kupffer cells (KuLOs) by recapitulating fetal liver hematopoiesis using human induced pluripotent stem cell (hiPSC)-derived erythro-myeloid progenitors (EMPs), the origin of tissue-resident macrophages, and hiPSC-derived LOs. Remarkably, LOs actively promote EMP hematopoiesis toward myeloid and erythroid lineages. Moreover, supplementing with macrophage colony-stimulating factor (M-CSF) proves crucial in sustaining the hematopoietic population during the establishment of KuLOs. Exposing KuLOs to sepsis-like endotoxins leads to significant …

A Novel Machine Learning Algorithm Selects Proteome Signature To Specifically Identify Cancer Exosomes, Bingrui Li, Fernanda G Kugeratski, Raghu Kalluri

Faculty, Staff and Student Publications

Non-invasive early cancer diagnosis remains challenging due to the low sensitivity and specificity of current diagnostic approaches. Exosomes are membrane-bound nanovesicles secreted by all cells that contain DNA, RNA, and proteins that are representative of the parent cells. This property, along with the abundance of exosomes in biological fluids makes them compelling candidates as biomarkers. However, a rapid and flexible exosome-based diagnostic method to distinguish human cancers across cancer types in diverse biological fluids is yet to be defined. Here, we describe a novel machine learning-based computational method to distinguish cancers using a panel of proteins associated with exosomes. Employing …

The Genomic And Evolutionary Landscapes Of Anaplastic Thyroid Carcinoma, Peter Y F Zeng, Stephenie D Prokopec, Stephen Y Lai, Nicole Pinto, Michelle A Chan-Seng-Yue, Roderick Clifton-Bligh, Michelle D Williams, Christopher J Howlett, Paul Plantinga, Matthew J Cecchini, Alfred K Lam, Iram Siddiqui, Jianxin Wang, Ren X Sun, John D Watson, Reju Korah, Tobias Carling, Nishant Agrawal, Nicole Cipriani, Douglas Ball, Barry Nelkin, Lisa M Rooper, Justin A Bishop, Cathie Garnis, Ken Berean, Norman G Nicolson, Paul Weinberger, Ying C Henderson, Christopher M Lalansingh, Mao Tian, Takafumi N Yamaguchi, Julie Livingstone, Adriana Salcedo, Krupal Patel, Frederick Vizeacoumar, Alessandro Datti, Liu Xi, Yuri E Nikiforov, Robert Smallridge, John A Copland, Laura A Marlow, Martin D Hyrcza, Leigh Delbridge, Stan Sidhu, Mark Sywak, Bruce Robinson, Kevin Fung, Farhad Ghasemi, Keith Kwan, S Danielle Macneil, Adrian Mendez, David A Palma, Mohammed I Khan, Mushfiq Shaikh, Kara M Ruicci, Bret Wehrli, Eric Winquist, John Yoo, Joe S Mymryk, James W Rocco, David Wheeler, Steve Scherer, Thomas J Giordano, John W Barrett, William C Faquin, Anthony J Gill, Gary Clayman, Paul C Boutros, Anthony C Nichols

Faculty, Staff and Student Publications

Anaplastic thyroid carcinoma is arguably the most lethal human malignancy. It often co-occurs with differentiated thyroid cancers, yet the molecular origins of its aggressivity are unknown. We sequenced tumor DNA from 329 regions of thyroid cancer, including 213 from patients with primary anaplastic thyroid carcinomas. We also whole genome sequenced 9 patients using multi-region sequencing of both differentiated and anaplastic thyroid cancer components. Using these data, we demonstrate thatanaplastic thyroid carcinomas have a higher burden of mutations than other thyroid cancers, with distinct mutational signatures and molecular subtypes. Further, different cancer driver genes are mutated in anaplastic and differentiated thyroid …

Identifying Potential Dietary Treatments For Inherited Metabolic Disorders Using Drosophila Nutrigenomics, Felipe Martelli, Jiayi Lin, Sarah Mele, Wendy Imlach, Oguz Kanca, Christopher K Barlow, Jefferson Paril, Ralf B Schittenhelm, John Christodoulou, Hugo J Bellen, Matthew D W Piper, Travis K Johnson

Faculty, Staff and Students Publications

Inherited metabolic disorders are a group of genetic conditions that can cause severe neurological impairment and child mortality. Uniquely, these disorders respond to dietary treatment; however, this option remains largely unexplored because of low disorder prevalence and the lack of a suitable paradigm for testing diets. Here, we screened 35 Drosophila amino acid disorder models for disease-diet interactions and found 26 with diet-altered development and/or survival. Using a targeted multi-nutrient array, we examine the interaction in a model of isolated sulfite oxidase deficiency, an infant-lethal disorder. We show that dietary cysteine depletion normalizes their metabolic profile and rescues development, neurophysiology, …

Extend The Benchmarking Indel Set By Manual Review Using The Individual Cell Line Sequencing Data From The Sequencing Quality Control 2 (Seqc2) Project, Binsheng Gong, Dan Li, Yifan Zhang, Rebecca Kusko, Samir Lababidi, Zehui Cao, Mingyang Chen, Ning Chen, Qiaochu Chen, Qingwang Chen, Jiacheng Dai, Qiang Gan, Yuechen Gao, Mingkun Guo, Gunjan Hariani, Yujie He, Wanwan Hou, He Jiang, Garima Kushwaha, Jian-Liang Li, Jianying Li, Yulan Li, Liang-Chun Liu, Ruimei Liu, Shiming Liu, Edwin Meriaux, Mengqing Mo, Mathew Moore, Tyler J Moss, Quanne Niu, Ananddeep Patel, Luyao Ren, Nedda F Saremi, Erfei Shang, Jun Shang, Ping Song, Siqi Sun, Brent J Urban, Danke Wang, Shangzi Wang, Zhining Wen, Xiangyi Xiong, Jingcheng Yang, Lihui Yin, Chao Zhang, Ruolan Zhang, Ambica Bhandari, Wanshi Cai, Agda Karina Eterovic, Dalila B Megherbi, Tieliu Shi, Chen Suo, Ying Yu, Yuanting Zheng, Natalia Novoradovskaya, Renee L Sears, Leming Shi, Wendell Jones, Weida Tong, Joshua Xu

Faculty, Staff and Student Publications

Accurate indel calling plays an important role in precision medicine. A benchmarking indel set is essential for thoroughly evaluating the indel calling performance of bioinformatics pipelines. A reference sample with a set of known-positive variants was developed in the FDA-led Sequencing Quality Control Phase 2 (SEQC2) project, but the known indels in the known-positive set were limited. This project sought to provide an enriched set of known indels that would be more translationally relevant by focusing on additional cancer related regions. A thorough manual review process completed by 42 reviewers, two advisors, and a judging panel of three researchers significantly …

Tumor Treating Fields Suppress Tumor Cell Growth And Neurologic Decline In Models Of Spinal Metastases, Daniel Ledbetter, Romulo Augusto Andrade De Almeida, Xizi Wu, Ariel Naveh, Chirag B Patel, Queena Gonzalez, Thomas H Beckham, Robert North, Laurence Rhines, Jing Li, Amol Ghia, David Aten, Claudio Tatsui, Christopher Alvarez-Breckenridge

Faculty, Staff and Student Publications

Spinal metastases can result in severe neurologic compromise and decreased overall survival. Despite treatment advances, local disease progression is frequent, highlighting the need for novel therapies. Tumor treating fields (TTFields) impair tumor cell replication and are influenced by properties of surrounding tissue. We hypothesized that bone's dielectric properties will enhance TTFields-mediated suppression of tumor growth in spinal metastasis models. Computational modeling of TTFields intensity was performed following surgical resection of a spinal metastasis and demonstrated enhanced TTFields intensity within the resected vertebral body. Additionally, luciferase-tagged human KRIB osteosarcoma and A549 lung adenocarcinoma cell lines were cultured in demineralized bone grafts …

Gut Microbiota Composition Is Associated With The Efficacy Of Delta-24-Rgdox In Malignant Gliomas, Natalie M Meléndez-Vázquez, Teresa T Nguyen, Xuejun Fan, Andrés R López-Rivas, Juan Fueyo, Candelaria Gomez-Manzano, Filipa Godoy-Vitorino

Faculty, Staff and Student Publications

Glioblastoma, the most common primary brain tumor, has a 6.8% survival rate 5 years post diagnosis. Our team developed an oncolytic adenovirus with an OX-40L expression cassette named Delta-24-RGDOX. While studies have revealed the interaction between the gut microbiota and immunotherapy agents, there are no studies linking the gut microbiota with viroimmunotherapy efficacy. We hypothesize that gut bacterial signatures will be associated with oncolytic viral therapy efficacy. To test this hypothesis, we evaluated the changes in gut microbiota in two mouse cohorts: (1) GSC-005 glioblastoma-bearing mice treated orally with indoximod, an immunotherapeutic agent, or with Delta-24-RGDOX by intratumoral injection and …

Correction: Detecting The Percent Of Peripheral Blood Mononuclear Cells Displaying P-Stat-3 In Malignant Glioma Patients, William Humphries, Yongtao Wang, Wei Qiao, Chantal Reina-Ortiz, Mohamed K Abou-Ghazal, Lamonne M Crutcher, Jun Wei, Ling-Yuan Kong, Raymond Sawaya, Ganesh Rao, Jeffrey Weinberg, Sujit S Prabhu, Gregory N Fuller, Amy B Heimberger

Faculty, Staff and Student Publications

No abstract provided.

Gut Microbiota Composition Is Associated With The Efficacy Of Delta-24-Rgdox In Malignant Gliomas, Natalie M Meléndez-Vázquez, Teresa T Nguyen, Xuejun Fan, Andrés R López-Rivas, Juan Fueyo, Candelaria Gomez-Manzano, Filipa Godoy-Vitorino

Faculty, Staff and Student Publications

Glioblastoma, the most common primary brain tumor, has a 6.8% survival rate 5 years post diagnosis. Our team developed an oncolytic adenovirus with an OX-40L expression cassette named Delta-24-RGDOX. While studies have revealed the interaction between the gut microbiota and immunotherapy agents, there are no studies linking the gut microbiota with viroimmunotherapy efficacy. We hypothesize that gut bacterial signatures will be associated with oncolytic viral therapy efficacy. To test this hypothesis, we evaluated the changes in gut microbiota in two mouse cohorts: (1) GSC-005 glioblastoma-bearing mice treated orally with indoximod, an immunotherapeutic agent, or with Delta-24-RGDOX by intratumoral injection and …

Understanding Heterogeneity In Individual Responses To Digital Lifestyle Intervention Through Self-Monitoring Adherence Trajectories In Adults With Overweight Or Obesity: Secondary Analysis Of A 6-Month Randomized Controlled Trial, Shiyu Li, Yan Du, Hongyu Miao, Kumar Sharma, Chengdong Li, Zenong Yin, Bradley Brimhall, Jing Wang

Faculty, Staff and Student Publications

Background: Achieving clinically significant weight loss through lifestyle interventions for obesity management is challenging for most individuals. Improving intervention effectiveness involves early identification of intervention nonresponders and providing them with timely, tailored interventions. Early and frequent self-monitoring (SM) adherence predicts later weight loss success, making it a potential indicator for identifying nonresponders in the initial phase.

Objective: This study aims to identify clinically meaningful participant subgroups based on longitudinal adherence to SM of diet, activity, and weight over 6 months as well as psychological predictors of participant subgroups from a self-determination theory (SDT) perspective.

Methods: This was a secondary data …

Prediabetes And Associated Risk Of Cardiovascular Events And Chronic Kidney Disease Among Adult Survivors Of Childhood Cancer In The St Jude Lifetime Cohort, Stephanie B Dixon, Fang Wang, Lu Lu, Carmen L Wilson, Daniel M Green, Thomas E Merchant, Deo Kumar Srivastava, Angela Delaney, Rebecca M Howell, John L Jefferies, Leslie L Robison, Kirsten K Ness, Melissa M Hudson, Wassim Chemaitilly, Gregory T Armstrong

Faculty, Staff and Student Publications

Purpose: Little is known about the prevalence of prediabetes and associated risk of cardiovascular events and chronic kidney disease (CKD) with this reversable condition in survivors.

Methods: Prevalence of prediabetes (fasting plasma glucose 100-125 mg/dL or hemoglobin A1c 5.7%-6.4%) and diabetes was clinically assessed in 3,529 adults ≥5 years from childhood cancer diagnosis and 448 controls stratified by age. Cox proportional hazards regression estimated progression from prediabetes to diabetes, and risk of future cardiac events, stroke, CKD, and death.

Results: Among survivors, median age 30 years (IQR, 18-65), and the prevalence of prediabetes was 29.2% (95% CI, 27.7 to 30.7) …

Epigenetic Modulators Link Mitochondrial Redox Homeostasis To Cardiac Function In A Sex-Dependent Manner, Zaher Elbeck, Mohammad Bakhtiar Hossain, Humam Siga, Nikolay Oskolkov, Fredrik Karlsson, Julia Lindgren, Anna Walentinsson, Dominique Koppenhöfer, Rebecca Jarvis, Roland Bürli, Tanguy Jamier, Elske Franssen, Mike Firth, Andrea Degasperi, Claus Bendtsen, Robert I Menzies, Katrin Streckfuss-Bömeke, Michael Kohlhaas, Alexander G Nickel, Lars H Lund, Christoph Maack, Ákos Végvári, Christer Betsholtz

Faculty, Staff and Student Publications

While excessive production of reactive oxygen species (ROS) is a characteristic hallmark of numerous diseases, clinical approaches that ameliorate oxidative stress have been unsuccessful. Here, utilizing multi-omics, we demonstrate that in cardiomyocytes, mitochondrial isocitrate dehydrogenase (IDH2) constitutes a major antioxidative defense mechanism. Paradoxically reduced expression of IDH2 associated with ventricular eccentric hypertrophy is counterbalanced by an increase in the enzyme activity. We unveil redox-dependent sex dimorphism, and extensive mutual regulation of the antioxidative activities of IDH2 and NRF2 by a feedforward network that involves 2-oxoglutarate and L-2-hydroxyglutarate and mediated in part through unconventional hydroxy-methylation of cytosine residues present in introns. …

Summit-Fa: A New Resource For Improved Transcriptome Imputation Using Functional Annotations, Hunter J Melton, Zichen Zhang, Chong Wu

Faculty, Staff and Student Publications

Transcriptome-wide association studies (TWAS) integrate gene expression prediction models and genome-wide association studies (GWAS) to identify gene-trait associations. The power of TWAS is determined by the sample size of GWAS and the accuracy of the expression prediction model. Here, we present a new method, the Summary-level Unified Method for Modeling Integrated Transcriptome using Functional Annotations (SUMMIT-FA), which improves gene expression prediction accuracy by leveraging functional annotation resources and a large expression quantitative trait loci (eQTL) summary-level dataset. We build gene expression prediction models in whole blood using SUMMIT-FA with the comprehensive functional database MACIE and eQTL summary-level data from the …

Single-Cell Analysis Of Age-Related Changes In Leukocytes Of Diabetic Mouse Hindpaws, James M Nichols, Hoang Vu Pham, Eric F Lee, Rajasekaran Mahalingam, Andrew J Shepherd

Faculty, Staff and Student Publications

Complications associated with Type 1 and Type 2 diabetes, such as diabetic peripheral neuropathy and diabetic foot ulcers, are a growing health-care concern. In addition, this concern increases as diabetic patients age due to their increased susceptibility to complications. To address this growing problem, it is important to understand fluctuations in physiology which lead to pathological changes associated with the metabolic disturbances of diabetes. Our study explores dysregulation of immune cell populations in the hindpaws of healthy and diabetic mice at 12 and 21 weeks of age using single-cell RNA sequencing to provide insight into immune disruptions occurring in the …

Visual Outcome And Ocular Complications In Patients With Lacrimal Gland Carcinoma After Eye-Sparing Surgery And Adjuvant Radiation Therapy, Zhenyang Zhao, Steven Jay Frank, Jing Ning, Jiawei Zhao, Xinyang Jiang, Xin A Wang, Amy C Schefler, Ehab Hanna, Amy Moreno, Brandon Gunn, Renata Ferrarotto, Bita Esmaeli

Faculty, Staff and Student Publications

Background: We report visual outcomes and ocular complications in patients with lacrimal gland carcinoma who had eye-sparing surgery followed by radiotherapy.

Methods: This review included consecutive patients with lacrimal gland carcinoma who underwent eye-sparing surgery and adjuvant radiotherapy or concurrent chemoradiation therapy between 2007 and 2018. Clinical data, including details of ophthalmological examinations and radiation treatment were reviewed.

Results: The study included 23 patients, 15 males and 8 females, with median age 51 years. Twenty patients (87%) received intensity-modulated proton therapy; 3 (13%) received intensity-modulated radiotherapy. Nineteen patients (83%) received concurrent chemotherapy. After a median follow-up time of 37 months …

Polyamine-Mediated Ferroptosis Amplification Acts As A Targetable Vulnerability In Cancer, Guoshu Bi, Jiaqi Liang, Yunyi Bian, Guangyao Shan, Yiwei Huang, Tao Lu, Huan Zhang, Xing Jin, Zhencong Chen, Mengnan Zhao, Hong Fan, Qun Wang, Boyi Gan, Cheng Zhan

Faculty, Staff and Student Publications

Targeting ferroptosis, an iron-dependent form of regulated cell death triggered by the lethal overload of lipid peroxides, in cancer therapy is impeded by our limited understanding of the intersection of tumour’s metabolic feature and ferroptosis vulnerability. In the present study, arginine is identified as a ferroptotic promoter using a metabolites library. This effect is mainly achieved through arginine’s conversion to polyamines, which exerts their potent ferroptosis-promoting property in an H2O2-dependent manner. Notably, the expression of ornithine decarboxylase 1 (ODC1), the critical enzyme catalysing polyamine synthesis, is significantly activated by the ferroptosis signal——iron overload——through WNT/MYC signalling, as well as the subsequent …

Durvalumab And Tremelimumab Before Surgery In Patients With Hormone Receptor Positive, Her2-Negative Stage Ii-Iii Breast Cancer, Haven R Garber, Sreyashi Basu, Sonali Jindal, Zhong He, Khoi Chu, Akshara Singareeka Raghavendra, Clinton Yam, Lumarie Santiago, Beatriz E Adrada, Padmanee Sharma, Elizabeth A Mittendorf, Jennifer K Litton

Faculty, Staff and Student Publications

A clinical trial was conducted to assess the feasibility of enrolling patients with Stage II or III hormone receptor positive (HR+)/HER2-negative breast cancer to pre-operative dual PD-L1/CTLA-4 checkpoint inhibition administered prior to neoadjuvant chemotherapy (NACT). Eight eligible patients were treated with upfront durvalumab and tremelimumab for two cycles. Patients then received NACT prior to breast surgery. Seven patients had baseline and interval breast ultrasounds after combination immunotherapy and the responses were mixed: 3/7 patients experienced a ≥30% decrease in tumor volume, 3/7 a ≥30% increase, and 1 patient had stable disease. At the time of breast surgery, 1/8 patients had …

Three-Dimensional Optothermal Manipulation Of Light-Absorbing Particles In Phase-Change Gel Media, Pavana Siddhartha Kollipara, Zilong Wu, Kan Yao, Dongdong Lin, Zhengyu Ju, Xiaotian Zhang, Taizhi Jiang, Hongru Ding, Jie Fang, Jingang Li, Brian A Korgel, Joan M Redwing, Guihua Yu, Yuebing Zheng

Faculty, Staff and Student Publications

Rational manipulation and assembly of discrete colloidal particles into architected superstructures have enabled several applications in materials science and nanotechnology. Optical manipulation techniques, typically operated in fluid media, facilitate the precise arrangement of colloidal particles into superstructures by using focused laser beams. However, as the optical energy is turned off, the inherent Brownian motion of the particles in fluid media impedes the retention and reconfiguration of such superstructures. Overcoming this fundamental limitation, we present on-demand, three-dimensional (3D) optical manipulation of colloidal particles in a phase-change solid medium made of surfactant bilayers. Unlike liquid crystal media, the lack of fluid flow …

Synthetic Pet From Ct Improves Diagnosis And Prognosis For Lung Cancer: Proof Of Concept, Morteza Salehjahromi, Tatiana V Karpinets, Sheeba J Sujit, Mohamed Qayati, Pingjun Chen, Muhammad Aminu, Maliazurina B Saad, Rukhmini Bandyopadhyay, Lingzhi Hong, Ajay Sheshadri, Julie Lin, Mara B Antonoff, Boris Sepesi, Edwin J Ostrin, Iakovos Toumazis, Peng Huang, Chao Cheng, Tina Cascone, Natalie I Vokes, Carmen Behrens, Jeffrey H Siewerdsen, John D Hazle, Joe Y Chang, Jianhua Zhang, Yang Lu, Myrna C B Godoy, Caroline Chung, David Jaffray, Ignacio Wistuba, J Jack Lee, Ara A Vaporciyan, Don L Gibbons, Gregory Gladish, John V Heymach, Carol C Wu, Jianjun Zhang, Jia Wu

Faculty, Staff and Student Publications

[18F]Fluorodeoxyglucose positron emission tomography (FDG-PET) and computed tomography (CT) are indispensable components in modern medicine. Although PET can provide additional diagnostic value, it is costly and not universally accessible, particularly in low-income countries. To bridge this gap, we have developed a conditional generative adversarial network pipeline that can produce FDG-PET from diagnostic CT scans based on multi-center multi-modal lung cancer datasets (n = 1,478). Synthetic PET images are validated across imaging, biological, and clinical aspects. Radiologists confirm comparable imaging quality and tumor contrast between synthetic and actual PET scans. Radiogenomics analysis further proves that the dysregulated cancer hallmark pathways of …

Fungi Of The Order Mucorales Express A “Sealing-Only” Trna Ligase, Khondakar Sayef Ahammed, Ambro Van Hoof

Faculty, Staff and Student Publications

Some eukaryotic pre-tRNAs contain an intron that is removed by a dedicated set of enzymes. Intron-containing pre-tRNAs are cleaved by tRNA splicing endonuclease, followed by ligation of the two exons and release of the intron. Fungi use a "heal and seal" pathway that requires three distinct catalytic domains of the tRNA ligase enzyme, Trl1. In contrast, humans use a "direct ligation" pathway carried out by RTCB, an enzyme completely unrelated to Trl1. Because of these mechanistic differences, Trl1 has been proposed as a promising drug target for fungal infections. To validate Trl1 as a broad-spectrum drug target, we show that …

Hematopoietic Stem Cells With Granulo-Monocytic Differentiation State Overcome Venetoclax Sensitivity In Patients With Myelodysplastic Syndromes, Juan Jose Rodriguez-Sevilla, Irene Ganan-Gomez, Feiyang Ma, Kelly Chien, Monica Del Rey, Sanam Loghavi, Guillermo Montalban-Bravo, Vera Adema, Bethany Wildeman, Rashmi Kanagal-Shamanna, Alexandre Bazinet, Helen T Chifotides, Natthakan Thongon, Xavier Calvo, Jesús María Hernández-Rivas, Maria Díez-Campelo, Guillermo Garcia-Manero, Simona Colla

Faculty, Staff and Student Publications

The molecular mechanisms of venetoclax-based therapy failure in patients with acute myeloid leukemia were recently clarified, but the mechanisms by which patients with myelodysplastic syndromes (MDS) acquire secondary resistance to venetoclax after an initial response remain to be elucidated. Here, we show an expansion of MDS hematopoietic stem cells (HSCs) with a granulo-monocytic-biased transcriptional differentiation state in MDS patients who initially responded to venetoclax but eventually relapsed. While MDS HSCs in an undifferentiated cellular state are sensitive to venetoclax treatment, differentiation towards a granulo-monocytic-biased transcriptional state, through the acquisition or expansion of clones with STAG2 or RUNX1 mutations, affects HSCs' …

Neoadjuvant Chemotherapy Alone Or Combined With Egfr-Directed Targeted Therapy Or Anti-Pd-1 Immunotherapy For Locally Advanced Lacrimal Sac And Nasolacrimal Duct Carcinomas, Jeremy Goldfarb, Janet Fan, Luana Guimaraes De Sousa, Neal Akhave, Jeffrey Myers, Ryan Goepfert, Krish Manisundaram, Jiawei Zhao, Steven J Frank, Amy Moreno, Renata Ferrarotto, Bita Esmaeli

Faculty, Staff and Student Publications

Background/aims: We describe our findings in patients with locally advanced lacrimal sac and nasolacrimal duct (NLD) carcinoma who received neoadjuvant systemic therapy.

Methods: We identified patients with locally advanced primary lacrimal sac/NLD carcinoma treated with neoadjuvant systemic intravenous therapy at our institution during 2017-2019.

Results: The study included seven patients, four men and three women; the mean age was 60.4 years (range: 43-76). All patients had locally advanced disease with significant orbital soft tissue invasion with or without skull base invasion making eye-sparing surgery not feasible as an initial step. Three patients had poorly differentiated squamous cell carcinoma; two, invasive …

Ultrasound Biomicroscopy As A Novel, Potential Modality To Evaluate Anterior Segment Ophthalmic Structures During Spaceflight: An Analysis Of Current Technology, Benjamin Soares, Joshua Ong, Daniela Osteicoechea, Cihan Mehmet Kadipasaoglu, Ethan Waisberg, Prithul Sarker, Nasif Zaman, Alireza Tavakkoli, Gianmarco Vizzeri, Andrew G Lee

Faculty, Staff and Student Publications

Ocular health is currently a major concern for astronauts on current and future long-duration spaceflight missions. Spaceflight-associated neuro-ocular syndrome (SANS) is a collection of ophthalmic and neurologic findings that is one potential physiologic barrier to interplanetary spaceflight. Since its initial report in 2011, our understanding of SANS has advanced considerably, with a primary focus on posterior ocular imaging including fundus photography and optical coherence tomography. However, there may be changes to the anterior segment that have not been identified. Additional concerns to ocular health in space include corneal damage and radiation-induced cataract formation. Given these concerns, precision anterior segment imaging …

Long Noncoding Rna Malat1 Protects Against Osteoporosis And Bone Metastasis, Yang Zhao, Jingyuan Ning, Hongqi Teng, Yalan Deng, Marisela Sheldon, Lei Shi, Consuelo Martinez, Jie Zhang, Annie Tian, Yutong Sun, Shinichi Nakagawa, Fan Yao, Hai Wang, Li Ma

Faculty, Staff and Student Publications

MALAT1, one of the few highly conserved nuclear long noncoding RNAs (lncRNAs), is abundantly expressed in normal tissues. Previously, targeted inactivation and genetic rescue experiments identified MALAT1 as a suppressor of breast cancer lung metastasis. On the other hand, Malat1-knockout mice are viable and develop normally. On a quest to discover the fundamental roles of MALAT1 in physiological and pathological processes, we find that this lncRNA is downregulated during osteoclastogenesis in humans and mice. Remarkably, Malat1 deficiency in mice promotes osteoporosis and bone metastasis of melanoma and mammary tumor cells, which can be rescued by genetic add-back of Malat1. Mechanistically, …

Downregulation Of Irf8 In Alveolar Macrophages By G-Csf Promotes Metastatic Tumor Progression, Stephanie L Tzetzo, Elliot D Kramer, Hemn Mohammadpour, Minhyung Kim, Spencer R Rosario, Han Yu, Melissa R Dolan, Chetan C Oturkar, Brian G Morreale, Paul N Bogner, Aimee B Stablewski, Fernando J Benavides, Craig M Brackett, John M L Ebos, Gokul M Das, Mateusz Opyrchal, Michael J Nemeth, Sharon S Evans, Scott I Abrams

Faculty, Staff and Student Publications

Tissue-resident macrophages (TRMs) are abundant immune cells within pre-metastatic sites, yet their functional contributions to metastasis remain incompletely understood. Here, we show that alveolar macrophages (AMs), the main TRMs of the lung, are susceptible to downregulation of the immune stimulatory transcription factor IRF8, impairing anti-metastatic activity in models of metastatic breast cancer. G-CSF is a key tumor-associated factor (TAF) that acts upon AMs to reduce IRF8 levels and facilitate metastasis. Translational relevance of IRF8 downregulation was observed among macrophage precursors in breast cancer and a

Validation Of A Multiomic Model Of Plasma Extracellular Vesicle Pd-L1 And Radiomics For Prediction Of Response To Immunotherapy In Nsclc, Diego De Miguel-Perez, Murat Ak, Priyadarshini Mamindla, Alessandro Russo, Serafettin Zenkin, Nursima Ak, Vishal Peddagangireddy, Luis Lara-Mejia, Muthukumar Gunasekaran, Andres F Cardona, Aung Naing, Fred R Hirsch, Oscar Arrieta, Rivka R Colen, Christian Rolfo

Faculty, Staff and Student Publications

BACKGROUND: Immune-checkpoint inhibitors (ICIs) have showed unprecedent efficacy in the treatment of patients with advanced non-small cell lung cancer (NSCLC). However, not all patients manifest clinical benefit due to the lack of reliable predictive biomarkers. We showed preliminary data on the predictive role of the combination of radiomics and plasma extracellular vesicle (EV) PD-L1 to predict durable response to ICIs.

MAIN BODY: Here, we validated this model in a prospective cohort of patients receiving ICIs plus chemotherapy and compared it with patients undergoing chemotherapy alone. This multiparametric model showed high sensitivity and specificity at identifying non-responders to ICIs and outperformed …

Case Report: Molecular Profiling Facilitates The Diagnosis Of A Challenging Case Of Lung Cancer With Choriocarcinoma Features, Hui Li, Xin Hu, Matthew S Ning, Gregory N Fuller, John M Stewart, Jared C Gilliam, Jia Wu, Xiuning Le, Ara A Vaporciyan, J Jack Lee, Don L Gibbons, John V Heymach, Andrew Futreal, Jianjun Zhang

Faculty, Staff and Student Publications

Accurate diagnoses are crucial in determining the most effective treatment across different cancers. In challenging cases, morphology-based traditional pathology methods have important limitations, while molecular profiling can provide valuable information to guide clinical decisions. We present a 35-year female with lung cancer with choriocarcinoma features. Her disease involved the right lower lung, brain, and thoracic lymph nodes. The pathology from brain metastasis was reported as "metastatic choriocarcinoma" (a germ cell tumor) by local pathologists. She initiated carboplatin and etoposide, a regimen for choriocarcinoma. Subsequently, her case was assessed by pathologists from an academic cancer center, who gave the diagnosis of …

The Digital Transition: Are Adults Aged 65 Years Or Older Willing To Complete Online Forms And Questionnaires In Patient Portals?, Nancy P Gordon, Sherry Zhang, Joan C Lo, Christina F Li

Faculty, Staff and Student Publications

INTRODUCTION: Patients are being encouraged to complete forms electronically using patient portals rather than on paper, but willingness of older adults to make this transition is uncertain.

METHODS: The authors analyzed data for 4105 Kaiser Permanente Northern California 2020 Member Health Survey respondents aged 65-85 years who answered a question about willingness to complete online forms and questionnaires using a patient portal. Data weighted to the Kaiser Permanente Northern California membership were used to estimate percentages of older adults willing to complete patient portal forms and questionnaires. Chi-square tests and log-Poisson regression models that included sociodemographic, internet use, and patient …

Sabr For Sarcoma Lung Metastases: Indications For Treatment And Guidance For Patient Selection, Ahsan S Farooqi, Alison K Yoder, Heather Y Lin, Dario Pasalic, Jeremy Erasmus, Sonia Betancourt, Cort Wernz, Devarati Mitra, Maria A Zarzour, Neeta Somaiah, Anthony Conley, Ravin Ratan, Andrew Livingston, Dejka M Araujo, Christina Roland, Christopher Scally, Emily Keung, Saumil N Gandhi, B Ashleigh Guadagnolo, Quynh-Nhu Nguyen, Andrew J Bishop

Faculty, Staff and Student Publications

Purpose: The lungs are the most common site of metastasis for patients with soft tissue sarcoma. SABR is commonly employed to treat lung metastases among select patients with sarcoma with limited disease burden. We sought to evaluate outcomes and patterns of failure among patients with sarcoma treated with SABR for their lung metastases.

Methods and materials: We performed a retrospective review of patients treated at a tertiary cancer center between 2006 and 2020. Patient disease status at the time of SABR was categorized as either oligorecurrent or oligoprogressive. The Kaplan-Meier method was used to estimate disease outcomes. Uni- and multivariable …

Phase I Study Of Oric-101, A Glucocorticoid Receptor Antagonist, In Combination With Enzalutamide In Patients With Metastatic Castration-Resistant Prostate Cancer Progressing On Enzalutamide, Wassim Abida, Andrew W Hahn, Neal Shore, Neeraj Agarwal, Paul Sieber, Matthew R Smith, Tanya Dorff, Paul Monk, Matthew Rettig, Rupal Patel, Anne Page, Maureen Duff, Rongda Xu, Jian Wang, Shravani Barkund, Aleksandr Pankov, Amber Wang, Melissa R Junttila, Pratik S Multani, Anneleen Daemen, Edna Chow Maneval, Christopher J Logothetis, Michael J Morris

Faculty, Staff and Student Publications

Purpose: Increased glucocorticoid receptor (GR) signaling is a proposed compensatory mechanism of resistance to androgen receptor (AR) inhibition in metastatic castration-resistant prostate cancer (mCRPC). ORIC-101 is a potent and selective orally-bioavailable GR antagonist.

Patients and methods: Safety, pharmacokinetic/pharmacodynamic, and antitumor activity of ORIC-101 in combination with enzalutamide were studied in patients with mCRPC progressing on enzalutamide. ORIC-101 doses ranging from 80 to 240 mg once daily were tested in combination with enzalutamide 160 mg once daily. Pharmacokinetics/pharmacodynamics was assessed after a single dose and at steady state. Disease control rate (DCR) at 12 weeks was evaluated at the recommended phase …