Uniformed Services University Of The Health Sciences Research Articles

Abstract 4820: Comparison of Black and White patients in treatment for papillary thyroid cancer in an equal access health system

Abstract Introduction: In the U.S., Black patients with papillary thyroid cancer (PTC) are less likely to receive treatment than non-Hispanic White patients. Access to care and insurance status may be related to these disparities. We aimed to compare Black and White patients in receipt of cancer care for PTC in the equal access Military Health System. Materials and Methods: We used the MilCanEpi database to identify a cohort of men and women aged 18 or older who were diagnosed with PTC between January 1, 1998 and December 31, 2014. Patients were assessed for treatment by surgery (e.g., lobectomy, thyroidectomy), adjuvant radioactive iodine (RAI), or active surveillance. Treatment appropriate for risk status (low-risk or high-risk) was compared between non-Hispanic White and Black patients using multivariable logistic regression and expressed as adjusted odds ratios (aOR) with 95% confidence intervals (CIs). Results: Among 3,511 patients with PTC, 65.0% White and 65.5% Black received surgical treatment (aOR 0.97, 95% CI 0.80-1.18 for Black vs. White). For patients with low-risk PTC, overall receipt of either surgery or active surveillance (aOR 0.86, 95% CI 0.67-1.10 for Black vs. White) was similar between races. For patients with high-risk PTC, overall receipt of surgery (aOR 1.19, 95% CI 0.71-2.01) or adjuvant RAI (aOR 1.44, 95% CI 0.60-3.44) was similar for Black compared to White patients. Conclusions: In an equal access health system, there were no overall racial differences in receipt of surgical treatment for PTC. Further, in analysis by risk status, there were no significant racial differences in receipt of active surveillance for low-risk PTC nor receipt of adjuvant RAI for high-risk PTC. This suggests the role of access to care in reducing racial disparities in treatment for PTC observed in the general U.S. population. Funding and Acknowledgement: The authors thank the Joint Pathology Center (JPC) for providing the DoD cancer registry data and the Defense Health Agency (DHA) for providing the MHS data repository (MDR) data. This project was supported by the Murtha Cancer Center Research Program (MCCRP) of the Department of Surgery, Uniformed Services University of the Health Sciences (USUHS) under the auspices of the Henry M. Jackson Foundation for the Advancement of Military Medicine (HJF, Inc.), grant numbers HHU0001-16-2-0014 and HU0001-18-2-0032 awarded to C.S. Disclaimer: The contents of this abstract are the sole responsibility of the authors and do not necessarily reflect the views, assertions, opinions, or policies of the Uniformed Services University of the Health Sciences, the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., the Department of Defense, or the Departments of the Army, Navy, or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. government. Citation Format: Yvonne L. Eaglehouse, Sarah Darmon, Craig D. Shriver, Kangmin Zhu. Comparison of Black and White patients in treatment for papillary thyroid cancer in an equal access health system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4820.

Long Term Cancer Risk of U.S. Service Members Exposed to Burn Pits during Military Deployment to Iraq from 2006-2008: A Retrospective Cohort Study

Introduction: Burn pits have known individual carcinogenic byproducts, including polyaromatic hydrocarbons and volatile organic compounds, which have a presumptive link between deployment exposure and tumorigenesis. However, there are a dearth of epidemiologic data describing the long-term cancer incidence in U.S. service members who were exposed to burn pits during deployment to Iraq. A retrospective cohort study was carried out with the goal of assessing long-term cancer risk in service members who deployed to Iraq and reported exposure to burn pits. Methods: Data were collected from the Armed Forces Health Surveillance Division. Inclusion criteria were any service member who deployed to Iraq (Joint Base Balad or Camp Taji) between January 1st, 2005 to June 30th, 2007, whose deployment lasted at least 180 days, who reported burn pit exposure on their post-deployment health assessment form, who were at least 35 years old at the time of their deployment, who remained in the military for at least 10 years post-deployment, and who had post-deployment serum available in the DoD Serum Repository. Controls were individually matched to the research cohort by age (+/- 3 years), sex, branch of service, rank, and occupation category. To minimize confounding from the “healthy deployer effect”, controls were also required to have deployed to Germany for at least 180 days, and to have been at least 35 years old at the time of their deployment. Controls could not have ever deployed to Southwest Asia or reported burn pit exposure. Cancer incidence was captured via ICD-9 and -10 codes of 140-209 and C00-C96, respectively. Primary endpoint was assessment of serum monoclonal gammopathy in deployed, exposed personnel vs. non- deployed controls. The secondary endpoint was assessment of long-term neoplasia development via ICD-code, which is reported here. A Fisher test was used for comparison of post- deployment malignancies between deployed/exposed service members and controls. This study was exempt from full IRB review and funded by Murtha Cancer Center Research Program. Results: 534 deployed/exposed service members and 534 matched controls met inclusion criteria. Median age at deployment was 37 (range: 35-55). Most service members were white enlisted males in the Army. Mean follow up from the end of deployment was 14 years for deployed/exposed members and 10 years for controls. In each cohort, 39 service members (7%) developed malignancy post-deployment (p=1.0), of which solid tumors were exceedingly more common as shown in Table 1. Only two hematologic malignancies were diagnosed, both in the deployed/exposed cohort, consisting of multiple myeloma and a lymphoid malignancy. There were no differences in the number of service members with multiple primary tumor types between the exposed and unexposed groups. There were also no differences in the number of service members with anemia, hypercalcemia or kidney disease; however, exposed personnel were more likely to develop obesity after their deployment (n=171 vs. 159, p=0.002). Serum monoclonal gammopathy results will be reported separately. Conclusions: Service members who deployed to Iraq between 2006-2008 for at least 180 days, who reported burn pit exposure, and who were followed for an average of 14 years post deployment did not have higher rates of plasma cell disorders or any other malignancy than matched controls who deployed to Germany. Limitations of epidemiologic studies on service members include response bias on post-deployment health assessment forms, inability to capture service members who leave the military, and lack of details on Veterans seeking healthcare through the VA system or civilian healthcare system. It is possible that with a more expansive patient cohort that includes Veterans and longer follow up, that a difference in cancer incidence could emerge. Further research is needed to better understand cancer risk factors in service members. Disclaimer: The contents of this publication are the sole responsibility of the author(s) and do not necessarily reflect the views, opinions or policies of Uniformed Services University of the Health Sciences (USUHS), The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., the Department of Defense (DoD) or the Departments of the Army, Navy, or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government.

Abstract B036: Immune cell profiling of human prostate tumors identifies a protective and pathological role for intratumoral mast cells in the development of biochemical recurrence and metastasis

Abstract Background: Immunobiological factors may, in part, contribute to racial disparities in prostate cancer (PCa), the second leading cause of cancer-related death for US men. African American (AA) men face a greater risk of developing PCa and having a poorer outcome of this disease, compared to Caucasian American (CA) men. The goal of this study is to identify immune-specific differences influencing PCa health disparity as well as PCa progression. Methods: Ex vivo tumor biopsies were obtained following radical prostatectomy (RP) from 51 treatment-naïve patients (26 AA, 25 CA) under approved IRB protocols. Total RNA from fresh frozen tissue was isolated and amplified by PCR using NanoString multiplexed target enrichment protocols. We evaluated differences in resulting transcripts by self-reported race, pathology, and other clinical and pathologic features. Relative abundances of immune cell subsets were determined using computational methods, including previously published deconvolution algorithms, to estimate cellular content. Results: We identified differentially expressed genes between AA and CA tumors that are characterized by genes regulating Natural Killer (NK) cell function and Wnt signaling cancer pathways. Among the entire cohort, high expression of two of these differentially expressed genes, DVL2 and MAP3K5, were associated with worse biochemical recurrence (BCR)-free and metastasis-free survival. No difference in immune cell abundance was observed by self-reported race. Strikingly, among the entire cohort, low abundance of intratumoral mast cells was also associated with worse PCa pathology and poorer BCR-free and metastasis-free survival. Conclusions: Using a race-matched military cohort, we found that AA and CA tumors differ in the expression levels of Wnt and NK signaling-related pathways, yet cellular estimations of immune abundance did not significantly differ. Remarkably, the level of mast cell abundance within tumors at time of RP may be protective and prolong BCR-free and metastasis-free survival of patients. These types of in-depth immune profiling assessments have the potential to guide precision medicine and treatment decisions in the clinic. Disclaimer: The contents of this publication are the sole responsibility of the author(s) and do not necessarily reflect the views, opinions or policies of Uniformed Services University of the Health Sciences (USUHS), The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., the Department of Defense (DoD), the Departments of the Army, Navy, or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government. Citation Format: Cara Schafer, Jiji Jiang, Sally Elsamanoudi, Darryl Nousome, Denise Young, Yingjie Song, Isabell Sesterhenn, Gregory Chesnut, Shyh-Han Tan. Immune cell profiling of human prostate tumors identifies a protective and pathological role for intratumoral mast cells in the development of biochemical recurrence and metastasis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B036.

Abstract B062: ERGi-USU selectively inhibit ERG positive prostate cancer through ATF3 mediated ferroptosis

Abstract Introduction: Prostate cancer (PCa) is the second leading cause of cancer deaths among men in the United States. Approximately 50% of patients with PCa harbor an oncogenic TMPRRS2- ERG gene fusion in their primary and 35% of patients with metastatic castration resistant prostate cancer that often coincides with defective PTEN. We have identified a small molecule, ERGi-USU, with previously described metal chelator activity that binds to the atypical kinase RIOK2 and selectively inhibits the growth of ERG positive cancer cells in vitro and in vivo. ERGi- USU is also effective in inhibiting the growth of tumorigenic mouse prostate organoids harboring TMPRSS2-ERG in Pten null background. We developed a salt formulated derivative of ERGi-USU with improved tumor growth inhibition activity. The objective of our study is to gain insights into the mechanism of action of parental and new ERGi-USU compounds. Methods: The anti-tumorigenic activities of ERGi-USU, was assessed in the hormone-refractory metastatic tissue derived ERG positive prostate cancer cell line (VCaP) and mouse prostate derived TMPRSS2-ERG/Pten null organoids. We monitored cell cycle proteins and ferroptosis pathways and RIOK2 in response to treatment with ERGi-USU compounds. The normal primary endothelium derived HUVEC cells were used as normal control due to the normal endogenous expression of ERG in endothelial cells. Results: Cell growth of tumorigenic ERG positive mouse prostate organoids were inhibited in response to ERGi-USU treatments. Consistent with the response of VCaP cells the ERG and RIOK2 protein levels were down regulated by ERGi-USU treatment in ERG positive tumorigenic mouse prostate organoids. Altered levels of ferroptosis associated proteins were found indicating the involvement of ferroptosis in the activity of ERGi-USU compounds. Conclusions: Our results showed that ferroptosis, the iron-dependent form of programmed cell- death may be involved in the cancer selective activity of ERGi-USU compounds. Disclaimer: The contents of this publication are the sole responsibility of the author(s) and do not necessarily reflect the views, opinions or policies of Uniformed Services University of the Health Sciences (USUHS), The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., the Department of Defense (DoD), the Departments of the Army, Navy, or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government. Citation Format: Binil Eldhose, Katherine Beck, Cyrus Eghtedari, Gartrell C. Bowling, Mallesh Pandrala, Sanjay V. Malhotra, Xiaofeng A. Su, Albert Dobi. ERGi-USU selectively inhibit ERG positive prostate cancer through ATF3 mediated ferroptosis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B062.

Is There a Role for Adjuvant Therapy in Patients with Large Juvenile Nasopharyngeal Angiofibromas?

The LaryngoscopeEarly View Triological Society Best Practice Is There a Role for Adjuvant Therapy in Patients with Large Juvenile Nasopharyngeal Angiofibromas? Charles A. Riley MD, Corresponding Author Charles A. Riley MD [email protected] orcid.org/0000-0002-1993-7018 Department of Otolaryngology—Head and Neck Surgery, Walter Reed National Military Medical Center, Bethesda, Maryland, USA Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA Send correspondence to Charles A. Riley, MD, Department of Otolaryngology—Head and Neck Surgery, Walter Reed National Military Medical Center, 8901 Rockville Pike, Bethesda, MD 20889, USA. Email: [email protected]Search for more papers by this authorDavid A. Gudis MD, David A. Gudis MD orcid.org/0000-0002-1938-9349 Department of Otolaryngology – Head and Neck Surgery, Columbia University Medical Center, New York Presbyterian Hospital, New York City, New York, USASearch for more papers by this author Charles A. Riley MD, Corresponding Author Charles A. Riley MD [email protected] orcid.org/0000-0002-1993-7018 Department of Otolaryngology—Head and Neck Surgery, Walter Reed National Military Medical Center, Bethesda, Maryland, USA Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA Send correspondence to Charles A. Riley, MD, Department of Otolaryngology—Head and Neck Surgery, Walter Reed National Military Medical Center, 8901 Rockville Pike, Bethesda, MD 20889, USA. Email: [email protected]Search for more papers by this authorDavid A. Gudis MD, David A. Gudis MD orcid.org/0000-0002-1938-9349 Department of Otolaryngology – Head and Neck Surgery, Columbia University Medical Center, New York Presbyterian Hospital, New York City, New York, USASearch for more papers by this author First published: 30 May 2023 https://doi.org/10.1002/lary.30797 Editor's Note: This Manuscript was accepted for publication on May 18, 2023 The authors have no other funding, or financial relationships to disclose. The authors whose names are listed above certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript. The contents of this publication are the sole responsibility of the author(s) and do not necessarily reflect the views, opinions, or policies of Uniformed Services University of the Health Sciences (USUHS), the Department of Defense (DoD), the Departments of the Army, Navy, or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. BIBLIOGRAPHY 1McAfee WJ, Morris CG, Amdur RJ, Werning JW, Mendenhall WM. Definitive radiotherapy for juvenile nasopahryngeal angiofibroma. Am J Clin Oncol. 2006; 29(2): 168- 170. 2Mallick S, Benson R, Bhasker S, Mohanti BK. Long-term treatment outcomes of juvenile nasopharyngeal angiofibroma treated with radiotherapy. Acta Otorhinolaryngol Ital. 2015; 35(2): 75- 79. 3Amdur RJ, Yeung AR, Fitzgerald BM, Mancuso AA, Werning JW, Mendenhal WM. Radiotherapy for juvenile nasopharyngeal angiofibroma. Pract Radiot Oncol. 2011; 1(4): 271- 278. 4Thakar A, Gupta G, Bhalla AS, et al. Adjuvant therapy with flutamide for presurgical volume reduction in JNA. Head Neck. 2011; 33(12): 1747- 1753. 5Labra A, Chavolla-Magana R, Lopez-Ugalde A, Alanis-Calderon J, Huerta-Delgado A. Flutamide as a preoperative treatment in juvenile angiofibroma (JA) with intracranial invasion: report of 7 cases. Otolaryngol Head Neck Surg. 2004; 130(4): 466- 469. Early ViewOnline Version of Record before inclusion in an issue ReferencesRelatedInformation

Addressing HPSP Learner Needs: A Pilot Study of a "Fundamentals of Military Medicine" Course.

Military medicine is uniquely different from civilian medicine, and military physicians in the USA are primarily recruited through the Health Professions Scholarship Program (HPSP) and the Uniformed Services University of the Health Sciences (USUHS). Medical students at the USUHS receive more than 650 hours of military-specific curriculum and spend 21 days engaged in field exercises. HPSP students complete two 4-week officer training sessions during their 4 years of medical school. There is a clear discrepancy in preparation for military medicine between HPSP and USUHS students. The USUHS School of Medicine undertook an initiative to develop a fully online self-paced course on the fundamentals of military medicine topics to help HPSP students bridge the gap in their preparation. This article will describe how the online self-paced course was designed and present feedback from the pilot offering of this course. As proof of concept of the effectiveness of an online self-paced course for teaching the fundamentals of military medicine to HPSP students, two chapters from the "Fundamentals of Military Medicine" published by the Borden Institute were transferred to an online format. Each chapter was offered as a module. In addition to the chapters, an introduction and closing module were added to the pilot course. The pilot course was offered over 6 weeks. Data for this study were obtained from module feedback surveys, pre- and post-course quizzes, participant focus groups, and course evaluation surveys. Pre- and post-test scores were analyzed to evaluate content knowledge. The open-ended survey questions on the feedback forms and focus group transcripts were collated and analyzed as textual data. Fifty-six volunteers enrolled in the study, and 42 completed the pre- and post-course quizzes. This participant pool included HPSP students (79%, n = 44) and military residents in civilian graduate medical education programs (21%, n = 12). The module feedback surveys showed that most participants spent 1 to 3 hours on each of the modules, which they rated as extremely or quite reasonable (Module 1: 64%, Module 2: 86%, Module 3: 83%). There was not much difference between the overall quality of the three modules. The participants found content on application to the military-specific context very valuable. Of the different course elements, video content was rated as the most effective. Participant feedback clearly highlighted that HPSP students want a course that informs them about the fundamentals of military medicine and demonstrates how the information would apply to their lives. Overall, the course was effective. HPSP students showed knowledge gains and self-reported satisfaction with the course's objectives. They were able to locate information easily and understand the course expectations. This pilot study has shown that there is a need for a course that provides the fundamentals of military medicine to HPSP students. A fully online self-paced course provides flexibility for the students and improves access.

Critical COVID-19 disease explained by type I interferon autoantibodies found in patients within the Military Health System.

Abstract Neutralizing auto-antibodies (auto-Abs) that target type I interferons (IFN), a group of cytokines that induce innate immune responses upon viral infection, are found within approximately 10–20% of patients with critical COVID-19. We sought to determine if neutralizing type I IFN auto-Abs contribute to severe COVID-19 in patients within the Military Health System (MHS). The Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases with Pandemic Potential (EPICC) cohort collected demographic data, clinical data and sera from SARS-CoV-2 infected patients enrolled across 10 U.S. military treatment facilities. We screened sera collected <21 days post-symptom onset from 214 COVID-19 inpatients and 312 COVID-19 outpatients for IFN auto-Ab positivity and neutralizing activity using Luminex and intracellular flow cytometry, respectively. Similar to previous reports, we detected neutralizing auto-Abs against IFN-α and/or IFN-ω in a significantly higher frequency of inpatients (9 total, 4.2%) versus outpatients (1, 0.32%) (p=0.009). Remarkably, IFN auto-Abs persisted 6–12 months post-infection in most inpatients, including several with a prior history of autoimmune disease. Among inpatients, multivariate logistic regression analyses demonstrated that type I IFN auto-Abs were associated with a greater risk of severe and critical COVID-19 (adjusted odds ratio (aOR) = 16.40 and 6.44, respectively) after adjusting for age, sex and comorbidity burden. Our results confirm a robust association between critical COVID-19 and the presence of type I IFN auto-Abs, which may predispose to other severe respiratory viral infections that cause substantial morbidity and mortality in the MHS. This work was supported by awards from the Defense Health Program (HU00012020067) and the National Institute of Allergy and Infectious Disease (HU00011920111). The protocol was executed by the Infectious Disease Clinical Research Program (IDCRP), a Department of Defense (DoD) program executed by the Uniformed Services University of the Health Sciences (USUHS) through a cooperative agreement by the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. (HJF).

Abstract 4868: Targeting of ERG positive prostate cancers with ERGi-USU-6 salt derivative

Abstract Introduction: Prostate cancer (PCa) is the second leading cause of cancer deaths among men in the United States. Approximately 50% of patients with PCa harbor an oncogenic TMPRRS2- ERG gene fusion in their primary tumor and 35% of patients with metastatic castration resistant prostate cancers have the gene fusion. We have identified a potent small molecule inhibitor, ERGi-USU-6 salt derivative 7b, that selectively inhibits the growth of ERG positive tumor. This small molecule inhibitor is also effective in inhibiting the growth of benign and cancerous mouse prostate organoids expressing TMPRSS2-ERG (ERG positive organoids). To gain insights into the cancer-selective properties of ERGi-USU-6 salt 7b we evaluated pathways associated in ERGi-USU induced inhibition. Methods: The biological activities of salt derivative 7b, were assessed in hormone- refractory metastatic tumor derived ERG positive prostate cancer cell line, VCaP along with organoids. We monitored the pathways associated in the mechanism of drug action through, cell cycle-regulator proteins by immunoblot assays, cell cycle and ferroptosis related analyses in response to 7b treatment. We also monitored the levels of the RIOK2 kinase, previously shown to bind the parental ERGi-USU compound. The normal primary endothelium derived HUVEC cells were used as normal control due to the normal endogenous expression of ERG in endothelial cells including HUVEC. Results: Cell growth and immunoblot analysis indicated the inhibition of ERG positive prostate organoid upon ERGi-USU treatments resulting in the downregulation of ERG and RIOK2 protein levels. The cell cycle analyses, pathway mapping by protein assessment and ferroptotic assays suggests that salt derivative 7b treatment inhibits the ERG positive prostate cancer through ferroptosis along with RIOK2 inhibition. Conclusions: Our results showed that the ferroptosis inducer ATF3 gene is involved in the cancer-selective activity of ERGi-USU-6 salt derivative 7b. Further, based on our observations we hypothesize that ferroptosis, the iron-dependent form of programmed cell-death, may be the mechanism of cancer selective activity of salt derivative 7b. Disclaimer: The contents of this publication are the sole responsibility of the author(s) and do not necessarily reflect the views, opinions or policies of Uniformed Services University of the Health Sciences (USUHS), The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., the Department of Defense (DoD), the Departments of the Army, Navy, or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government. Citation Format: Binil Eldhose, Katherine Beck, Cyrus Eghtedari, Gartrell C. Bowling, Mallesh Pandrala, Sanjay V. Malhotra, Xiaofeng A. Su, Albert Dobi. Targeting of ERG positive prostate cancers with ERGi-USU-6 salt derivative. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4868.

Abstract P2-17-04: Pharmacological inhibition of LY6K induced cell cycle arrest and DNA damage by disrupting the LY6K-Histone-Aurora B signaling axis

Abstract Pharmacological inhibition of LY6K induced cell cycle arrest and DNA damage by disrupting the LY6K-Histone-Aurora B signaling axis Benson C. Selvanesan1,2, Sheelu Varghese1,2, Justyna Andrys5, Ricardo H. Arriaza6, Rahul Prakash6, Purushottam B Tiwari7, Cara Olsen8, Daniel Hupalo2,4, Yuriy Gusev5, Megha N. Patel6, Sara Contente1, Miloslav Sanda9, Aykut Uren7, Matthew D. Wilkerson3,4, Clifton L. Dalgard3,4, Linda S. Shimizu6, Maksymilian Chruszcz6, Tomasz Borowski5, Geeta Upadhyay 1,3,7. Affiliations 1 Department of Pathology, 2 Henry M. Jackson Foundation, 3 Murtha Cancer Center, 4 Department of Anatomy, Physiology, and Genetics 8 Department of Preventive Medicine and Biostatistics Uniformed Services University of the Health Sciences, Bethesda, MD, USA. 5 Jerzy Haber Institute of Catalysis and Surface Chemistry Polish Academy of Sciences, Cracow, Poland. 6 Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC, USA. 7 Department of Oncology, Georgetown University Medical Center, Washington, DC, USA. 9 Max Planck Institute for Heart and Lung Research, Ludwigstrasse, 43, 61231 Bad Nauheim, Germany. Correspond Disclaimer The opinions expressed herein are those of the authors and are not necessarily representative of the official policies of the Uniformed Services University of the Health Sciences (USUHS), the Department of Defense (DOD), the United States Army/Navy/Air Force, the U.S. Government, or any other funding agencies Conflict of Interest None Acknowledgments NIH, NCI, R01 CA227694. NIH, NCI, R21CA256424. DOD, USUHS, VPR-NFP-74-9824. Biomedical Instrumentation Center, USUHS. The American Genome Center, USUHS. Antibody Characterization Program, Clinical Proteomics Tumor Analysis Consortium (CPTAC), National Cancer Institute, National Institute of Health. The Polish Grid Infrastructure, Cracow, Poland. NIH P30CA51008 and 1S10OD019982-01 to Biacore Molecular Interaction Shared Resource (BMISR), Georgetown University. ABSTRACT Increased expression of LY6K is significantly associated with poor survival outcomes in many solid cancers, including triple-negative and estrogen receptor-positive breast, ovarian, gastric, head and neck, neuroblastoma, bladder, and lung cancers. Inhibition of LY6K signaling is an ideal therapeutic approach for cancer, since the LY6K protein is not involved in vital organ function. Previously, we identified the small molecule NSC243928 as a binder of LY6K using surface plasmon resonance screening and showed that its activity was dependent on LY6K expression in triple-negative breast cancer cells. Here, we demonstrate the structural basis of the molecular interaction of NSC243928 with LY6K protein and the subsequent inhibition of LY6K function in mitosis and cell division via Aurora B-histone pathway. We observed that LY6K interacts with phosphorylated histones and Aurora B kinases during mitosis and that this interaction was disrupted in the presence of NSC243928. Disruption of LY6K function in mitosis/cytokinesis leads to DNA damage, senescence, and apoptosis of cancer cells. We observed that NSC243928 led to increased binding of LY6K to phosphorylated gammaH2X at S139, which was dependent on NSC243928 interaction with LY6K on phenylalanine 79. Furthermore, we observed increased levels of phosphorylated gammaH2X at S139 and increased caspase-3 activation in the tumor isografts of 4T1 and E0771 mammary tumors treated with NSC243928. These data reveal that LY6K is a novel cell cycle target for therapeutic development in triple-negative breast cancer and other solid cancers with high expression of LY6K, such as bladder cancer, head and neck, and lung cancer. Citation Format: Benson Selvanesan, Sheelu Varghese, Justyna Andrys, Ricardo Arriaza, Rahul Prakash, Purushottam Tiwari, Cara Olsen, Daniel Huplo, yuriy Gusev, Megha Patel, Sara Contente, Miloslav Sanda, Matthew Wilkerson, Clifton Dalgard, Linda S. Shimizu, Maksymilian Chruszcz, Tomasz Borowski, Geeta Upadhyay. Pharmacological inhibition of LY6K induced cell cycle arrest and DNA damage by disrupting the LY6K-Histone-Aurora B signaling axis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-17-04.

TriService Nursing Research Program: A critical component to support military nursing science

TriService Nursing Research Program: A critical component to support military nursing science

PD16-12 AGE AND RACE SPECIFIC GENE SIGNATURE: AN INDEPENDENT PREDICTOR OF PROSTATE CANCER IN RACIALLY DIVERSE MILITARY COHORT OF AFRICAN AND CAUCASIAN AMERICAN PATIENTS

You have accessJournal of UrologyCME1 May 2022PD16-12 AGE AND RACE SPECIFIC GENE SIGNATURE: AN INDEPENDENT PREDICTOR OF PROSTATE CANCER IN RACIALLY DIVERSE MILITARY COHORT OF AFRICAN AND CAUCASIAN AMERICAN PATIENTS Shashwat Sharad, Darryl Nousome, Gregory Chesnut, and Hua Li Shashwat SharadShashwat Sharad More articles by this author , Darryl NousomeDarryl Nousome More articles by this author , Gregory ChesnutGregory Chesnut More articles by this author , and Hua LiHua Li More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002548.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Age and Racial disparities in prostate cancer (PCa) is a serious challenge and the PCa mortality rates are nearly three times higher in African American (AA) men younger than age 65 than White Caucasian American (CA) men. Young age prostate cancer is more likely to be an aggressive cancer commonly seen in AA population. The objective of this study is to examine the age and racial disparities associated gene signatures for disease progression, patient stratification and targeted therapeutic options. METHODS: Specimens collected from radical prostatectomy patients (41 CA and 20 AA) who provided written consent under protocols (#393738, #GT90CM/385525 and #908925) approved by the Institutional Review Boards of the Walter Reed National Military Medical Center (WRNMMC) and the Uniformed Services University of the Health Sciences (USUHS). We used a cohort of non-familial PCa patients of AA and CA origin. Total RNA was extracted from tumor, and adjacent normal epithelium of formalin-fixed-paraffin-embedded (FFPE) specimens by Laser capture microdissection (LCM). Differential gene expression in tumor versus normal tissues between young and old AA and CA patients were analyzed by NanoString using a customized CodeSet of 151 probes sets. The panel was designed to detect 135 target transcripts, which were compiled from 34 genes implicated in or associated with prostate cancer progression, 27 prostate cancer specific gene fusions, 25 cancer associated genes, five genes encoding the ETS-family of transcription factors and genes over-expressed (27) or under-expressed (17) in PCa compared to matched benign epithelium. In addition, five prostate stroma or epithelium specific genes were selected as control and 11 housekeeping genes were included for biological normalization. RESULTS: The differentially expressed genes related to tumor-normal differences between the old (66–73 yrs) and young (42–58 yrs) AA and CA prostate cancer patients with Gleason (3+3 and 3+4) were identified. After controlling for false discovery rates, we identified a panel of nine genes (ANXA2, C-MYC, VEGFR1, ERG, NPY, PSMA/FOLH1, TWIST1, MAOA, MYCN) uniquely associated with the age and race. The tumor vs. normal ratios of ANXA2 and c-MYC expression in prostate tumors of old and young patients were found to be significant. We found a clear association of VEGFR1 gene expression with CA young and c-MYC gene with AA young PCa. Our study highlights the potential of using FFPE tissue as a source for the analysis of prognostic biomarkers for PCa. CONCLUSIONS: An unmet challenge in PCa is the identification of biomarkers for early detection of aggressive disease. Effective biomarkers with high specificity will provide early treatment options for high-risk patients. Using Age and Race as the endpoint, we identified ANXA2, c-MYC and VEGFR1 as age and race associated PCa gene which needs to be further validated in the lager cohort. Our findings clearly highlight distinct racial and age-related differences and addresses the clinical utility of available genetic tests across old and young AA and CA men. Source of Funding: This study was supported by CPDR, USUHS, HU0001-10-2-0002 © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e273 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Shashwat Sharad More articles by this author Darryl Nousome More articles by this author Gregory Chesnut More articles by this author Hua Li More articles by this author Expand All Advertisement PDF DownloadLoading ...

Joining the Navy to Become a Physician: The Typical Experience.

The decision to enter the Navy as a physician is a major career choice. However, there are no published studies that address the typical Navy physician's experience in the Health Professions Scholarship Program (HPSP) and Uniformed Services University of the Health Sciences (USUHS) programs. The purpose of this qualitative study is to describe the typical Navy physician's experience in the HPSP and USUHS programs. An anonymous online survey containing 47 questions was distributed to 63 Navy HPSP and USUHS physicians who started internships from 2008 to 2015. Participants were chosen by using purposeful, criterion, and snowball sampling methods with whom the author had a professional relationship during his military experience. The survey data were plotted in Excel spreadsheets and graphs according to six sub-research questions. Mean, SD, Likert scale 1-5, and grouping of free text responses were recorded. A total of 54 out of 63 Navy physicians (85.7%) responded to the survey. Navy physicians got their first-choice residency selection of 67.3% of the time, 34.6% went straight through residency without interruptions, 44.2% answered definitely or probably that military match changed their residency selection compared to them applying for civilian residency, and 46.2% answered definitely or probably that it was more difficult to get into military versus civilian residency. Participants answered definitely or probably that military experience puts them ahead of civilians in terms of leadership (82.7%), prior medical experience (46.2%), and applying for civilian residency (76.2%). Common positive themes of free-text answers included having financial stability, unique life experiences, and serving their country. Common negative themes included lack of career control, lack of knowledge regarding HPSP/USUHS programs, and delay in residency and career. The principal findings in this study are that most Navy physicians favored paid medical school/financial support, working overseas and in unique operational climates, having unique life experiences, leadership skills, and prior military experience put them ahead of their civilian colleagues, thought the Navy experience was worth it, and would join again if given the opportunity. However, most Navy physicians had a lack of career control due to needs of the Navy, lack of knowledge regarding residency selection, operational billets, and active duty service obligation, had more difficulty getting into a military residency of their choice versus civilians, and had interrupted residency training/training delays. The Navy would possibly benefit from a nationwide HPSP/USUHS physician mentorship program and an educational seminar to increase medical student applicant knowledge, which may improve recruiting and retention.

Abstract P3-14-04: Genetic testing in non-Hispanic Black women with breast cancer treated within an equal-access healthcare system

Abstract Purpose: Identification of women with hereditary forms of cancer allows for use of precision medicine approaches to improve survival. Non-Hispanic Black (NHB) women in the US general population are less likely to undergo genetic testing or utilize risk-reducing strategies. Whether these disparities exist within the equal-access military healthcare system of the Department of Defense is not known. Methods: Genetic test information and surgical procedures were extracted for all NHB and Non-Hispanic Whites (NHW) with invasive breast cancer who were diagnosed and treated at the Murtha Cancer Center at Walter Reed National Military Medical Center and enrolled in the Clinical Breast Care Project. National Comprehensive Cancer Network criteria from the year of diagnosis were assessed for all patients. Data were analyzed using chi-square analysis with p<0.05 defining significance. Results: NHB were significantly (p=0.009) more likely to meet criteria for genetic testing compared to NHW, however, test uptake did not differ significantly between populations (p=0.292). Pathogenic variant frequency (p=0.597), prophylactic mastectomy (p=0.915) and oophorectomy (p=0.076) did not differ significantly between populations. Conclusion: These data demonstrate that when barriers, such as cost and lack of insurance barriers were removed, NHB were as willing to pursue testing and risk-reducing strategies as their NHW counterparts. Increasing the availability of testing and clinical management for NHB with hereditary forms of cancer may help reduce disparate survival seen in the US general population. The contents of this publication are the sole responsibility of the author(s) and do not necessarily reflect the views, opinions or policies of Uniformed Services University of the Health Sciences (USUHS), The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., the Department of Defense (DoD) or the Departments of the Army, Navy, or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government. Citation Format: Rachel Ellsworth, Ashlee Vargason, Clesson Turner, Craig Shriver. Genetic testing in non-Hispanic Black women with breast cancer treated within an equal-access healthcare system [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-14-04.

ADSP follow‐up study: NCRAD biospecimens

The National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD) is collaborating with the Alzheimer's Disease Sequencing Project (ADSP) to ensure that subjects with sequencing have available biospecimens. The latest phase of the ADSP, the Follow-Up Study (ADSP-FUS), is generating sequencing on additional subjects from diverse populations and ethnic groups; many of these subjects have samples available at NCRAD for validation and extension studies.NCRAD collects, stores, and distributes biospecimens from subjects in studies included in the ADSP-FUS, such as the National Institute on Aging Late Onset Alzheimer's Disease (NIA-LOAD) Family Based Study, the Alzheimer's Disease Neuroimaging Initiative (ADNI), and subjects accrued by Alzheimer's Disease Research Centers (ADRCs). DNA for subjects in these studies is shipped to The American Genome Center (TAGC), under the direction of Dr. Clifton Dalgard, at the Uniformed Services University of the Health Sciences (USUHS), for whole genome sequencing. NCRAD has online catalogs for many of these cohorts, including information on biospecimens as well as demographic and clinical data, to help investigators identify and request biospecimens.NCRAD has shipped >6,000 DNA samples to USUHS for sequencing and inclusion in ADSP-FUS from subjects with additional biospecimens housed at NCRAD. Many of these subjects have unique data sets or unique phenotypes, including the >1,000 early onset Alzheimer's disease (AD) samples, 773 samples from ADNI, and >3,000 AD cases/controls with clinical and/or autopsy data. The remainder were samples from cohorts focused on diverse populations and ethnic groups. For ADNI, genomic and cell line DNA, RNA, and lymphoblastoid cell lines (LCLs) are available to approved investigators; for NIA-LOAD, genomic and cell line DNA and LCLs are available, with a subset also having peripheral blood mononuclear cells (PBMCs). For ADRC subjects, in addition to genomic or cell line DNA, RNA, plasma, serum, and PBMCs are available for select subjects. Currently, there are also iPSCs or fibroblasts available for 18 ADSP-FUS subjects. NCRAD catalogs are currently available for the ADRCs and for NIA-LOAD.NCRAD has extensive biospecimens available for investigators interested in validation or extension studies leveraging the whole genome sequencing data available through the ADSP-FUS.

The Alzheimer's Disease Sequencing Project - Follow Up Study (ADSP-FUS): Increasing ethnic diversity in Alzheimer's genetics research with the addition of potential new cohorts.

The ADSP-FUS is a National Institute on Aging (NIA) initiative focused on identifying genetic risk and protective variants for late-onset Alzheimer Disease (LOAD). A concern in AD genetic studies is a lack of racial-ethnic diversity. The ADSP-FUS collects and sequences existing ethnically diverse and unique cohorts with clinical data to expand the utility of new discoveries for individuals from all populations. Additional multi-ethnic cohorts are presently being recruited (e.g., Amerindian, Asian and Indian). The cohorts consist of participants from studies of AD, dementia, and aging-related conditions. Clinical classification (i.e., AD, dementia, and non-affected) is implemented using algorithms based on a minimal set of criteria derived from standard measures (e.g., global cognitive screeners, dementia rating scales, etc.) and clinical history. Data dictionaries are curated for each cohort by the FUS clinical staff. In total, the ADSP-FUS intends to sequence over 60,000 individuals. Biospecimens are processed and DNA is prepared and allocated through the National Centralized Repository for Alzheimer's (NCRAD). The DNA is delivered to the Uniformed Services University of the Health Sciences (USUHS) for whole genome sequencing (WGS). The resulting raw sequence data is conveyed to the Genome Center for Alzheimer's Disease (GCAD) for processing and harmonization followed QC analysis at University of Pennsylvania and University of Miami resulting in analysis-ready genotype data. Lastly, all clinical, genotype and sequence data are sent to the NIA Genetics of Alzheimer Disease Data Storage Site (NIAGADS), serving as the ASDP-FUS data storage, management and sharing center. Over 60,000 samples have been ascertained and are distributed by ancestry as follows: 7,686 African; 9,652 Hispanic; 40,575 non-Hispanic white (1,400 EOAD and 3,745 autopsy); 89 Amerindian; 4,003 Asian and 2,000 Indian. To date, we have sequenced 8,208 NHW; 5,528 African; 6,149 Hispanic & 89 Amerindian. The ADSP-FUS will enhance ongoing efforts to identify shared and novel genetic risk factors for LOAD among different populations. This project will expand our knowledge of potential genetic risk and protective variants for LOAD across all populations with the hope of developing new treatments that work for everyone.

Assessment of Dermal and Inhalation Exposure to Permethrin During Field Treatment of Military Uniforms.

Permethrin is a common pesticide spray-applied to civilian clothing and military uniforms for protection against biting arthropods in an effort to reduce risks to arthropod-borne diseases. During mass clothing spray events, exposure is possible through the dermal, inhalation, and ingestion routes. The potentially exposed population during a spray event includes the pesticide applicator(s) and working party (personnel who handle clothing/uniforms by positioning on the ground, flipping, and removing after spraying is complete). Previous investigation is limited regarding permethrin exposure via multiple routes of entry. Additionally, most exposure assessments are limited to pesticide applicators rather than working party that support applicator personnel. The purpose of this investigation was to conduct a multi-route exposure assessment for all personnel normally participating in mass permethrin military uniform treatments. The protocol and Informed Consent Document were approved by the Uniformed Services University of the Health Sciences (USUHS) Institutional Review Board (IRB) before fieldwork initiation (IRB number: USUHS.2019-032). Sampling occurred during routine spray events performed by 14 U.S. Navy personnel (3 applicators and 11 working party) over 2 days. Personal exposures were measured with dermal sampling, and airborne concentrations were measured with area air sampling. Permethrin area air sampling and analysis were conducted using OSHA Versatile Sampler-2 sampling media (n = 36). Dermal exposure was measured using dosimeter gloves (n = 26) and a dermal patch (n = 26) worn by study participants. All air samples were reported below the 0.4 µg limit of quantification. Glove sample results ranged from 45 to 120,000 µg and patch results ranged from 0.57 to 45 µg. A repeated-measures ANOVA showed non-statistically significant differences in dermal concentrations (P-value = .8340) between the applicators and working party in patches and gloves. Results suggest dermal contact is the primary route of exposure compared to inhalation when mass spraying clothing with permethrin. Similar dermal exposures between these two occupations may necessitate reconsidering risk assessment procedures, training and personal protective equipment (PPE) requirements for mass spray uniform treatments. Specifically, while PPE requirements for applicators are highly regulated by the Armed Forces Pest Management Board and include items such as Tyvek suits, chemical protective gloves, and air-purifying respirators, PPE was not regulated for working party personnel before this investigation.

Abstract PS7-38: Pathologic characteristics of African American women with breast cancer treated at the DoD’s Murtha Cancer Center: Understanding why survival cancer is not disparate to European American women when treated within the US Military Healthcare System

Abstract Background: In the United States, breast cancer mortality rates in African American women (AAW) are significantly higher than in European American women (EAW). In contrast, within the Department of Defense Military Healthcare System (DoD MHS) healthcare system, overall survival did not differ significantly between AAW and EAW with early-stage breast cancer. In this study, we evaluated pathological factors of AAW treated within the Murtha Cancer Center at Walter Reed National Military Medical Center to identify factors associated with this lack of disparate outcomes within the DoD MHS. Methods: Between 2001-2018, 345 AAW and 759 EAW treated at MCC/WRNMMC enrolled in the Clinical Breast Care Project (CBCP). Extracted demographic data included BMI, Charlson comorbidity index (CCI), education level and marital and smoking status. All diagnoses were performed by a single breast pathologist and included stage, grade, size, lymph node, hormone receptor and HER2 status. Statistical analyses included odds ratio (OR) and log-rank analyses. Results: Within this cohort, AAW were not at increased risk for having higher CCI scores, cigarette use or a college education, however, AAW were significantly more likely to be obese (OR 2.07, 95% CI 1.5, 2.9) and unmarried (OR 2.4, 95% CI 1.8, 3.2). The average age at diagnosis was 56.1 years in AAW and 57.5 years in EAW with 11% of AAW and 8% of EAW diagnosed <40 years of age. AAW were more likely to have higher stage (OR 1.6, 95% CI 1.3, 2.1), high-grade (OR 2.6, 95% CI 1.9, 3.6), larger (OR 1.6, 95% CI 1.2, 2.1) tumors. AAW were at increased risk for having triple negative tumors (OR 2.1, 95% CI 1.5, 2.9). Neither 5-year nor 10-year survival differed significantly between populations. Conclusion: While a previous study found no overall survival difference in early-stage AAW and EAW treated within the DoD MHS, this study found that across all stages of breast cancer breast cancer-specific survival was not inferior for AAW treated at MCC/WRNMMC. Critically, AAW did not have disparate survival despite having tumors with less favorable pathological characteristics, similar to those seen in the US general population. Evaluation of pre- and post-diagnostic care within DoD MHS should be performed to determine how breast care is provided to AAW within an equal-access healthcare setting and the results used as a model of care template to reduce breast cancer disparities within the US general population. The contents of this publication are the sole responsibility of the author(s) and do not necessarily reflect the views, opinions or policies of Uniformed Services University of the Health Sciences (USUHS), The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., the Department of Defense (DoD) or the Departments of the Army, Navy, or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government. Citation Format: Rachel Ellsworth, Leann Lovejoy, Craig Shriver. Pathologic characteristics of African American women with breast cancer treated at the DoD’s Murtha Cancer Center: Understanding why survival cancer is not disparate to European American women when treated within the US Military Healthcare System [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-38.

The Alzheimer’s disease sequencing project–follow up study (ADSP‐FUS): Increasing ethnic diversity in Alzheimer’s genetics research with addition of potential new cohorts

AbstractBackgroundThe ADSP‐FUS is a National Institute on Aging (NIA) initiative focused on identifying genetic risk and protective variants for late‐onset Alzheimer Disease (LOAD). A major concern in AD genetic studies is a lack of racial‐ethnic diversity. The ADSP‐FUS collects and sequences existing both ethnically diverse and unique cohorts with extensive clinical data to expand the utility of new discoveries for individuals from all populations. Additional multi‐ethnic cohorts are presently being recruited (e.g. Amerindian, Korean and Indian).MethodThe cohorts consist of participants from studies of AD, dementia, and aging‐related conditions. Clinical classification (i.e., AD, dementia, and non‐affected) is implemented using algorithms based on a minimal set of criteria derived from standard measures (e.g., global cognitive screeners, dementia rating scales, etc.) and pertinent clinical history. Data dictionaries are generated for each cohort by clinical staff at Columbia University and University of Miami (UM). In total, ADSP‐FUS intends to sequence over 40,000 individuals. Existing biospecimens were obtained and processed through the National Centralized Repository for Alzheimer’s (NCRAD), the primary site for preparation and allocation of DNA, which is then delivered to the Uniformed Services University of the Health Sciences (USUHS) for whole genome sequencing (WGS). The resulting raw sequence data is delivered to the Genome Center for Alzheimer’s Disease (GCAD) for processing and harmonization followed by quality control analysis at University of Pennsylvania and University of Miami into analysis‐ready genotype data. The final step is delivery of clinical, genotype and sequence data to the NIA Genetics of Alzheimer Disease Data Storage Site (NIAGADS), which serves as the ASDP‐FUS data storage, management and sharing center.ResultsOver 30,000 samples have been ascertained and are distributed as follows: 7,896 with African ancestry; 9,475 with Hispanic ancestry; 13,531 with non‐Hispanic white ancestry (1,400 EOAD and 3,745 autopsy) and 89 with Amerindian ancestry.ConclusionThe ADSP‐FUS is designed to enhance ongoing efforts for the identification of shared and novel genetic risk factors for LOAD among different populations. This project will expand our current knowledge of potential genetic risk and protective variants for LOAD across all populations with the hope of developing new treatments.

Assessing health literacy in rhinologic patients.

International Forum of Allergy & RhinologyVolume 11, Issue 4 p. 818-821 RESEARCH NOTE Assessing health literacy in rhinologic patients Jakob L. Fischer MD, Jakob L. Fischer MD Department of Otolaryngology–Head and Neck Surgery, Walter Reed National Military Medical Center, Bethesda, MDSearch for more papers by this authorNora L. Watson PhD, Nora L. Watson PhD Department of Research Programs, Walter Reed National Military Medical Center, Bethesda, MDSearch for more papers by this authorAnthony M. Tolisano MD, Anthony M. Tolisano MD Department of Otolaryngology–Head and Neck Surgery, Walter Reed National Military Medical Center, Bethesda, MD Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MDSearch for more papers by this authorCharles A. Riley MD, Corresponding Author Charles A. Riley MD Rileycaf@gmail.com orcid.org/0000-0002-1993-7018 Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD Division of Otolaryngology–Head and Neck Surgery, Fort Belvoir Community Hospital, Fort Belvoir, VA Correspondence to: Charles A. Riley, MD, 9300 DeWitt Loop, Fort Belvoir, VA 22060, Oaks Pavilion, Floor 2, Reception 4, Fort Belvoir, VA 22060; e-mail: Rileycaf@gmail.comSearch for more papers by this author Jakob L. Fischer MD, Jakob L. Fischer MD Department of Otolaryngology–Head and Neck Surgery, Walter Reed National Military Medical Center, Bethesda, MDSearch for more papers by this authorNora L. Watson PhD, Nora L. Watson PhD Department of Research Programs, Walter Reed National Military Medical Center, Bethesda, MDSearch for more papers by this authorAnthony M. Tolisano MD, Anthony M. Tolisano MD Department of Otolaryngology–Head and Neck Surgery, Walter Reed National Military Medical Center, Bethesda, MD Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MDSearch for more papers by this authorCharles A. Riley MD, Corresponding Author Charles A. Riley MD Rileycaf@gmail.com orcid.org/0000-0002-1993-7018 Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD Division of Otolaryngology–Head and Neck Surgery, Fort Belvoir Community Hospital, Fort Belvoir, VA Correspondence to: Charles A. Riley, MD, 9300 DeWitt Loop, Fort Belvoir, VA 22060, Oaks Pavilion, Floor 2, Reception 4, Fort Belvoir, VA 22060; e-mail: Rileycaf@gmail.comSearch for more papers by this author First published: 13 November 2020 https://doi.org/10.1002/alr.22733Citations: 4 Potential conflict of interest: None provided The contents of this publication are the sole responsibility of the author(s) and do not necessarily reflect the views, opinions or policies of Uniformed Services University of the Health Sciences (USUHS), the Department of Defense (DoD), the Departments of the Army, Navy, or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume11, Issue4April 2021Pages 818-821 RelatedInformation

Abstract 4322: EXOSC4, a novel gene at chromosome 8q24 loci is linked with breast cancer progression and is a prognostic marker for breast cancer survival

Abstract The chromosome 8q24 gene contains functional risk loci for multiple cancers, including prostate, colon, and breast. Breast cancer (BrCa) is one of the deadliest diseases among women. Our previous studies using TCGA clinical survival data (Cell. 2018; 173(2):400-416.e11) indicated that several genes are contributed significantly towards the survival of patients with BrCa. Over 75 such most significant genes were screened for further studies in terms of their contribution towards BrCa patient's survival. We found two genes (EXOSC4 and VPS28) with over 10% genetic copy number alterations located at chromosome 8q24 gene loci. Exosome Component 4 (EXOSC4) is located at 8q24.3 and associated with a non-catalytic component of the RNA exosome complex, which has 3' to 5' exoribonuclease activity. It also participates in cellular RNA processing and degradation events. However, the functional role of EXOSC4 towards BrCa progression or survival remains unknown. To understand the molecular basis of an elevated level of EXOSC4 in BrCa propagation, we screened the expression of this protein in different BrCa cell-lines. We also compared the expression of VPS28 within same cell lines. Data indicated that EXOSC4 was co-expressed with VPS28 and Myc, and was also secreted into extracellular space. Therefore, we next evaluated the level of EXOSC4 in patient's serum samples by reverse phase protein array (RPPA). We have well defined and categorized BrCa patients serum samples (n=240) from the Clinical Breast Care Project. The data indicated that the elevated level of EXOSC4 is associated with worse overall survival. In addition, results also showed that the high level of EXOSC4 is linked with breast cancer recurrence.In summary, through multiple modality studies we have confirmed the copy number alteration of EXOSC4 is associated with BrCa patient survival. Once validated, serum level of EXOSC4 could be a predictive biomarker for BrCa progression and survival. Additional experiments are ongoing to evaluate the regulatory role of the EXOSC4 gene which has the potential to develop into a novel therapeutic intervention of BrCa. Funding Sources: This work was supported by the grant to Dr. Meera Srivastava (DoD, DAMD17-03-1-0107). The work was also supported by the Collaborative Health Initiative Research Program (CHIRP) funding (CHIRP ID# IAA-A-HL-14-007). Disclaimers: The contents of this publication are the sole responsibility of the author(s) and do not necessarily reflect the views, opinions or policies of The Uniformed Services University of the Health Sciences (USUHS), The Henry M. Jackson Foundation (HJF), the Department of Defense (DoD), the Departments of the Army, Navy, or Air Force. Correspondence: Email: meera.srivastava@usuhs.edu Citation Format: Alakesh Bera, John Karaian, Madhan Subramanian, Michael Eklund, Eric Russ, Harvey B. Pollard, Hai Hu, Craig D. Shriver, Meera Srivastava. EXOSC4, a novel gene at chromosome 8q24 loci is linked with breast cancer progression and is a prognostic marker for breast cancer survival [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4322.