Medical Specialties Commons^™

Robust And Efficient Assessment Of Potency (Reap) As A Quantitative Tool For Dose-Response Curve Estimation, Shouhao Zhou, Xinyi Liu, Xinying Fang, Vernon M Chinchilli, Michael Wang, Hong-Gang Wang, Nikolay V Dokholyan, Chan Shen, J Jack Lee

Faculty, Staff and Student Publications

The median-effect equation has been widely used to describe the dose-response relationship and identify compounds that activate or inhibit specific disease targets in contemporary drug discovery. However, the experimental data often contain extreme responses, which may significantly impair the estimation accuracy and impede valid quantitative assessment in the standard estimation procedure. To improve the quantitative estimation of the dose-response relationship, we introduce a novel approach based on robust beta regression. Substantive simulation studies under various scenarios demonstrate solid evidence that the proposed approach consistently provides robust estimation for the median-effect equation, particularly when there are extreme outcome observations. Moreover, simulation …

Artificial Intelligence In The Radiomic Analysis Of Glioblastomas: A Review, Taxonomy, And Perspective, Ming Zhu, Sijia Li, Yu Kuang, Virigina B. Hill, Amy B. Heimberger, Lijie Zhai, Shenjie Zhai

Electrical & Computer Engineering Faculty Research

Radiological imaging techniques, including magnetic resonance imaging (MRI) and positron emission tomography (PET), are the standard-of-care non-invasive diagnostic approaches widely applied in neuro-oncology. Unfortunately, accurate interpretation of radiological imaging data is constantly challenged by the indistinguishable radiological image features shared by different pathological changes associated with tumor progression and/or various therapeutic interventions. In recent years, machine learning (ML)-based artificial intelligence (AI) technology has been widely applied in medical image processing and bioinformatics due to its advantages in implicit image feature extraction and integrative data analysis. Despite its recent rapid development, ML technology still faces many hurdles for its broader applications …

Muscle And Adipose Tissue Segmentations At The Third Cervical Vertebral Level In Patients With Head And Neck Cancer, Kareem A Wahid, Brennan Olson, Rishab Jain, Aaron J Grossberg, Dina El-Habashy, Cem Dede, Vivian Salama, Moamen Abobakr, Abdallah S R Mohamed, Renjie He, Joel Jaskari, Jaakko Sahlsten, Kimmo Kaski, Clifton D Fuller, Mohamed A Naser

Faculty, Staff and Student Publications

The accurate determination of sarcopenia is critical for disease management in patients with head and neck cancer (HNC). Quantitative determination of sarcopenia is currently dependent on manually-generated segmentations of skeletal muscle derived from computed tomography (CT) cross-sectional imaging. This has prompted the increasing utilization of machine learning models for automated sarcopenia determination. However, extant datasets currently do not provide the necessary manually-generated skeletal muscle segmentations at the C3 vertebral level needed for building these models. In this data descriptor, a set of 394 HNC patients were selected from The Cancer Imaging Archive, and their skeletal muscle and adipose tissue was …

Ribonucleotide Reductase Subunit Switching In Hepatoblastoma Drug Response And Relapse, Anthony Brown

Theses and Dissertations (ETD)

Hepatoblastoma is the most common primary liver cancer in infants and young children. Despite being a very rare cancer that accounts for only 0.5-2% if all childhood cancer cases, HB has the largest increase in incidence among childhood cancers in the United States and worldwide. The five-year survival rate of children with the aggressive forms of HB, including those that have developed metastatic or recurrent diseases, is less than 40% due to the lack of effective treatment. We aim to identify targetable mechanisms underlying the progression and drug resistance of high-risk HB. Our recent work on HB mouse and organoid …

Establishing The Content Validity Of A Student Pharmacist Patient Counseling Competency Assessment In Oncology, Matthew Newman, Emily Pherson, Bradley Burton, Eric C. Nemec

Physician Associate Studies Faculty Publications

Objective. The main goal of this project was to establish content validity and describe internal consistency of a patient counseling competency assessment instrument used to evaluate student pharmacists practicing in an oncology setting. Methods A modified e-Delphi panel of oncology clinical pharmacy specialists, clinical pharmacy generalists, and oncology pharmacy residents was employed. Iterative rounds of the e-Delphi process were conducted until consensus was reached on a majority of the instrument items. Consensus was defined as agreement by at least 75% of participants that an item was, or was not important. Internal consistency of defined sections of the instrument was determined …

Ovario Phase Ii Trial Of Combination Niraparib Plus Bevacizumab Maintenance Therapy In Advanced Ovarian Cancer Following First-Line Platinum-Based Chemotherapy With Bevacizumab., Melissa M Hardesty, Thomas C Krivak, Gail S Wright, Erika Hamilton, Evelyn L Fleming, Jimmy Belotte, Erika K Keeton, Ping Wang, Divya Gupta, Aine Clements, Heidi J Gray, Gottfried E Konecny, Richard G Moore, Debra L Richardson

Oncology Articles

OBJECTIVE: To assess safety and efficacy of niraparib + bevacizumab as a first-line maintenance therapy for patients with newly diagnosed advanced ovarian cancer.

METHODS: This multicenter, phase II, single-arm, open-label study enrolled adult patients with stage IIIB to IV ovarian, fallopian tube, or primary peritoneal cancer (NCT03326193). Patients were required to have an attempt at debulking surgery and have a complete response, partial response, or no evidence of disease following first-line, platinum-based chemotherapy with ≥3 cycles of bevacizumab. The primary endpoint was the progression-free survival (PFS) rate at 18 months. Secondary endpoints included PFS, overall survival, and safety.

RESULTS: Among …

Gaps In Patient Education On Safe Handling And Disposal Of Oral Chemotherapy Drugs: A Pilot Prospective Cohort Survey Study, Sun Yang, Priya Patel, Alexandra Corcoran, Eric Dobberpuhl, Samantha Isidro, Dustin Le, Analise Klassen, Jay Rho, David Tran, Richard Beuttler, Neda Noori Nassr, Katherine Gruenberg, Siu-Fun Wong

Pharmacy Faculty Articles and Research

Background

Oral anticancer chemotherapy (OC) has been misperceived as being safer than intravenous chemotherapy, leading to its increased risk of improper handling and disposal. This survey study assessed the knowledge, practices and attitudes of pharmacists and patients regarding OC handling and disposal, gaps in knowledge and barriers to patient education. Methods

Surveys were developed based on literature review and pilot study validation results. Patients completed a 33-item paper or electronic survey whereas pharmacists completed a 38-item electronic survey. Descriptive statistics and Fisher’s exact test computed using the R Project were used for analyses. Results

Pharmacist group (16/25, 62.5%) and patient …

Receptor Tyrosine Kinase (Rtk) Targeting In Pediatric High-Grade Glioma And Diffuse Midline Glioma: Pre-Clinical Models And Precision Medicine., Kallen Schwark, Dana Messinger, Jessica R. Cummings, Joshua Bradin, Abed Kawakibi, Clarissa M. Babila, Samantha Lyons, Sunjong Ji, Rodrigo T. Cartaxo, Seongbae Kong, Evan Cantor, Carl Koschmann, Viveka Nand Yadav

Manuscripts, Articles, Book Chapters and Other Papers

Pediatric high-grade glioma (pHGG), including both diffuse midline glioma (DMG) and non-midline tumors, continues to be one of the deadliest oncologic diagnoses (both henceforth referred to as "pHGG"). Targeted therapy options aimed at key oncogenic receptor tyrosine kinase (RTK) drivers using small-molecule RTK inhibitors has been extensively studied, but the absence of proper in vivo modeling that recapitulate pHGG biology has historically been a research challenge. Thankfully, there have been many recent advances in animal modeling, including Cre-inducible transgenic models, as well as intra-uterine electroporation (IUE) models, which closely recapitulate the salient features of human pHGG tumors. Over 20% of …

Defining The Cooperation Between Mhc-I And Mhc-Ii Neoantigen-Driven T Cell Responses To Develop Effective Personalized Immunotherapies, Charmelle Williams

Dissertations and Theses (Open Access)

Immune checkpoint therapy (ICT) (e.g. anti-CTLA-4 (α-CTLA-4), anti-PD-1 (α-PD-1)) enables durable T cell-dependent anti-tumor immunity in certain cancer patients. Since a subset of patients respond to ICT, this work aims at developing a more in-depth understanding of T-cell responses to MHC class I (MHC-I) and MHC class II (MHC-II) tumor antigens that are derived from aberrant expression of non-mutant antigens or driver and passenger somatic alterations that can function as tumor neoantigens. We used a poorly immunogenic Braf^v600e Pten^-/- Cdkn2a^-/- YUMM1.7 (Y1.7) murine melanoma line with a paucity of endogenous neoantigens that is unresponsive to ICT, and …

Case Report: Axilla Fibroadenoma - An Atypical Presentation, Safna Naozer Virji, Lubna Mushtaque Vohra, Syeda Sakina Abidi, Romana Idress

Department of Surgery Docs

No abstract provided.

Charting The Proteome Landscape In Major Psychiatric Disorders: From Biomarkers To Biological Pathways Towards Drug Discovery, Brisa S Fernandes, Yulin Dai, Peilin Jia, Zhongming Zhao

Faculty, Staff and Student Publications

Schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD) are major mental disorders that affect a significant proportion of the global population. Advancing our knowledge of the pathophysiology of these disorders and identifying biomarkers are urgent needs for developing objective diagnostic tests and new therapeutics. In this study, we performed a systematic review and then extracted, curated, and analyzed proteomics data from published studies, aiming to assess the proteome in peripheral blood of individuals with SZ, BD, or MDD. Then, we performed pathway and network analyses to illuminate the biological themes concatenated by the differentially expressed proteins by systematically …

Genome-Wide Bidirectional Crispr Screens Identify Mucins As Host Factors Modulating Sars-Cov-2 Infection, Scott B Biering, Sylvia A Sarnik, Eleanor Wang, James R Zengel, Sarah R Leist, Alexandra Schäfer, Varun Sathyan, Padraig Hawkins, Kenichi Okuda, Cyrus Tau, Aditya R Jangid, Connor V Duffy, Jin Wei, Rodney C Gilmore, Mia Madel Alfajaro, Madison S Strine, Xammy Nguyenla, Erik Van Dis, Carmelle Catamura, Livia H Yamashiro, Julia A Belk, Adam Begeman, Jessica C Stark, D Judy Shon, Douglas M Fox, Shahrzad Ezzatpour, Emily Huang, Nico Olegario, Arjun Rustagi, Allison S Volmer, Alessandra Livraghi-Butrico, Eddie Wehri, Richard R Behringer, Dong-Joo Cheon, Julia Schaletzky, Hector C Aguilar, Andreas S Puschnik, Brian Button, Benjamin A Pinsky, Catherine A Blish, Ralph S Baric, Wanda K O'Neal, Carolyn R Bertozzi, Craig B Wilen, Richard C Boucher, Jan E Carette, Sarah A Stanley, Eva Harris, Silvana Konermann, Patrick D Hsu

Faculty, Staff and Student Publications

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a range of symptoms in infected individuals, from mild respiratory illness to acute respiratory distress syndrome. A systematic understanding of host factors influencing viral infection is critical to elucidate SARS-CoV-2-host interactions and the progression of Coronavirus disease 2019 (COVID-19). Here, we conducted genome-wide CRISPR knockout and activation screens in human lung epithelial cells with endogenous expression of the SARS-CoV-2 entry factors ACE2 and TMPRSS2. We uncovered proviral and antiviral factors across highly interconnected host pathways, including clathrin transport, inflammatory signaling, cell-cycle regulation, and transcriptional and epigenetic regulation. We further identified mucins, a …

A Retrospective Study For Prognostic Significance Of Type Ii Diabetes Mellitus And Hemoglobin A1c Levels In Non-Small Cell Lung Cancer Patients Treated With Pembrolizumab, Yinchen Shen, Jiaqi Li, Huiping Qiang, Yuqiong Lei, Qing Chang, Runbo Zhong, Giulia Maria Stella, Francesco Gelsomino, Yeon Wook Kim, Afaf Abed, Jialin Qian, Tianqing Chu

Research outputs 2022 to 2026

Background:

Diabetes mellitus (DM) is common and recognized as a risk factor for developing non-small cell lung cancer (NSCLC) while the prognostic evaluation is still controversial. As immunotherapy is widely used in clinical practice, its efficacy and survival should be investigated in patients with DM.

Methods:

We retrospectively recruited 266 locally advanced and metastatic NSCLC patients who received pembrolizumab alone or in combination with chemotherapy. Patients' clinicopathological data, including age, history of DM, hemoglobin A1c (HbA1c), genetic tumor profiling, and survival data were collected. Associations between clinical characteristics and survival were evaluated by univariate and multivariate analyses.

Results:

In this …

Determinants Of Blood Acylcarnitine Concentrations In Healthy Individuals Of The European Prospective Investigation Into Cancer And Nutrition, Roland Wedekind, Joseph A. Rothwell, Vivian Viallon, Pekka Keski-Rahkonen, Julie A. Schmidt, Veronique Chajes, Vna Katzke, Theron Johnson, Maria Santucci De Magistris, Vittorio Krogh, Pilar Amiano, Carlotta Sacerdote, Daniel Redondo-Sánchez, José María Huerta, Anne Tjønneland, Pratik Pokharel, Paula Jakszyn, Rosario Tumino, Eva Ardanaz, Torkjel M. Sandanger, Anna Winkvist, Johan Hultdin, Matthias B. Schulze, Elisabete Weiderpass, Marc J. Gunter, Inge Huybrechts

Research outputs 2022 to 2026

Background & aims: Circulating levels of acylcarnitines (ACs) have been associated with the risk of various diseases such as cancer and type 2 diabetes. Diet and lifestyle factors have been shown to influence AC concentrations but a better understanding of their biological, lifestyle and metabolic determinants is needed. Methods: Circulating ACs were measured in blood by targeted (15 ACs) and untargeted metabolomics (50 ACs) in 7770 and 395 healthy participants of the European Prospective Investigation into Cancer and Nutrition (EPIC), respectively. Associations with biological and lifestyle characteristics, dietary patterns, self-reported intake of individual foods, estimated intake of carnitine and fatty …

Use Of Active Video Games With Or Without Videoconferencing On Health Outcomes In Adolescent And Young Adult Cancer Survivors: A Systematic Review, Ursela Christopherson, Stephanie J Wells, Nathan Parker, Elizabeth J Lyons, Michael D Swartz, Anna Blozinski, Karen Basen-Engquist, Susan Peterson, Maria C Swartz

Faculty, Staff and Student Publications

PURPOSE: Adolescent and young adult (AYA) cancer survivors experience greater functional deficits compared to non-cancer peers or older survivors with a similar diagnosis. Physical activity (PA) is a key strategy for mitigating functional decline, and motivation and peer support are critical PA facilitators in AYA cancer survivors. Active video games (AVGs) may be a "gateway" method to promote PA. Further, integrating AVGs into group videoconferencing, a medium used by AYAs to socialize, can capitalize on peer support needed for PA motivation. Thus, we examined the use of AVGs and/or videoconferencing in PA interventions that included AYA survivors and the effect …

Absolute Quantification Of Tc-99m Activity Distributions Using A Planar Molecular Breast Imaging Commercial System, Benjamin P. Lopez

Dissertations and Theses (Open Access)

Molecular breast imaging (MBI) uses two dedicated-breast semiconductor detectors to visualize the preferential uptake of technetium-99m-sestamibi (^99mTc-sestamibi) by breast cancer cells relative to surrounding benign breast tissues. Clinically, MBI is used primarily as a supplementary tool to standard-of-care mammography because of its improved detection of breast cancers, especially in women with mammographically-dense breasts. Because of a lack of image corrections, MBI applications are currently limited to qualitative evaluations of relative pixel intensities between image regions with suspected lesions and normal tissue.

The objective of this dissertation was to use Monte Carlo simulations to better characterize the MBI imaging …

Development Of Advanced Mr-Guided Adaptive Radiation Therapy Methods For Head & Neck Cancers On The 1.5t Mr-Linac, Brigid Mcdonald

Dissertations and Theses (Open Access)

The 1.5T hybrid MRI/linear accelerator (MR-linac) has recently been introduced into clinical practice and used for the treatment of head and neck cancers (HNC). This device enables on-line adaptive radiation therapy (ART) based on anatomical changes throughout treatment and variations in patient position. This novel technology also has the potential for advanced ART strategies such as dose-optimized ART, in which the treatment plan is optimized based on the accumulated dose over previous fractions, or biological image-guided ART, in which the plan is adapted based on individual tumor response as measured through quantitative imaging techniques such as diffusion-weighted imaging (DWI). The …

The Role Of The Hypoxia-Inducible Factor 2 In Pancreatic Cancer: Mechanisms Of Tumor Immunosuppression And Intestinal Radioprotection, Carolina Garcia Garcia

Dissertations and Theses (Open Access)

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with dismal prognosis. The only curative option for patients is surgery, but over 80% of patients are not surgical candidates. Unfortunately, PDAC is resistant to the three remaining options. PDAC is characterized by a profoundly hypoxic and immunosuppressive stroma, which contributes to its therapeutic recalcitrance. Alpha-smooth muscle actin+ (αSMA+) cancer-associated fibroblasts (CAFs) are the most abundant stromal component, as well as mediators of stromal deposition. The hypoxia-inducible factors (HIF1 and HIF2) coordinate responses to hypoxia, yet, despite their known association to poor patient outcomes, their functions within the PDAC tumor microenvironment (TME) …

Racial And Ethnic Disparities In The Refusal Of Surgical Treatment In Women 40 Years And Older With Breast Cancer In The Usa Between 2010 And 2017, Pierre Fwelo, Zenab I Yusuf, Abigail Adjei, Gabriel Huynh, Xianglin L Du

Faculty, Staff and Student Publications

PURPOSE: Although surgical resection is the main modality of treatment for breast cancer, some patients elect to refuse the recommended surgery. We assessed racial and ethnic differences in women 40 years and older who received or refused to receive surgical treatment for breast cancer in the USA and whether racial disparities in mortality were affected by their differences in the prevalence of refusal for surgical treatment.

METHODS: We studied 277,127 women with breast cancer using the Surveillance, Epidemiology, and End Results (SEER) data and performed multivariable logistic regressions to investigate the association between surgery status of breast cancer and race/ethnicity. …

Impact Of Somatic Mutations On Survival Outcomes In Patients With Anaplastic Thyroid Carcinoma, Jennifer Rui Wang, Matthew Montierth, Li Xu, Maitrayee Goswami, Xiao Zhao, Gilbert Cote, Wenyi Wang, Priyanka Iyer, Ramona Dadu, Naifa L Busaidy, Stephen Y Lai, Neil D Gross, Renata Ferrarotto, Charles Lu, Gary Brandon Gunn, Michelle D Williams, Mark Routbort, Mark E Zafereo, Maria E Cabanillas

Faculty, Staff and Student Publications

PURPOSE: Anaplastic thyroid carcinoma (ATC) uniformly present with aggressive disease, but the mutational landscape of tumors varies. We aimed to determine whether tumor mutations affect survival outcomes in ATC.

MATERIALS AND METHODS: Patients who underwent mutation sequencing using targeted gene panels between 2005 and 2019 at a tertiary referral center were included. Associations between mutation status and survival outcomes were assessed using Cox proportional hazards models.

RESULTS: A total of 202 patients were included, where 122 died of ATC (60%). The median follow-up was 31 months (interquartile range, 18-45 months). The most common mutations were in

CONCLUSION: Mutation analysis provides …

Immune Checkpoint Inhibitors In Luminal Gastrointestinal Malignancies: Going Beyond Msi-H/Dmmr, Tmb And Pd-L1, Daniel S. Lefler, Adam E. Snook, Babar Bashir

Department of Medical Oncology Faculty Papers

In luminal gastrointestinal tumors, immune checkpoint inhibitors (ICIs) targeting PD-1, PD-L1 and CTLA-4 have been investigated in multiple settings. The indications for these drugs are primarily dependent on specific biomarkers that imply immunogenicity: overexpression of PD-L1, tumor mutational burden, loss of mismatch repair proteins (dMMR) and/or high microsatellite instability status. Although these markers can be both predictive and prognostic, there is variability in how they are measured and used to guide therapies. Moreover, the use of ICIs can be further refined with a better understanding of the tumor microenvironment and interactions with other available therapies. The purpose of this review …

Mediating And Maintaining Methylation While Minimizing Mutation: Recent Advances On Mammalian Dna Methyltransferases, Xiaodong Cheng, Robert M Blumenthal

Faculty, Staff and Student Publications

Mammalian genomes are methylated on carbon-5 of many cytosines, mostly in CpG dinucleotides. Methylation patterns are maintained during mitosis via DNMT1, and regulatory factors involved in processes that include histone modifications. Methylation in a sequence longer than CpG can influence the binding of sequence-specific transcription factors, thus affecting gene expression. 5-Methylcytosine deamination results in C-to-T transition. While some mutations are beneficial, most are not; so boosting C-to-T transitions can be dangerous. Given the role of DNMT3A in establishing de novo DNA methylation during development, it is this CpG methylation and deamination that provide the major mutagenic impetus in the DNMT3A …

Assessing The Practicality Of Using A Single Knowledge-Based Planning Model For Multiple Linac Vendors, Raphael J Douglas, Adenike Olanrewaju, Lifei Zhang, Beth M Beadle, Laurence E Court

Faculty, Staff and Student Publications

Purpose: Knowledge-based planning (KBP) has been shown to be an effective tool in quality control for intensity-modulated radiation therapy treatment planning and generating high-quality plans. Previous studies have evaluated its ability to create consistent plans across institutions and between planners within the same institution as well as its use as teaching tool for inexperienced planners. This study evaluates whether planning quality is consistent when using a KBP model to plan across different treatment machines.

Materials and methods: This study used a RapidPlan model (Varian Medical Systems) provided by the vendor, to which we added additional planning objectives, maximum dose limits, …

Love And Fear: A Special Issue, C Sue Carter, Robert Dantzer

Faculty, Staff and Student Publications

Love and fear were forged by the same fundamental evolutionary processes that permitted life on Earth. Both love and fear are deeply interwoven with the adaptive management of stress and disease. Love and fear share common roots and both can play a role in reproduction, survival, perceived safety and wellbeing. This special issue of Comprehensive Psychoneuroendocrinology focuses specifically on the causes and consequences of love from the interactive perspectives of evolution, neurobiology and culture.

Clinical Activity Of Mitogen-Activated Protein Kinase-Targeted Therapies In Patients With Non-V600 Braf-Mutant Tumors, Matthew Dankner, Yifan Wang, Rouhi Fazelzad, Benny Johnson, Caroline A Nebhan, Ibiayi Dagogo-Jack, Nathaniel J Myall, Georg Richtig, Jillian W P Bracht, Marco Gerlinger, Eiji Shinozaki, Takayuki Yoshino, Daisuke Kotani, Jason R Fangusaro, Oliver Gautschi, Julien Mazieres, Jeffrey A Sosman, Scott Kopetz, Vivek Subbiah, Michael A Davies, Anna L Groover, Ryan J Sullivan, Keith T Flaherty, Douglas B Johnson, Andrea Benedetti, David W Cescon, Anna Spreafico, George Zogopoulos, April A N Rose

Faculty, Staff and Student Publications

Purpose: Non-V600 mutations comprise approximately 35% of all BRAF mutations in cancer. Many of these mutations have been identified as oncogenic drivers and can be classified into three classes according to molecular characteristics. Consensus treatment strategies for class 2 and 3 BRAF mutations have not yet been established.

Methods: We performed a systematic review and meta-analysis with published reports of individual patients with cancer harboring class 2 or 3 BRAF mutations from 2010 to 2021, to assess treatment outcomes with US Food and Drug Administration-approved mitogen-activated protein kinase (MAPK) pathway targeted therapy (MAPK TT) according to BRAF class, cancer type, …

Selinexor In Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial, Mrinal M Gounder, Albiruni Abdul Razak, Neeta Somaiah, Sant Chawla, Javier Martin-Broto, Giovanni Grignani, Scott M Schuetze, Bruno Vincenzi, Andrew J Wagner, Bartosz Chmielowski, Robin L Jones, Richard F Riedel, Silvia Stacchiotti, Elizabeth T Loggers, Kristen N Ganjoo, Axel Le Cesne, Antoine Italiano, Xavier Garcia Del Muro, Melissa Burgess, Sophie Piperno-Neumann, Christopher Ryan, Mary F Mulcahy, Charles Forscher, Nicolas Penel, Scott Okuno, Anthony Elias, Lee Hartner, Tony Philip, Thierry Alcindor, Bernd Kasper, Peter Reichardt, Lore Lapeire, Jean-Yves Blay, Christine Chevreau, Claudia Maria Valverde Morales, Gary K Schwartz, James L Chen, Hari Deshpande, Elizabeth J Davis, Garth Nicholas, Stefan Gröschel, Helen Hatcher, Florence Duffaud, Antonio Casado Herráez, Roberto Diaz Beveridge, Giuseppe Badalamenti, Mikael Eriksson, Christian Meyer, Margaret Von Mehren, Brian A Van Tine, Katharina Götze, Filomena Mazzeo, Alexander Yakobson, Aviad Zick, Alexander Lee, Anna Estival Gonzalez, Andrea Napolitano, Mark A Dickson, Dayana Michel, Changting Meng, Lingling Li, Jianjun Liu, Osnat Ben-Shahar, Dane R Van Domelen, Christopher J Walker, Hua Chang, Yosef Landesman, Jatin J Shah, Sharon Shacham, Michael G Kauffman, Steven Attia

Faculty, Staff and Student Publications

Purpose: Antitumor activity in preclinical models and a phase I study of patients with dedifferentiated liposarcoma (DD-LPS) was observed with selinexor. We evaluated the clinical benefit of selinexor in patients with previously treated DD-LPS whose sarcoma progressed on approved agents.

Methods: SEAL was a phase II-III, multicenter, randomized, double-blind, placebo-controlled study. Patients age 12 years or older with advanced DD-LPS who had received two-five lines of therapy were randomly assigned (2:1) to selinexor (60 mg) or placebo twice weekly in 6-week cycles (crossover permitted). The primary end point was progression-free survival (PFS). Patients who received at least one dose of …

Regulation And Function Of Id2 In Plasmacytoid Dendritic Cells, Rachel L Babcock, Yifan Zhou, Bhakti Patel, Taylor T Chrisikos, Laura M Kahn, Allison M Dyevoich, Yusra B Medik, Stephanie S Watowich

Faculty, Staff and Student Publications

Plasmacytoid dendritic cells (pDCs) are specialized type I interferon (IFN-I) producing cells that promote anti-viral immune responses and contribute to autoimmunity. Development of pDCs requires the transcriptional regulator E2-2 and is opposed by inhibitor of DNA binding 2 (Id2). Prior work indicates Id2 is induced in pDCs upon maturation and may affect pDC IFN-I production via suppression of E2-2, suggesting an important yet uncharacterized role in this lineage. We found TLR7 agonists stimulate Id2 mRNA and protein expression in pDCs. We further show that transcriptional activation of Id2 is dependent on the E2 ubiquitin-conjugating enzyme Ubc13, but independent of IFN-I …

Probing The Structure And Function Of Polymerase Θ Helicase-Like Domain, Scott Vanson, Yuzhen Li, Richard D Wood, Sylvie Doublié

Faculty, Staff and Student Publications

DNA Polymerase θ is the key actuator of the recently identified double-strand break repair pathway, theta-mediated end joining (TMEJ). It is the only known polymerase to have a 3-domain architecture containing an independently functional family A DNA polymerase tethered by a long central region to an N-terminal helicase-like domain (HLD). Full-length polymerase θ and the isolated HLD hydrolyze ATP in the presence of DNA, but no processive DNA duplex unwinding has been observed. Based on sequence and structure conservation, the HLD is classified as a member of helicase superfamily II and, more specifically, the Ski2-like family. The specific subdomain composition …

Management Of Adrenocorticotropic Hormone-Secreting Neuroendocrine Tumors And The Role Of Bilateral Adrenalectomy In Ectopic Cushing Syndrome, Jace P Landry, Uriel Clemente-Gutierrez, Carolina R C Pieterman, Yi-Ju Chiang, Steven G Waguespack, Camilo Jimenez, Mouhammed A Habra, Daniel M Halperin, Sarah B Fisher, Paul H Graham, Nancy D Perrier

Faculty, Staff and Student Publications

BACKGROUND: Neuroendocrine tumors can cause ectopic Cushing syndrome, and most patients have metastatic disease at diagnosis. We identified risk factors for outcome, evaluated ectopic Cushing syndrome management, and explored the role of bilateral adrenalectomy in this population.

METHODS: This was a retrospective study including patients with diagnosis of ectopic Cushing Syndrome secondary to neuroendocrine tumors with adrenocorticotropic hormone secretion treated at our quaternary referral center over a 40-year period (1980-2020).

RESULTS: Seventy-six patients were included. Mean age at diagnosis was 46.3 ± 15.8 years. Most patients (N = 61, 80%) had metastases at ectopic Cushing syndrome diagnosis. Average follow-up was …

Dynamic Expression Of Schlafen 11 (Slfn11) In Circulating Tumour Cells As A Liquid Biomarker In Small Cell Lung Cancer, Bingnan Zhang, C Allison Stewart, Qi Wang, Robert J Cardnell, Pedro Rocha, Junya Fujimoto, Luisa M Solis Soto, Runsheng Wang, Veronica Novegil, Peter Ansell, Lei He, Luisa Fernandez, Adam Jendrisak, Cole Gilbertson, Joseph D Schonhoft, Jiyun Byun, Joshua Jones, Amanda K L Anderson, Ana Aparicio, Hai Tran, Marcelo V Negrao, Jianjun Zhang, Wei-Lien Wang, Ignacio I Wistuba, Jing Wang, Rick Wenstrup, Lauren A Byers, Carl M Gay

Faculty, Staff and Student Publications

Introduction: Small cell lung cancer (SCLC) is an aggressive malignancy with no established biomarkers. Schlafen 11(SLFN11), a DNA/RNA helicase that sensitises cancer cells to DNA-damaging agents, has emerged as a promising predictive biomarker for several drug classes including platinum and PARP inhibitors. Detection of SLFN11 in circulating tumour cells (CTCs) may provide a valuable alternative to tissue sampling.

Methods: SLFN11 expression was evaluated in tumour samples and characterised in circulating tumour cells (CTC) longitudinally to determine its potential role as a biomarker of response.

Results: Among 196 SCLC tumours, 51% expressed SLFN11 by IHC. In addition, 20/29 extra-thoracic high-grade neuroendocrine …