Digital Commons Network^™

Clinical Acceptability Of Fully Automated External Beam Radiotherapy For Cervical Cancer With Three Different Beam Delivery Techniques, Dong Joo Rhee, Anuja Jhingran, Kai Huang, Tucker J Netherton, Nazia Fakie, Ingrid White, Alicia Sherriff, Carlos E Cardenas, Lifei Zhang, Surendra Prajapati, Stephen F Kry, Beth M Beadle, William Shaw, Frederika O'Reilly, Jeannette Parkes, Hester Burger, Chris Trauernicht, Hannah Simonds, Laurence E Court

Faculty, Staff and Student Publications

Purpose: To fully automate CT-based cervical cancer radiotherapy by automating contouring and planning for three different treatment techniques.

Methods: We automated three different radiotherapy planning techniques for locally advanced cervical cancer: 2D 4-field-box (4-field-box), 3D conformal radiotherapy (3D-CRT), and volumetric modulated arc therapy (VMAT). These auto-planning algorithms were combined with a previously developed auto-contouring system. To improve the quality of the 4-field-box and 3D-CRT plans, we used an in-house, field-in-field (FIF) automation program. Thirty-five plans were generated for each technique on CT scans from multiple institutions and evaluated by five experienced radiation oncologists from three different countries. Every plan was …

Development And Validation Of A Checklist For Use With Automatically Generated Radiotherapy Plans, Kelly A Nealon, Laurence E Court, Raphael J Douglas, Lifei Zhang, Eun Young Han

Faculty, Staff and Student Publications

Purpose: To develop a checklist that improves the rate of error detection during the plan review of automatically generated radiotherapy plans.

Methods: A custom checklist was developed using guidance from American Association of Physicists in Medicine task groups 275 and 315 and the results of a failure modes and effects analysis of the Radiation Planning Assistant (RPA), an automated contouring and treatment planning tool. The preliminary checklist contained 90 review items for each automatically generated plan. In the first study, eight physicists were recruited from our institution who were familiar with the RPA. Each physicist reviewed 10 artificial intelligence-generated resident …

Dynamic S-Acylation Of The Er-Resident Protein Stromal Interaction Molecule 1 (Stim1) Is Required For Store-Operated Ca2+ Entry, Goutham Kodakandla, Savannah J West, Qiaochu Wang, Ritika Tewari, Michael X Zhu, Askar M Akimzhanov, Darren Boehning

Faculty, Staff and Student Publications

Many cell surface stimuli cause calcium release from endoplasmic reticulum (ER) stores to regulate cellular physiology. Upon ER calcium store depletion, the ER-resident protein stromal interaction molecule 1 (STIM1) physically interacts with plasma membrane protein Orai1 to induce calcium release-activated calcium (CRAC) currents that conduct calcium influx from the extracellular milieu. Although the physiological relevance of this process is well established, the mechanism supporting the assembly of these proteins is incompletely understood. Earlier we demonstrated a previously unknown post-translational modification of Orai1 with long-chain fatty acids, known as S-acylation. We found that S-acylation of Orai1 is dynamically regulated in a …

Idh1 Prr32h Ctdna And D-2-Hydroxyglutarate As Csf Biomarkers In Patients With Idh-Mutant Gliomas, Yoko Fujita, Luis Nunez-Rubiano, Antonio Dono, Allison Bellman, Mauli Shah, Juan C Rodriguez, Vasanta Putluri, Abu Hena Mostafa Kamal, Nagireddy Putluri, Roy F Riascos, Jay-Jiguang Zhu, Yoshua Esquenazi, Leomar Y Ballester

Faculty, Staff and Student Publications

INTRODUCTION: We aimed to evaluate IDH1 p.R132H mutation and 2-hydroxyglutarate (2HG) in cerebrospinal fluid (CSF) as biomarkers for patients with IDH-mutant gliomas.

METHODS: CSF was collected from patients with infiltrating glioma, and 2HG levels were measured by liquid chromatography-mass spectrometry. IDH1 p.R132H mutant allele frequency (MAF) in CSF-ctDNA was measured by digital droplet PCR (ddPCR). Tumor volume was measured from standard-of-care magnetic resonance images.

RESULTS: The study included 48 patients, 6 with IDH-mutant and 42 with IDH-wildtype gliomas, and 57 samples, 9 from the patients with IDH-mutant and 48 from the patients with IDH-wildtype gliomas. ctDNA was detected in 7 …

Automation Of Radiation Treatment Planning For Rectal Cancer, Kai Huang, Prajnan Das, Adenike M Olanrewaju, Carlos Cardenas, David Fuentes, Lifei Zhang, Donald Hancock, Hannah Simonds, Dong Joo Rhee, Sam Beddar, Tina M Briere, Laurence Court

Faculty, Staff and Student Publications

PURPOSE: To develop an automated workflow for rectal cancer three-dimensional conformal radiotherapy (3DCRT) treatment planning that combines deep learning (DL) aperture predictions and forward-planning algorithms.

METHODS: We designed an algorithm to automate the clinical workflow for 3DCRT planning with field aperture creations and field-in-field (FIF) planning. DL models (DeepLabV3+ architecture) were trained, validated, and tested on 555 patients to automatically generate aperture shapes for primary (posterior-anterior [PA] and opposed laterals) and boost fields. Network inputs were digitally reconstructed radiographs, gross tumor volume (GTV), and nodal GTV. A physician scored each aperture for 20 patients on a 5-point scale (>3 …

Genetic Loci And Prioritization Of Genes For Kidney Function Decline Derived From A Meta-Analysis Of 62 Longitudinal Genome-Wide Association Studies, Mathias Gorski, Humaira Rasheed, Alexander Teumer, Laurent F Thomas, Sarah E Graham, Gardar Sveinbjornsson, Thomas W Winkler, Felix Günther, Klaus J Stark, Jin-Fang Chai, Bamidele O Tayo, Matthias Wuttke, Yong Li, Adrienne Tin, Tarunveer S Ahluwalia, Johan Ärnlöv, Bjørn Olav Åsvold, Stephan J L Bakker, Bernhard Banas, Nisha Bansal, Mary L Biggs, Ginevra Biino, Michael Böhnke, Eric Boerwinkle, Erwin P Bottinger, Hermann Brenner, Ben Brumpton, Robert J Carroll, Layal Chaker, John Chalmers, Miao-Li Chee, Miao-Ling Chee, Ching-Yu Cheng, Audrey Y Chu, Marina Ciullo, Massimiliano Cocca, James P Cook, Josef Coresh, Daniele Cusi, Martin H De Borst, Frauke Degenhardt, Kai-Uwe Eckardt, Karlhans Endlich, Michele K Evans, Mary F Feitosa, Andre Franke, Sandra Freitag-Wolf, Christian Fuchsberger, Piyush Gampawar, Ron T Gansevoort, Mohsen Ghanbari, Sahar Ghasemi, Vilmantas Giedraitis, Christian Gieger, Daniel F Gudbjartsson, Stein Hallan, Pavel Hamet, Asahi Hishida, Kevin Ho, Edith Hofer, Bernd Holleczek, Hilma Holm, Anselm Hoppmann, Katrin Horn, Nina Hutri-Kähönen, Kristian Hveem, Shih-Jen Hwang, M Arfan Ikram, Navya Shilpa Josyula, Bettina Jung, Mika Kähönen, Irma Karabegović, Chiea-Chuen Khor, Wolfgang Koenig, Holly Kramer, Bernhard K Krämer, Brigitte Kühnel, Johanna Kuusisto, Markku Laakso, Leslie A Lange, Terho Lehtimäki, Man Li, Wolfgang Lieb, Lifelines Cohort Study, Lars Lind, Cecilia M Lindgren, Ruth J F Loos, Mary Ann Lukas, Leo-Pekka Lyytikäinen, Anubha Mahajan, Pamela R Matias-Garcia, Christa Meisinger, Thomas Meitinger, Olle Melander, Yuri Milaneschi, Pashupati P Mishra, Nina Mononen, Andrew P Morris, Josyf C Mychaleckyj, Girish N Nadkarni, Mariko Naito, Masahiro Nakatochi, Mike A Nalls, Matthias Nauck, Kjell Nikus, Boting Ning, Ilja M Nolte, Teresa Nutile, Michelle L O'Donoghue, Jeffrey O'Connell, Isleifur Olafsson, Marju Orho-Melander, Afshin Parsa, Sarah A Pendergrass, Brenda W J H Penninx, Mario Pirastu, Michael H Preuss, Bruce M Psaty, Laura M Raffield, Olli T Raitakari, Myriam Rheinberger, Kenneth M Rice, Federica Rizzi, Alexander R Rosenkranz, Peter Rossing, Jerome I Rotter, Daniela Ruggiero, Kathleen A Ryan, Charumathi Sabanayagam, Erika Salvi, Helena Schmidt, Reinhold Schmidt, Markus Scholz, Ben Schöttker, Christina-Alexandra Schulz, Sanaz Sedaghat, Christian M Shaffer, Karsten B Sieber, Xueling Sim, Mario Sims, Harold Snieder, Kira J Stanzick, Unnur Thorsteinsdottir, Hannah Stocker, Konstantin Strauch, Heather M Stringham, Patrick Sulem, Silke Szymczak, Kent D Taylor, Chris H L Thio, Johanne Tremblay, Simona Vaccargiu, Pim Van Der Harst, Peter J Van Der Most, Niek Verweij, Uwe Völker, Kenji Wakai, Melanie Waldenberger, Lars Wallentin, Stefan Wallner, Judy Wang, Dawn M Waterworth, Harvey D White, Cristen J Willer, Tien-Yin Wong, Mark Woodward, Qiong Yang, Laura M Yerges-Armstrong, Martina Zimmermann, Alan B Zonderman, Tobias Bergler, Kari Stefansson, Carsten A Böger, Cristian Pattaro, Anna Köttgen, Florian Kronenberg, Iris M Heid

Faculty, Staff and Student Publications

Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine …

Tumor Immune Microenvironment Changes By Multiplex Immunofluorescence Staining In A Pilot Study Of Neoadjuvant Talazoparib For Early-Stage Breast Cancer Patients With A Hereditary Brca Mutation, Tapsi Kumar, Evie Hobbs, Fei Yang, Jeffrey T Chang, Alejandro Contreras, Edwin Roger Parra Cuentas, Haven Garber, Sanghoon Lee, Yiling Lu, Marion E Scoggins, Beatriz E Adrada, Gary J Whitman, Banu K Arun, Elizabeth A Mittendorf, Jennifer K Litton

Faculty, Staff and Student Publications

PURPOSE: The immunological profile of early-stage breast cancer treated with neoadjuvant PARP inhibitors has not been described. The aim of this study was to delineate the changes in the tumor immune microenvironment (TiME) induced by talazoparib.

PATIENTS AND METHODS: Patients with operable germline BRCA1/2 pathogenic variant (gBRCA1/2+) breast cancer were enrolled in a feasibility study of neoadjuvant talazoparib. Thirteen patients who received 8 weeks of neoadjuvant talazoparib were available for analysis, including 11 paired pre- and post-talazoparib core biopsies. Treatment-related changes in tumor-infiltrating lymphocytes were examined and immune cell phenotypes and their spatial distribution in the TiME were identified and …

Cisplatin And Gemcitabine Exert Opposite Effects On Immunotherapy With Pd-1 Antibody In K-Ras-Driven Cancer, Christophe Glorieux, Xiaojun Xia, Xin You, Zining Wang, Yi Han, Jing Yang, Gauthier Noppe, Christophe De Meester, Jianhua Ling, Annie Robert, Hui Zhang, Sheng-Ping Li, Huamin Wang, Paul J Chiao, Li Zhang, Xiaobing Li, Peng Huang

Faculty, Staff and Student Publications

INTRODUCTION: Immunochemotherapy using PD-1/PD-L1 antibodies in combination with chemotherapeutic agents has become a mainstream treatment for cancer patients, but it remains unclear which drug combinations would produce best therapeutic outcome.

OBJECTIVES: The purpose of this study was to investigate two common chemotherapeutic drugs, gemcitabine and cisplatin, for their impacts on the therapeutic efficacy of PD-1 antibody in K-ras-driven cancers known to overexpress PD-L1.

METHODS: Both in vitro assays and syngeneic mouse tumor models were used in this study. Biochemical and molecular assays were used to determine the effects of drugs on T cell functions in cell culture models and in …

A Decade's Experience In Pediatric Chromosomal Microarray Reveals Distinct Characteristics Across Ordering Specialties, Mariam T Mathew, Austin Antoniou, Naveen Ramesh, Min Hu, Jeffrey Gaither, Danielle Mouhlas, Sayaka Hashimoto, Maggie Humphrey, Theodora Matthews, Jesse M Hunter, Shalini Reshmi, Matthew Schultz, Kristy Lee, Ruthann Pfau, Catherine Cottrell, Kim L Mcbride, Nicholas E Navin, Bimal P Chaudhari, Marco L Leung

Faculty, Staff and Student Publications

Chromosomal microarray (CMA) is a testing modality frequently used in pediatric patients; however, published data on its utilization are limited to the genetic setting. We performed a database search for all CMA testing performed from 2010 to 2020, and delineated the diagnostic yield based on patient characteristics, including sex, age, clinical specialty of providers, indication of testing, and pathogenic finding. The indications for testing were further categorized into Human Phenotype Ontology categories for analysis. This study included a cohort of 14,541 patients from 29 different medical specialties, of whom 30% were from the genetics clinic. The clinical indications for testing …

Addressing Patient Heterogeneity In Disease Predictive Model Development, Xu Gao, Weining Shen, Jing Ning, Ziding Feng, Jianhua Hu

Faculty, Staff and Student Publications

This paper addresses patient heterogeneity associated with prediction problems in biomedical applications. We propose a systematic hypothesis testing approach to determine the existence of patient subgroup structure and the number of subgroups in patient population if subgroups exist. A mixture of generalized linear models is considered to model the relationship between the disease outcome and patient characteristics and clinical factors, including targeted biomarker profiles. We construct a test statistic based on expectation maximization (EM) algorithm and derive its asymptotic distribution under the null hypothesis. An important computational advantage of the test is that the involved parameter estimates under the complex …

Impact Of Medicaid Expansion Under The Affordable Care Act On Receipt Of Surgery For Breast Cancer, Leisha C Elmore, Meng Li, Heather Lin, Yu Shen, Simona F Shaitelman, Gildy Babiera, Nina Tamirisa, Isabelle Bedrosian

Faculty, Staff and Student Publications

To determine whether Medicaid expansion under the 2010 Affordable Care Act affected rates of breast cancer surgery.

Background: Data regarding the impact of Medicaid expansion on access to surgical treatment of breast cancer are limited.

Methods: Patients in the National Cancer Database diagnosed with non-metastatic breast cancer between January 1, 2010 and December 31, 2017 and residing in a state that expanded Medicaid in January 2014 or in a state that opted out of expansion were included. A quasi-experimental, difference-in-differences (DID) approach was used to assess rate of omission of surgical treatment.

Results: Of 624,237 patients diagnosed with invasive breast …

International Expert Consensus On Immunotherapy For Early-Stage Non-Small Cell Lung Cancer, Wenhua Liang, Kaican Cai, Qingdong Cao, Chun Chen, Haiquan Chen, Jun Chen, Ke-Neng Chen, Qixun Chen, Tianqing Chu, Yuchao Dong, Jiang Fan, Wentao Fang, Junke Fu, Xiangning Fu, Shugeng Gao, Di Ge, Guojun Geng, Qing Geng, Jie He, Jian Hu, Jie Hu, Wei-Dong Hu, Feng Jiang, Tao Jiang, Wenjie Jiao, He-Cheng Li, Qiang Li, Shanqing Li, Shuben Li, Xiangnan Li, Yong-De Liao, Changhong Liu, Hongxu Liu, Yang Liu, Zhuming Lu, Qingquan Luo, Haitao Ma, Xiaojie Pan, Guibin Qiao, Shengxiang Ren, Weiyu Shen, Yong Song, Daqiang Sun, Guangsuo Wang, Jie Wang, Mengzhao Wang, Qiwen Wang, Wen-Xiang Wang, Li Wei, Ming Wu, Nan Wu, Hui Xia, Shi-Dong Xu, Fan Yang, Kang Yang, Yue Yang, Fenglei Yu, Zhen-Tao Yu, Dong-Sheng Yue, Lanjun Zhang, Weidong Zhang, Zhenfa Zhang, Guofang Zhao, Jian Zhao, Xiaojing Zhao, Chengzhi Zhou, Qinghua Zhou, Kunshou Zhu, Yuming Zhu, Toyoaki Hida, Wolfram C M Dempke, Antonio Rossi, Marc De Perrot, Robert A Ramirez, Mariano Provencio, Jay M Lee, Antonio Passaro, Lorenzo Spaggiari, Jonathan Spicer, Nicolas Girard, Patrick M Forde, Tony S K Mok, Tina Cascone, Jianxing He

Faculty, Staff and Student Publications

No abstract provided.

An Interdisciplinary Consensus On The Management Of Brain Metastases In Patients With Renal Cell Carcinoma, Elshad Hasanov, Debra Nana Yeboa, Mathew D Tucker, Todd A Swanson, Thomas Hendrix Beckham, Brian Rini, Chibawanye I Ene, Merve Hasanov, Sophie Derks, Marion Smits, Shaan Dudani, Daniel Y C Heng, Priscilla K Brastianos, Axel Bex, Sahin Hanalioglu, Jeffrey S Weinberg, Laure Hirsch, Maria I Carlo, Ayal Aizer, Paul David Brown, Mehmet Asim Bilen, Eric Lin Chang, Jerry Jaboin, James Brugarolas, Toni K Choueiri, Michael B Atkins, Bradley A Mcgregor, Lia M Halasz, Toral R Patel, Scott G Soltys, David F Mcdermott, James Bradley Elder, Mustafa K Baskaya, James B Yu, Robert Timmerman, Michelle Miran Kim, Melike Mut, James Markert, Kathryn Beal, Nizar M Tannir, George Samandouras, Frederick F Lang, Rachel Giles, Eric Jonasch

Faculty, Staff and Student Publications

Brain metastases are a challenging manifestation of renal cell carcinoma. We have a limited understanding of brain metastasis tumor and immune biology, drivers of resistance to systemic treatment, and their overall poor prognosis. Current data support a multimodal treatment strategy with radiation treatment and/or surgery. Nonetheless, the optimal approach for the management of brain metastases from renal cell carcinoma remains unclear. To improve patient care, the authors sought to standardize practical management strategies. They performed an unstructured literature review and elaborated on the current management strategies through an international group of experts from different disciplines assembled via the network of …

Repeatability And Reproducibility Assessment Of The Apparent Diffusion Coefficient In The Prostate: A Trial Of The Ecog-Acrin Research Group (Acrin 6701), Michael A Boss, Bradley S Snyder, Eunhee Kim, Dena Flamini, Sarah Englander, Karthik M Sundaram, Naveen Gumpeni, Suzanne L Palmer, Haesun Choi, Adam T Froemming, Thorsten Persigehl, Matthew S Davenport, Dariya Malyarenko, Thomas L Chenevert, Mark A Rosen

Faculty, Staff and Student Publications

Background: Uncertainty regarding the reproducibility of the apparent diffusion coefficient (ADC) hampers the use of quantitative diffusion-weighted imaging (DWI) in evaluation of the prostate with magnetic resonance imaging MRI. The quantitative imaging biomarkers alliance (QIBA) profile for quantitative DWI claims a within-subject coefficient of variation (wCV) for prostate lesion ADC of 0.17. Improved understanding of ADC reproducibility would aid the use of quantitative diffusion in prostate MRI evaluation.

Purpose: Evaluation of the repeatability (same-day) and reproducibility (multi-day) of whole-prostate and focal-lesion ADC assessment in a multi-site setting.

Study type: Prospective multi-institutional.

Subjects: Twenty-nine males, ages 53 to 80 (median 63) …

Patient-Reported Bowel And Urinary Function In Long-Term Survivors Of Squamous Cell Carcinoma Of The Anus Treated With Definitive Intensity Modulated Radiation Therapy And Concurrent Chemotherapy, Brian De, Kelsey L Corrigan, Michael K Rooney, Ethan B Ludmir, Prajnan Das, Grace L Smith, Cullen M Taniguchi, Bruce D Minsky, Eugene J Koay, Albert Koong, Van K Morris, Craig A Messick, Y Nancy You, George J Chang, O Lenaine Westney, Graciela M Nogueras Gonzalez, Emma B Holliday

Faculty, Staff and Student Publications

Purpose: Definitive radiation therapy with concurrent chemotherapy is curative for nonmetastatic squamous cell carcinoma of the anus (SCCA). However, the true effect of chemoradiation on long-term functional outcomes is poorly understood owing to limited follow-up and patient-reported outcomes (PROs).

Methods and materials: We conducted a cross-sectional survey of 248 patients with SCCA treated with definitive intensity modulated radiation and concurrent chemotherapy from 2010 to 2018 who were alive and without recurrence. PRO measures were collected, including Functional Assessment of Cancer Therapy-General (FACT-G7), Fecal Incontinence Quality of Life (FIQoL), Low Anterior Resection Syndrome (LARS), and International Consultation on Incontinence Questionnaires (ICIQ). …

Metagenomes Of Rectal Swabs In Larger, Advanced Stage Cervical Cancers Have Enhanced Mucus Degrading Functionalities And Distinct Taxonomic Structure, Tatiana V Karpinets, Xiaogang Wu, Travis Solley, Molly B El Alam, Travis T Sims, Kyoko Yoshida-Court, Erica Lynn, Mustapha Ahmed-Kaddar, Greyson Biegert, Jingyan Yue, Xingzhi Song, Huandong Sun, Joseph F Petrosino, Melissa P Mezzari, Pablo Okhuysen, Patricia J Eifel, Anuja Jhingran, Lilie L Lin, Kathleen M Schmeler, Lois Ramondetta, Nadim Ajami, Robert R Jenq, Andrew Futreal, Jianhua Zhang, Ann H Klopp, Lauren E Colbert

Faculty, Staff and Student Publications

BACKGROUND: Gut microbiome community composition differs between cervical cancer (CC) patients and healthy controls, and increased gut diversity is associated with improved outcomes after treatment. We proposed that functions of specific microbial species adjoining the mucus layer may directly impact the biology of CC.

METHOD: Metagenomes of rectal swabs in 41 CC patients were examined by whole-genome shotgun sequencing to link taxonomic structures, molecular functions, and metabolic pathway to patient's clinical characteristics.

RESULTS: Significant association of molecular functions encoded by the metagenomes was found with initial tumor size and stage. Profiling of the molecular function abundances and their distributions identified …

Changes In Apparent Diffusion Coefficient (Adc) In Serial Weekly Mri During Radiotherapy In Patients With Head And Neck Cancer: Results From The Predict-Hn Study, Sweet Ping Ng, Carlos E Cardenas, Houda Bahig, Baher Elgohari, Jihong Wang, Jason M Johnson, Amy C Moreno, Shalin J Shah, Adam S Garden, Jack Phan, G Brandon Gunn, Steven J Frank, Yao Ding, Lumine Na, Ying Yuan, Diana Urbauer, Abdallah S R Mohamed, David I Rosenthal, William H Morrison, Michael P Macmanus, Clifton D Fuller

Faculty, Staff and Student Publications

Background: The PREDICT-HN study aimed to systematically assess the kinetics of imaging MR biomarkers during head and neck radiotherapy.

Methods: Patients with intact squamous cell carcinoma of the head and neck were enrolled. Pre-, during, and post-treatment MRI were obtained. Serial GTV and ADC measurements were recorded. The correlation between each feature and the GTV was calculated using Spearman’s correlation coefficient. The linear mixed model was used to evaluate the change in GTV over time.

Results: A total of 41 patients completed the study. The majority (76%) had oropharyngeal cancer. A total of 36 patients had intact primary tumours that …

Comparative Risks Of Initial Aortic Events Associated With Genetic Thoracic Aortic Disease, Ellen S Regalado, Shaine A Morris, Alan C Braverman, Ellen M Hostetler, Julie De Backer, Ruosha Li, Reed E Pyeritz, Anji T Yetman, Elena Cervi, Sherene Shalhub, Richmond Jeremy, Scott Lemaire, Maral Ouzounian, Arturo Evangelista, Catherine Boileau, Guillaume Jondeau, Dianna M Milewicz

Faculty, Staff and Student Publications

BACKGROUND: Pathogenic variants in 11 genes predispose individuals to heritable thoracic aortic disease (HTAD), but limited data are available to stratify the risk for aortic events associated with these genes.

OBJECTIVES: This study sought to compare the risk of first aortic event, specifically thoracic aortic aneurysm surgery or an aortic dissection, among 7 HTAD genes and variant types within each gene.

METHODS: A retrospective cohort of probands and relatives with rare variants in 7 genes for HTAD (n = 1,028) was assessed for the risk of first aortic events based on the gene altered, pathogenic variant type, sex, proband status, …

Molecular Analysis Of Short- Versus Long-Term Survivors Of High-Grade Serous Ovarian Carcinoma, Elaine Stur, Emine Bayraktar, Graziela Zibetti Dal Molin, Sherry Y Wu, Lingegowda S Mangala, Hui Yao, Ying Wang, Prahlad T Ram, Sara Corvigno, Hu Chen, Han Liang, Shelley S Tworoger, Douglas A Levine, Susan K Lutgendorf, Jinsong Liu, Kathleen N Moore, Keith A Baggerly, Beth Y Karlan, Anil K Sood

Faculty, Staff and Student Publications

Despite having similar histologic features, patients with high-grade serous ovarian carcinoma (HGSC) often experience highly variable outcomes. The underlying determinants for long-term survival (LTS, ≥10 years) versus short-term survival (STS, < 3 years) are largely unknown. The present study sought to identify molecular predictors of LTS for women with HGSC. A cohort of 24 frozen HGSC samples was collected (12 LTS and 12 STS) and analyzed at DNA, RNA, and protein levels. OVCAR5 and OVCAR8 cell lines were used for in vitro validation studies. For in vivo studies, we injected OVCAR8 cells into the peritoneal cavity of female athymic nude mice. From RNAseq analysis, 11 genes were found to be differentially expressed between the STS and LTS groups (fold change > 2; false discovery rate < 0.01). In the subsequent validation cohort, transmembrane protein 62 (TMEM62) was found to be related to LTS. CIBERSORT analysis showed that T cells (follicular helper) were found at higher levels in tumors from LTS than STS groups. In vitro data using OVCAR5 and OVCAR8 cells showed decreased proliferation with TMEM62 overexpression and positive correlation with a longevity-regulating pathway (KEGG HSA04213) at the RNA level. In vivo analysis using the OVCAR8-TMEM62-TetON model showed decreased tumor burden in mice with high- vs. low-expressing TMEM62 tumors. Our results demonstrate that restoring TMEM62 may be a novel approach for treatment of HGSC. These findings may have implications for biomarker and intervention strategies to help improve patient outcomes

Contributions Of Circulating Micrornas For Early Detection Of Lung Cancer, Jody Vykoukal, Johannes F Fahrmann, Nikul Patel, Masayoshi Shimizu, Edwin J Ostrin, Jennifer B Dennison, Cristina Ivan, Gary E Goodman, Mark D Thornquist, Matt J Barnett, Ziding Feng, George A Calin, Samir M Hanash

Faculty, Staff and Student Publications

There is unmet need to develop circulating biomarkers that would enable earlier interception of lung cancer when more effective treatment options are available. Here, a set of 30 miRNAs, selected from a review of the published literature were assessed for their predictive performance in identifying lung cancer cases in the pre-diagnostic setting. The 30 miRNAs were assayed using sera collected from 102 individuals diagnosed with lung cancer within one year following blood draw and 212 controls matched for age, sex, and smoking status. The additive performance of top-performing miRNA candidates in combination with a previously validated four-protein marker panel (4MP) …

Fiber Bragg Grating Array For Shape Reconstruction In Structural Elements, Edson A Souza, Leandro C Macedo, Anselmo Frizera, Carlos Marques, Arnaldo Leal-Junior

Faculty, Staff and Student Publications

This paper presents the development, analysis and application of a fiber Bragg grating (FBG) array for two-dimensional (2D) shape reconstruction in a cantilever beam. The structural elements made of Pinus wood and Nylon 6.0 were numerically analyzed using the finite element method for the strain distribution when constant loading is applied at the free end of the beam. In addition, the temperature compensation method is proposed to decouple the temperature cross-sensitivity in the deflection analysis. In this case, the temperature sensitivities of all sensing elements of the 5-FBG array were obtained. An additional FBG was encapsulated in a silicone mold …

Bone Marrow Endothelial Cells Increase Prostate Cancer Cell Apoptosis In 3d Triculture Model Of Reactive Stroma, Lindsey K Sablatura, Tristen V Tellman, Aemin Kim, Mary C Farach-Carson

Faculty, Staff and Student Publications

The bone marrow tumor microenvironment (BMTE) is a complex network of cells, extracellular matrix, and sequestered signaling factors that initially act as a hostile environment for disseminating tumor cells (DTCs) from the cancerous prostate. Three-dimensional (3D) culture systems offer an opportunity to better model these complex interactions in reactive stroma, providing contextual behaviors for cancer cells, stromal cells, and endothelial cells. Using a new system designed for the triculture of osteoblastic prostate cancer (PCa) cells, stromal cells, and microvascular endothelial cells, we uncovered a context-specific pro-apoptotic effect of endothelial cells of the bone marrow different from those derived from the …

Disposable E-Cigarettes And Associated Health Risks: An Experimental Study, Hsien-Chang Lin, Anne Buu, Wei-Chung Su

Faculty, Staff and Student Publications

The use of electronic nicotine delivery systems (ENDS), including disposable e-cigarettes, has been prevalent. Existing chemical analyses of ENDS focused on e-liquids rather than aerosols and failed to consider particle sizes and aerosol respiratory deposition fractions, which are key factors for inhalation doses. This study investigated the organic chemical and metal constituents in size-segregated ENDS aerosol and assessed the deposited doses and health risks of these substances. Aerosol chemical analyses were conducted on two popular disposable ENDS products: Puff Bar (Grape) and Air Bar (Watermelon Ice). An ENDS aerosol was generated and delivered into a Micro-Orifice Uniform Deposit Impactor to …

A Patient With Erdheim-Chester Disease Limited To Central Nervous System, Rajesh K Gupta, Anam Haque, Thejasvi A Reddy, Carlos A Pérez

Faculty, Staff and Student Publications

Erdheim-Chester disease (ECD) is a rare, sporadic, non-Langerhans cell histiocytosis, a multisystem disorder, which has higher mortality when presented with CNS involvement. We report a 46-year-old woman who has ECD with exclusive CNS involvement. She presented with intracranial hemorrhage and had a poor response to corticosteroid and interferon. She required multiple debulking procedures and eventually responded well to cobimetinib. She has not had any other organ involvement thus far. This report highlights that CNS involvement may be the only manifestation of ECD and sometimes may require a repeat biopsy with IHC testing for excellent treatment outcomes.

Pancancer Analysis Of A Potential Gene Mutation Model In The Prediction Of Immunotherapy Outcomes, Lishan Yu, Caifeng Gong

Faculty, Staff and Student Publications

Background: Immune checkpoint blockade (ICB) represents a promising treatment for cancer, but predictive biomarkers are needed. We aimed to develop a cost-effective signature to predict immunotherapy benefits across cancers.

Methods: We proposed a study framework to construct the signature. Specifically, we built a multivariate Cox proportional hazards regression model with LASSO using 80% of an ICB-treated cohort (n = 1661) from MSKCC. The desired signature named SIGP was the risk score of the model and was validated in the remaining 20% of patients and an external ICB-treated cohort (n = 249) from DFCI.

Results: SIGP was based on …

Modeling Neonatal Intraventricular Hemorrhage Through Intraventricular Injection Of Hemoglobin, Brandon A Miller, Shelei Pan, Peter H Yang, Catherine Wang, Amanda L Trout, Dakota Defreitas, Sruthi Ramagiri, Scott D Olson, Jennifer M Strahle

Faculty, Staff and Student Publications

Neonatal intraventricular hemorrhage (IVH) is a common consequence of premature birth and leads to brain injury, posthemorrhagic hydrocephalus (PHH), and lifelong neurological deficits. While PHH can be treated by temporary and permanent cerebrospinal fluid (CSF) diversion procedures (ventricular reservoir and ventriculoperitoneal shunt, respectively), there are no pharmacological strategies to prevent or treat IVH-induced brain injury and hydrocephalus. Animal models are needed to better understand the pathophysiology of IVH and test pharmacological treatments. While there are existing models of neonatal IVH, those that reliably result in hydrocephalus are often limited by the necessity for large-volume injections, which may complicate modeling of …

Double-Inlet Left Ventricle, P Syamasundar Rao

Faculty, Staff and Student Publications

Double-inlet left ventricle (DILV) is most frequent among univentricular atrioventricular connections. In DILV, there is a single functioning ventricle, most commonly with left ventricular structure. This chamber receives both atrioventricular valves and is connected to an outlet chamber with morphologic features of the right ventricle. The great vessels are often transposed, and pulmonary stenosis is seen in two-thirds of patients. The anatomy and pathophysiology can be defined by echo-Doppler studies with a rare need for other imaging studies. The management is mostly related to the nature of associated heart defects and the degree of pathophysiological abnormality. When the infants present …

Number-Time Interaction: Search For A Common Magnitude System In A Cross-Modal Setting, Anuj Shukla, Raju S Bapi

Faculty, Staff and Student Publications

A theory of magnitude (ATOM) suggests that a generalized magnitude system in the brain processes magnitudes such as space, time, and numbers. Numerous behavioral and neurocognitive studies have provided support to ATOM theory. However, the evidence for common magnitude processing primarily comes from the studies in which numerical and temporal information are presented visually. Our current understanding of such cross-dimensional magnitude interactions is limited to visual modality only. However, it is still unclear whether the ATOM-framework accounts for the integration of cross-modal magnitude information. To examine the cross-modal influence of numerical magnitude on temporal processing of the tone, we conducted …

A Sparse Representation Strategy To Eliminate Pseudo-Hfo Events From Intracranial Eeg For Seizure Onset Zone Localization, Behrang Fazli Besheli, Zhiyi Sha, Jay R Gavvala, Candan Gurses, Sacit Karamursel, Michael M Quach, Daniel J Curry, Sameer A Sheth, David J Francis, Thomas R Henry, Nuri F Ince

Faculty, Staff and Student Publications

Objective.

High-frequency oscillations (HFOs) are considered a biomarker of the epileptogenic zone in intracranial EEG recordings. However, automated HFO detectors confound true oscillations with spurious events caused by the presence of artifacts.

Approach.

We hypothesized that, unlike pseudo-HFOs with sharp transients or arbitrary shapes, real HFOs have a signal characteristic that can be represented using a small number of oscillatory bases. Based on this hypothesis using a sparse representation framework, this study introduces a new classification approach to distinguish true HFOs from the pseudo-events that mislead seizure onset zone (SOZ) localization. Moreover, we further classified the HFOs into ripples and …

Grk3 Is A Poor Prognosticator And Serves As A Therapeutic Target In Advanced Gastric Adenocarcinoma, Yuan Li, Yibo Fan, Jinbang Xu, Longfei Huo, Ailing W Scott, Jiankang Jin, Boxuan Yang, Shan Shao, Lang Ma, Ying Wang, Xiaodan Yao, Melissa Pool Pizzi, Matheus Sewastjanow Da Silva, Guoliang Zhang, Lijuan Zhuo, Eun Jeong Cho, Kevin N Dalby, Namita D Shanbhag, Zhenning Wang, Wenliang Li, Shumei Song, Jaffer A Ajani

Faculty, Staff and Student Publications

Background: G protein-coupled receptor (GPCR) is the most targeted protein family by the FDA-approved drugs. GPCR-kinase 3 (GRK3) is critical for GPCR signaling. Our genomic analysis showed that GRK3 expression correlated with poor prognosis of gastric adenocarcinoma (GAC) patients. However, GRK3's functions and clinical utility in GAC progression and metastases are unknown.

Methods: We studied GRK3 expression in normal, primary, and metastatic GAC tissues. We identified a novel GRK3 inhibitor, LD2, through a chemical-library screen. Through genetic and pharmacologic modulations of GRK3, a series of functional and molecular studies were performed in vitro and in vivo. Impact of GRK3 on …