Medical Genetics Commons^™

2021 Aapm Equity, Diversity, And Inclusion Climate Survey Executive Summary, Kristi R G Hendrickson, Stephen M Avery, Richard Castillo, Laura Cervino, Ashley Cetnar, Nolan L Gagne, Wendy Harris, Amirh Johnson, Megan E Lipford, Nadia Octave, Kelly C Paradis, Angélica Pérez-Andújar, Surendra Prajapati, Julianne Pollard-Larkin

Faculty, Staff and Student Publications

Purpose: The American Association of Physicists in Medicine (AAPM) shares the results, conclusions, and recommendations from the initial Equity, Diversity, and Inclusion Climate Survey conducted in 2021.

Methods and materials: The climate survey targeted medical physicists who are full members of the AAPM and included demographic inquiries and questions intended to assess the working environmental climate in terms of a sense of belonging and inclusion, experiences of discrimination and harassment, and obstacles to participation within the AAPM. The survey invitation was sent to 5,500 members. Responses were collected from 1385 members (response rate of 25%) between January and February 2021. …

Irf7 And Unc93b1 Variants In An Infant With Recurrent Herpes Simplex Virus Infection., Megan H. Tucker, Wei Yu, Heather Menden, Sheng Xia, Carl F. Schreck, Margaret Gibson, Daniel A. Louiselle, T Pastinen, Nikita Raje, Venkatesh Sampath

Manuscripts, Articles, Book Chapters and Other Papers

Neonatal herpes simplex virus (HSV) infection is a devastating disease with substantial morbidity and mortality. The genetic basis of susceptibility to HSV in neonates remains undefined. We evaluated a male infant with neonatal skin/eye/mouth (SEM) HSV-1 disease, who had complete recovery after acyclovir but developed HSV-1 encephalitis at 1 year of age. An immune workup showed an anergic PBMC cytokine response to TLR3 stimulation but no other TLRs. Exome sequencing identified rare missense variants in IFN-regulatory factor 7 (IRF7) and UNC-93 homolog B1 (UNC93B1). PBMC single-cell RNA-Seq done during childhood revealed decreased expression of several innate immune genes and a …

Inference For Set-Based Effects In Genetic Association Studies With Interval-Censored Outcomes, Ryan Sun, Liang Zhu, Yimei Li, Yutaka Yasui, Leslie Robison

Faculty, Staff and Student Publications

The rapid acceleration of genetic data collection in biomedical settings has recently resulted in the rise of genetic compendiums filled with rich longitudinal disease data. One common feature of these data sets is their plethora of interval-censored outcomes. However, very few tools are available for the analysis of genetic data sets with interval-censored outcomes, and in particular, there is a lack of methodology available for set-based inference. Set-based inference is used to associate a gene, biological pathway, or other genetic construct with outcomes and is one of the most popular strategies in genetics research. This work develops three such tests …

Targeting Chemotherapy Resistance In Mesenchymal Triple-Negative Breast Cancer: A Phase Ii Trial Of Neoadjuvant Angiogenic And Mtor Inhibition With Chemotherapy, Nour Abuhadra, Ryan Sun, Roland L Bassett, Lei Huo, Jeffrey T Chang, Mediget Teshome, Alyson R Clayborn, Jason B White, Elizabeth E Ravenberg, Beatriz E Adrada, Rosalind P Candelaria, Wei Yang, Qingqing Ding, W Fraser Symmans, Banu Arun, Senthil Damodaran, Kimberly B Koenig, Rachel M Layman, Bora Lim, Jennifer K Litton, Alastair Thompson, Naoto T Ueno, Helen Piwnica-Worms, Gabriel N Hortobagyi, Vicente Valero, Debu Tripathy, Gaiane M Rauch, Stacy Moulder, Clinton Yam

Faculty, Staff and Student Publications

Background:: Metaplastic histology and mesenchymal differentiation have been associated with chemotherapy resistance in triple-negative breast cancer (TNBC). In the neoadjuvant setting, suboptimal on-treatment clinical response to chemotherapy is associated with low rates of pathological complete response (pCR). Given the previously demonstrated activity of pegylated liposomal doxorubicin, bevacizumab, and mTOR inhibition with temsirolimus (DAT) or everolimus (DAE) in metastatic, metaplastic TNBC, we conducted a phase II study of DAT/DAE as the second phase of neoadjuvant therapy in patients with metaplastic and/or mesenchymal TNBC experiencing suboptimal clinical response to neoadjuvant doxorubicin and cyclophosphamide (AC) (NCT02456857).

Patients and Methods:: Patients received …

Efficacy And Adverse Effects Of Ketamine Versus Electroconvulsive Therapy For Major Depressive Disorder: A Systematic Review And Meta-Analysis, Debora De A Simoes Moreira, Luís Eduardo Gauer, Guilherme Teixeira, Amanda Carolina Fonseca Da Silva, Stefanie Cavalcanti, João Quevedo

Faculty, Staff and Student Publications

Background: ECT is considered the fastest and most effective treatment for TRD. Ketamine seems to be an attractive alternative due to its rapid-onset antidepressant effects and impact on suicidal thoughts. This study aimed to compare efficacy and tolerability of ECT and ketamine for different depression outcomes (PROSPERO/CRD42022349220).

Methods: We searched MEDLINE, Web of Science, Embase, PsycINFO, Google Scholar, Cochrane Library and trial registries, which were the ClinicalTrials.gov and the World Health Organization's International Clinical Trials Registry Platform, without restrictions on publication date.

Selection criteria: randomized controlled trials or cohorts comparing ketamine versus ECT in patients with TRD.

Results: Eight studies …

Flt3 Inhibitors Upregulate Cxcr4 And E-Selectin Ligands Via Erk Suppression In Aml Cells And Cxcr4/E-Selectin Inhibition Enhances Anti-Leukemia Efficacy Of Flt3-Targeted Therapy In Aml, Yannan Jia, Weiguo Zhang, Mahesh Basyal, Kyung Hee Chang, Lauren Ostermann, Jared K Burks, Charlie Ly, Hong Mu-Mosley, Qi Zhang, Xin Han, William E Fogler, John L Magnani, Arnaud Lesegretain, Anna A Zal, Tomasz Zal, Michael Andreeff

Faculty, Staff and Student Publications

No abstract provided.

Aibp Regulates Trpv1 Activation In Chemotherapy-Induced Peripheral Neuropathy By Controlling Lipid Raft Dynamics And Proximity To Tlr4 In Dorsal Root Ganglion Neurons, Juliana M Navia-Pelaez, Julia Borges Paes Lemes, Leonardo Gonzalez, Lauriane Delay, Luciano Dos Santos Aggum Capettini, Jenny W Lu, Gilson Gonçalves Dos Santos, Ann M Gregus, Patrick M Dougherty, Tony L Yaksh, Yury I Miller

Faculty, Staff and Student Publications

Nociceptive afferent signaling evoked by inflammation and nerve injury is mediated by the opening of ligand-gated and voltage-gated receptors or channels localized to cholesterol-rich lipid raft membrane domains. Dorsal root ganglion (DRG) nociceptors express high levels of toll-like receptor 4 (TLR4), which also localize to lipid rafts. Genetic deletion or pharmacologic blocking of TLR4 diminishes pain associated with chemotherapy-induced peripheral neuropathy (CIPN). In DRGs of mice with paclitaxel-induced CIPN, we analyzed DRG neuronal lipid rafts, expression of TLR4, activation of transient receptor potential cation channel subfamily V member 1 (TRPV1), and TLR4-TRPV1 interaction. Using proximity ligation assay, flow cytometry, and …

Impact Of Cross-Ancestry Genetic Architecture On Gwass In Admixed Populations, Rachel Mester, Kangcheng Hou, Yi Ding, Gillian Meeks, Kathryn S Burch, Arjun Bhattacharya, Brenna M Henn, Bogdan Pasaniuc

Faculty, Staff and Student Publications

Genome-wide association studies (GWASs) have identified thousands of variants for disease risk. These studies have predominantly been conducted in individuals of European ancestries, which raises questions about their transferability to individuals of other ancestries. Of particular interest are admixed populations, usually defined as populations with recent ancestry from two or more continental sources. Admixed genomes contain segments of distinct ancestries that vary in composition across individuals in the population, allowing for the same allele to induce risk for disease on different ancestral backgrounds. This mosaicism raises unique challenges for GWASs in admixed populations, such as the need to correctly adjust …

X-Linked Variations In Shroom4 Are Implicated In Congenital Anomalies Of The Urinary Tract And The Anorectal, Cardiovascular And Central Nervous Systems, Caroline M. Kolvenbach, Tim Felger, Luca Schierbaum, Isabelle Thiffault, T Pastinen, Maria Szczepańska, Marcin Zaniew, Piotr Adamczyk, Allan Bayat, Öznur Yilmaz, Tobias T. Lindenberg, Holger Thiele, Friedhelm Hildebrandt, Katrin Hinderhofer, Ute Moog, Alina C Hilger, Bonnie Sullivan, Lauren E. Bartik, Piotr Gnyś, Phillip Grote, Benjamin Odermatt, Heiko M. Reutter, Gabriel C. Dworschak

Manuscripts, Articles, Book Chapters and Other Papers

Background: SHROOM4 is thought to play an important role in cytoskeletal modification and development of the early nervous system. Previously, single-nucleotide variants (SNVs) or copy number variations (CNVs) in SHROOM4 have been associated with the neurodevelopmental disorder Stocco dos Santos syndrome, but not with congenital anomalies of the urinary tract and the visceral or the cardiovascular system.

Methods: Here, exome sequencing and CNV analyses besides expression studies in zebrafish and mouse and knockdown (KD) experiments using a splice blocking morpholino in zebrafish were performed to study the role of SHROOM4 during embryonic development.

Results: In this study, we identified putative …

Causal Linkage Of Presence Of Mutant Npm1 To Efficacy Of Novel Therapeutic Agents Against Aml Cells With Mutant Npm1, Christopher P Mill, Warren Fiskus, Kaberi Das, John A Davis, Christine E Birdwell, Tapan M Kadia, Courtney D Dinardo, Naval Daver, Koichi Takahashi, Koji Sasaki, Gerard M Mcgeehan, Xinjia Ruan, Xiaoping Su, Sanam Loghavi, Hagop Kantarjian, Kapil N Bhalla

Faculty, Staff and Student Publications

In AML with NPM1 mutation causing cytoplasmic dislocation of NPM1, treatments with Menin inhibitor (MI) and standard AML chemotherapy yield complete remissions. However, the causal and mechanistic linkage of mtNPM1 to the efficacy of these agents has not been definitively established. Utilizing CRISPR-Cas9 editing to knockout (KO) or knock-in a copy of mtNPM1 in AML cells, present studies demonstrate that KO of mtNPM1 from AML cells abrogates sensitivity to MI, selinexor (exportin-1 inhibitor), and cytarabine. Conversely, the knock-in of a copy of mtNPM1 markedly sensitized AML cells to treatment with MI or cytarabine. Following AML therapy, most elderly patients with …

Characterization Of Gafchromictm Ebt4 Film With Clinical Kv/Mv Photons And Mev Electrons, Fada Guan, Huixiao Chen, Emily Draeger, Yuting Li, Resat Aydin, Christopher J Tien, Zhe Chen

Faculty, Staff and Student Publications

Objective: A newly developed GafchromicTM EBT4 film model was released recently. According to the vendor-stated specifications, this new model maintains major features of its more recent predecessor, EBT3, but has a great improvement in the signal-to-noise ratio (SNR). The purpose of this study was to fully characterize the EBT4 model by testing its dose response dependence on beam energy using clinical photon and electron beams and validating its improvement in SNR.

Methods: In the beam energy dependence experiments, 6 MV and 15 MV photon beams, 6 MeV, 12 MeV and 20 MeV electron beams, 120 kVp and two 250 kVp …

Five-Year Overall Survival With Ipilimumab And Stereotactic Ablative Radiotherapy For Metastatic Disease, Kewen He, David S Hong, Chad Tang, Duygu Sezen, Livia Cox, Aurian Maleki, Genevieve Bertolet, Quynh-Nhu Nguyen, Nathan I Comeaux, Lily Schuda, Dawei Chen, James W Welsh

Faculty, Staff and Student Publications

Purpose: Ipilimumab plus stereotactic ablative radiotherapy (SABR) demonstrate satisfactory short-term clinical benefit and low toxicities in metastatic cancers. Here, we report the 5-year overall survival (OS) rates for patients with metastatic disease treated with this combined-modality therapy in a phase II trial (NCT02239900).

Methods and materials: SABR was delivered to patients with metastatic lesions in the liver and lung either during the first dose (concurrent) or 1 week after the second dose (sequential) of ipilimumab (every 3 weeks for 4 cycles). SABR was administered to liver or lung metastases as 50 Gy in 4 fractions or 60 Gy …

Phase I/Ii Sequencing Study Of Azacitidine, Epacadostat, And Pembrolizumab In Advanced Solid Tumors, Jason J Luke, Marwan Fakih, Charles Schneider, E Gabriela Chiorean, Johanna Bendell, Rebecca Kristeleit, Razelle Kurzrock, Sarah P Blagden, Irene Brana, Laura W Goff, Kevin O'Hayer, Ryan Geschwindt, Michael Smith, Feng Zhou, Aung Naing

Faculty, Staff and Student Publications

Background: Indoleamine 2,3-dioxygenase 1 (IDO1), an interferon-inducible enzyme, contributes to tumor immune intolerance. Immune checkpoint inhibition may increase interferon levels; combining IDO1 inhibition with immune checkpoint blockade represents an attractive strategy. Epigenetic agents trigger interferon responses and may serve as an immunotherapy priming method. We evaluated whether epigenetic therapy plus IDO1 inhibition and immune checkpoint blockade confers clinical benefit to patients with advanced solid tumors.

Methods: ECHO-206 was a Phase I/II study where treatment-experienced patients with advanced solid tumors (N = 70) received azacitidine plus an immunotherapy doublet (epacadostat [IDO1 inhibitor] and pembrolizumab). Sequencing of treatment was also assessed. Primary …

Clinicopathologic Features Of Therapy-Related Myeloid Neoplasms In Patients With Myeloma In The Era Of Novel Therapies, Fatima Zahra Jelloul, Andres E Quesada, Richard K Yang, Shaoying Li, Wei Wang, Jie Xu, Guilin Tang, C Cameron Yin, Hong Fang, Siba El Hussein, Joseph Khoury, Roland L Bassett, Guillermo Garcia-Manero, Elizabet E Manasanch, Robert Z Orlowski, Muzaffar H Qazilbash, Keyur P Patel, L Jeffrey Medeiros, Pei Lin

Faculty, Staff and Student Publications

The development of therapy-related myeloid neoplasms (t-MN) is a rare complication that can occur in myeloma patients treated primarily with novel therapies. To better understand t-MNs in this context, we reviewed 66 such patients and compared them with a control group of patients who developed t-MN after cytotoxic therapies for other malignancies. The study group included 50 men and 16 women, with a median age of 68 years (range, 48-86 years). Therapies included proteasome inhibitors, immunomodulatory agents, and high-dose melphalan-based autologous stem cell transplantation (HDM-ASCT) in 64 (97%), 65 (98.5%), and 64 (97%) patients, respectively; 29 (43.9%) patients were exposed …

The Lure Of Cardiac Metabolism In The Diagnosis, Prevention, And Treatment Of Heart Failure, Daniele Rodolico, Gabriele G Schiattarella, Heinrich Taegtmeyer

Faculty, Staff and Student Publications

Energy substrate metabolism and contractile function are tightly coupled in the heart. Within this framework, heart failure may be viewed as a state of impaired energy transfer. The metabolic changes in the failing heart are linked to functional and structural changes. A worthwhile goal is to measure metabolic flux and its regulation quantitatively, and to do this in a manner that leads to targeted interventions. For several good reasons, this goal has been elusive until now. The development of new analytical and imaging techniques offers the potential of exploring the landscape of metabolic changes across the different stages of heart …

Author Correction: Pan-Cancer Analysis Of Whole Genomes Identifies Driver Rearrangements Promoted By Line-1 Retrotransposition, Bernardo Rodriguez-Martin, Eva G Alvarez, Adrian Baez-Ortega, Jorge Zamora, Fran Supek, Jonas Demeulemeester, Martin Santamarina, Young Seok Ju, Javier Temes, Daniel Garcia-Souto, Harald Detering, Yilong Li, Jorge Rodriguez-Castro, Ana Dueso-Barroso, Alicia L Bruzos, Stefan C Dentro, Miguel G Blanco, Gianmarco Contino, Daniel Ardeljan, Marta Tojo, Nicola D Roberts, Sonia Zumalave, Paul A Edwards, Joachim Weischenfeldt, Montserrat Puiggròs, Zechen Chong, Ken Chen, Eunjung Alice Lee, Jeremiah A Wala, Keiran M Raine, Adam Butler, Sebastian M Waszak, Fabio C P Navarro, Steven E Schumacher, Jean Monlong, Francesco Maura, Niccolo Bolli, Guillaume Bourque, Mark Gerstein, Peter J Park, David C Wedge, Rameen Beroukhim, David Torrents, Jan O Korbel, Iñigo Martincorena, Rebecca C Fitzgerald, Peter Van Loo, Haig H Kazazian, Kathleen H Burns, Cawg Structural Variation Working Group, Peter J Campbell, Jose M C Tubio, Pcawg Consortium

Faculty, Staff and Student Publications

No abstract provided.

Antioxidant Activity And Total Phenolic Compounds Of Commiphora Gileadensis Extracts Obtained By Ultrasonic-Assisted Extraction, With Monitoring Antiaging And Cytotoxicity Activities, Hani Ahmed, Marwan M A Rashed, Marwan Almoiliqy, Mohammed Abdalla, Mohanad Bashari, Mohamed Y Zaky, Zhu Hailin, Taha A A Naji, Ahmed Eibaid, Jinpeng Wang, Li-Ping Jiang

Faculty, Staff and Student Publications

Commiphora gileadensis (C. gileadensis) has been identified and linked with various health benefits and pharmaceutical potential for its phytochemical activities and chemical constituents. This study aimed to evaluate ultrasonic‐assisted extraction (USE) technique for total phenols content from C. gileadensis leaf compared to the hydrodistillation extraction (HDE). Our results showed that the USE operating conditions were identified as: MeOH·H2O solvent‐to‐fresh sample ratio of 80:20 (v/v); ultrasonic power/frequency at 150 W/20 kHz; and a temperature of 40 ± 1°C; subjected to acoustic waves intermittently for a calculated time (5 min) during the total programmed time of 12 min. The USE …

Publisher Correction: Targeting Pd-L2-Rgmb Overcomes Microbiome-Related Immunotherapy Resistance, Joon Seok Park, Francesca S Gazzaniga, Meng Wu, Amalia K Luthens, Jacob Gillis, Wen Zheng, Martin W Lafleur, Sarah B Johnson, Golnaz Morad, Elizabeth M Park, Yifan Zhou, Stephanie S Watowich, Jennifer A Wargo, Gordon J Freeman, Dennis L Kasper, Arlene H Sharpe

Faculty, Staff and Student Publications

No abstract provided.

Test-Retest Reliability Of Virtual Reality Devices In Quantifying For Relative Afferent Pupillary Defect, Prithul Sarker, Nasif Zaman, Joshua Ong, Phani Paladugu, Molly Aldred, Ethan Waisberg, Andrew G Lee, Alireza Tavakkoli

Faculty, Staff and Student Publications

Background: The swinging flashlight test (SFT) is one of the most prominent clinical tests for detecting the relative afferent pupillary defect (RAPD). A positive RAPD localizes the lesion to the affected afferent pupil pathway and is a critical part of any ophthalmic exam. Testing for an RAPD, however, can be challenging (especially when small), and there is significant intrarater and interrater variability.

Methods: Prior studies have shown that the pupillometer can improve the detection and measurement of RAPD. In our previous research, we have demonstrated an automatic SFT by utilizing virtual reality (VR), named VR-SFT. We applied our methods to …

A Phase Ii Study Of Neoadjuvant Atezolizumab And Nab-Paclitaxel In Patients With Anthracycline-Resistant Early-Stage Triple-Negative Breast Cancer, Clinton Yam, Elizabeth A Mittendorf, Haven R Garber, Ryan Sun, Senthil Damodaran, Rashmi K Murthy, David Ramirez, Meghan Karuturi, Rachel M Layman, Nuhad Ibrahim, Gaiane M Rauch, Beatriz E Adrada, Rosalind P Candelaria, Jason B White, Elizabeth Ravenberg, Alyson Clayborn, Qing Qing Ding, W Fraser Symmans, Sabitha Prabhakaran, Alastair M Thompson, Vicente Valero, Debu Tripathy, Lei Huo, Stacy L Moulder, Jennifer K Litton

Faculty, Staff and Student Publications

Purpose: Neoadjuvant anti-PD-(L)1 therapy improves the pathological complete response (pCR) rate in unselected triple-negative breast cancer (TNBC). Given the potential for long-term morbidity from immune-related adverse events (irAEs), optimizing the risk-benefit ratio for these agents in the curative neoadjuvant setting is important. Suboptimal clinical response to initial neoadjuvant therapy (NAT) is associated with low rates of pCR (2-5%) and may define a patient selection strategy for neoadjuvant immune checkpoint blockade. We conducted a single-arm phase II study of atezolizumab and nab-paclitaxel as the second phase of NAT in patients with doxorubicin and cyclophosphamide (AC)-resistant TNBC (NCT02530489).

Methods: Patients …

Hrd Effects On First-Line Adjuvant Chemotherapy And Parpi Maintenance Therapy In Chinese Ovarian Cancer Patients, Lei Li, Yu Gu, Mengpei Zhang, Xiaohua Shi, Zhe Li, Xinyun Xu, Tianqi Sun, Yu Dong, Chao Xue, Xiaoru Zhu, Ran Lv, Kai Jiao, Xuwo Ji, Li-Juan Wang, Yang Zhang, Zhiyong Liang, Ying Jin, Rutie Yin, Ming Wu, Han Liang

Faculty, Staff and Student Publications

Homologous recombination deficiency (HRD) testing has been approved by FDA for selecting epithelial ovarian cancer (EOC) patients who may benefit from the first-line poly (ADP-ribose) polymerase inhibitor (PARPi) maintenance therapy. However, the effects of HRD on the clinical outcomes of first-line chemotherapy and first-line PARPi maintenance therapy have not been rigorously evaluated in Chinese EOC patients. Here, we developed an HRD assay and applied it to two large retrospectively collected Chinese EOC patient cohorts. In the first-line adjuvant chemotherapy cohort (FACT, N = 380), HRD status significantly improved PFS (median, 15.6 months vs. 9.4 months; HR, 0.688; 95% CI, 0.526-0.899; …

Heritable Aortic Root Aneurysms, Maral Ouzounian, Scott A Lemaire, Dianna M Milewicz

Faculty, Staff and Student Publications

No abstract provided.

Differential Gene Expression Of Fresh Tissue And Patient-Derived Explants’ Matricellular Proteins Augment Inflammatory Breast Cancer Metastasis: The Possible Role Of Il-6 And Mcp-1, Alshaimaa Tarek, Hossam Taha Mohamed, Aya Ali El-Sharkawy, Shrouk Khalaf El-Sayed, Jon Mark Hirshon, Wendy A Woodward, Mohamed El-Shinawi, Mona Mostafa Mohamed

Faculty, Staff and Student Publications

BACKGROUND: Matricellular proteins comprising matrisome and adhesome are responsible for structure integrity and interactions between cells in the tumour microenvironment of breast cancer. Changes in the gene expression of matrisome and adhesome augment metastasis. Since inflammatory breast cancer (IBC) is characterized by high metastatic behaviour. Herein, we compared the gene expression profile of matrisome and adhesome in non-IBC and IBC in fresh tissue and ex vivo patient-derived explants (PDEs) and we also compared the secretory inflammatory mediators of PDEs in non-IBC and IBC to identify secretory cytokines participate in cross-talk between cells via interactions with matrisome and adhisome.

METHODS: Fifty …

Genome-Wide Association Study Of Lung Adenocarcinoma In East Asia And Comparison With A European Population, Jianxin Shi, Kouya Shiraishi, Jiyeon Choi, Keitaro Matsuo, Tzu-Yu Chen, Juncheng Dai, Rayjean J Hung, Kexin Chen, Xiao-Ou Shu, Young Tae Kim, Maria Teresa Landi, Dongxin Lin, Wei Zheng, Zhihua Yin, Baosen Zhou, Bao Song, Jiucun Wang, Wei Jie Seow, Lei Song, I-Shou Chang, Wei Hu, Li-Hsin Chien, Qiuyin Cai, Yun-Chul Hong, Hee Nam Kim, Yi-Long Wu, Maria Pik Wong, Brian Douglas Richardson, Karen M Funderburk, Shilan Li, Tongwu Zhang, Charles Breeze, Zhaoming Wang, Batel Blechter, Bryan A Bassig, Jin Hee Kim, Demetrius Albanes, Jason Y Y Wong, Min-Ho Shin, Lap Ping Chung, Yang Yang, She-Juan An, Hong Zheng, Yasushi Yatabe, Xu-Chao Zhang, Young-Chul Kim, Neil E Caporaso, Jiang Chang, James Chung Man Ho, Michiaki Kubo, Yataro Daigo, Minsun Song, Yukihide Momozawa, Yoichiro Kamatani, Masashi Kobayashi, Kenichi Okubo, Takayuki Honda, Dean H Hosgood, Hideo Kunitoh, Harsh Patel, Shun-Ichi Watanabe, Yohei Miyagi, Haruhiko Nakayama, Shingo Matsumoto, Hidehito Horinouchi, Masahiro Tsuboi, Ryuji Hamamoto, Koichi Goto, Yuichiro Ohe, Atsushi Takahashi, Akiteru Goto, Yoshihiro Minamiya, Megumi Hara, Yuichiro Nishida, Kenji Takeuchi, Kenji Wakai, Koichi Matsuda, Yoshinori Murakami, Kimihiro Shimizu, Hiroyuki Suzuki, Motonobu Saito, Yoichi Ohtaki, Kazumi Tanaka, Tangchun Wu, Fusheng Wei, Hongji Dai, Mitchell J Machiela, Jian Su, Yeul Hong Kim, In-Jae Oh, Victor Ho Fun Lee, Gee-Chen Chang, Ying-Huang Tsai, Kuan-Yu Chen, Ming-Shyan Huang, Wu-Chou Su, Yuh-Min Chen, Adeline Seow, Jae Yong Park, Sun-Seog Kweon, Kun-Chieh Chen, Yu-Tang Gao, Biyun Qian, Chen Wu, Daru Lu, Jianjun Liu, Ann G Schwartz, Richard Houlston, Margaret R Spitz, Ivan P Gorlov, Xifeng Wu, Ping Yang, Stephen Lam, Adonina Tardon, Chu Chen, Stig E Bojesen, Mattias Johansson, Angela Risch, Heike Bickeböller, Bu-Tian Ji, H-Erich Wichmann, David C Christiani, Gadi Rennert, Susanne Arnold, Paul Brennan, James Mckay, John K Field, Sanjay S Shete, Loic Le Marchand, Geoffrey Liu, Angeline Andrew, Lambertus A Kiemeney, Shan Zienolddiny-Narui, Kjell Grankvist, Mikael Johansson, Angela Cox, Fiona Taylor, Jian-Min Yuan, Philip Lazarus, Matthew B Schabath, Melinda C Aldrich, Hyo-Sung Jeon, Shih Sheng Jiang, Jae Sook Sung, Chung-Hsing Chen, Chin-Fu Hsiao, Yoo Jin Jung, Huan Guo, Zhibin Hu, Laurie Burdett, Meredith Yeager, Amy Hutchinson, Belynda Hicks, Jia Liu, Bin Zhu, Sonja I Berndt, Wei Wu, Junwen Wang, Yuqing Li, Jin Eun Choi, Kyong Hwa Park, Sook Whan Sung, Li Liu, Chang Hyun Kang, Wen-Chang Wang, Jun Xu, Peng Guan, Wen Tan, Chong-Jen Yu, Gong Yang, Alan Dart Loon Sihoe, Ying Chen, Yi Young Choi, Jun Suk Kim, Ho-Il Yoon, In Kyu Park, Ping Xu, Qincheng He, Chih-Liang Wang, Hsiao-Han Hung, Roel C H Vermeulen, Iona Cheng, Junjie Wu, Wei-Yen Lim, Fang-Yu Tsai, John K C Chan, Jihua Li, Hongyan Chen, Hsien-Chih Lin, Li Jin, Jie Liu, Norie Sawada, Taiki Yamaji, Kathleen Wyatt, Shengchao A Li, Hongxia Ma, Meng Zhu, Zhehai Wang, Sensen Cheng, Xuelian Li, Yangwu Ren, Ann Chao, Motoki Iwasaki, Junjie Zhu, Gening Jiang, Ke Fei, Guoping Wu, Chih-Yi Chen, Chien-Jen Chen, Pan-Chyr Yang, Jinming Yu, Victoria L Stevens, Joseph F Fraumeni, Nilanjan Chatterjee, Olga Y Gorlova, Chao Agnes Hsiung, Christopher I Amos, Hongbing Shen, Stephen J Chanock, Nathaniel Rothman, Takashi Kohno, Qing Lan

Faculty, Staff and Student Publications

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European …

The Longitudinal Analysis Of Convergent Antibody Vdj Regions In Sars-Cov-2-Positive Patients Using Rna-Seq, Kate J Liu, Monika A Zelazowska, Kevin M Mcbride

Faculty, Staff and Student Publications

Severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) is an ongoing pandemic that continues to evolve and reinfect individuals. To understand the convergent antibody responses that evolved over the course of the pandemic, we evaluated the immunoglobulin repertoire of individuals infected by different SARS-CoV-2 variants for similarity between patients. We utilized four public RNA-seq data sets collected between March 2020 and March 2022 from the Gene Expression Omnibus (GEO) in our longitudinal analysis. This covered individuals infected with Alpha and Omicron variants. In total, from 269 SARS-CoV-2-positive patients and 26 negative patients, 629,133 immunoglobulin heavy-chain variable region V(D)J sequences were reconstructed from …

An Unknown Essential Function Of Trna Splicing Endonuclease Is Linked To The Integrated Stress Response And Intron Debranching, Jennifer E Hurtig, Ambro Van Hoof

Faculty, Staff and Student Publications

tRNA splicing endonuclease (TSEN) has a well-characterized role in transfer RNA (tRNA) splicing but also other functions. For yeast TSEN, these other functions include degradation of a subset of mRNAs that encode mitochondrial proteins and an unknown essential function. In this study, we use yeast genetics to characterize the unknown tRNA-independent function(s) of TSEN. Using a high-copy suppressor screen, we found that sen2 mutants can be suppressed by overexpression of SEN54. This effect was seen both for tRNA-dependent and tRNA-independent functions indicating that SEN54 is a general suppressor of sen2, likely through structural stabilization. A spontaneous suppressor screen identified mutations …

New Actions On Actionable Mutations In Lung Cancers, Xiuning Le, Yasir Y Elamin, Jianjun Zhang

Faculty, Staff and Student Publications

Actionable mutations refer to DNA alterations that, if detected, would be expected to affect patients' response to treatments [...].

Publisher Correction: A Randomized Pilot Study Of Oncology Massage To Treat Chemotherapy-Induced Peripheral Neuropathy, Gabriel Lopez, Cathy Eng, Michael Overman, David Ramirez, Wenli Liu, Curtiss Beinhorn, Pamela Sumler, Sarah Prinsloo, Yisheng Li, Minxing Chen, Eduardo Bruera, Lorenzo Cohen

Faculty, Staff and Student Publications

No abstract provided.

The Deleted In Oral Cancer (Doc1 Aka Cdk2ap1) Tumor Suppressor Gene Is Downregulated In Oral Squamous Cell Carcinoma By Multiple Micrornas, Roberto Stabile, Mario Román Cabezas, Mathijs P Verhagen, Francesco A Tucci, Thierry P P Van Den Bosch, Maria J De Herdt, Berdine Van Der Steen, Alex L Nigg, Meng Chen, Cristina Ivan, Masayoshi Shimizu, Senada Koljenović, Jose A Hardillo, C Peter Verrijzer, Robert J Baatenburg De Jong, George A Calin, Riccardo Fodde

Faculty, Staff and Student Publications

Cyclin-dependent kinase 2-associated protein 1 (CDK2AP1; also known as deleted in oral cancer or DOC1) is a tumor suppressor gene known to play functional roles in both cell cycle regulation and in the epigenetic control of embryonic stem cell differentiation, the latter as a core subunit of the nucleosome remodeling and histone deacetylation (NuRD) complex. In the vast majority of oral squamous cell carcinomas (OSCC), expression of the CDK2AP1 protein is reduced or lost. Notwithstanding the latter (and the DOC1 acronym), mutations or deletions in its coding sequence are extremely rare. Accordingly, CDK2AP1 protein-deficient oral cancer cell lines express as …

Magrolimab In Combination With Azacitidine In Patients With Higher-Risk Myelodysplastic Syndromes: Final Results Of A Phase Ib Study, David A Sallman, Monzr M Al Malki, Adam S Asch, Eunice S Wang, Joseph G Jurcic, Terrence J Bradley, Ian W Flinn, Daniel A Pollyea, Suman Kambhampati, Tiffany N Tanaka, Joshua F Zeidner, Guillermo Garcia-Manero, Deepa Jeyakumar, Rami Komrokji, Jeffrey Lancet, Hagop M Kantarjian, Lin Gu, Yajia Zhang, Anderson Tan, Mark Chao, Carol O'Hear, Giridharan Ramsingh, Indu Lal, Paresh Vyas, Naval G Daver

Faculty, Staff and Student Publications

Purpose: Magrolimab is a monoclonal antibody that blocks cluster of differentiation 47, a don't-eat-me signal overexpressed on cancer cells. Cluster of differentiation 47 blockade by magrolimab promotes macrophage-mediated phagocytosis of tumor cells and is synergistic with azacitidine, which increases expression of eat-me signals. We report final phase Ib data in patients with untreated higher-risk myelodysplastic syndromes (MDS) treated with magrolimab and azacitidine (ClinicalTrials.gov identifier: NCT03248479).

Patients and methods: Patients with previously untreated Revised International Prognostic Scoring System intermediate-/high-/very high-risk MDS received magrolimab intravenously as a priming dose (1 mg/kg) followed by ramp-up to a 30 mg/kg once-weekly or once-every-2-week …