Genetic Phenomena Commons^™

Survival Outcomes Of Patients With Her2/Neu-Positive Breast Cancer With Germline Brca Mutations, Fatma Nihan Akkoc Mustafayev, Mihir Amitabh Shukla, Amanda Lanier, Denái R Milton, Angelica M Gutierrez, Stephen K Gruschkus, John E Lewis, Rashmi K Murthy, Banu K Arun

Faculty, Staff and Student Publications

Background: Breast cancer (BC) with germline BRCA1/2 mutations and their association with triple-negative BC has been thoroughly investigated. However, some carriers of BRCA1/2 mutations have human epidermal growth factor receptor 2 (HER2/neu)-positive BC, which has a different targeted therapy approach, and data are scarce for this patient population. The authors sought to characterize the clinical characteristics and outcomes of patients with HER2/neu-positive BC who had germline BRCA1/2 mutations.

Methods: This was a retrospective analysis of data from 1099 patients diagnosed with HER2/neu-positive BC who were screened for germline BRCA mutations between 1996 and 2022. Clinicopathologic features and survival rates were …

A Novel Sik2 Inhibitor Sic-19 Exhibits Synthetic Lethality With Parp Inhibitors In Ovarian Cancer, Fang Wang, Xuejiao Yu, Jun Qian, Yumin Cao, Shunli Dong, Shenghua Zhan, Zhen Lu, Robert C Bast, Qingxia Song, Youguo Chen, Yi Zhang, Jinhua Zhou

Faculty, Staff and Student Publications

Purpose: Ovarian cancer patients with HR proficiency (HRP) have had limited benefits from PARP inhibitor treatment, highlighting the need for improved therapeutic strategies. In this study, we developed a novel SIK2 inhibitor, SIC-19, and investigated its potential to enhance the sensitivity and expand the clinical utility of PARP inhibitors in ovarian cancer.

Methods: The SIK2 protein was modeled using a Molecular Operating Environment (MOE), and the most favorable model was selected based on a GBVI/WSA dG scoring function. The Chembridge Compound Library was screened, and the top 20 candidate compounds were tested for their interaction with SIK2 and downstream substrates, …

Safety And Tolerability Of Online Adaptive High-Field Magnetic Resonance-Guided Radiotherapy, Jasmijn M Westerhoff, Lois A Daamen, John P Christodouleas, Erwin L A Blezer, Ananya Choudhury, Rosalyne L Westley, Beth A Erickson, Clifton D Fuller, Shaista Hafeez, Uulke A Van Der Heide, Martijn P W Intven, Anna M Kirby, Susan Lalondrelle, Bruce D Minsky, Stella Mook, Marlies E Nowee, Corrie A M Marijnen, Kristina M Orrling, Arjun Sahgal, Christopher J Schultz, Corinne Faivre-Finn, Robbert J H A Tersteeg, Alison C Tree, Chia-Lin Tseng, Tine Schytte, Dustin M Silk, Dave Eggert, Marco Luzzara, Jochem R N Van Der Voort Van Zyp, Helena M Verkooijen, William A Hall

Faculty, Staff and Student Publications

Importance: In 2018, the first online adaptive magnetic resonance (MR)-guided radiotherapy (MRgRT) system using a 1.5-T MR-equipped linear accelerator (1.5-T MR-Linac) was clinically introduced. This system enables online adaptive radiotherapy, in which the radiation plan is adapted to size and shape changes of targets at each treatment session based on daily MR-visualized anatomy.

Objective: To evaluate safety, tolerability, and technical feasibility of treatment with a 1.5-T MR-Linac, specifically focusing on the subset of patients treated with an online adaptive strategy (ie, the adapt-to-shape [ATS] approach).

Design, setting, and participants: This cohort study included adults with solid tumors treated with a …

Circulating Immune Signatures In Chronic Pancreatitis With And Without Preceding Acute Pancreatitis: A Pilot Study, Rasmus Hagn-Meincke, Dhiraj Yadav, Dana K Andersen, Santhi Swaroop Vege, Evan L Fogel, Jose Serrano, Melena D Bellin, Mark D Topazian, Darwin L Conwell, Liang Li, Stephen K Van Den Eeden, Asbjørn M Drewes, Stephen J Pandol, Chris E Forsmark, William E Fisher, Phil A Hart, Søren S Olesen, Walter G Park, Consortium For The Study Of Chronic Pancreatitis, Diabetes, And Pancreatic Cancer (Cpdpc)

Faculty, Staff and Student Publications

Objective: To investigate profiles of circulating immune signatures in healthy controls and chronic pancreatitis patients (CP) with and without a preceding history of acute pancreatitis (AP).

Methods: We performed a phase 1, cross-sectional analysis of prospectively collected serum samples from the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translation StuDies (PROCEED) study. All samples were collected during a clinically quiescent phase. CP subjects were categorized into two subgroups based on preceding episode(s) of AP. Healthy controls were included for comparison. Blinded samples were analyzed using an 80-plex Luminex assay of cytokines, chemokines, and adhesion molecules. Group and pairwise comparisons …

A West African Ancestry-Associated Snp On 8q24 Predicts A Positive Biopsy In African American Men With Suspected Prostate Cancer Following Psa Screening, Jian Gu, Lisly Chery, Graciela M Nogueras González, Chad Huff, Sara Strom, Jeffrey A Jones, Donald P Griffith, Steven E Canfield, Xuemei Wang, Xuelin Huang, Pamela Roberson, Qing H Meng, Patricia Troncoso, Michael Ittmann, Michael Covinsky, Michael Scheurer, Margarita Irizarry Ramirez, Curtis A Pettaway

Faculty, Staff and Student Publications

BACKGROUND: African American (AA) men have the highest incidence and mortality rates of prostate cancer (PCa) among all racial groups in the United States. While race is a social construct, for AA men, this overlaps with west African ancestry. Many of the PCa susceptibility variants exhibit distinct allele frequencies and risk estimates across different races and contribute substantially to the large disparities of PCa incidence among races. We previously reported that a single-nucleotide polymorphism (SNP) in 8q24, rs7824364, was strongly associated with west African ancestry and increased risks of PCa in both AA and Puerto Rican men. In this study, …

Proton Therapy Mediates Dose Reductions To Brain Structures Associated With Cognition In Children With Medulloblastoma, Julianna Sienna, Lisa S Kahalley, Donald Mabbott, David Grosshans, Anna Theresa Santiago, Arnold Dela Cruz Paulino, Thomas E Merchant, Gohar S Manzar, Hitesh Dama, David C Hodgson, Murali Chintagumpala, Mehmet Fatih Okcu, William E Whitehead, Normand Laperriere, Vijay Ramaswamy, Ute Bartels, Uri Tabori, Julie M Bennett, Anirban Das, Tim Craig, Derek S Tsang

Faculty, Staff and Student Publications

Purpose: Emerging evidence suggests proton radiation therapy may offer cognitive sparing advantages over photon radiation therapy, yet dosimetry has not been compared previously. The purpose of this study was to examine dosimetric correlates of cognitive outcomes in children with medulloblastoma treated with proton versus photon radiation therapy.

Methods and materials: In this retrospective, bi-institutional study, dosimetric and cognitive data from 75 patients (39 photon and 36 proton) were analyzed. Doses to brain structures were compared between treatment modalities. Linear mixed-effects models were used to create models of global IQ and cognitive domain scores.

Results: The mean dose and dose to …

Targeted Accurate Rna Consensus Sequencing (Tarc-Seq) Reveals Mechanisms Of Replication Error Affecting Sars-Cov-2 Divergence, Catherine C Bradley, Chen Wang, Alasdair J E Gordon, Alice X Wen, Pamela N Luna, Matthew B Cooke, Brendan F Kohrn, Scott R Kennedy, Vasanthi Avadhanula, Pedro A Piedra, Olivier Lichtarge, Chad A Shaw, Shannon E Ronca, Christophe Herman

Duncan NRI Faculty and Staff Publications

RNA viruses, like SARS-CoV-2, depend on their RNA-dependent RNA polymerases (RdRp) for replication, which is error-prone. Monitoring replication errors is crucial for understanding the virus’s evolution. Current methods lack the precision to detect rare de novo RNA mutations, particularly in low-input samples such as those from patients. Here, we introduce a new targeted Accurate RNA Consensus sequencing method (tARC-seq) to accurately determine the mutation frequency and types in SARS-CoV-2, both in cell culture and clinical samples. Our findings show an average of 2.68×10−5 new errors per cycle with a C>T bias that cannot be solely attributed to APOBEC …

Consensus Guidelines For The Diagnosis And Management Of Succinic Semialdehyde Dehydrogenase Deficiency, Itay Tokatly Latzer, Mariarita Bertoldi, Nenad Blau, Melissa L Dibacco, Sarah H Elsea, Àngels García-Cazorla, K Michael Gibson, Andrea L Gropman, Ellen Hanson, Carolyn Hoffman, Kathrin Jeltsch, Natalia Juliá-Palacios, Ina Knerr, Henry H C Lee, Patrizia Malaspina, Alice Mcconnell, Thomas Opladen, Mari Oppebøen, Alexander Rotenberg, Mark Walterfang, Lee Wang-Tso, Ron A Wevers, Jean-Baptiste Roullet, Phillip L Pearl

Faculty, Staff and Students Publications

Succinic semialdehyde dehydrogenase deficiency (SSADHD) (OMIM #271980) is a rare autosomal recessive metabolic disorder caused by pathogenic variants of ALDH5A1. Deficiency of SSADH results in accumulation of γ-aminobutyric acid (GABA) and other GABA-related metabolites. The clinical phenotype of SSADHD includes a broad spectrum of non-pathognomonic symptoms such as cognitive disabilities, communication and language deficits, movement disorders, epilepsy, sleep disturbances, attention problems, anxiety, and obsessive-compulsive traits. Current treatment options for SSADHD remain supportive, but there are ongoing attempts to develop targeted genetic therapies. This study aimed to create consensus guidelines for the diagnosis and management of SSADHD. Thirty relevant statements were …

Financial Hardship And Neighborhood Socioeconomic Disadvantage In Long-Term Childhood Cancer Survivors, Alex J Fauer, Weiyu Qiu, I-Chan Huang, Patricia A Ganz, Jacqueline N Casillas, K Robin Yabroff, Gregory T Armstrong, Wendy Leisenring, Rebecca Howell, Carrie R Howell, Anne C Kirchhoff, Yutaka Yasui, Paul C Nathan

Faculty, Staff and Student Publications

Background: Long-term survivors of childhood cancer face elevated risk for financial hardship. We evaluate whether childhood cancer survivors live in areas of greater deprivation and the association with self-reported financial hardships.

Methods: We performed a cross-sectional analysis of data from the Childhood Cancer Survivor Study between 1970 and 1999 and self-reported financial information from 2017 to 2019. We measured neighborhood deprivation with the Area Deprivation Index (ADI) based on current zip code. Financial hardship was measured with validated surveys that captured behavioral, material and financial sacrifice, and psychological hardship. Bivariate analyses described neighborhood differences between survivors and siblings. Generalized linear …

Nestedbd: Bayesian Inference Of Phylogenetic Trees From Single-Cell Copy Number Profiles Under A Birth-Death Model, Yushu Liu, Mohammadamin Edrisi, Zhi Yan, Huw A Ogilvie, Luay Nakhleh

Faculty, Staff and Student Publications

Copy number aberrations (CNAs) are ubiquitous in many types of cancer. Inferring CNAs from cancer genomic data could help shed light on the initiation, progression, and potential treatment of cancer. While such data have traditionally been available via “bulk sequencing,” the more recently introduced techniques for single-cell DNA sequencing (scDNAseq) provide the type of data that makes CNA inference possible at the single-cell resolution. We introduce a new birth-death evolutionary model of CNAs and a Bayesian method, NestedBD, for the inference of evolutionary trees (topologies and branch lengths with relative mutation rates) from single-cell data. We evaluated NestedBD’s performance using …

Angiotensin-Converting-Enzyme Inhibitors And Angiotensin Receptor Blockers For Preventing The Progression Of Diabetic Kidney Disease, Patrizia Natale, Suetonia C Palmer, Sankar D Navaneethan, Jonathan C Craig, Giovanni Fm Strippoli

Faculty, Staff and Students Publications

Background: Guidelines suggest that adults with diabetes and kidney disease receive treatment with angiotensin-converting-enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB). This is an update of a Cochrane review published in 2006.

Objectives: We compared the efficacy and safety of ACEi and ARB therapy (either as monotherapy or in combination) on cardiovascular and kidney outcomes in adults with diabetes and kidney disease.

Search methods: We searched the Cochrane Kidney and Transplants Register of Studies to 17 March 2024 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of …

Utility Of Clinical Next Generation Sequencing Tests In Kit/Pdgfra/Sdh Wild-Type Gastrointestinal Stromal Tumors, Ryan A Denu, Cissimol P Joseph, Elizabeth S Urquiola, Precious S Byrd, Richard K Yang, Ravin Ratan, Maria Alejandra Zarzour, Anthony P Conley, Dejka M Araujo, Vinod Ravi, Elise F Nassif Haddad, Michael S Nakazawa, Shreyaskumar Patel, Wei-Lien Wang, Alexander J Lazar, Neeta Somaiah

Faculty, Staff and Student Publications

Objective: The vast majority of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in KIT, PDGFRA, or components of the succinate dehydrogenase (SDH) complex (SDHA, SDHB, SDHC, and SDHD genes). A small fraction of GISTs lack alterations in KIT, PDGFRA, and SDH. We aimed to further characterize the clinical and genomic characteristics of these so-called "triple-negative" GISTs.

Methods: We extracted clinical and genomic data from patients seen at MD Anderson Cancer Center with a diagnosis of GIST and available clinical next generation sequencing data to identify "triple-negative" patients.

Results: Of …

Histone Proteoform Analysis Reveals Epigenetic Changes In Adult Mouse Brown Adipose Tissue In Response To Cold Stress, Bethany C Taylor, Loic H Steinthal, Michelle Dias, Hari Krishna Yalamanchili, Scott A Ochsner, Gladys E Zapata, Nitesh R Mehta, Neil J Mckenna, Nicolas L Young, Alli M Nuotio-Antar

Faculty, Staff and Students Publications

BACKGROUND: Regulation of the thermogenic response by brown adipose tissue (BAT) is an important component of energy homeostasis with implications for the treatment of obesity and diabetes. Our preliminary analyses of RNA-Seq data uncovered many nodes representing epigenetic modifiers that are altered in BAT in response to chronic thermogenic activation. Thus, we hypothesized that chronic thermogenic activation broadly alters epigenetic modifications of DNA and histones in BAT.

RESULTS: Motivated to understand how BAT function is regulated epigenetically, we developed a novel method for the first-ever unbiased top-down proteomic quantitation of histone modifications in BAT and validated our results with a …

New Insights Into Macrophage Polarization And Its Prognostic Role In Patients With Colorectal Cancer Liver Metastasis, Isha Khanduri, Harufumi Maki, Anuj Verma, Riham Katkhuda, Gayathri Anandappa, Renganayaki Pandurengan, Shanyu Zhang, Alicia Mejia, Zhimin Tong, Luisa M Solis Soto, Akshaya Jadhav, Ignacio I Wistuba, David Menter, Scott Kopetz, Edwin R Parra, Jean-Nicolas Vauthey, Dipen M Maru

Faculty, Staff and Student Publications

Background: As liver metastasis is the most common cause of mortality in patients with colorectal cancer, studying colorectal cancer liver metastasis (CLM) microenvironment is essential for improved understanding of tumor biology and to identify novel therapeutic targets.

Methods: We used a multiplex immunofluorescence platform to study tumor associated macrophage (TAM) polarization and adaptive T cell subtypes in tumor samples from 105 CLM patients (49 without and 56 with preoperative chemotherapy).

Results: CLM exhibited M2 macrophage polarization, and helper T cells were the prevalent adaptive T cell subtype. The density of total, M2 and TGFβ-expressing macrophages, and regulatory T cells was …

Chromosomal 3q Amplicon Encodes Essential Regulators Of Secretory Vesicles That Drive Secretory Addiction In Cancer, Xiaochao Tan, Shike Wang, Guan-Yu Xiao, Chao Wu, Xin Liu, Biyao Zhou, Jiang Yu, Dzifa Yawa Duose, Yuanxin Xi, Jing Wang, Kunika Gupta, Apar Pataer, Jack A Roth, Michael P Kim, Fengju Chen, Chad J Creighton, William K Russell, Jonathan M Kurie

Faculty, Staff and Student Publications

Cancer cells exhibit heightened secretory states that drive tumor progression. Here, we identify a chromosome 3q amplicon that serves as a platform for secretory regulation in cancer. The 3q amplicon encodes multiple Golgi-resident proteins, including the scaffold Golgi integral membrane protein 4 (GOLIM4) and the ion channel ATPase Secretory Pathway Ca2+ Transporting 1 (ATP2C1). We show that GOLIM4 recruits ATP2C1 and Golgi phosphoprotein 3 (GOLPH3) to coordinate calcium-dependent cargo loading and Golgi membrane bending and vesicle scission. GOLIM4 depletion disrupts the protein complex, resulting in a secretory blockade that inhibits the progression of 3q-amplified malignancies. In addition to its role …

Evolution Of Chromosome-Arm Aberrations In Breast Cancer Through Genetic Network Rewiring, Elena Kuzmin, Toby M Baker, Tom Lesluyes, Jean Monlong, Kento T Abe, Paula P Coelho, Michael Schwartz, Joseph Del Corpo, Dongmei Zou, Genevieve Morin, Alain Pacis, Yang Yang, Constanza Martinez, Jarrett Barber, Hellen Kuasne, Rui Li, Mathieu Bourgey, Anne-Marie Fortier, Peter G Davison, Atilla Omeroglu, Marie-Christine Guiot, Quaid Morris, Claudia L Kleinman, Sidong Huang, Anne-Claude Gingras, Jiannis Ragoussis, Guillaume Bourque, Peter Van Loo, Morag Park

Faculty, Staff and Student Publications

The basal breast cancer subtype is enriched for triple-negative breast cancer (TNBC) and displays consistent large chromosomal deletions. Here, we characterize evolution and maintenance of chromosome 4p (chr4p) loss in basal breast cancer. Analysis of The Cancer Genome Atlas data shows recurrent deletion of chr4p in basal breast cancer. Phylogenetic analysis of a panel of 23 primary tumor/patient-derived xenograft basal breast cancers reveals early evolution of chr4p deletion. Mechanistically we show that chr4p loss is associated with enhanced proliferation. Gene function studies identify an unknown gene, C4orf19, within chr4p, which suppresses proliferation when overexpressed-a member of the PDCD10-GCKIII kinase module …

Six-Year Follow-Up And Subgroup Analyses Of A Phase 2 Trial Of Venetoclax For Del(17p) Chronic Lymphocytic Leukemia, Stephan Stilgenbauer, Eugen Tausch, Andrew W Roberts, Matthew S Davids, Barbara Eichhorst, Michael Hallek, Peter Hillmen, Christof Schneider, Johannes Schetelig, Sebastian Böttcher, Arnon P Kater, Yanwen Jiang, Michelle Boyer, Relja Popovic, Majd T Ghanim, Michael Moran, Wendy J Sinai, Xifeng Wang, Nabanita Mukherjee, Brenda Chyla, William G Wierda, John F Seymour

Faculty, Staff and Student Publications

Chromosome 17p deletion (del[17p]) is associated with poor prognosis in patients with chronic lymphocytic leukemia (CLL). Venetoclax is approved for treatment of previously untreated and relapsed/refractory (R/R) CLL, including patients with del(17p), based on the open-label, multicenter, phase 2 M13-982 trial (NCT01889186). Here, we detail the 6-year follow-up analysis for M13-982. A total of 158 patients with previously untreated (n = 5) or R/R (n = 153) del(17p) CLL received 400 mg venetoclax daily after initial ramp-up until progressive disease. After a median follow-up of 70 months, the best objective response rate (ORR) was 77% (21% complete remission …

Th2 Cells Are Associated With Tumor Recurrence Following Radiation, Mohamed K Abdelhakiem, Riyue Bao, Phillip M Pifer, David Molkentine, Jessica Molkentine, Andrew Hefner, Beth Beadle, John V Heymach, Jason J Luke, Robert L Ferris, Curtis R Pickering, Jing H Wang, Ravi B Patel, Heath D Skinner

Faculty, Staff and Student Publications

The curative treatment of multiple solid tumors, including head and neck squamous cell carcinoma (HNSCC), utilizes radiation. The outcomes for HPV/p16-negative HNSCC are significantly worse than HPV/p16-positive tumors, with increased radiation resistance leading to worse locoregional recurrence (LRR) and ultimately death. This study analyzed the relationship between immune function and outcomes following radiation in HPV/p16-negative tumors to identify mechanisms of radiation resistance and prognostic immune biomarkers. A discovery cohort of 94 patients with HNSCC treated uniformly with surgery and adjuvant radiation and a validation cohort of 97 similarly treated patients were utilized. Tumor immune infiltrates were derived from RNAseq gene …

Sequential Requirements For Distinct Polθ Domains During Theta-Mediated End Joining, Carel Fijen, Lea Drogalis Beckham, Dante Terino, Yuzhen Li, Dale A Ramsden, Richard D Wood, Sylvie Doublié, Eli Rothenberg

Faculty, Staff and Student Publications

DNA polymerase θ (Polθ) plays a central role in a DNA double-strand break repair pathway termed theta-mediated end joining (TMEJ). TMEJ functions by pairing short-sequence "microhomologies" (MHs) in single-stranded DNA at each end of a break and subsequently initiating DNA synthesis. It is not known how the Polθ helicase domain (HD) and polymerase domain (PD) operate to bring together MHs and facilitate repair. To resolve these transient processes in real time, we utilized in vitro single-molecule FRET approaches and biochemical analyses. We find that the Polθ-HD mediates the initial capture of two ssDNA strands, bringing them in close proximity. The …

Human Dna Polymerase Θ Does Not Harbor Intrinsic Nuclease Activity, Denisse Carvajal-Maldonado, Karl Zahn, Ryan Jensen, Richard D Wood, Sylvie Doublié

Faculty, Staff and Student Publications

No abstract provided.

Fourteen-Day Vonoprazan-Based Bismuth Quadruple Therapy For H Pylori Eradication In An Area With High Clarithromycin And Levofloxacin Resistance: A Prospective Randomized Study (Vq-Hp Trial), Nuttapat Tungtrongchitr, Phubordee Bongkotvirawan, Sarita Ratana-Amornpin, Sith Siramolpiwat, Thanee Eiamsitrakoon, Pornpen Gamnarai, Arti Wongcha-Um, Yoshio Yamaoka, Kammal Kumar Pawa, Ratha-Korn Vilaichone

Faculty, Staff and Students Publications

Potassium-competitive acid blockers (P-CABs) provide potent acid inhibition, yet studies on P-CAB-based quadruple therapy for H. pylori eradication are limited. We theorized that integrating bismuth subsalicylate into a quadruple therapy regimen could enhance eradication rates. However, data on the efficacy of vonoprazan bismuth quadruple therapy are notably scarce. Therefore, the aim of this study was to evaluate the efficacy of vonoprazan-based bismuth quadruple therapy in areas with high clarithromycin and levofloxacin resistance. This was a prospective, single-center, randomized trial conducted to compare the efficacy of 7-day and 14-day vonoprazan-based bismuth quadruple therapy for H. pylori eradication between June 1, 2021, …

Revolutionizing Diabetic Foot Ulcer Care: The Senotherapeutic Approach, Guiqin Zhang, Priyadarshani Nadeeshika Samarawickrama, Li Gui, Yuan Ma, Mei Cao, Hong Zhu, Wei Li, Honglin Yang, Kecheng Li, Yang Yang, Enfang Zhu, Wen Li, Yonghan He

Faculty, Staff and Student Publications

Diabetic foot ulcers (DFUs) are a prevalent and profoundly debilitating complication that afflicts individuals with diabetes mellitus (DM). These ulcers are associated with substantial morbidity, recurrence rates, disability, and mortality, imposing substantial economic, psychological, and medical burdens. Timely detection and intervention can mitigate the morbidity and disparities linked to DFU. Nevertheless, current therapeutic approaches for DFU continue to grapple with multifaceted limitations. A growing body of evidence emphasizes the crucial role of cellular senescence in the pathogenesis of chronic wounds. Interventions that try to delay cellular senescence, eliminate senescent cells (SnCs), or suppress the senescence-associated secretory phenotype (SASP) have shown …

Genetic Testing For Supravalvar Aortic Stenosis: What To Do When It Is Not Williams Syndrome, Sara B Stephens, Tyler Novy, Gabrielle N Spurzem, Benjamin Jacob, Taylor Beecroft, Emily Soludczyk, Beth A Kozel, Justin Weigand, Shaine A Morris

Faculty, Staff and Students Publications

Background: We aimed to describe the frequency and yield of genetic testing in supravalvar aortic stenosis (SVAS) following negative evaluation for Williams-Beuren syndrome (WS).

Methods and results: This retrospective cohort study included patients with SVAS at our institution who had a negative evaluation for WS from May 1991 to September 2021. SVAS was defined as (1) peak supravalvar velocity of ≥2 meters/second, (2) sinotubular junction or ascending aortic Z score < -2.0, or (3) sinotubular junction Z score < -1.5 with family history of SVAS. Patients with complex congenital heart disease, aortic valve disease as the primary condition, or only postoperative SVAS were excluded. Genetic testing and diagnoses were reported. Of 162 patients who were WS negative meeting inclusion criteria, 61 had genetic testing results available (38%). Chromosomal microarray had been performed in 44 of 61 and was nondiagnostic for non-WS causes of SVAS. Sequencing of 1 or more genes was performed in 47 of 61. Of these, 39 of 47 underwent ELN sequencing, 20 of 39 (51%) of whom had a diagnostic variant. Other diagnoses made by gene sequencing were Noonan syndrome (3 PTPN11, 1 RIT1), Alagille …

Sensitivity Analysis With Iterative Outlier Detection For Systematic Reviews And Meta-Analyses, Zhuo Meng, Jingshen Wang, Lifeng Lin, Chong Wu

Faculty, Staff and Student Publications

Meta-analysis is a widely used tool for synthesizing results from multiple studies. The collected studies are deemed heterogeneous when they do not share a common underlying effect size; thus, the factors attributable to the heterogeneity need to be carefully considered. A critical problem in meta-analyses and systematic reviews is that outlying studies are frequently included, which can lead to invalid conclusions and affect the robustness of decision-making. Outliers may be caused by several factors such as study selection criteria, low study quality, small-study effects, and so on. Although outlier detection is well-studied in the statistical community, limited attention has been …

Afamitresgene Autoleucel For Advanced Synovial Sarcoma And Myxoid Round Cell Liposarcoma (Spearhead-1): An International, Open-Label, Phase 2 Trial, Sandra P D'Angelo, Dejka M Araujo, Albiruni R Abdul Razak, Mark Agulnik, Steven Attia, Jean-Yves Blay, Irene Carrasco Garcia, John A Charlson, Edwin Choy, George D Demetri, Mihaela Druta, Edouard Forcade, Kristen N Ganjoo, John Glod, Vicki L Keedy, Axel Le Cesne, David A Liebner, Victor Moreno, Seth M Pollack, Scott M Schuetze, Gary K Schwartz, Sandra J Strauss, William D Tap, Fiona Thistlethwaite, Claudia Maria Valverde Morales, Michael J Wagner, Breelyn A Wilky, Cheryl Mcalpine, Laura Hudson, Jean-Marc Navenot, Tianjiao Wang, Jane Bai, Stavros Rafail, Ruoxi Wang, Amy Sun, Lilliam Fernandes, Erin Van Winkle, Erica Elefant, Colin Lunt, Elliot Norry, Dennis Williams, Swethajit Biswas, Brian A Van Tine

Faculty, Staff and Student Publications

Background: Afamitresgene autoleucel (afami-cel) showed acceptable safety and promising efficacy in a phase 1 trial (NCT03132922). The aim of this study was to further evaluate the efficacy of afami-cel for the treatment of patients with HLA-A*02 and MAGE-A4-expressing advanced synovial sarcoma or myxoid round cell liposarcoma.

Methods: SPEARHEAD-1 was an open-label, non-randomised, phase 2 trial done across 23 sites in Canada, the USA, and Europe. The trial included three cohorts, of which the main investigational cohort (cohort 1) is reported here. Cohort 1 included patients with HLA-A*02, aged 16-75 years, with metastatic or unresectable synovial sarcoma or myxoid …

Phase 1b Study Of Intraperitoneal Ipilimumab And Nivolumab In Patients With Recurrent Gynecologic Malignancies With Peritoneal Carcinomatosis, Anne Knisely, Emily Hinchcliff, Bryan Fellman, Ann Mosley, Kathryn Lito, Sara Hull, Shannon N Westin, Anil K Sood, Kathleen M Schmeler, Jolyn S Taylor, Steven Y Huang, Rahul A Sheth, Karen H Lu, Amir A Jazaeri

Faculty, Staff and Student Publications

Background: Intravenous immune checkpoint blockade (ICB) has shown poor response rates in recurrent gynecologic malignancies. Intraperitoneal (i.p.) ICB may result in enhanced T cell activation and anti-tumor immunity.

Methods: In this phase 1b study, registered at Clinical.

Trials: gov (NCT03508570), initial cohorts received i.p. nivolumab monotherapy, and subsequent cohorts received combination i.p. nivolumab every 2 weeks and i.p. ipilimumab every 6 weeks, guided by a Bayesian design. The primary objective was determination of the recommended phase 2 dose (RP2D) of the combination. Secondary outcomes included toxicity, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).

Findings: …

Nivolumab Plus Chemotherapy In Epidermal Growth Factor Receptor-Mutated Metastatic Non-Small-Cell Lung Cancer After Disease Progression On Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: Final Results Of Checkmate 722, Tony Mok, Kazuhiko Nakagawa, Keunchil Park, Yuichiro Ohe, Nicolas Girard, Hye Ryun Kim, Yi-Long Wu, Justin Gainor, Se-Hoon Lee, Chao-Hua Chiu, Sang-We Kim, Cheng-Ta Yang, Chien Liang Wu, Lin Wu, Meng-Chih Lin, Jens Samol, Kazuya Ichikado, Mengzhao Wang, Xiaoqing Zhang, Judi Sylvester, Sunney Li, Ann Forslund, James Chih-Hsin Yang

Faculty, Staff and Student Publications

PURPOSE: The phase III CheckMate 722 trial (ClinicalTrials.gov identifier: NCT02864251) evaluated nivolumab plus chemotherapy versus chemotherapy in patients with epidermal growth factor receptor (

METHODS: Patients with disease progression after first- or second-generation EGFR TKI therapy (without

RESULTS: Overall, 294 patients were randomly assigned. At final analysis (median follow-up, 38.1 months), PFS was not significantly improved with nivolumab plus chemotherapy versus chemotherapy (median, 5.6

CONCLUSION: Nivolumab plus chemotherapy did not significantly improve PFS versus chemotherapy in patients with

Fusobacterium Nucleatum Subsp Animalis Comes To The Spotlight In Oral Diseases, Bibek G C, Peng Zhou, Chenggang Wu

Faculty, Staff and Student Publications

Krieger et al.'s study in this issue of Cell Host & Microbe reveals that Fusobacterium nucleatum subsp. animalis strains, previously underestimated, are significant in disease-affected oral areas. This challenges the long-held notion of the dominance of Fusobacterium nucleatum subsp. nucleatum, reshaping our understanding of Fusobacterium distribution in the oral microbiome.

Fusobacterium Nucleatum Subsp Animalis Comes To The Spotlight In Oral Diseases, Bibek G C, Peng Zhou, Chenggang Wu

Faculty, Staff and Student Publications

Krieger et al.'s study in this issue of Cell Host & Microbe reveals that Fusobacterium nucleatum subsp. animalis strains, previously underestimated, are significant in disease-affected oral areas. This challenges the long-held notion of the dominance of Fusobacterium nucleatum subsp. nucleatum, reshaping our understanding of Fusobacterium distribution in the oral microbiome.

Synovial Fibroblast Gene Expression Is Associated With Sensory Nerve Growth And Pain In Rheumatoid Arthritis, Zilong Bai, Nicholas Bartelo, Maryam Aslam, Elisabeth A Murphy, Caryn R Hale, Nathalie E Blachere, Salina Parveen, Edoardo Spolaore, Edward Dicarlo, Ellen M Gravallese, Melanie H Smith, Accelerating Medicines Partnership Ra/Sle Network, Mayu O Frank, Caroline S Jiang, Haotan Zhang, Christina Pyrgaki, Myles J Lewis, Shafaq Sikandar, Costantino Pitzalis, Joseph B Lesnak, Khadijah Mazhar, Theodore J Price, Anne-Marie Malfait, Rachel E Miller, Fan Zhang, Susan Goodman, Robert B Darnell, Fei Wang, Dana E Orange

Faculty, Staff and Student Publications

It has been presumed that rheumatoid arthritis (RA) joint pain is related to inflammation in the synovium; however, recent studies reveal that pain scores in patients do not correlate with synovial inflammation. We developed a machine-learning approach (graph-based gene expression module identification or GbGMI) to identify an 815-gene expression module associated with pain in synovial biopsy samples from patients with established RA who had limited synovial inflammation at arthroplasty. We then validated this finding in an independent cohort of synovial biopsy samples from patients who had early untreated RA with little inflammation. Single-cell RNA sequencing analyses indicated that most of …