Medical Genetics Commons^™

Transfer Learning Via Distributed Brain Recordings Enables Reliable Speech Decoding, Aditya Singh, Tessy Thomas, Jinlong Li, Greg Hickok, Xaq Pitkow, Nitin Tandon

Faculty, Staff and Student Publications

Speech brain-computer interfaces (BCIs) combine neural recordings with large language models to achieve real-time intelligible speech. However, these decoders rely on dense, intact cortical coverage and are challenging to scale across individuals with heterogeneous brain organization. To derive scalable transfer learning strategies for neural speech decoding, we used minimally invasive stereo-electroencephalography recordings in a large cohort performing a demanding speech motor task. A sequence-to-sequence model enabled decoding of variable-length phonemic sequences prior to and during articulation. This enabled development of a cross-subject transfer learning framework to isolate shared latent manifolds while enabling individual model initialization. The group-derived decoder significantly outperformed …

Precemtabart Tocentecan, An Anti-Ceacam5 Antibody-Drug Conjugate, In Metastatic Colorectal Cancer: A Phase 1 Trial, Scott Kopetz, Valentina Boni, Ken Kato, Kanwal P S Raghav, Maria Vieito, Athanasios Pallis, Christina Habermehl, Abdul Siddiqui, Perrine Courlet, Willem Sloot, Sabine Raab-Westphal, Felix Hart, Ildefonso Rodriguez-Rivera

Faculty, Staff and Student Publications

CEACAM5, a cell surface protein, is overexpressed in colorectal cancer (CRC). Precemtabart tocentecan (Precem-TcT, previously M9140) is an anti-CEACAM5 antibody–drug conjugate with the topoisomerase 1 inhibitor exatecan as payload. Precem-TcT demonstrated strong antitumor activity and potent bystander activity in preclinical models. Its toxicity profile in cynomolgus monkeys was consistent with that of exatecan. In the dose-escalation stage of the phase 1 trial of Precem-TcT (PROCEADE-CRC-01), 40 heavily pretreated patients with irinotecan-refractory metastatic CRC received Precem-TcT every 3 weeks across seven dose levels (DLs, 0.6–3.2 mg kg−1). Primary endpoints were dose-limiting toxicities (DLTs), adverse events and preliminary clinical activity to establish …

Updated Estimates Of Patients With Oropharyngeal Cancer In The Us, Caineng Cao, Anna Lee, Jung Julie Kang, Irini Yacoub, Kaveh Zakeri, Edward Christopher Dee, Nadeem Riaz, Achraf Shamseddine, Yao Yu, Jennifer Ma, Teeradon Treechairusame, Marc A Cohen, Jennifer R Cracchiolo, Richard J Wong, Winston Wong, Lara A Dunn, Eric J Sherman, Nancy Y Lee

Faculty, Staff and Student Publications

Importance: Updated estimates of oropharyngeal cancer (OPC) in the US are needed.

Objective: To calculate the most recent epidemiologic estimates of OPC in the US and provide projections for future trends up to 2040.

Design, setting, and participants: This cross-sectional epidemiological analysis used data from the recent National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program. The SEER-22 (excluding Illinois and Massachusetts) database provided data for incidence, prevalence, survival, and initial treatment by OPC stage. Patients with OPC diagnosed according to International Classification of Diseases for Oncology, Third Edition morphology codes were included. The analysis was conducted from September …

Ideate-Lung02: A Phase 3 Study Of Second-Line Ifinatamab Deruxtecan In Patients With Relapsed Small Cell Lung Cancer, Taofeek K Owonikoko, Lauren Byers, Ying Cheng, Hidetoshi Hayashi, Luis Paz-Ares, Maurice Pérol, Haichuan Hu, Meng Qian, Cecilio Roi Garcia, Juliette Godard, Mei Tang, Charles M Rudin

Faculty, Staff and Student Publications

Patients with small cell lung cancer (SCLC) have poor prognosis and limited treatment options beyond first-line therapy. B7 homolog 3 (B7-H3) is minimally expressed in normal tissues but highly expressed in SCLC. Ifinatamab deruxtecan (I-DXd), a B7-H3-directed antibody-drug conjugate, has demonstrated promising efficacy and a manageable safety profile in various tumours, including SCLC. IDeate-Lung02 is a global, randomized, open-label Phase 3 study of ~540 patients with relapsed SCLC. Adults with one prior line of platinum-based systemic therapy, ECOG performance status 0-1, and ≥1 measurable lesion (per RECIST 1.1) are eligible for study participation. Patients with asymptomatic untreated or previously treated …

Cervical And Tumor-Associated Microbiomes In Botswana Women With And Without Hiv With Carcinoma Of The Cervix Before And After Definitive Chemoradiation, Travis T Sims, Kyoko Yoshida-Court, Molly B El Alam, Pleasure Ramatlho, Rebecca Ketlametswe, Matthew S Ning, Erle S Robertson, Kathleen M Schmeler, Lauren E Colbert, Ann H Klopp, Surbhi Grover

Faculty, Staff and Student Publications

Purpose: Cervical cancer remains a significant public health concern globally and particularly in sub-Saharan Africa, where high rates of HIV infection exacerbate cervical cancer incidence. Understanding the cervical microbiome and its role in cancer progression is essential, especially in regions where both cervical cancer incidence and HIV prevalence are high. This study aimed to characterize the cervical microbiome in women living with HIV (WLWH) and HIV-negative women with squamous cell carcinoma of the cervix in Botswana, compare the microbiome between before and after chemoradiation therapy (CRT) in WLWH, and assess the prognostic value of specific microbial taxa for overall survival …

Imaging- And Tumor Biomarker-Based Multivariable Model For Early Prediction Of Pathologic Complete Response To Neoadjuvant Systemic Therapy In Triple-Negative Breast Cancer, Beatriz E Adrada, Mary S Guirguis, Lei Huo, Clinton Yam, Debu Tripathy, Rosalind Candelaria, Wei Yang, Miral Patel, Tanya Moseley, Gary J Whitman, Jessica W T Leung, Huong Le-Petross, Deanna L Lane, Nour Abuhadra, Jennifer Litton, Vicente Valero, Kelly K Hunt, Banu Arun, Rania Mohamed, Jia Sun, Anil Korkut, Sanaz Pashapoor, Jason White, Alastair Thompson, Peng Wei, Jingfei Ma, Stacy Moulder, Gaiane M Rauch

Faculty, Staff and Student Publications

Purpose: The response of triple-negative breast cancer (TNBC) to neoadjuvant therapy (NAT) varies widely. This study aimed to determine the performance of clinicopathologic biomarkers and volumetric changes on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in predicting pathologic complete response (pCR) to NAT in patients with TNBC.

Patients and methods: This study included 264 patients with stage I to III TNBC enrolled in a prospective clinical trial. These patients underwent DCE-MRI at baseline and after two and/or after four cycles of dose-dense anthracycline and cyclophosphamide. Tumor volume (TV) was calculated by measuring three tumor dimensions at each time point. Clinicopathologic markers …

Bi-Allelic Loss-Of-Function Variants In Poc5 Cause A Syndromic Retinal, Endocrine, And Neuromuscular Ciliopathy, Anneke T Vulto-Van Silfhout, Ingrid M Jazet, Suzanne Yzer, Jeroen Pas, Serwet Demirdas, Elisabeth F C Van Rossum, Alberta A H J Thiadens, Ronald Van Beek, Lonneke Haer-Wigman, Daniela Q C M Barge-Schaapveld, Charlotte Brasch-Andersen, Simon Frost, Miriam Bauwens, Elfride De Baere, Irina Balikova, Filip Van Den Broeck, Monika Weisz-Hubshman, Pascal Joset, Peter Miny, Isabel Filges, Susanne Kohl, Pietro De Angeli, Laura Kühlewein, Jan-Philipp Bodenbender, Tobias Haack, Karin Poths, Lidia Fernandez-Caballero, Marta Corton, Fiona Blanco Kelly, Carmen Ayuso, Peggy Martínez-Esteban, John Vissing, Jordi Díaz-Manera, Volker Straub, Ana Töpf, Siying Lin, Gavin Arno, William L Macken, Jennifer Spillane, Radha Ramachandran, Erik De Vrieze, Tjakko Van Ham, Susanne Roosing, Machteld M Oud

Faculty, Staff and Students Publications

Purpose: A homozygous loss-of-function (LoF) variant in POC5 was previously described in an individual with retinitis pigmentosa. We identified POC5 variants in 12 probands with a syndromic phenotype. We aim to define the phenotype spectrum and molecular mechanism associated with biallelic POC5 LoF variants.

Methods: We studied a cohort of 12 families with bi-allelic LoF POC5 variants and performed detailed phenotype analysis. POC5 localization studies were performed in 3 proband-derived fibroblast cell lines.

Results: Detailed phenotyping of probands with POC5 variants expands the phenotype spectrum beyond ocular manifestations. This syndrome causes not only rod-cone dystrophy but also diabetes mellitus with …

Poziotinib For Egfr Exon 20-Insertion Nsclc: Clinical Efficacy Of The Phase 2 Zenith Trial And Differential Impact Of Egfr Exon 20 Insertion Location On Sensitivity, Xiuning Le, Jacqulyne P Robichaux, Monique Nilsson, R S K Vijayan, Ashwin Ravichandran, Jia Wu, Yasir Y Elamin, Lingzhi Hong, Jun Pei, Jun He, Sonia Patel, Hibiki Udagawa, Sriramvignesh Mani, Chang Woon Jang, Jeffrey M Clarke, Nishan Tchekmedyian, Jonathan W Goldman, Mark Socinski, Gajanan Bhat, Sharon Leu, Veronica Bunn, Zhenqiang Su, Sylvie Vincent, John W Lawson, Jason B Cross, John V Heymach

Faculty, Staff and Student Publications

EGFRex20 insertions (EGFRex20ins) can be classified as near- and far-loop based on the insertion location, however, the impact of location on responses to various EGFR tyrosine kinase inhibitors (TKIs) is poorly understood. In vitro studies show that afatinib, poziotinib, and zipalertinib more potently inhibited near-loop than far-loop insertions, whereas mobocertinib has similar IC50 in both groups. Molecular dynamics simulations reveal that near-loop insertions have multiple conformational states and lower transitional energy than far-loop insertions. ZENITH20 trial cohort 1 (NCT03318939) evaluates poziotinib in EGFRex20 NSCLC patients (n = 115) and demonstrates an objective response rate of 14.8% (95% Confidence …

Impacts Of The Conductive Networks On Solid-State Battery Operation, Shimao Deng, Yixian Wang, Tianxiao Sun, Wenlong Li, Mingyuan Ge, Jian Wang, Peter Cloetens, Piero Pianetta, David Mitlin, Yijin Liu

Faculty, Staff and Student Publications

The micromorphology of composite cathodes is known to play a vital role in determining all‐solid‐state battery (ASSB) performance. However, much of our current understanding is derived from empirical observations, lacking a deeper mechanistic foundation. The “rocking chair” concept of battery chemistry requires maintaining charge neutrality, emphasizing the necessity of examining electrode micromorphology from the perspective of conductive networks. This study systematically investigates the microscopic electrochemical impacts of conductive network micromorphology by varying the Li+‐to‐e− channel ratio in cathodes comprising LiNbO3‐coated LiNi0.8Co0.1Mn0.1O2, Li6PS5Cl, and carbon fibers. Utilizing multiscale synchrotron‐based spectro‐microscopy, we unravel that unbalanced Li+ and e− conducting channels intensify charge …

A Phase 2 Study Of Obinutuzumab Combined With Lenalidomide In Previously Untreated High Tumor Burden Follicular Lymphoma, Neha Akkad, Lei Feng, Jason R Westin, Fredrick B Hagemeister, Hun Ju Lee, Luis Fayad, Sairah Ahmed, Ranjit Nair, Maria Alma Rodriguez, Paolo Strati, Dai Chihara, Christopher R Flowers, Linda Claret, Karina Ibanez, Michael Wang, Nathan H Fowler, Jared Henderson, R Eric Davis, Sattva S Neelapu, Michael Green, Loretta J Nastoupil

Faculty, Staff and Student Publications

Follicular lymphoma (FL) has a clinical course that is often characterized by high response rates to first-line therapy, followed by multiple relapses over a prolonged natural history. Currently, there are multiple possible approaches to frontline therapy for untreated advanced-stage FL, but there is an ongoing debate around what is the preferred approach. Based on the benefits seen with combining lenalidomide, an immunomodulatory agent, with rituximab, an anti-CD20 antibody, we aimed to evaluate the safety and efficacy of lenalidomide in combination with obinuzutumab, an anti-CD20 antibody with enhanced antibody-dependent cellular cytotoxicity. The eligibility criteria included a diagnosis of FL, grade 1 …

Fruquintinib In Less Pretreated Patients: Multivariate Profile-Matching Analysis Of Fresco-2 To Fresco, Arvind Dasari, Cathy Eng, Sara Lonardi, Rocio Garcia-Carbonero, Toshiki Masuishi, Chiara Cremolini, François Ghiringhelli, Joleen Hubbard, Tanios Bekaii-Saab, Jeremy Jones, Rui-Hua Xu, Lin Shen, Jianming Xu, Yuxian Bai, Yanhong Deng, Ying Yuan, Wei Wei, Jianchang Lin, Lucy Chen, Zhao Yang, William R Schelman, Shukui Qin, Jin Li

Faculty, Staff and Student Publications

Background: In the phase 3 FRESCO (NCT02314819) and FRESCO-2 (NCT04322539) studies, fruquintinib vs placebo, plus best supportive care, significantly improved overall survival (OS) in patients with metastatic colorectal cancer (mCRC). These studies were conducted in temporally and geographically diverse populations that received distinct prior therapies; FRESCO patients were less pretreated than FRESCO-2 patients. This analysis assessed the efficacy and safety of fruquintinib in a less pretreated global population than the FRESCO-2 intention-to-treat (ITT) population.

Methods: In FRESCO and FRESCO-2, patients were randomized 2:1 to receive oral fruquintinib 5 mg or matched placebo. Profile matching was undertaken …

Identifying Bio-Behavioural Signatures Of Persistent Opioid Use Risk In Trauma Injury Patients: A Protocol For A Prospective Cohort Study, Joy M Schmitz, Jin Ho Yoon, Bruno Kluwe-Schiavon, John A Harvin, Preethi H Gunaratne, Darrion Mouton, Kandice Motley, Erin E Fox, Jessica Vincent, Megan Tarbet, Consuelo Walss-Bass

Faculty, Staff and Student Publications

Introduction: Exposure to prescription opioids following traumatic injury can increase the risk of developing tolerance, persistent opioid use and opioid use disorder. The mechanisms underlying opioid tolerance or dependence are not well understood, and no biomarkers predict risk. Opioid exposure causes epigenetic modifications, including alterations in microRNA (miRNA) expression. Several miRNAs, which regulate synaptic plasticity, are hypothesised to underlie substance use disorders and influence µ-opioid receptor levels, modulating opioid tolerance. This project aims to develop a bio-behavioural signature to predict persistent opioid use and chronic pain up to 6 months post-discharge.

Methods and analysis: The study will use a prospective …

Intronic Fgf14 Gaa Repeat Expansions Impact Progression And Survival In Multiple System Atrophy., Viorica Chelban, David Pellerin, Nirosen Vijiaratnam, Hamin Lee, Yen Yee Goh, Lauren Brown, Sara Sambin, Danielle Seilhean, Stephane Lehericy, Pablo Iruzubieta, Rahema Mohammad, Eleanor Self, Annarita Scardamaglia, Cameron Lee, Miriama Ostrozovicova, Marie-Josée Dicaire, Christine Girges, Emil K. Gustavsson, David Murphy, Toby Curless, Joshua Laß, Joanne Trinh, Timothy Rittman, James B. Rowe, Marios Hadjivassiliou, Neil Archibald, Matt C. Danzi, Catherine Ashton, Virginie Roth, Marion Wandzel, Warren A. Cheung, Djordje O. Gveric, Bart De Vil, Jordan Follett, P Nigel Leigh, Lukas Beichert, Tomi Pastinen, Céline Bonnet, Mathilde Renaud, Wassilios G. Meissner, Anne Sieben, David Crosiers, Patrick Cras, Stephan Zuchner, Jean-Christophe Corvol, Matthew J. Farrer, Matthis Synofzik, Bernard Brais, Tom Warner, Huw R. Morris, Zane Jaunmuktane, Tom Foltynie, Henry Houlden

Manuscripts, Articles, Book Chapters and Other Papers

Partial phenotypic overlap has been suggested between multiple system atrophy and spinocerebellar ataxia 27B, the autosomal dominant ataxia caused by an intronic GAA•TTC repeat expansion in FGF14. In this study, we investigated the frequency of FGF14 GAA•TTC repeat expansion in clinically diagnosed and pathologically confirmed multiple system atrophy cases. We screened 657 multiple system atrophy cases (193 clinically diagnosed and 464 pathologically confirmed) and 1003 controls. The FGF14 repeat locus was genotyped using long-range PCR and bidirectional repeat-primed PCRs, and expansions were confirmed with targeted long-read Oxford Nanopore Technologies sequencing. We identified 19 multiple system atrophy cases carrying an FGF14 …

Trends In Radiation Use From 2004 To 2020 Among Adolescents And Young Adults With Hodgkin Lymphoma, Kelsey L Corrigan, Amy M Berkman, Jillian Gunther, Clark R Andersen, Susan Wu, Amber Gibson, Branko Cuglievan, Miriam B Garcia, Gohar Manzar, Penny Fang, Brian De, Sairah Ahmed, Cesar Nunez, Michelle A T Hildebrandt, David C Mccall, Susan K Parsons, Michael E Roth

Faculty, Staff and Student Publications

Background: Hodgkin lymphoma has excellent survival rates in adolescents and young adults (AYA, diagnosed between ages 15 and 39 years). However, survivors are at risk of treatment-related late effects. Whereas radiotherapy (RT) de-escalation/omission has emerged as an approach to minimize late effects, no prior studies have evaluated RT use over time in AYAs with Hodgkin lymphoma.

Methods: Using the National Cancer Database, we identified 40,717 AYAs diagnosed with Hodgkin lymphoma between 2004 and 2020. Differences in sociodemographic and clinical variables were assessed using a two-sample two-sided t test or χ2 test. RT use was summarized per year by frequency with …

The Effect Of Tert Promoter Mutation On Predicting Meningioma Outcomes: A Multi-Institutional Cohort Analysis, Karenna J Groff, Ruchit V Patel, Yang Feng, Hia S Ghosh, Miguel A Millares Chavez, Joseph O'Brien, William C Chen, Vijay Nitturi, Akshay V Save, Mark W Youngblood, Craig M Horbinski, James P Chandler, Felix Ehret, Chloe Gui, Justin Z Wang, Kristen Park, Sonia Ajmera, Marc Rosenblum, Abigail K Suwala, Catena Kresbach, Christopher W Mount, Ulrich Schüller, Sandro Santagata, Felix Sahm, Tejus A Bale, Christina Jackson, Timothy E Richardson, Chunyu Cai, Farshad Nassiri, Gelareh Zadeh, David Kaul, David Capper, Stephen T Magill, John G Golfinos, Chandra Sen, Akash J Patel, David R Raleigh, Jennifer Moliterno, Donato Pacione, Matija Snuderl, Wenya Linda Bi

Duncan NRI Faculty and Staff Publications

Background: Molecular aberrations have been incorporated into tumour classification guidelines of meningioma. TERT-promoter (TERTp) mutation is associated with worse prognosis and is designated a WHO grade 3 biomarker. However, it remains unclear whether TERTp mutation is context-dependent, with other co-occurring genetic alterations potentially driving its association with prognosis. We sought to characterise the role of TERTp mutation in meningioma and guide TERTp sequencing.

Methods: We identified 1492 patients of all ages who had previously received surgery for meningioma across 14 medical centres in the USA, Canada, and Germany. Patients were eligible if they had post-surgical clinical or radiographical assessment of …

Diagnostic Yield Of Exome Sequencing For Pregnancies With And Without Fetal Anomalies And For Stillbirth, Roni Zemet, Christian M Parobek, April D Adams, Mohamad Ali Maktabi, Lena Shay, Linyan Meng, Pengfei Liu, Hongzheng Dai, Fan Xia, Christine Eng, Ignatia B Van Den Veyver, Liesbeth Vossaert

Duncan NRI Faculty and Staff Publications

Objective: Exome sequencing (ES) benefits the genetic work-up for fetuses with structural anomalies, but data on its utility for fetuses without anomalies and stillbirths is more limited. We report our experience with prenatal ES for all three indications.

Method: We retrospectively reviewed results from 344 trio-ES performed for fetuses with structural anomalies (N = 262), stillbirths (N = 39), and fetuses without anomalies (N = 43), many of which had a relevant family history. We classified pathogenic variants (P), likely pathogenic variants (LP), or variants of uncertain significance (VUS) favoring pathogenicity in a gene consistent with the fetal phenotype as …

Leveraging Existing Cohort Studies Of Mexican Women To Better Understand Hispanic Health And Cancer Risk, Dalia Stern, Liliana Gomez-Flores-Ramos, Britton Trabert, V Wendy Setiawan, Loïc Le Marchand, Henry Gomez, Paul A Scheet, Humberto Parada, Amber Pirzada, Martin Lajous, Leslie V Farland

Faculty, Staff and Student Publications

Background: Hispanics have been historically underrepresented in epidemiologic cancer research. Existing cohort studies focused on recruiting Hispanic participants have been relatively small, making studying cancer outcomes challenging. Therefore, we aimed to compare the distribution of cancer risk factors among Hispanic women of Mexican heritage (HWMH) participating in existing cohorts to explore the possibility of future data pooling efforts.

Methods: We used baseline data of HWMH from three US-based studies, the Mexican American Cohort (MAC; n = 19,797; 2001-2017), the Multiethnic Cohort (MEC; n = 18,007; 1993-1996), and the Hispanic Community Health Study/Study of Latinos (HCHS/SOL; n = 4,022; 2008-2011), and …

Sex Disparities In Chlamydia And Gonorrhea Treatment In Us Adult Emergency Departments: A Systematic Review And Meta-Analysis, Rachel E Solnick, Rahi Patel, Ethan Chang, Carmen Vargas-Torres, Maaz Munawar, Carlin Pendell, Judith E Smith, Ethan Cowan, Keith E Kocher, Roland C Merchant

Faculty, Staff and Student Publications

BACKGROUND: Empiric antibiotic treatment for gonorrhea (GC) and chlamydia (CT) is common in U.S. emergency departments (EDs) due to the delayed availability of test results. Local studies have identified sex-based disparities in sexually transmitted infection (STI) care, with females potentially receiving less empiric treatment than males. This study evaluates how STI treatment aligns with laboratory-confirmed results to quantify potential overtreatment and undertreatment rates and investigates sex differences for these outcomes.

METHODS: We conducted a preregistered (PROSPERO #241429) systematic review and meta-analysis of studies published between January 2010 and January 2025 in U.S. EDs, excluding studies conducted exclusively in pediatric settings. …

The Late Positive Potential Predicts Contingency Management Outcomes For Cocaine Use Disorder, Heather E Webber, Douglas J Calvillo, Francesco Versace, Constanza De Dios, Robert Suchting, Charles E Green, Scott D Lane, Joy M Schmitz

Faculty, Staff and Student Publications

Contingency management (CM) relies on motivation and reward processing and is among the most effective treatments available for cocaine use disorder (CUD), yet success rates do not meet desired clinical efficacy. To improve treatment-individual fit, we investigated the late positive potential (LPP), a measure of incentive salience to cues, as a predictor of treatment response. Treatment-seeking adults with CUD (N = 58) completed an EEG task where they viewed pleasant, unpleasant, cocaine, and neutral images. Participants received CM and counseling for four weeks. Urine was collected thrice weekly. We defined incentive salience to cues by A) cluster analyses on LPP …

Which Score For What? Operationalizing Standardized Cognitive Test Performance For The Assessment Of Change, Cristan Farmer, Audrey Thurm, Tanvi Das, E Martina Bebin, Jonathan A Bernstein, Elizabeth Berry-Kravis, Joseph D Buxbaum, Charis Eng, Thomas Frazier, Antonio Y Hardan, Alexander Kolevzon, Darcy A Krueger, Julian A Martinez-Agosto, Hope Northrup, Craig M Powell, Latha Valluripalli Soorya, Joyce Y Wu, Mustafa Sahin, Developmental Synaptopathies Consortium

Faculty, Staff and Student Publications

Developmental domains, such as cognitive, language, and motor, are key concepts of interest in longitudinal studies of intellectual and developmental disabilities (IDD). Normative scores (e.g., IQ) are often used to operationalize performance on standardized tests of these concepts, but it is the interval-distributed person-ability scores that are intended for the assessment of within-individual change. Here we illustrate the use and interpretation of several Stanford Binet, 5th Edition score types (IQ, extended IQ, Z-normalized raw score, developmental quotient, raw sum score, age equivalent, and ability score) using data from two longitudinal studies of rare genetic conditions associated with IDD. We found …

Trop2 Expression In Salivary Gland Adenoidcystic Carcinoma (Acc) According To Histologic Subtype: Therapeutic Implications, Juliana Mota Siqueira, Yoshitsugu Mitani, Mario L Marques-Piubelli, Camilla Oliveira Hoff, Flavia Bonini, Luana Guimaraes De Sousa, Mutsumi Mitani, Giovanna Lopes Carvalho, Fabio Daumas Nunes, Leandro Luongo Matos, Shiaw-Yih Lin, Michael T Spiotto, Ehab Y Hanna, Daniel J Mcgrail, Adel K El-Naggar, Renata Ferrarotto

Faculty, Staff and Student Publications

Background: Adenoid cystic carcinoma (ACC) is a common salivary gland carcinoma with high recurrence and distant metastasis rates. Currently, there is no standard systemic treatment available. TROP2 is a transmembrane glycoprotein involved in the oncogenesis of several tumors that can be therapeutically targeted by a TROP2-antibody-drug conjugate (ADC). We aimed to characterize TROP2 expression in ACC and assess TROP2 as a potential therapeutic target.

Methods: TROP2 immunohistochemistry was performed in a tissue microarray including 165 ACC of salivary gland. The tumors were grouped according to the histological pattern as non-solid, solid + non-solid, or solid. TROP2 protein expression in ACC …

Risk Of Second Primary Lung Cancer Among Cancer Survivors Stratified By The Site Of First Primary Cancer And The Lung Cancer Screening Eligibility Status, Sara Nofal, Edwin J Ostrin, Jianjun Zhang, Jia Wu, Paul Scheet, Mara B Antonoff, John V Heymach, Iakovos Toumazis

Faculty, Staff and Student Publications

Personal history of cancer is an independent risk factor for developing lung cancer. However, it is not considered in the current US lung cancer screening (LCS) guidelines. In this study, we assessed the risk of developing lung cancer among cancer survivors across 24 different sites of first primary cancer stratified by their LCS eligibility status. Using data from the Patient History Database at the University of Texas MD Anderson Cancer Center, we calculated and compared the cumulative incidence of second primary lung cancer, the overall and the LCS eligibility status-specific, stratified by the site of first primary cancer among cancer …

Mucinous Cystic Neoplasms Of The Pancreas And Liver Share A Similar Dna Methylation Profile With Mucinous Ovarian Tumors, Zoe Leoni, Teodor G Calina, Tobias Janik, Elena Grafenhorst, Eliane T Taube, Christopher Cm Neumann, Baoqing Chen, Elena I Braicu, Jalid Sehouli, Thomas Malinka, Wenzel Schöning, Johann Pratschke, George A Calin, David S Klimstra, Jamal K Benhamida, Irene Esposito, Markus Möbs, David Horst, Simon Schallenberg, David Capper, Mihnea P Dragomir

Faculty, Staff and Student Publications

The origin of mucinous cystic neoplasms (MCNs) remains a major challenge in hepato-pancreato-biliary pathology. These cystic tumors are defined by their mucinous epithelium and ovarian-like stroma, with an estimated 10% risk of progression to invasive carcinoma. The origin of the ovarian-like stroma remains a subject of debate. In this study, we conducted immunohistochemical profiling, targeted DNA sequencing, and genome-wide DNA methylation analysis on a cohort of 15 pancreatic MCNs (MCN-P) and six hepatic MCNs (MCN-L). Using immunohistochemistry and targeted DNA sequencing, we unequivocally established the diagnosis of MCN. Unsupervised DNA methylation profile analysis of reference classes of pancreatic neoplasms (11 …

Generation Of Human Induced Pluripotent Stem Cell Line From A Familial Alzheimer’S Disease Patient Carrying Missense Mutations In Psen1 And Mapt Genes, Ashaq H Najar, Sofia E Sepulveda, Camila Gherardelli, Fatemeh Elahian, Amber Fontenot-Roberts, Aleksandar Bajic, David H Hunter, Claudio Soto, Paul E Schulz, Abhisek Mukherjee

Faculty, Staff and Student Publications

Alzheimer's disease (AD), pathologically characterized by misfolding and accumulation of amyloid beta (Aβ) and hyperphosphorylated tau, is the leading cause of neurodegenerative dementia, accounting for 60-80 % of cases. The familial form of AD is caused by mutations in amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) genes. Here, we report the generation of an iPSC line from a 39-year-old AD patient carrying a missense mutation in PSEN1 (F177S), leading to very early onset of AD. The patient also carries a rare variant Q49E in the microtubule-associated protein tau gene (MAPT) with an as yet unknown clinical significance.

Eugenics And Polygenic Embryo Screening: Public, Clinician, And Patient Perceptions Of Conditions Versus Traits, Dorit Barlevy, Rémy A Furrer, Asha Kalapatapu, Abigail Martinez, Todd Lencz, Shai Carmi, Gabriel Lázaro-Muñoz, Stacey Pereira

Center for Medical Ethics and Health Policy Staff Publications

Purpose: Polygenic embryo screening (PES) estimates an embryo's genetic chances of developing complex conditions (eg, cancer) and traits (eg, height). Stakeholders have raised concerns that PES promotes eugenic practices and ideology.

Methods: We surveyed a nationally representative sample of the US public on approval of screening embryos for 12 conditions and 12 traits and examined the association between disapproval and concern about eugenics. We also conducted semistructured interviews with US-based reproductive endocrinology and infertility specialists and patients undergoing in vitro fertilization on their perspectives toward PES.

Results: Among the US public (n = 1423), disapproval of screening embryos for traits …

Heightened Risk: Childhood Trauma And Anticipatory Grief Exacerbate The Impact Of Loneliness On Depressive Symptoms And Lps-Stimulated Cytokines In Dementia Caregivers, Kelly N Brice, Jensine Paoletti-Hatcher, E Lydia Wu-Chung, Vincent D Lai, Daniel L Argueta, Michelle A Chen, Itee Mahant, Bryan T Denny, Charles Green, Luis D Medina, Paul Schulz, Jennifer Stinson, Samantha K Henry, Cobi Heijnen, Christopher P Fagundes

Faculty, Staff and Student Publications

Dementia spousal caregivers are at a disproportionate risk for adverse mental and physical health outcomes. Loneliness is associated with depressive symptoms and proinflammatory cytokine production among caregivers. Additionally, childhood trauma, anticipatory grief, and poor sleep quality are all associated with enhanced stress reactivity. This study used a cross-sectional design to investigate whether loneliness is associated with proinflammatory cytokine production and depressive symptoms in caregivers, and whether these relationships are strongest among caregivers who report high levels of childhood trauma, high amounts of anticipatory grief, or poor sleep quality. A sample of 111 dementia spousal caregivers provided blood samples and completed …

Heterozygous Variants In Plcg1 Affect Hearing, Vision, Cardiac, And Immune Function, Mengqi Ma, Yiming Zheng, Mingxi Deng, Shenzhao Lu, Xueyang Pan, Xi Luo, Michelle Etoundi, David Li-Kroeger, Kim C Worley, Lindsay C Burrage, Lauren S Blieden, Aimee Allworth, Wei-Liang Chen, Giuseppe Merla, Barbara Mandriani, Catherine E Otten, Pierre Blanc, Jill A Rosenfeld, Debdeep Dutta, Shinya Yamamoto, Michael F Wangler, Ian A Glass, Jingheng Chen, Elizabeth Blue, Paolo Prontera, Jeremie Rosain, Sandrine Marlin, Seema R Lalani, Hugo J Bellen, Undiagnosed Diseases Network

Duncan NRI Faculty and Staff Publications

Phospholipase C isozymes (PLCs) hydrolyze phosphatidylinositol 4,5-bisphosphate (PIP₂) into inositol 1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG), important signaling molecules involved in many cellular processes including Ca²⁺ release from the endoplasmic reticulum (ER). PLCG1 encodes the PLCγ1 isozyme that is broadly expressed. Hyperactive somatic mutations of PLCG1 are observed in multiple cancers, but only one germline variant has been reported. Here, we describe seven individuals with heterozygous missense variants in PLCG1 [p.(Asp1019Gly), p.(His380Arg), p.(Asp1165Gly), and p.(Leu597Phe)] who present with hearing impairment (5/7), ocular pathology (4/7), cardiac septal defects (3/6), and various immunological issues (5/7). To model these …

Kdm2b Variants In The Cxxc Domain Impair Its Dna-Binding Ability And Cause A Distinct Neurodevelopmental Syndrome, Amber S E Van Oirsouw, Michael A Hadders, Martijn Koetsier, Edith D J Peters, Nurit Assia Batzir, Tahsin Stefan Barakat, Diana Baralle, Adelyn Beil, Marie-Noëlle Bonnet-Dupeyron, Philip M Boone, Arjan Bouman, Deanna Alexis Carere, Benjamin Cogne, Leslie Dunnington, Laura S Farach, Casie A Genetti, Bertrand Isidor, Louis Januel, Aakash Joshi, Nayana Lahiri, Kristen N Lee, Idit Maya, Meriel Mcentagart, Hope Northrup, Mathilde Pujalte, Kate Richardson, Susan Walker, Bobby P C Koeleman, Mariëlle Alders, Richard H Van Jaarsveld, Renske Oegema

Faculty, Staff and Student Publications

Rare variants affecting the epigenetic regulator KDM2B cause a recently delineated neurodevelopmental disorder. Interestingly, we previously identified both a general KDM2B-associated episignature and a subsignature specific to variants in the DNA-binding CxxC domain. In light of the existence of a distinct subsignature, we set out to determine if KDM2B CxxC variants are associated with a unique phenotype and disease mechanism. We recruited individuals with heterozygous CxxC variants and assessed the variants' effect on protein expression and DNA-binding ability. We analyzed clinical data from 19 individuals, including ten previously undescribed individuals with seven novel CxxC variants. The core phenotype of the …

Randomised, Placebo-Controlled Trial Of Oral Hymecromone In Adults With Pulmonary Hypertension, Kathryn Czepiel, Nadine Nagy, Tamera Panjalingam, Anissa Kalinowski, Adam R Frymoyer, Harry Karmouty-Quintana, Bo Gu, Haley Hedlin, Gernot Kaber, Sylvie Dobrota Lai, Joelle I Rosser, Paul L Bollyky, Vinicio De Jesus Perez, Roham T Zamanian

Faculty, Staff and Student Publications

Background: Pulmonary hypertension (PH) is a progressive cardiopulmonary condition associated with increased morbidity and mortality. The extracellular matrix component hyaluronan (HA) is linked to vascular remodelling and interstitial fibrosis in PH. We hypothesised that inhibition of HA synthesis with hymecromone could serve as a reverse-remodelling therapy in PH.

Methods: We performed a proof-of-concept phase IIa randomised, double-blind, placebo-controlled study in adults with pulmonary arterial hypertension and PH associated with interstitial lung disease (PH-ILD). Patients were randomised to a 5:3 ratio and stratified by PH group to receive oral hymecromone or placebo two times per day over 24 weeks. The primary …

Clinical, Tumor, And Product Features Associated With Outcomes After Axicabtagene Ciloleucel Therapy In Follicular Lymphoma, Soumya Poddar, Jiali Yan, Gayatri Tiwari, Darawan Rinchai, Justin Budka, Wangshu Zhang, Weixin Peng, Shruti Salunkhe, Madison Davis, Qinghua Song, Sara Beygi, Harry Miao, Mike Mattie, Rhine S Shen, Caron A Jacobson, Davide Bedognetti, Simone Filosto, Sattva S Neelapu

Faculty, Staff and Student Publications

Background: Axicabtagene ciloleucel (axi-cel), anti-CD19 chimeric antigen receptor (CAR) T cell therapy, demonstrated remarkable efficacy with manageable toxicity in relapsed/refractory indolent B cell lymphomas in the ZUMA-5 trial.

Methods:Here, we report associations of product attributes, serum biomarkers, clinical features, and tumor characteristics with outcome in 124 patients with follicular lymphoma (FL).

Results: In univariate and multivariate analyses, pretreatment inflammatory markers, including TNF-α and IL-12p40, as well as total metabolic tumor volume (TMTV), associated with disease progression. Conversely, T-naive–like product phenotype associated with improved outcome, particularly in patients with high TMTV. These covariates improved risk stratification when combined with the …