Medical Genetics Commons^™

Multi-Modal Spatial Characterization Of Tumor Immune Microenvironments Identifies Targetable Inflammatory Niches In Diffuse Large B Cell Lymphoma, Yibo Dai, Atish Kizhakeyil, Dai Chihara, Xubin Li, Yunhe Liu, Tania Patricia Sainz Zuniga, Ashley Wilson, Jared Henderson, Daniil Vibe, Arman Petrosyants, Connor Jacobson, Alexander Sarachakov, Krystle Nomie, Kirill Kryukov, Aleksander Bagaev, Ayushi Chauhan, Jason R Westin, Christopher R Flowers, Francisco Vega, Linghua Wang, Michael R Green

Faculty, Staff and Student Publications

Diffuse large B cell lymphomas (DLBCLs) are a heterogeneous group of malignancies that can arise in lymph nodes or extranodal locations, including immune-privileged sites. Here, we applied highly multiplexed spatial transcriptomics and proteomics together with genomic profiling to characterize the immune microenvironment architecture of 78 DLBCL tumors. We define seven distinct cellular niches, each characterized by unique cellular compositions, spatial organizations and patterns of intercellular communication associated with niche-specific phenotypes of both T cells and tumor B cells. Among these, DLBCLs from immune-privileged sites showed abundant T cell infiltration into diffuse niches, where immune cells were intermixed with tumor B …

Basal Cell Carcinoma Risk Prediction In Survivors Of Childhood Cancer, Cindy Im, Christina Boull, Zhe Lu, Kenneth Liao, Hasibul Hasan, Linwan Xu, Yadav Sapkota, Rebecca M Howell, Michael A Arnold, Miriam R Conces, Ashley J Housten, Judith Gebauer, Thorsten Langer, Jop C Teepen, Leontien C M Kremer, Louis S Constine, Yutaka Yasui, Melissa M Hudson, Kirsten K Ness, Gregory T Armstrong, Joseph P Neglia, Yan Yuan, Lucie M Turcotte

Faculty, Staff and Student Publications

Background: Survivors of childhood cancer face excess risk of developing basal cell carcinoma. Age-specific basal cell carcinoma risk prediction models for survivors may support targeted screening recommendations.

Methods: We developed models predicting basal cell carcinoma risk by ages 40 and 50 years featuring detailed cancer treatment predictors, utilizing statistical and machine-learning algorithms and data from 23 166 five-year survivors in the Childhood Cancer Survivor Study, a multi-institutional retrospective cohort study. Selected models were externally validated in 5314 survivors in the St Jude Lifetime Cohort. Model discrimination and precision were evaluated using the area under the receiver operating characteristic curve (AUROC) …

Study Of 18 F-Fluciclovine Pet For Serial Assessment Of Glioblastoma Tumor Volumes During Surgery And Radiotherapy, Samir A Dagher, Jason M Johnson, Rania M M Mohamed, Shehbaz Ansari, Osama Mawlawi, Ho-Ling Liu, Max Wintermark, Dawid Schellingerhout, Lesley Flynt, Debra N Yeboa, Jeffrey S Weinberg, Sherise D Ferguson, Maria K Gule-Monroe

Faculty, Staff and Student Publications

PURPOSE: Recent evidence supports incorporating 18 F-Fluciclovine PET for glioblastoma treatment planning and monitoring, as it better captures tumor infiltration compared to conventional MRI. However, the relationship between PET- and MRI-defined tumor volumes remains unclear, particularly in the post-treatment setting. This study prospectively compares tumor volumes on MRI and PET at multiple timepoints throughout the treatment course and evaluates volumetric changes with therapy.

METHODS: We prospectively enrolled 8 adults with IDH-wildtype glioblastoma treated with surgery and chemoradiation between September 2019 and 2021. Participants underwent paired 18 F-Fluciclovine PET/CT and conventional MRI at four timepoints: preoperatively, pre-radiation, and at one- and …

Acute Kidney Injury Is Associated With Elevated Urinary Endotrophin, Amanda J Clark, Brenda Mendoza Flores, Marie Christelle Saade, Kyle Q Vu, Isaac J Pence, Ningyan Zhang, Zhiqiang An, Dawei Bu, Philipp E Scherer, Samir M Parikh

Faculty, Staff and Student Publications

Acute kidney injury (AKI) is prevalent among hospitalized patients. Novel biomarkers are needed to diagnose AKI and target therapies. Endotrophin (ETP) is a molecule released during collagen type VI formation that may promote injury and fibrosis. Although serum ETP elevation has been associated with adverse outcomes in AKI, urinary ETP has not been assessed in AKI, nor has ETP been evaluated in a pediatric population. Urine samples were collected from a tertiary children's hospital. Medical records were reviewed, and patients who met criteria were sorted into three categories:

In Silico Assessment Of Cellular Damage From Lu-177, Ac-225, And Pb-212 Therapeutic Radionuclides, Konstantinos P Chatzipapas, Konstantinos Papachristou, Dimitris Visvikis, Sebastien Incerti, John D Hazle, George C Kagadis

Faculty, Staff and Student Publications

Background: Targeted radionuclide therapy (TRT) has emerged as a unique and effective treatment modality for cancer. Monte Carlo simulations have greatly advanced investigations into radiation-caused DNA damage, including the complexity of this damage.

Purpose: This study aimed to evaluate DNA damage induced by high-linear energy transfer therapeutic radionuclides used in TRT, specifically 225Ac, 177Lu, and 212Pb, using Geant4-DNA Monte Carlo simulations.

Methods: The Geant4-DNA toolkit, incorporating the "molecularDNA" example, was employed to simulate radiation interactions within a human fibroblast cell model featuring a fractal chromatin fiber geometry within an ellipsoidal nucleus. Three source geometries (membrane, cytoplasm, nucleus) were modeled to …

Surgical Outcomes With Neoadjuvant Durvalumab Plus Chemotherapy Followed By Adjuvant Durvalumab In Resectable Nsclc, Tetsuya Mitsudomi, John V Heymach, Martin Reck, Janis M Taube, Shugeng Gao, Yoshitsugu Horio, Jian You, Gaofeng Li, Dinh Van Luong, Somcharoen Saeteng, Fumihiro Tanaka, Stefan B Watzka, Laszlo Urban, Zsuzsanna Szalai, Hiroaki Akamatsu, Jin Hyoung Kang, Francisco J Orlandi, Guzel Z Mukhametshina, Andreas Pircher, Carlos Henrique Andrade Teixeira, Mike Aperghis, Gary J Doherty, Ruth Doake, Tamer M Fouad, David Harpole

Faculty, Staff and Student Publications

Introduction: In AEGEAN, perioperative durvalumab plus neoadjuvant chemotherapy, versus neoadjuvant chemotherapy alone, significantly improved event-free survival (p = 0.004) and pathologic complete response (p < 0.001; primary end points; modified intention-to-treat [mITT] population, which excluded patients with known EGFR or ALK aberrations) with a manageable safety profile in patients with resectable (R)-NSCLC. Here, we report surgical outcomes from AEGEAN.

Methods: Patients with treatment-naive R-NSCLC (stage II-IIIB [N2]) and Eastern Cooperative Oncology Group performance status 0 or 1 were randomized (1:1) to platinum-based chemotherapy plus durvalumab or placebo intravenously (every 3 wk, 4 cycles) before surgery, followed by durvalumab or placebo (every 4 wk, 12 cycles). Surgical outcomes were summarized for the mITT population using descriptive statistics.

Results: A total of 737 out of 740 mITT patients received treatment, 366 and 371 in the durvalumab and …

Neurodevelopmental Abnormalities Underlying Behavioral Deficits In A Model Of Pediatric Obstructive Sleep Apnea, Arvind Chandrakantan, Michael R Williamson, Vaishnav Krishnan, Mahyar J Hedayatpour, Adam C Adler, Nandani Adyapak, Chris S Ward, Russell Ray, David Durgan, Farrah Kheradmand, Benjamin Deneen

Faculty, Staff and Students Publications

Rationale: Pediatric Obstructive Sleep Apnea (POSA) is a relatively common childhood sleep disorder whose neurodevelopmental phenotype includes deficits in learning and memory, olfaction, and fine motor abilities.

Objectives: To date, there has not been a validated preclinical model of POSA, hampering efforts in understanding how nocturnal episodes of intermittent hypoxia disrupt neurodevelopmental trajectories. The objective of this study was to create a faithful sculpting of the human condition in a preclinical murine model.

Methods: We used clinical data from children with POSA to develop and validate a mouse model of POSA that faithfully recapitulates several behavioral deficits seen in the …

Information Theory Analysis Of Ctx Shows Consistent Clinical Presentation, Jennifer Hanson, Penelope E Bonnen

Faculty, Staff and Students Publications

Cerebrotendinous xanthomatosis (CTX) is a rare, metabolic disorder caused by pathogenic variants in CYP27A1. The classic clinical presentation includes infantile-onset chronic diarrhea, juvenile-onset bilateral cataracts, with development of tendon xanthomas and progressive neurological dysfunction. These multisystem clinical features typically appear in different decades of life often confounding diagnosis of CTX. Further complicating diagnosis is the generally held belief that the clinical presentation of CTX varies highly between individuals and even within families. We applied information theory analyses to CTX patient data to quantitatively assess clinical variability in CTX. We conducted a systematic review of the literature to identify all CTX …

Mutations In The Key Autophagy Tethering Factor Epg5 Link Neurodevelopmental And Neurodegenerative Disorders Including Early-Onset Parkinsonism, Hormos Salimi Dafsari, Celine Deneubourg, Kritarth Singh, Reza Maroofian, Zita Suprenant, Ay Lin Kho, Neil J Ingham, Karen P Steel, Preethi Sheshadri, Franciska Baur, Lea Hentrich, Birgit Gerisch, Mina Zamani, Cesar Alves, Ata Siddiqui, Haidar S Dafsari, Mehri Salari, Anthony E Lang, Michael Harris, Alice Abdelaleem, Saeid Sadeghian, Reza Azizimalamiri, Hamid Galehdari, Gholamreza Shariati, Alireza Sedaghat, Jawaher Zeighami, Daniel Calame, Dana Marafi, Ruizhi Duan, Adrian Boehnke, Gary D Clark, Jill A Rosenfeld, Carrie A Mohila, Dora Steel, Saurabh Chopra, Suvasini Sharma, Nicolai Kohlschmidt, Steffi Patzer, Afshin Saffari, Darius Ebrahimi-Fakhari, Büşra Eser Çavdartepe, Irene J Chang, Erika Beckman, Renate Peters, Andrew Paul Fennell, Bernice Lo, Luisa Averdunk, Felix Distelmaier, Martina Baethmann, Frances Elmslie, Kairit Joost, Sheela Nampoothiri, Dhanya Yesodharan, Hanna Mandel, Amy Kimball, Antonie D Kline, Cyril Mignot, Boris Keren, Vincent Laugel, Katrin Õunap, Kalpana Devadathan, Frederique M C Van Berkestijn, Arpana Silwal, Saskia Koene, Sumit Verma, Mohammed Yousuf Karim, Chahynez Boubidi, Majid Aziz, Gehad Elghazali, Lauren Mattas, Mohammad Miryounesi, Farzad Hashemi-Gorji, Shahryar Alavi, Nayereh Nouri, Mehrdad Noruzinia, Saeideh Kavousi, Arveen Kamath, Sandeep Jayawant, Russell Saneto, Nourelhoda A Haridy, Pinar Ozkan Kart, Ali Cansu, Madeleine Joubert, Claire Beneteau, Kyra E Stuurman, Martina Wilke, Tahsin Stefan Barakat, Homa Tajsharghi, Annarita Scardamaglia, Sadeq Vallian, Semra Hız, Ali Shoeibi, Reza Boostani, Narges Hashemi, Meisam Babaei, Norah Saleh Alsaleh, Julie Porter, Tania Attié-Bitach, Pauline Marzin, Dorota Wicher, Jessica I Gold, Elisabeth Schuler, Amna Kashgari, Rakan F Alanazi, Wafaa Eyaid, Marc Engelen, Mirjam Langeveld, Burkhard Stüve, Yun Li, Gökhan Yigit, Bernd Wollnik, Mariana H G Monje, Dimitri Krainc, Niccolò E Mencacci, Somayeh Bakhtiari, Michael Kruer, Emanuela Argilli, Elliott Sherr, Yalda Jamshidi, Ehsan Ghayoor Karimiani, Yiu Wing Sunny Cheung, Ivan Karin, Giovanni Zifarelli, Peter Bauer, Wendy K Chung, James R Lupski, Manju A Kurian, Jörg Dötsch, Jürgen-Christoph Von Kleist-Retzow, Thomas Klopstock, Matias Wagner, Calvin Yip, Andreas Roos, Rita Carsetti, Carlo Dionisi-Vici, Mathias Gautel, Michael R Duchen, Adam Antebi, Henry Houlden, Manolis Fanto, Heinz Jungbluth

Faculty, Staff and Students Publications

Objective: Autophagy is a fundamental biological pathway with vital roles in intracellular homeostasis. During autophagy, defective cargoes including mitochondria are targeted to lysosomes for clearance and recycling. Recessive truncating variants in the autophagy gene EPG5 have been associated with Vici syndrome, a severe early-onset neurodevelopmental disorder with extensive multisystem involvement. Here, we aimed to delineate the extended, age-dependent EPG5-related disease spectrum.

Methods: We investigated clinical, radiological, and molecular features from the largest cohort of EPG5-related patients identified to date, complemented by experimental investigation of cellular and animal models of EPG5 defects.

Results: Through worldwide collaboration, we identified 211 patients, 97 …

Apol2 Stabilizes Ku80 To Confer Nhej-Mediated Radioresistance In Gastric Cancer, Dan Zu, Qimei Bao, Hanyi He, Yuke Zhong, Mingcong Deng, Yangchan Hu, Chunkai Zhang, Chen Liang, Yixing Huang, Haidong Liu, Xiao Li, Yanhua He, Guoyan Luo, Weixin Wu, Fenghui Guan, Shengfeng Xu, Min Liu, Albino Bacolla, Ji Jing, Yian Du, John A Tainer, Yin Shi, Zu Ye, Xiangdong Cheng

Faculty, Staff and Student Publications

Radiotherapy is one of the most important adjuvant treatment methods for gastric cancer (GC). However, radioresistance remains a major clinical obstacle. In this study, APOL2 is identified as a key player in promoting non-homologous end joining (NHEJ)-mediated double-strand break (DSB) repair and enhancing radioresistance in GC. Bioinformatics and clinical data revealed that high APOL2 expression is correlated with poor prognosis in GC patients. Functional experiments showed that APOL2 overexpression enhances genomic stability by accelerating DSB repair via the NHEJ pathway, while APOL2 knockout impairs repair capacity. Mechanistically, APOL2 binds to and stabilizes Ku80 by enhancing USP7-mediated deubiquitylation, thereby increasing Ku80 …

Genome Sequencing Reveals The Impact Of Pseudoexons In Rare Genetic Disease, Georgia Pitsava, Megan Hawley, Light Auriga, Ivan De Dios, Arthur Ko, Sofia Marmolejos, Miguel Almalvez, Ingrid Chen, Kaylee Scozzaro, Jianhua Zhao, Rebekah Barrick, Nicholas Ah Mew, Vincent A Fusaro, Jonathan Lotempio, Matthew Taylor, Luisa Mestroni, Sharon Graw, Dianna Milewicz, Dongchuan Guo, David R Murdock, Kinga M Bujakowska, Changrui Xiao, Emmanuèle C Délot, Seth I Berger, Eric Vilain

Faculty, Staff and Student Publications

Purpose: Advancements in sequencing technologies have significantly improved clinical genetic testing; yet, the diagnostic yield remains around 30% to 40%. Emerging technologies are now being deployed to address the remaining diagnostic gap.

Methods: We tested whether short-read genome sequencing could increase the diagnostic yield in individuals enrolled into the UCI-GREGoR research study, who had suspected Mendelian conditions and prior inconclusive testing. Two other collaborative research cohorts, focused on aortopathy and dilated cardiomyopathy, consisted of individuals who were undiagnosed but had not undergone harmonized prior testing.

Results: We sequenced 353 families (754 participants) and found a molecular diagnosis in 54 (15.3%) …

Final Analysis Of The Resonate-2 Study: Up To 10 Years Of Follow-Up Of First-Line Ibrutinib Treatment For Cll/Sll, Jan A Burger, Paul M Barr, Tadeusz Robak, Carolyn Owen, Alessandra Tedeschi, Anita Sarma, Piers E M Patten, Sebastian Grosicki, Helen Mccarthy, Fritz Offner, Edith Szafer-Glusman, Cathy Zhou, Anita Szoke, Lynne Neumayr, James P Dean, Paolo Ghia, Thomas J Kipps

Faculty, Staff and Student Publications

With up to 10 years of follow-up, we report results from the final analysis of RESONATE- 2, a phase 3 study of first-line ibrutinib vs chlorambucil for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Patients aged ≥65 years with previously untreated CLL/SLL without del(17p) were randomly assigned to receive either single-agent ibrutinib (420 mg/d; n = 136) or chlorambucil (0.5-0.8 mg/kg; ≤12 cycles; n = 133). With a median follow-up of 9.6 years in the ibrutinib arm, the median progression-free survival (PFS) was 8.9 years (95% confidence interval [CI], 7.0 to not estimable [NE]) vs 1.3 years (95% …

Nuclear Poly(A)-Binding Protein And Nucleolin Utilize Their Rna Recognition Motifs To Read Par Chains, Leilei Shi, Morgan Dasovich, John R Horton, Hongrui Liu, Qiansheng Zhan, Swarnalatha Manickavinayaham, Collene R Jeter, Isaiah J Mixon, Nicholas M Zehrbach, Charles A Ishak, Je-Hyun Yoon, Xiaodong Cheng, Anthony K L Leung, Mark T Bedford

Faculty, Staff and Student Publications

Poly(ADP-ribosyl)ation (PARylation) is a post-translational modification mediated by ADP-ribosyltransferases, known as PARPs, which attach ADP-ribose units onto proteins, forming negatively charged multimeric chains. This modification relaxes chromatin at DNA damage sites, facilitating repair machinery access. Additionally, PAR polymers serve as docking platforms for effector proteins, termed PAR "readers", commonly involved in DNA repair. The recruitment of these proteins is mediated through conserved protein domains, including RNA recognition motifs (RRMs). Using an array of hundreds of recombinant RNA-binding domains, we systematically examined RRM interactions with PAR chains of varying lengths. Despite their chemical similarity to RNA, only a small subset of …

Long-Term Results From The Agile Study Of Azacitidine Plus Ivosidenib Vs Placebo In Newly Diagnosed Idh1-Mutated Aml, Pau Montesinos, Dylan M Marchione, Christian Recher, Michael Heuser, Susana Vives, Ewa Zarzycka, Jianxiang Wang, Marta Riva, Rodrigo T Calado, Andre C Schuh, Su-Peng Yeh, Adriana E Tron, Jianan Hui, Diego A Gianolio, Sung Choe, Prapti Patel, Stéphane De Botton, Courtney D Dinardo, Hartmut Döhner

Faculty, Staff and Student Publications

In the phase 3 AGILE study, after a 12.4-month median follow-up, ivosidenib, a mutant isocitrate dehydrogenase 1 (IDH1) inhibitor, combined with azacitidine significantly improved event-free survival, overall survival (OS), and complete remission rates compared with placebo-azacitidine in patients with newly diagnosed IDH1-mutated acute myeloid leukemia (AML), who were unfit for intensive chemotherapy. This post hoc analysis reports long-term follow-up results from AGILE after a median follow-up of 28.6 months. Overall, 148 patients were randomized to receive ivosidenib-azacitidine (n = 73) or placebo-azacitidine (n = 75). Median OS was significantly longer with ivosidenib (29.3 months; 95% confidence interval …

Signs, Symptoms, And Health-Related Quality Of Life In Melas: Measuring What’S Important From The Patient And Clinician Perspectives, Paolo Medrano, Benjamin Banderas, Marisa Brimmer, Lily Settel, Sari Berger, Alan Shields, Amy Goldstein, Amel Karaa, Austin Larson, Sumit Parikh, Fernando Scaglia, Karra Danyelle Harrington, Chris James Edgar, Pamela Ventola, Matthew Webster, Jennifer Chickering, Chad Gwaltney, Phebe Wilson, Chad Glasser

Faculty, Staff and Students Publications

Background and objectives: Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is a rare genetic syndrome mostly associated with pathogenic variants in mitochondrial DNA. As there is limited research on the life experience of patients with MELAS, this study aimed to develop an understanding of the patient experience of MELAS through qualitative interviews to identify, describe, and substantiate important and relevant signs, symptoms, and health-related quality-of-life (HRQoL) impact (S/S/I) concepts.

Methods: Clinician and patient interviews were conducted virtually using semi-structured interview guides. During 60-minute interviews with five experts in the United States, clinicians were asked for their perspective on …

Transdiagnostic Alterations In White Matter Microstructure Associated With Suicidal Thoughts And Behaviours In The Enigma Suicidal Thoughts And Behaviours Consortium, Laura S Van Velzen, Lejla Colic, Zuriel Ceja, Maria R Dauvermann, Luca M Villa, Hannah S Savage, Yara J Toenders, Niousha Dehestani, Alyssa H Zhu, Adrian I Campos, Lauren E Salminen, Martin Alda, Ingrid Agartz, Nina Alexander, Rosa Ayesa-Arriola, Elizabeth D Ballard, Nerisa Banaj, Carlotta Barkhau, Zeynep Başgöze, Jochen Bauer, Francesco Benedetti, Klaus Berger, Bianca Besteher, Katharina Brosch, Manuel Canal-Rivero, Simon Cervenka, Romain Colle, Colm G Connolly, Emmanuelle Corruble, Philippe Courtet, Baptiste Couvy-Duchesne, Benedicto Crespo-Facorro, Kathryn R Cullen, Udo Dannlowski, Jeremy Deverdun, Ana M Diaz-Zuluaga, Lorielle M F Dietze, Jennifer W Evans, Negar Fani, Kira Flinkenflügel, Naomi P Friedman, Ian H Gotlib, Nynke A Groenewold, Dominik Grotegerd, Tomas Hajek, Alexander S Hatoum, Marco Hermesdorf, Ian B Hickie, Yoshiyuki Hirano, Tiffany C Ho, Yuki Ikemizu, Frank Iorfino, Jonathan C Ipser, Yuko Isobe, Andrea P Jackowski, Fabrice Jollant, Tilo Kircher, Melissa Klug, Sheri-Michelle Koopowitz, Anna Kraus, Axel Krug, Emmanuelle Le Bars, Elisabeth J Leehr, Meng Li, Elizabeth T C Lippard, Carlos Lopez-Jaramillo, Ivan I Maximov, Andrew M Mcintosh, Katie A Mclaughlin, Sean R Mcwhinney, Susanne Meinert, Elisa Melloni, Philip B Mitchell, Benson Mwangi, Igor Nenadić, Stener Nerland, Emilie Olie, Victor Ortiz-García De La Foz, Pedro M Pan, Fabricio Pereira, Fabrizio Piras, Federica Piras, Sara Poletti, Andrew E Reineberg, Gloria Roberts, Rafael Romero-García, Matthew D Sacchet, Giovanni A Salum, Anca-Larisa Sandu, Carl M Sellgren, Eiji Shimizu, Harry R Smolker, Jair C Soares, J Douglas Steele, Frederike Stein, Dan J Stein, Benjamin Straube, Lea Teutenberg, Florian Thomas-Odenthal, Paula Usemann, Romain Valabregue, Johanna Valencia-Echeverry, Gerd Wagner, Gordon Waiter, Martin Walter, Heather C Whalley, Mon-Ju Wu, Tony T Yang, Carlos A Zarate, Andre Zugman, Giovana B Zunta-Soares, Kees Van Heeringen, Sanne J H Van Rooij, Nic Van Der Wee, Steven Van Der Werff, Paul M Thompson, Hilary P Blumberg, Anne-Laura Van Harmelen, Miguel E Rentería, Neda Jahanshad, Enigma Suicidal Thoughts And Behaviours Consortium, Lianne Schmaal

Faculty, Staff and Student Publications

Previous studies have suggested that alterations in white matter (WM) microstructure are implicated in suicidal thoughts and behaviours (STBs). However, findings of diffusion tensor imaging (DTI) studies have been inconsistent. In this large-scale mega-analysis conducted by the ENIGMA Suicidal Thoughts and Behaviours (ENIGMA-STB) consortium, we examined WM alterations associated with STBs. Data processing was standardised across sites, and resulting WM microstructure measures (fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity and radial diffusivity) for 24 WM tracts and one global measure were pooled across 40 cohorts. We compared these measures among individuals with a psychiatric diagnosis and lifetime history of …

Distinct Spatiotemporal Patterns Of White Matter Hyperintensity Progression, Jinyong Chung, Gilsoon Park, Wi-Sun Ryu, Dawid Schellingerhout, Hang-Rai Kim, Dong-Seok Gwak, Elizabeth Haddad, Neda Jahanshad, Beom Joon Kim, Keun-Sik Hong, Hyerin Oh, Sang-Wuk Jeong, Joon-Tae Kim, Man Seok Park, Kang-Ho Choi, Kyungbok Lee, Tai Hwan Park, Sang-Soon Park, Jong-Moo Park, Kyusik Kang, Kyung-Ho Yu, Mi Sun Oh, Soo Joo Lee, Jae Guk Kim, Jae-Kwan Cha, Dae-Hyun Kim, Jun Lee, Moon-Ku Han, Yong-Jin Cho, Byung-Chul Lee, Philip M Bath, Joanna M Wardlaw, Hee-Joon Bae, Hosung Kim, Dong-Eog Kim

Faculty, Staff and Student Publications

White matter hyperintensity, a key imaging biomarker for brain health, has prognostic implications for stroke. Using a multicenter MRI dataset of 9179 stroke patients plus the UK Biobank (n = 36,210 low/high risk controls), we employ Subtype and Stage Inference modeling and identify three distinct white matter hyperintensity progression subtypes: fronto-parietal, radial, and temporo-occipital. Longitudinal validation confirms classification stability. The fronto-parietal subtype shows delayed onset and more hypertension, while the temporo-occipital subtype has more atrial fibrillation and coronary heart disease. The fronto-parietal and radial subtypes are linked to small vessel stroke, while the temporo-occipital subtype is linked to cardioembolism. The …

Leptin As A Key Driver For Organ Fibrogenesis, Xue-Nan Sun, Shiuhwei Chen, Shangang Zhao, Jan-Bernd Funcke, Megan Virostek, Line Pedersen, Chao Li, Chanmin Joung, Qian Lin, Yan Li, Ayanna Cobb, May-Yun Wang, Kyounghee Min, Lisandro Maya-Ramos, Giovanna Degasperi, Junquan Liu, Ningyan Zhang, Zhiqiang An, Diana R Tomchick, R Max Wynn, Da Young Oh, Philipp E Scherer

Faculty, Staff and Student Publications

Leptin, a hormone primarily secreted by adipocytes, regulates energy balance and systemic metabolism through its interaction with the leptin receptor (LEPR). Beyond these functions, leptin signaling has been implicated in the pathogenesis of tissue fibrosis. Here, we report the x-ray crystal structures of a leptin-neutralizing antibody (hLep3) in the unbound and leptin-bound states. The interaction of this antibody with leptin mimics the interaction of the LEPR with leptin, providing direct insights into the mechanism by which the antibody disrupts leptin signaling. We furthermore evaluate the therapeutic potential of neutralizing leptin with this antibody across distinct mouse models of fibrosis affecting …

Lorbin: Efficient Binning Of Long-Read Metagenomes By Multiscale Adaptive Clustering And Evaluation, Wei Xue, Zuo Liu, Yaozhong Zhang, Waseem Raza, Yarong Li, Li Jiang, Ye Tao, Jun Qian, Jousset Alexandre, Fang-Jie Zhao, Yangchun Xu, Fritz Sedlazeck, Qirong Shen, Gaofei Jiang, Zhong Wei

Faculty, Staff and Students Publications

Long-read sequencing has transformed metagenomics and improved the quality of metagenome-assembled genomes (MAGs). However, current binning methods struggle with identifying unknown species and managing imbalanced species distributions. Here, we present LorBin, an unsupervised binner specially designed to reconstruct MAGs in natural microbiomes. LorBin deploys a two-stage multiscale adaptive DBSCAN and BIRCH clustering with evaluation decision models using single-copy genes to maximize MAG recovery. LorBin outperforms six competing binners in both simulated and real microbiomes, including oral, gut, and marine samples. LorBin generated 15-189% more high-quality MAGs with high serendipity and identified 2.4-17 times more novel taxa than state-of-the-art binning methods. …

Whole-Genome Sequencing Reveals Individual And Cohort Level Insights Into Chromosome 9p Syndromes, Yingxi Wang, Eleanor I Sams, Rachel Slaugh, Sandra Crocker, Emily Cordova Hurtado, Sophia Tracy, Ying-Chen Claire Hou, Christopher Markovic, Kostandin Valle, Victoria Tate, Khadija Belhassan, Elizabeth Appelbaum, Titilope Akinwe, Rodrigo T Starosta, Yang Cao, Amber Neilson, Yu Liu, Nathaniel Jensen, Reza Ghasemi, Tina Lindsay, Juana Manuel, Sophia Couteranis, Milinn Kremitzki, Jack Ustanik, Thomas Antonacci, Jeffrey K Ng, Andrew Emory, Laura Metz, Tracie Deluca, Katherine N Lyons, Toni Sinnwell, Brianne Thomeczek, Kymme Wang, Nick Sisneros, Megha Muraleedharan, Anantha Kethireddy, Marco Corbo, Harsha Gowda, Katherine A King, Christina A Gurnett, Susan K Dutcher, Catherine Gooch, Yang E Li, Matthew W Mitchell, Kevin A Peterson, Amjad Horani, Jill A Rosenfeld, Weimin Bi, Pawel Stankiewicz, Hsiao-Tuan Chao, Jennifer E Posey, Christopher M Grochowski, Zain Dardas, Erik G Puffenberger, Christopher E Pearson, Frank Kooy, Dale Annear, A Micheil Innes, Michael Heinz, Richard Head, Robert Fulton, Stephan Toutain, 9p-Arch, Lucinda Antonacci-Fulton, Xiaoxia Cui, Robi D Mitra, F Sessions Cole, Julie Neidich, Patricia I Dickson, Jeffrey Milbrandt, Tychele N Turner

Faculty, Staff and Students Publications

Background: Previous genomic efforts on chromosome 9p deletion and duplication syndromes have utilized low-resolution strategies (i.e., karyotypes, chromosome microarrays). These studies have provided important initial insights into these syndromes. This current study is the first large-scale whole-genome sequencing (WGS) study of 100 individuals from families with chromosome 9p syndromes.

Methods: Through the newly formed 9P-ARCH (Advanced Research in Chromosomal Health: Genomic, Phenotypic, and Functional Aspects of 9p-Related syndromes) research network, we assembled a cohort of individuals from families with chromosome 9p syndromes. WGS was applied to 100 individuals, and other genomic technologies were applied to a subset of individuals. To …

A Quantitative, Bayesian-Informed Approach To Gene-Specific Variant Classification: Updated Expert Panel Recommendations Improve Classification Of Tp53 Germline Variants For Li-Fraumeni Syndrome, Cristina Fortuno, Megan N Frone, Jessica Mester, Miguel De La Hoya, Phuong L Mai, Tina Pesaran, Maria Isabel Achatz, Rebecca Bassett, Carolina Bustamante, Stephanie Crowley, Kelvin Cesar De Andrade, D Gareth Evans, Bingjian Feng, Laura Fuqua, Maria Isabel Harrell, Jessica N Hatton, Robert Huether, Chimene Kesserwan, Kristy Lee, Suzanne P Macfarland, Jamie L Maciaszek, Kara Maxwell, Kelly Mcgoldrick, Maureen Murphy, Bita Nehoray, Judith Penkert, Emilia Modolo Pinto, Sharon E Plon, Alison Schwartz-Levine, Ashley S Thompson, Wenyi Wang, Gerard P Zambetti, Kristin Zelley, Paul A James, Sharon A Savage, Christian P Kratz, Amanda B Spurdle

Faculty, Staff and Students Publications

Background: Germline pathogenic variants in TP53 cause Li-Fraumeni syndrome, with significantly elevated cancer risk from infancy. Accurate classification of TP53 variants is essential to guide clinical management and surveillance, yet many variants remain classified as variants of uncertain significance (VUS). To improve classification accuracy and reduce the proportion of VUS, the ClinGen TP53 Variant Curation Expert Panel (VCEP) has updated its specifications.

Methods: The updated specifications incorporate the latest ClinGen recommendations and methodological advances, providing greater granularity for multiple evidence types, and also introduce the novel use of variant allele fraction as evidence of pathogenicity, particularly in the context of …

Apoa1 Binding Protein Promotes Lymphatic Cell Fate And Lymphangiogenesis By Relieving Caveolae-Mediated Inhibition Of Vegfr3 Signaling, Jun-Dae Kim, Surbhi Chaudhary, Weiqing Chen, Jonathan Astin, Philip S Crosier, Pengchun Yu, John P Cooke, Henry J Pownall, Hugo J Bellen, Nhat-Tu Le, Daniel L Kiss, Guangyu Wang, Stanley G Rockson, Hong Chen, Longhou Fang

Faculty, Staff and Students Publications

The lymphatic system maintains tissue fluid balance, and its dysfunction can result in lymphedema. Although cholesterol is essential for cellular function, its role in lymphatic development has remained unknown. Here, we identify APOA1 binding protein (AIBP) as a key regulator that promotes lymphatic endothelial cell fate specification and lymphangiogenesis. Mechanistically, AIBP reduces plasma membrane cholesterol content, thereby enhancing VEGFR3 signaling by disrupting caveolae—small plasma membrane invaginations formed by the scaffolding protein caveolin-1 (CAV-1)—and relieving CAV-1–mediated inhibition. In zebrafish and mice, AIBP loss impairs VEGFR3 signaling and lymphatic development, defects that can be rescued by CAV-1 deletion or by a VEGFR3 …

Insights, Opportunities, And Challenges Provided By Large Cell Atlases, Martin Hemberg, Federico Marini, Shila Ghazanfar, Ahmad Al Ajami, Najla Abassi, Benedict Anchang, Bérénice A Benayoun, Yue Cao, Ken Chen, Yesid Cuesta-Astroz, Zachary Debruine, Calliope A Dendrou, Iwijn De Vlaminck, Katharina Imkeller, Ilya Korsunsky, Alex R Lederer, Jessica Jingyi Li, Pieter Meysman, Clint L Miller, Kerry A Mullan, Uwe Ohler, Pratibha Panwar, Nikolaos Patikas, Jonas Schuck, Jacqueline H Y Siu, Timothy J Triche, Alex Tsankov, Sander W Van Der Laan, Masanao Yajima, Jean Yang, Fabio Zanini, Ivana Jelic

Faculty, Staff and Student Publications

The field of single-cell biology is growing rapidly, generating large amounts of data from a variety of species, disease conditions, tissues, and organs. Coordinated efforts such as CZI CELLxGENE, HuBMAP, Broad Institute Single Cell Portal, and DISCO allow researchers to access large volumes of curated datasets, including more than just scRNA-seq data. These resources have created an opportunity to build and expand the computational biology ecosystem to develop tools necessary for data reuse and for extracting novel biological insights. We highlight achievements made so far, areas where further development is needed, and specific challenges that need to be overcome.

Visualization Of Lysosomal Membrane Proteins By Cryo Electron Tomography, Bridget M Mcveigh, José J De Jesús-Pérez, Dirk H Siepe, Prerana Gogoi, Shrawan Kumar Mageswaran, Marian Kalocsay, Elaine M Mihelc, Vera Y Moiseenkova-Bell

Faculty, Staff and Student Publications

Lysosomes are essential organelles for cellular homeostasis and signaling, with dysfunction linked to neurological disorders, lysosomal storage diseases, and cancer. While proteomics has advanced our understanding of lysosomal composition, the structural characterization of lysosomal membrane proteins in their native environment remains a significant challenge. Here, we developed a cryo electron tomography workflow to visualize lysosomal membrane proteins within intact, native lysosomal membranes. We isolated endolysosomes by independently targeting two lysosomal membrane proteins, transient receptor potential mucolipin 1 and transmembrane protein 192, enriching organelles that exhibited the expected morphology and proteomic composition of the endolysosomal system. Sub-tomogram averaging enabled the structural …

Cep76 Impairment At The Centrosome-Cilium Interface Contributes To A Spectrum Of Ciliopathies, Kamal Khan, Erika Tavares, Katherine Bishara, Aysegul Ozanturk, Leila Qebibo, Stephan Frangakis, Daniel G Calame, Isabelle Meunier, Béatrice Bocquet, Rafal Ploski, Mohammad Ayman Al Khateeb, Dana Marafi, Luke Mansard, Lena Damaj, Richard A Lewis, Farid Ullah, Thomas Arbogast, Jackson P Ogden, Madeleine Harion, Marjolaine Willems, Maha S Zaki, Tobias Bartolomaeus, Anne-Françoise Roux, James R Lupski, Malgorzata Rydzanicz, Rami Abou Jamra, Francis Ramond, Elise Heon, Lydie Burglen, Erica E Davis

Faculty, Staff and Students Publications

Dysfunction at the centrosome-cilium interface underlies a broad range of ciliopathies. Here, we identify biallelic variants in CEP76, encoding a centrosomal protein, in eight unrelated individuals presenting with neurodevelopmental, ocular, and variable additional multisystem features. Proband-derived fibroblasts and CEP76-depleted RPE1 cells display ciliary deficits, including impaired cilium formation and length, disrupted transition zone architecture, and impaired IFT88-mediated anterograde intraflagellar transport. Zebrafish cep76 mutants recapitulate key clinical phenotypes, and in vitro complementation assays confirm pathogenicity for all tested human disease-associated variants. Proteomics analysis identifies CEP76 interactors, including known partners CCP110 and CEP97, and highlights clinically and functionally relevant candidates, including …

Tng260 Is A Small-Molecule Corest Inhibitor That Sensitizes Stk11-Mutant Tumors To Anti-Pd-1 Immunotherapy, Leanne G Ahronian, Soumyadip Sahu, Minjie Zhang, Ayushi S Patel, Ke Geng, Reshmee Bhattacharya, Gerald S Falchook, Jonathan W Goldman, Alexander I Spira, Salman R Punekar, David R Spigel, Judy S Wang, Ferdinandos Skoulidis, Janaye Stephens, Mary Meynardie, Jaylen M Powell, Alfonso Lopez, Michela Ranieri, Magdalena A Ploszaj, Yi Jer Tan, Yeuan Ting Lee, Yi Yu, Jiehui Deng, Ting Chen, Patrick Mccarren, Alice Tsai, Suleman S Hussain, Brian Doyon, Kenjie Amemiya, Jacques Ermolieff, Preksha Shahagadkar, Nikitha M Das, Lauren R Flynn, Julie A Shields, Laney Danielczyk, Brian J Mcmillan, Andre Mignault, Samuel R Meier, Hsin-Jung Wu, David J Guerin, Douglas A Whittington, Chengyin Min, Iga Sienczylo, John P Maxwell, Heather J Dibenedetto, Hideo Watanabe, Brian B Haines, Alan Huang, Adam Crystal, Jannik N Andersen, Xinyuan Wu, Kwok-Kin Wong

Faculty, Staff and Student Publications

Patients with non–small cell lung cancer (NSCLC) with loss of the tumor suppressor gene STK11 are resistant to immune checkpoint therapies like anti–PD-1. In this study, we conducted an in vivo CRISPR screen that identified histone deacetylase 1 as a target to reverse anti–PD-1 resistance driven by loss of STK11 and developed TNG260, a potent small-molecule inhibitor of the CoREST complex with selectivity exceeding previously generated inhibitors in this class in preclinical studies. Treatment with TNG260 led to increased expression of immunomodulatory genes in STK11-deficient cancer cells. When combined with anti–PD-1, TNG260 induced immune-mediated stasis and/or regression in STK11 …

Preoperative Brain Mapping Predicts Language Outcomes After Eloquent Tumor Resection, Matthew T Muir, Kyle Noll, Sarah Prinsloo, Hayley Michener, Jeffrey I Traylor, Vinodh A Kumar, Chibawanye I Ene, Sherise Ferguson, Ho-Ling Liu, Jeffrey S Weinberg, Frederick Lang, Brian A Taylor, Stephanie J Forkel, Sujit S Prabhu

Faculty, Staff and Student Publications

When operating on gliomas near critical language regions, surgeons risk either leaving residual tumor or inducing permanent postoperative language deficits (PLDs). Despite the advent of intraoperative mapping techniques, subjective judgments frequently determine important surgical decisions. We aim to inform data-driven surgery by constructing a non-invasive mapping approach that quantitatively predicts the impact of individual surgical decisions on long-term language function. This study included 79 consecutive patients undergoing resection of language-eloquent gliomas. Patients underwent preoperative navigated transcranial magnetic stimulation (TMS) language mapping to identify language-positive sites ("TMS points") and their associated white matter tracts ("TMS tracts") as well as formal language …

Landscape And Clinicopathologic Features Of Ras Pathway Mutations In Chronic Myelomonocytic Leukemia, Guillermo Montalban-Bravo, Sanam Loghavi, Ziyi Li, Kelly Chien, Rashmi Kanagal-Shamanna, Alex Bataller, Anuya Natu, Mark Gurney, Alexandre Bazinet, Danielle Hammond, Koji Sasaki, Gautam Borthakur, Mahesh Swaminathan, Courtney Dinardo, Tapan Kadia, Farhad Ravandi, Naval Daver, Nicholas Short, Naveen Pemmaraju, Ghayas Issa, Terra L Lasho, Christy M Finke, Aref Al-Kali, Clifford Csizmar, Hassan Alkhateeb, Naseema Gangat, Abhishek A Mangaonkar, Carlos Bueso-Ramos, Ayalew Tefferi, Hagop Kantarjian, Guillermo Garcia-Manero, Mrinal M Patnaik

Faculty, Staff and Student Publications

RAS pathway (RASp) mutations induce proliferative features, and promote transformation in chronic myelomonocytic leukemia (CMML). However, the unique clonal landscape and hierarchy of distinct RASp mutations remain unexplored. To characterize the landscape, architecture, and implications of unique RASp mutations in CMML, we evaluated a cohort of 814 patients with CMML. We identified 461 RASp mutations among 342 patients (42%). N/KRAS and CBL mutations were the most common, frequently involved the P-loop or RING domains, respectively, and frequently appeared as dominant events (63% and 65%, respectively). BRAF, NF1, and PTPN11 mutations spanned throughout the gene structure, and frequently appeared as subclonal …

Optimizing Genetic Ancestry Adjustment In Dna Methylation Studies: A Comparative Analysis Of Approaches, Kira D Höffler, Seyma Katrinli, Matthew W Halvorsen, Anne-Kristin Stavrum, Kevin S O'Connell, Alexey Shadrin, Srdjan Djurovic, Ole A Andreassen, James J Crowley, Jan Haavik, Kristen Hagen, Gerd Kvale, Kerry Ressler, Bjarne Hansen, Jair C Soares, Gabriel R Fries, Alicia K Smith, Stéphanie Le Hellard

Faculty, Staff and Student Publications

Background: Genetic ancestry is an important factor to account for in DNA methylation studies because genetic variation influences DNA methylation patterns. One approach uses principal components (PCs) calculated from CpG sites that overlap with common SNPs to adjust for ancestry when genotyping data is not available. However, this method does not remove technical and biological variations, such as sex and age, prior to calculating the PCs. The first PC is therefore often associated with factors other than ancestry.

Methods: We developed and adapted the adapted EpiAnceR+ approach, which includes (1) residualizing the CpG data overlapping with common SNPs for control …

Yx0798 Is A Highly Potent, Selective, And Orally Effective Cdk9 Inhibitor For Treating Aggressive Lymphoma, Vivian Jiang, Yu Xue, Hong Kim, Qingsong Cai, Tianci Zhang, Lei Nie, Joseph Mcintosh, Yang Liu, Haiying Chen, Jia Zhou, Michael Wang

Faculty, Staff and Student Publications

Nongenetic transcription evolution has been increasingly explored and recognized to drive tumor cell progression and therapeutic resistance. As the regulation hub of transcription machinery, cyclin-dependent kinase 9 (CDK9) is the gatekeeper of RNA polymerase II transcription, and CDK9 dysfunction results in transcriptomic reprogramming and tumor cell progression. We recently reported that the heat shock protein 90 (HSP90)-MYC-CDK9 network drives therapeutic resistance in mantle cell lymphoma (MCL) through transcriptomic reprogramming. We also showed that targeting CDK9 by AZD4573 and enitociclib is a safe and effective treatment in preclinical Mantle Cell Lymphoma (MCL) models, supporting CDK9 as a valid therapeutic target for …