Genetic Phenomena Commons^™

Somatic Mutational Landscape Of Hereditary Hematopoietic Malignancies Caused By Germline Variants In Runx1, Gata2, And Ddx41, Claire C Homan, Michael W Drazer, Kai Yu, David M Lawrence, Jinghua Feng, Luis Arriola-Martinez, Matthew J Pozsgai, Kelsey E Mcneely, Thuong Ha, Parvathy Venugopal, Peer Arts, Sarah L King-Smith, Jesse Cheah, Mark Armstrong, Paul Wang, Csaba Bödör, Alan B Cantor, Mario Cazzola, Erin Degelman, Courtney D Dinardo, Nicolas Duployez, Remi Favier, Stefan Fröhling, Ana Rio-Machin, Jeffery M Klco, Alwin Krämer, Mineo Kurokawa, Joanne Lee, Luca Malcovati, Neil V Morgan, Georges Natsoulis, Carolyn Owen, Keyur P Patel, Claude Preudhomme, Hana Raslova, Hugh Rienhoff, Tim Ripperger, Rachael Schulte, Kiran Tawana, Elvira Velloso, Benedict Yan, Erika Kim, Raman Sood, Amy P Hsu, Steven M Holland, Kerry Phillips, Nicola K Poplawski, Milena Babic, Andrew H Wei, Cecily Forsyth, Helen Mar Fan, Ian D Lewis, Julian Cooney, Rachel Susman, Lucy C Fox, Piers Blombery, Deepak Singhal, Devendra Hiwase, Belinda Phipson, Andreas W Schreiber, Christopher N Hahn, Hamish S Scott, Paul Liu, Lucy A Godley, Anna L Brown, Nisc Comparative Sequencing Program

Faculty, Staff and Student Publications

Individuals with germ line variants associated with hereditary hematopoietic malignancies (HHMs) have a highly variable risk for leukemogenesis. Gaps in our understanding of premalignant states in HHMs have hampered efforts to design effective clinical surveillance programs, provide personalized preemptive treatments, and inform appropriate counseling for patients. We used the largest known comparative international cohort of germline RUNX1, GATA2, or DDX41 variant carriers without and with hematopoietic malignancies (HMs) to identify patterns of genetic drivers that are unique to each HHM syndrome before and after leukemogenesis. These patterns included striking heterogeneity in rates of early-onset clonal hematopoiesis (CH), with a high …

Re-Stratification Of Patients With Copy-Number Low Endometrial Cancer By Clinicopathological Characteristics, Li Liwei, Li He, Dai Yibo, Zhao Luyang, Shen Zhihui, Kang Nan, Shen Danhua, Wang Junzhu, Wang Zhiqi, Wang Jianliu

Faculty, Staff and Student Publications

Objective: To stratify patients with copy-number low (CNL) endometrial cancer (EC) by clinicopathological characteristics.

Methods: EC patients who underwent surgery between June 2018 and June 2022 at Peking University People's Hospital were included and further classified according to TCGA molecular subtyping: POLE ultramutated, microsatellite instability high (MSI-H), CNL, and copy-number high (CNH). Clinicopathological characteristics and prognosis of CNL patients were retrospectively reviewed. The Cox proportional hazards regression model was applied to perform univariate and multivariate analysis, and independent risk factors were identified. Differentially expressed genes (DEGs) according to overall survival (OS) were screened based on the transcriptome of CNL cases …

Actinide-Lanthanide Single Electron Metal-Metal Bond Formed In Mixed-Valence Di-Metallofullerenes, Yingjing Yan, Laura Abella, Rong Sun, Yu-Hui Fang, Yannick Roselló, Yi Shen, Meihe Jin, Antonio Rodríguez-Fortea, Coen De Graaf, Qingyu Meng, Yang-Rong Yao, Luis Echegoyen, Bing-Wu Wang, Song Gao, Josep M Poblet, Ning Chen

Faculty, Staff and Student Publications

Understanding metal-metal bonding involving f-block elements has been a challenging goal in chemistry. Here we report a series of mixed-valence di-metallofullerenes, ThDy@C2n (2n = 72, 76, 78, and 80) and ThY@C2n (2n = 72 and 78), which feature single electron actinide-lanthanide metal-metal bonds, characterized by structural, spectroscopic and computational methods. Crystallographic characterization unambiguously confirmed that Th and Y or Dy are encapsulated inside variably sized fullerene carbon cages. The ESR study of ThY@D3h(5)-C78 shows a doublet as expected for an unpaired electron interacting with Y, and a SQUID magnetometric study of ThDy@ …

Focalizing Regions Of Biomarker Relevance Facilitates Biomarker Prediction On Histopathological Images, Jiefeng Gan, Hanchen Wang, Hui Yu, Zitong He, Wenjuan Zhang, Ke Ma, Lianghui Zhu, Yutong Bai, Zongwei Zhou, Alan Yullie, Xiang Bai, Mingwei Wang, Dehua Yang, Yanyan Chen, Guoan Chen, Joan Lasenby, Chao Cheng, Jia Wu, Jianjun Zhang, Xinggang Wang, Yaobing Chen, Guoping Wang, Tian Xia

Faculty, Staff and Student Publications

Image-based AI has thrived as a potentially revolutionary tool for predicting molecular biomarker statuses, which aids in categorizing patients for appropriate medical treatments. However, many methods using hematoxylin and eosin-stained (H&E) whole-slide images (WSIs) have been found to be inefficient because of the presence of numerous uninformative or irrelevant image patches. In this study, we introduced the region of biomarker relevance (ROB) concept to identify the morphological areas most closely associated with biomarkers for accurate status prediction. We actualized this concept within a framework called saliency ROB search (SRS) to enable efficient and effective predictions. By evaluating various lung adenocarcinoma …

Molecular And Biochemical Analysis Of Cytochrome P450 2c19 And 2d6, Reema Saleous

Thesis/ Dissertation Defenses

Pharmacogenomics (PGx) is a relatively new field of study. It links genetics to pharmacology since it deals with the influence of the genetic makeup of the individual on their ability to respond to specific medications. Some of the most important genes in this field, dubbed very important pharmacogenes (VIPs), belong to the cytochrome P450 (CYP) superfamily of drug metabolizing enzymes. The two members of this family that are the main focus of this thesis are CYP2C19 and CYP2D6. They play major roles in the metabolism of numerous medications, and it is therefore imperative that variations within those genes in various …

Author Correction: Global Proteomic Identifies Multiple Cancer-Related Signaling Pathways Altered By A Gut Pathobiont Associated With Colorectal Cancer, Ewa Pasquereau-Kotula, Giulia Nigro, Florent Dingli, Damarys Loew, Patrick Poullet, Yi Xu, Scott Kopetz, Jennifer Davis, Lucie Peduto, Catherine Robbe-Masselot, Philippe Sansonetti, Patrick Trieu-Cuot, Shaynoor Dramsi

Faculty, Staff and Student Publications

No abstract provided.

International Consensus On Differential Diagnosis And Management Of Patients With Danon Disease: Jacc State-Of-The-Art Review, Kimberly N Hong, Emily A Eshraghian, Michael Arad, Alessia Argirò, Michela Brambatti, Quan Bui, Oren Caspi, Fernando De Frutos, Barry Greenberg, Carolyn Y Ho, Juan Pablo Kaski, Iacopo Olivotto, Matthew R G Taylor, Abigail Yesso, Pablo Garcia-Pavia, Eric D Adler

Faculty, Staff and Students Publications

Danon disease is a rare X-linked autophagic vacuolar cardioskeletal myopathy associated with severe heart failure that can be accompanied with extracardiac neurologic, skeletal, and ophthalmologic manifestations. It is caused by loss of function variants in the LAMP2 gene and is among the most severe and penetrant of the genetic cardiomyopathies. Most patients with Danon disease will experience symptomatic heart failure. Male individuals generally present earlier than women and die of either heart failure or arrhythmia or receive a heart transplant by the third decade of life. Herein, the authors review the differential diagnosis of Danon disease, diagnostic criteria, natural history, …

Priorities And Progress In Gram-Positive Bacterial Infection Research By The Antibacterial Resistance Leadership Group: A Narrative Review, Sarah B Doernberg, Cesar A Arias, Deena R Altman, Ahmed Babiker, Helen W Boucher, C Buddy Creech, Sara E Cosgrove, Scott R Evans, Vance G Fowler, Stephanie A Fritz, Toshimitsu Hamasaki, Brendan J Kelly, Sixto M Leal, Catherine Liu, Thomas P Lodise, Loren G Miller, Jose M Munita, Barbara E Murray, Melinda M Pettigrew, Felicia Ruffin, Marc H Scheetz, Bo Shopsin, Truc T Tran, Nicholas A Turner, Derek J Williams, Smitha Zaharoff, Thomas L Holland

Faculty, Staff and Student Publications

The Antibacterial Resistance Leadership Group (ARLG) has prioritized infections caused by gram-positive bacteria as one of its core areas of emphasis. The ARLG Gram-positive Committee has focused on studies responding to 3 main identified research priorities: (1) investigation of strategies or therapies for infections predominantly caused by gram-positive bacteria, (2) evaluation of the efficacy of novel agents for infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci, and (3) optimization of dosing and duration of antimicrobial agents for gram-positive infections. Herein, we summarize ARLG accomplishments in gram-positive bacterial infection research, including studies aiming to (1) inform optimal vancomycin dosing, …

Guide-Specific Loss Of Efficiency And Off-Target Reduction With Cas9 Variants, Liang Zhang, Wei He, Rongjie Fu, Shuyue Wang, Yiwen Chen, Han Xu

Faculty, Staff and Student Publications

High-fidelity clustered regularly interspaced palindromic repeats (CRISPR)-associated protein 9 (Cas9) variants have been developed to reduce the off-target effects of CRISPR systems at a cost of efficiency loss. To systematically evaluate the efficiency and off-target tolerance of Cas9 variants in complex with different single guide RNAs (sgRNAs), we applied high-throughput viability screens and a synthetic paired sgRNA-target system to assess thousands of sgRNAs in combination with two high-fidelity Cas9 variants HiFi and LZ3. Comparing these variants against wild-type SpCas9, we found that ∼20% of sgRNAs are associated with a significant loss of efficiency when complexed with either HiFi or LZ3. …

Novobiocin Blocks Nucleic Acid Binding To Polθ And Inhibits Stimulation Of Its Atpase Activity, Aleem Syed, Frantisek Filandr, Jeffrey Patterson-Fortin, Albino Bacolla, Ramya Ravindranathan, Jia Zhou, Drew T Mcdonald, Mohammed E Albuhluli, Amy Verway-Cohen, Joseph A Newman, Miaw-Sheue Tsai, Darin E Jones, David C Schriemer, Alan D D'Andrea, John A Tainer

Faculty, Staff and Student Publications

Polymerase theta (Polθ) acts in DNA replication and repair, and its inhibition is synthetic lethal in BRCA1 and BRCA2-deficient tumor cells. Novobiocin (NVB) is a first-in-class inhibitor of the Polθ ATPase activity, and it is currently being tested in clinical trials as an anti-cancer drug. Here, we investigated the molecular mechanism of NVB-mediated Polθ inhibition. Using hydrogen deuterium exchange-mass spectrometry (HX-MS), biophysical, biochemical, computational and cellular assays, we found NVB is a non-competitive inhibitor of ATP hydrolysis. NVB sugar group deletion resulted in decreased potency and reduced HX-MS interactions, supporting a specific NVB binding orientation. Collective results revealed that NVB …

Unleashing The Potential Of 1,3-Diketone Analogues As Selective Lh2 Inhibitors, Juhoon Lee, Hou-Fu Guo, Shike Wang, Yazdan Maghsoud, Erik Antonio Vázquez-Montelongo, Zhifeng Jing, Rae M Sammons, Eun Jeong Cho, Pengyu Ren, G Andrés Cisneros, Jonathan M Kurie, Kevin N Dalby

Faculty, Staff and Student Publications

Lysyl hydroxylase 2 (LH2) catalyzes the formation of highly stable hydroxylysine aldehyde-derived collagen cross-links (HLCCs), thus promoting lung cancer metastasis through its capacity to modulate specific types of collagen cross-links within the tumor stroma. Using 1 and 2 from our previous high-throughput screening (HTS) as lead probes, we prepared a series of 1,3-diketone analogues, 1-18, and identified 12 and 13 that inhibit LH2 with IC50's of approximately 300 and 500 nM, respectively. Compounds 12 and 13 demonstrate selectivity for LH2 over LH1 and LH3. Quantum mechanics/molecular mechanics (QM/MM) modeling indicates that the selectivity of 12 and 13 …

Collective Motion In Hcp-Fe At Earth's Inner Core Conditions, Youjun Zhang, Yong Wang, Yuqian Huang, Junjie Wang, Zhixin Liang, Long Hao, Zhipeng Gao, Jun Li, Qiang Wu, Hong Zhang, Yun Liu, Jian Sun, Jung-Fu Lin

Faculty, Staff and Student Publications

Earth's inner core is predominantly composed of solid iron (Fe) and displays intriguing properties such as strong shear softening and an ultrahigh Poisson's ratio. Insofar, physical mechanisms to explain these features coherently remain highly debated. Here, we have studied longitudinal and shear wave velocities of hcp-Fe (hexagonal close-packed iron) at relevant pressure-temperature conditions of the inner core using in situ shock experiments and machine learning molecular dynamics (MLMD) simulations. Our results demonstrate that the shear wave velocity of hcp-Fe along the Hugoniot in the premelting condition, defined as

The Significant Impacts Of Interleukin-8 Genotypes On The Risk Of Colorectal Cancer In Taiwan, Chia-Wen Tsai, Wen-Shin Chang, Te-Cheng Yueh, Yun-Chi Wang, Yu-Ting Chin, Mei-Due Yang, Yi-Chih Hung, Mei-Chin Mong, Ya-Chen Yang, Jian Gu, Da-Tian Bau

Faculty, Staff and Student Publications

Interleukin-8 (IL-8), a pro-inflammatory cytokine, is upregulated in CRC and plays an important role in its development and progression. Genetic variants in the IL-8 gene may impact the risk of CRC by modulating IL-8 levels. Our primary objective was to investigate the role of IL-8 genotypes in the development of CRC. To accomplish this, we employed the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to analyze the genotypes of IL-8 rs4017, rs2227306, rs2227543, and rs1126647 in 362 CRC patients and 362 controls. Additionally, we evaluated the interactions between these genotypes and factors such as age, gender, smoking, alcohol consumption, …

Dendritic Cells As Shepherds Of T Cell Immunity In Cancer, Mikael J Pittet, Mauro Di Pilato, Christopher Garris, Thorsten R Mempel

Faculty, Staff and Student Publications

In cancer patients, dendritic cells (DCs) in tumor-draining lymph nodes can present antigens to naive T cells in ways that break immunological tolerance. The clonally expanded progeny of primed T cells are further regulated by DCs at tumor sites. Intratumoral DCs can both provide survival signals to and drive effector differentiation of incoming T cells, thereby locally enhancing antitumor immunity; however, the paucity of intratumoral DCs or their expression of immunoregulatory molecules often limits antitumor T cell responses. Here, we review the current understanding of DC-T cell interactions at both priming and effector sites of immune responses. We place emerging …

Enzyme-Mediated Depletion Of Methylthioadenosine Restores T Cell Function In Mtap-Deficient Tumors And Reverses Immunotherapy Resistance, Donjeta Gjuka, Elio Adib, Kendra Garrison, Jianfeng Chen, Yuxue Zhang, Wenjiao Li, Daniel Boutz, Candice Lamb, Yuri Tanno, Amin Nassar, Talal El Zarif, Neil Kale, Mehrdad Rakaee, Tarek H Mouhieddine, Sarah Abou Alaiwi, Alexander Gusev, Thomas Rogers, Jianjun Gao, George Georgiou, David J Kwiatkowski, Everett Stone

Faculty, Staff and Student Publications

Chromosomal region 9p21 containing tumor suppressors CDKN2A/B and methylthioadenosine phosphorylase (MTAP) is one of the most frequent genetic deletions in cancer. 9p21 loss is correlated with reduced tumor-infiltrating lymphocytes (TILs) and resistance to immune checkpoint inhibitor (ICI) therapy. Previously thought to be caused by CDKN2A/B loss, we now show that it is loss of MTAP that leads to poor outcomes on ICI therapy and reduced TIL density. MTAP loss causes accumulation of methylthioadenosine (MTA) both intracellularly and extracellularly and profoundly impairs T cell function via the inhibition of protein arginine methyltransferase 5 (PRMT5) and by adenosine receptor agonism. Administration of …

Pls3 Missense Variants Affecting The Actin-Binding Domains Cause X-Linked Congenital Diaphragmatic Hernia And Body-Wall Defects, Florence Petit, Mauro Longoni, Julie Wells, Richard S Maser, Eric L Bogenschutz, Matthew J Dysart, Hannah T M Contreras, Frederic Frénois, Barbara R Pober, Robin D Clark, Philip F Giampietro, Hilger H Ropers, Hao Hu, Maria Loscertales, Richard Wagner, Xingbin Ai, Harrison Brand, Anne-Sophie Jourdain, Marie-Ange Delrue, Brigitte Gilbert-Dussardier, Louise Devisme, Boris Keren, David J Mcculley, Lu Qiao, Rebecca Hernan, Julia Wynn, Tiana M Scott, Daniel G Calame, Zeynep Coban-Akdemir, Patricia Hernandez, Andres Hernandez-Garcia, Hagith Yonath, James R Lupski, Yufeng Shen, Wendy K Chung, Daryl A Scott, Carol J Bult, Patricia K Donahoe, Frances A High

Faculty, Staff and Student Publications

Congenital diaphragmatic hernia (CDH) is a relatively common and genetically heterogeneous structural birth defect associated with high mortality and morbidity. We describe eight unrelated families with an X-linked condition characterized by diaphragm defects, variable anterior body-wall anomalies, and/or facial dysmorphism. Using linkage analysis and exome or genome sequencing, we found that missense variants in plastin 3 (PLS3), a gene encoding an actin bundling protein, co-segregate with disease in all families. Loss-of-function variants in PLS3 have been previously associated with X-linked osteoporosis (MIM: 300910), so we used in silico protein modeling and a mouse model to address these seemingly disparate clinical …

Rare Variants In Long Non-Coding Rnas Are Associated With Blood Lipid Levels In The Topmed Whole-Genome Sequencing Study, Yuxuan Wang, Margaret Sunitha Selvaraj, Xihao Li, Zilin Li, Jacob A Holdcraft, Donna K Arnett, Joshua C Bis, John Blangero, Eric Boerwinkle, Donald W Bowden, Brian E Cade, Jenna C Carlson, April P Carson, Yii-Der Ida Chen, Joanne E Curran, Paul S De Vries, Susan K Dutcher, Patrick T Ellinor, James S Floyd, Myriam Fornage, Barry I Freedman, Stacey Gabriel, Soren Germer, Richard A Gibbs, Xiuqing Guo, Jiang He, Nancy Heard-Costa, Bertha Hildalgo, Lifang Hou, Marguerite R Irvin, Roby Joehanes, Robert C Kaplan, Sharon Lr Kardia, Tanika N Kelly, Ryan Kim, Charles Kooperberg, Brian G Kral, Daniel Levy, Changwei Li, Chunyu Liu, Don Lloyd-Jone, Ruth Jf Loos, Michael C Mahaney, Lisa W Martin, Rasika A Mathias, Ryan L Minster, Braxton D Mitchell, May E Montasser, Alanna C Morrison, Joanne M Murabito, Take Naseri, Jeffrey R O'Connell, Nicholette D Palmer, Michael H Preuss, Bruce M Psaty, Laura M Raffield, Dabeeru C Rao, Susan Redline, Alexander P Reiner, Stephen S Rich, Muagututi'a Sefuiva Ruepena, Wayne H-H Sheu, Jennifer A Smith, Albert Smith, Hemant K Tiwari, Michael Y Tsai, Karine A Viaud-Martinez, Zhe Wang, Lisa R Yanek, Wei Zhao, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Jerome I Rotter, Xihong Lin, Pradeep Natarajan, Gina M Peloso

Faculty, Staff and Student Publications

Long non-coding RNAs (lncRNAs) are known to perform important regulatory functions in lipid metabolism. Large-scale whole-genome sequencing (WGS) studies and new statistical methods for variant set tests now provide an opportunity to assess more associations between rare variants in lncRNA genes and complex traits across the genome. In this study, we used high-coverage WGS from 66,329 participants of diverse ancestries with measurement of blood lipids and lipoproteins (LDL-C, HDL-C, TC, and TG) in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program to investigate the role of lncRNAs in lipid variability. We aggregated rare variants …

An Update On Strategies To Deliver Protein And Peptide Drugs To The Eye, Sai H S Boddu, Devarshi Acharya, Vivek Hala, Harshil Jani, Sonal Pande, Chirag Patel, Moyad Shahwan, Renukuntla Jwala, Ketan M Ranch

Faculty, Staff and Student Publications

In the past few decades, advancements in protein engineering, biotechnology, and structural biochemistry have resulted in the discovery of various techniques that enhanced the production yield of proteins, targetability, circulating half-life, product purity, and functionality of proteins and peptides. As a result, the utilization of proteins and peptides has increased in the treatment of many conditions, including ocular diseases. Ocular delivery of large molecules poses several challenges due to their high molecular weight, hydrophilicity, unstable nature, and poor permeation through cellular and enzymatic barriers. The use of novel strategies for delivering protein and peptides such as glycoengineering, PEGylation, Fc-fusion, chitosan …

Endocrine Therapy Synergizes With Smac Mimetics To Potentiate Antigen Presentation And Tumor Regression In Hormone Receptor-Positive Breast Cancer, Francisco Hermida-Prado, Yingtian Xie, Shira Sherman, Zsuzsanna Nagy, Douglas Russo, Tara Akhshi, Zhengtao Chu, Avery Feit, Marco Campisi, Minyue Chen, Agostina Nardone, Cristina Guarducci, Klothilda Lim, Alba Font-Tello, Irene Lee, Juana García-Pedrero, Israel Cañadas, Judith Agudo, Ying Huang, Tal Sella, Qingchun Jin, Nabihah Tayob, Elizabeth A Mittendorf, Sara M Tolaney, Xintao Qiu, Henry Long, William F Symmans, Jia-Ren Lin, Sandro Santagata, Isabelle Bedrosian, Denise A Yardley, Ingrid A Mayer, Edward T Richardson, Giacomo Oliveira, Catherine J Wu, Eugene F Schuster, Mitch Dowsett, Alana L Welm, David Barbie, Otto Metzger, Rinath Jeselsohn

Faculty, Staff and Student Publications

Immunotherapies have yet to demonstrate significant efficacy in the treatment of hormone receptor-positive (HR+) breast cancer. Given that endocrine therapy (ET) is the primary approach for treating HR+ breast cancer, we investigated the effects of ET on the tumor immune microenvironment (TME) in HR+ breast cancer. Spatial proteomics of primary HR+ breast cancer samples obtained at baseline and after ET from patients enrolled in a neoadjuvant clinical trial (NCT02764541) indicated that ET upregulated β2-microglobulin and influenced the TME in a manner that promotes enhanced immunogenicity. To gain a deeper understanding of the underlying mechanisms, the intrinsic effects of …

Web-Grading-A Tool To Test Personal Grading Of Renal And Prostate Cancer, Glen Kristiansen, Matthias Schmid, Lars Egevad, Hemamali Samaratunga, Murali Varma, Kaan Inam, Hans-Jürgen Thiesen, Brett Delahunt, Yulin Dai

Faculty, Staff and Student Publications

Only a few pathologists have the opportunity to verify their personal grading through objective assessment. This study introduces a web-based grading platform to facilitate and validate the grading of renal cell carcinoma and prostate cancer. Two representative images of two clinically annotated cohorts of 100 cases each of prostate and renal cell carcinoma were used. Each participant was asked to grade a tumor series utilizing a three tiered grading system. Finally, a Kaplan-Meier curve was drawn, and the log-rank test was used for statistical testing of the p-value. The grading of 22 participants (68%) achieved prognostic significance. Further analysis highlighted …