Medical Specialties Commons^™

Flagellar Motility Is Mutagenic, Souvik Bhattacharyya, Shelby Lopez, Abhyudai Singh, Rasika M Harshey

Faculty, Staff and Student Publications

Flagella are highly complex rotary molecular machines that enable bacteria to not only migrate to optimal environments but also to promote range expansion, competitiveness, virulence, and antibiotic survival. Flagellar motility is an energy-demanding process, where the sum of its production (biosynthesis) and operation (rotation) costs has been estimated to total ~10% of the entire energy budget of an

Rapid Hyperspectral Photothermal Mid-Infrared Spectroscopic Imaging From Sparse Data For Gynecologic Cancer Tissue Subtyping, Reza Reihanisaransari, Chalapathi Charan Gajjela, Xinyu Wu, Ragib Ishrak, Sara Corvigno, Yanping Zhong, Jinsong Liu, Anil K Sood, David Mayerich, Sebastian Berisha, Rohith Reddy

Faculty, Staff and Student Publications

Ovarian cancer detection has traditionally relied on a multistep process that includes biopsy, tissue staining, and morphological analysis by experienced pathologists. While widely practiced, this conventional approach suffers from several drawbacks: it is qualitative, time-intensive, and heavily dependent on the quality of staining. Mid-infrared (MIR) hyperspectral photothermal imaging is a label-free, biochemically quantitative technology that, when combined with machine learning algorithms, can eliminate the need for staining and provide quantitative results comparable to traditional histology. However, this technology is slow. This work presents a novel approach to MIR photothermal imaging that enhances its speed by an order of magnitude. This …

Fast, Variable Stiffness-Induced Braided Coiled Artificial Muscles, Xinghao Hu, Xiangyu Wang, Jian Wang, Guorong Zhang, Shaoli Fang, Fengrui Zhang, Ye Xiao, Guanggui Cheng, Ray H Baughman, Jianning Ding

Faculty, Staff and Student Publications

Biomimetic actuation technologies with high muscle strokes, cycle rates, and work capacities are necessary for robotic systems. We present a muscle type that operates based on changes in muscle stiffness caused by volume expansion. This muscle is created by coiling a mechanically strong braid, in which an elastomer hollow tube is adhesively attached inside. We show that the muscle reversibly contracts by 47.3% when driven by an oscillating input air pressure of 120 kilopascals at 10 Hz. It generates a maximum power density of 3.0 W/g and demonstrates a mechanical contractile efficiency of 74%. The muscle's low-pressure operation allowed for …

The Impact Of A Web-Based Prognostic Calculator On Prognostic Confidence In Outpatient Palliative Care, David Hui, John P Maxwell, Allison De La Rosa, Kristofer Jennings, Marieberta Vidal, Akhila Reddy, Ahsan Azhar, Rony Dev, Kimberson Tanco, Yvonne Heung, Marvin Delgado-Guay, Donna Zhukovsky, Joseph Arthur, Suresh Reddy, Sriram Yennu, Amy Ontai, Eduardo Bruera

Faculty, Staff and Student Publications

Purpose: Clinicians are often uncertain about their prognostic estimates, which may impede prognostic communication and clinical decision-making. We assessed the impact of a web-based prognostic calculator on physicians' prognostic confidence.

Methods: In this prospective study, palliative care physicians estimated the prognosis of patients with advanced cancer in an outpatient clinic using the temporal, surprise, and probabilistic approaches for 6 m, 3 m, 2 m, 1 m, 2 w, 1 w, and 3 d. They then reviewed information from www.predictsurvival.com , which calculated survival estimates from seven validated prognostic scores, including the Palliative Prognostic Score, Palliative Prognostic Index, and Palliative Performance …

Ct Strain Metrics Allow For Earlier Diagnosis Of Bronchiolitis Obliterans Syndrome After Hematopoietic Cell Transplant, Husham Sharifi, Christopher D Bertini, Mansour Alkhunaizi, Maria Hernandez, Zayan Musa, Carlos Borges, Ihsan Turk, Lara Bashoura, Burton F Dickey, Guang-Shing Cheng, Gregory Yanik, Craig J Galban, Huawei Henry Guo, Myrna C B Godoy, Joseph M Reinhardt, Eric A Hoffman, Mario Castro, Gabriela Rondon, Amin M Alousi, Richard E Champlin, Elizabeth J Shpall, Ying Lu, Samuel Peterson, Keshav Datta, Mark R Nicolls, Joe Hsu, Ajay Sheshadri

Faculty, Staff and Student Publications

Bronchiolitis obliterans syndrome (BOS) after hematopoietic cell transplantation (HCT) is associated with substantial morbidity and mortality. Quantitative computed tomography (qCT) can help diagnose advanced BOS meeting National Institutes of Health (NIH) criteria (NIH-BOS) but has not been used to diagnose early, often asymptomatic BOS (early BOS), limiting the potential for early intervention and improved outcomes. Using pulmonary function tests (PFTs) to define NIH-BOS, early BOS, and mixed BOS (NIH-BOS with restrictive lung disease) in patients from 2 large cancer centers, we applied qCT to identify early BOS and distinguish between types of BOS. Patients with transient impairment or healthy lungs …

Atr Inhibition Radiosensitizes Cells Through Augmented Dna Damage And G2 Cell Cycle Arrest Abrogation, Scott J Bright, Mandira Manandhar, David B Flint, Rishab Kolachina, Mariam Ben Kacem, David Kj Martinus, Broderick X Turner, Ilsa Qureshi, Conor H Mcfadden, Poliana C Marinello, Simona F Shaitelman, Gabriel O Sawakuchi

Faculty, Staff and Student Publications

Ataxia telangiectasia and Rad3-related protein (ATR) is a key DNA damage response protein that facilitates DNA damage repair and regulates cell cycle progression. As such, ATR is an important component of the cellular response to radiation, particularly in cancer cells, which show altered DNA damage response and aberrant cell cycle checkpoints. Therefore, ATR's pharmacological inhibition could be an effective radiosensitization strategy to improve radiotherapy. We assessed the ability of an ATR inhibitor, AZD6738, to sensitize cancer cell lines of various histologic types to photon and proton radiotherapy. We found that radiosensitization took place through persistent DNA damage and abrogated G2 …

Tca Metabolism Regulates Dna Hypermethylation In Lps And Mycobacterium Tuberculosis–Induced Immune Tolerance, Abhimanyu, Santiago Carrero Longlax, Tomoki Nishiguchi, Malik Ladki, Daanish Sheikh, Amera L Martinez, Emily M Mace, Sandra L Grimm, Thaleia Caldwell, Alexandra Portillo Varela, Rajagopal V Sekhar, Anna M Mandalakas, Mandla Mlotshwa, Sibuse Ginidza, Jeffrey D Cirillo, Robert S Wallis, Mihai G Netea, Reinout Van Crevel, Cristian Coarfa, Andrew R Dinardo

Faculty, Staff and Students Publications

Severe and chronic infections, including pneumonia, sepsis, and tuberculosis (TB), induce long-lasting epigenetic changes that are associated with an increase in all-cause postinfectious morbidity and mortality. Oncology studies identified metabolic drivers of the epigenetic landscape, with the tricarboxylic acid (TCA) cycle acting as a central hub. It is unknown if the TCA cycle also regulates epigenetics, specifically DNA methylation, after infection-induced immune tolerance. The following studies demonstrate that lipopolysaccharide and Mycobacterium tuberculosis induce changes in DNA methylation that are mediated by the TCA cycle. Infection-induced DNA hypermethylation is mitigated by inhibitors of cellular metabolism (rapamycin, everolimus, metformin) and the TCA …

Gender And Sexuality Awareness In Medical Education And Practice: Mixed Methods Study, Rola Khamisy-Farah, Eden Biras, Rabie Shehadeh, Ruba Tuma, Hisham Atwan, Anna Siri, Manlio Converti, Francesco Chirico, Łukasz Szarpak, Carlo Biz, Raymond Farah, Nicola Bragazzi

Faculty, Staff and Students Publications

BACKGROUND: The integration of gender and sexuality awareness in health care is increasingly recognized as vital for patient outcomes. Despite this, there is a notable lack of comprehensive data on the current state of physicians' training and perceptions in these areas, leading to a gap in targeted educational interventions and optimal health care delivery.

OBJECTIVE: The study's aim was to explore the experiences and perceptions of attending and resident physicians regarding the inclusion of gender and sexuality content in medical school curricula and professional practice in Israel.

METHODS: This cross-sectional survey targeted a diverse group of physicians across various specializations …

Genetically Conditioned Interaction Among Microrna-155, Alpha-Klotho, And Intra-Renal Ras In Male Rats: Link To Ckd Progression, Lisa M. Harrison-Bernard, L. Raij, R. X. Tian, E. A. Jaimes

School of Graduate Studies Faculty Publications

Incident chronic kidney disease (CKD) varies in populations with hypertension of similar severity. Proteinuria promotes CKD progression in part due to activation of plasminogen to plasmin in the podocytes, resulting in oxidative stress-mediated injury. Additional mechanisms include deficiency of renal alpha-klotho, that inhibits Wnt/beta-catenin, an up regulator of intra-renal renin angiotensin system (RAS) genes. Alpha-klotho deficiency therefore results in upregulation of the intra-renal RAS via Wnt/beta-catenin. In hypertensive, Dahl salt sensitive (DS) and spontaneously hypertensive rats (SHR), we investigated renal and vascular injury, miR-155, AT1R, alpha-klotho, and TNF-α. Hypertensive high salt DS (DS-HS), but not SHR developed proteinuria, plasminuria, and …

Immunologic Signatures Of Response And Resistance To Nivolumab With Ipilimumab In Advanced Metastatic Cancer, Apostolia M Tsimberidou, Farah A Alayli, Kwame Okrah, Alexandra Drakaki, Danny N Khalil, Shivaani Kummar, Saad A Khan, F Stephen Hodi, David Y Oh, Christopher R Cabanski, Shikha Gautam, Stefanie L Meier, Meelad Amouzgar, Shannon M Pfeiffer, Robin Kageyama, Enjun Yang, Marko Spasic, Michael T Tetzlaff, Wai Chin Foo, Travis J Hollmann, Yanyun Li, Matthew Adamow, Phillip Wong, Jonni S Moore, Sharlene Velichko, Richard O Chen, Dinesh Kumar, Samantha Bucktrout, Ramy Ibrahim, Ute Dugan, Lisa Salvador, Vanessa M Hubbard-Lucey, Jill O'Donnell-Tormey, Sandra Santulli-Marotto, Lisa H Butterfield, Diane M Da Silva, Justin Fairchild, Theresa M Lavallee, Lacey J Padrón, Padmanee Sharma

Faculty, Staff and Student Publications

Identifying pan-tumor biomarkers that predict responses to immune checkpoint inhibitors (ICI) is critically needed. In the AMADEUS clinical trial (NCT03651271), patients with various advanced solid tumors were assessed for changes in intratumoral CD8 percentages and their response to ICI. Patients were grouped based on tumoral CD8 levels: those with CD8 <15% (CD8-low) received nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA4) and those with CD8 ≥15% (CD8-high) received nivolumab monotherapy. 79 patients (72 CD8-low and 7 CD8-high) were treated. The disease control rate was 25.0% (18/72; 95% CI: 15.8–35.2) in CD8-low and 14.3% (1/7; 95% CI: 1.1–43.8) in CD8-high. Tumors from 35.9% (14/39; 95% CI: 21.8–51.4) of patients converted from CD8 <15% pretreatment to ≥15% after treatment. Multiomic analyses showed that CD8-low responders had an inflammatory tumor microenvironment pretreatment, enhanced by an influx of CD8 T cells, CD4 T cells, B cells, and macrophages upon treatment. These findings reveal crucial pan-cancer immunological features for ICI response in patients with metastatic disease.

Rescue Of Scn5a Mis-Splicing Does Not Improve The Structural And Functional Heart Defects Of A Dm1 Heart Mouse Model, Larissa Nitschke, Rong-Chi Hu, Andrew N Miller, Thomas A Cooper

Faculty, Staff and Students Publications

Myotonic Dystrophy Type 1 (DM1) is an autosomal dominant multisystemic disorder for which cardiac features, including conduction delays and arrhythmias, are the second leading cause of disease mortality. DM1 is caused by expanded CTG repeats in the 3' untranslated region of the DMPK gene. Transcription of the expanded DMPK allele produces mRNAs containing long tracts of CUG repeats, which sequester the Muscleblind-Like family of RNA binding proteins, leading to their loss-of-function and the dysregulation of alternative splicing. A well-characterized mis-regulated splicing event in the DM1 heart is the increased inclusion of SCN5A exon 6A rather than the mutually exclusive exon …

An Iron-Rich Subset Of Macrophages Promotes Tumor Growth Through A Bach1-Ednrb Axis, Ian W Folkert, William A Molina Arocho, Tsun Ki Jerrick To, Samir Devalaraja, Irene S Molina, Jason Shoush, Hesham Mohei, Li Zhai, Md Naushad Akhtar, Veena Kochat, Emre Arslan, Alexander J Lazar, Khalida Wani, William P Israel, Zhan Zhang, Venkata S Chaluvadi, Robert J Norgard, Ying Liu, Ashley M Fuller, Mai T Dang, Robert E Roses, Giorgos C Karakousis, John T Miura, Douglas L Fraker, T S Karin Eisinger-Mathason, M Celeste Simon, Kristy Weber, Kai Tan, Yi Fan, Kunal Rai, Malay Haldar

Faculty, Staff and Student Publications

We define a subset of macrophages in the tumor microenvironment characterized by high intracellular iron and enrichment of heme and iron metabolism genes. These iron-rich tumor-associated macrophages (iTAMs) supported angiogenesis and immunosuppression in the tumor microenvironment and were conserved between mice and humans. iTAMs comprise two additional subsets based on gene expression profile and location-perivascular (pviTAM) and stromal (stiTAM). We identified the endothelin receptor type B (Ednrb) as a specific marker of iTAMs and found myeloid-specific deletion of Ednrb to reduce tumor growth and vascular density. Further studies identified the transcription factor Bach1 as a repressor of the iTAM transcriptional …

Longitudinal Single-Cell Profiling Reveals Molecular Heterogeneity And Tumor-Immune Evolution In Refractory Mantle Cell Lymphoma, Shaojun Zhang, Vivian Changying Jiang, Guangchun Han, Dapeng Hao, Junwei Lian, Yang Liu, Qingsong Cai, Rongjia Zhang, Joseph Mcintosh, Ruiping Wang, Minghao Dang, Enyu Dai, Yuanxin Wang, David Santos, Maria Badillo, Angela Leeming, Zhihong Chen, Kimberly Hartig, John Bigcal, Jia Zhou, Rashmi Kanagal-Shamanna, Chi Young Ok, Hun Lee, Raphael E Steiner, Jianhua Zhang, Xingzhi Song, Ranjit Nair, Sairah Ahmed, Alma Rodriquez, Selvi Thirumurthi, Preetesh Jain, Nicolaus Wagner-Bartak, Holly Hill, Krystle Nomie, Christopher Flowers, Andrew Futreal, Linghua Wang, Michael Wang

Faculty, Staff and Student Publications

The mechanisms driving therapeutic resistance and poor outcomes of mantle cell lymphoma (MCL) are incompletely understood. We characterize the cellular and molecular heterogeneity within and across patients and delineate the dynamic evolution of tumor and immune cell compartments at single cell resolution in longitudinal specimens from ibrutinib-sensitive patients and non-responders. Temporal activation of multiple cancer hallmark pathways and acquisition of 17q are observed in a refractory MCL. Multi-platform validation is performed at genomic and cellular levels in PDX models and larger patient cohorts. We demonstrate that due to 17q gain, BIRC5/survivin expression is upregulated in resistant MCL tumor cells and …

Author Correction: Longitudinal Single-Cell Profiling Reveals Molecular Heterogeneity And Tumor-Immune Evolution In Refractory Mantle Cell Lymphoma, Shaojun Zhang, Vivian Changying Jiang, Guangchun Han, Dapeng Hao, Junwei Lian, Yang Liu, Qingsong Cai, Rongjia Zhang, Joseph Mcintosh, Ruiping Wang, Minghao Dang, Enyu Dai, Yuanxin Wang, David Santos, Maria Badillo, Angela Leeming, Zhihong Chen, Kimberly Hartig, John Bigcal, Jia Zhou, Rashmi Kanagal-Shamanna, Chi Young Ok, Hun Lee, Raphael E Steiner, Jianhua Zhang, Xingzhi Song, Ranjit Nair, Sairah Ahmed, Alma Rodriquez, Selvi Thirumurthi, Preetesh Jain, Nicolaus Wagner-Bartak, Holly Hill, Krystle Nomie, Christopher Flowers, Andrew Futreal, Linghua Wang, Michael Wang

Faculty, Staff and Student Publications

No abstract provided.

Conserved Signaling Modules Regulate Filamentous Growth In Fungi: A Model For Eukaryotic Cell Differentiation, Matthew D Vandermeulen, Michael C Lorenz, Paul J Cullen

Faculty, Staff and Student Publications

Eukaryotic organisms are composed of different cell types with defined shapes and functions. Specific cell types are produced by the process of cell differentiation, which is regulated by signal transduction pathways. Signaling pathways regulate cell differentiation by sensing cues and controlling the expression of target genes whose products generate cell types with specific attributes. In studying how cells differentiate, fungi have proved valuable models because of their ease of genetic manipulation and striking cell morphologies. Many fungal species undergo filamentous growth-a specialized growth pattern where cells produce elongated tube-like projections. Filamentous growth promotes expansion into new environments, including invasion into …

Alzheimer’S Disease Risk Gene Cd2ap Is A Dose-Sensitive Determinant Of Synaptic Structure And Plasticity, Matea Pavešković, Ruth B De-Paula, Shamsideen A Ojelade, Evelyne K Tantry, Mikhail Y Kochukov, Suyang Bao, Surabi Veeraragavan, Alexandra R Garza, Snigdha Srivastava, Si-Yuan Song, Masashi Fujita, Duc M Duong, David A Bennett, Philip L De Jager, Nicholas T Seyfried, Mary E Dickinson, Jason D Heaney, Benjamin R Arenkiel, Joshua M Shulman

Duncan NRI Faculty and Staff Publications

CD2-Associated protein (CD2AP) is a candidate susceptibility gene for Alzheimer's disease, but its role in the mammalian central nervous system remains largely unknown. We show that CD2AP protein is broadly expressed in the adult mouse brain, including within cortical and hippocampal neurons, where it is detected at pre-synaptic terminals. Deletion of Cd2ap altered dendritic branching and spine density, and impaired ubiquitin-proteasome system activity. Moreover, in mice harboring either one or two copies of a germline Cd2ap null allele, we noted increased paired-pulse facilitation at hippocampal Schaffer-collateral synapses, consistent with a haploinsufficient requirement for pre-synaptic release. Whereas conditional Cd2ap knockout in …

The Fundamentals Of Antiseizure Medications: A Through Z, Timothy E Welty, Jeannine M Conway, Jacquelyn Bainbridge, Kristen Park, David G Vossler, Archana A Patel, Alica Goldman

Faculty, Staff and Students Publications

Since bromides were first used in 1857 to treat epilepsy, numerous antiseizure medications (ASM) have been developed. Many of these are available for the treatment of epilepsy and status epilepticus today. With so many ASM available, questions arise as to whether all of these medications are needed and when should they be used. As precision medicine begins to play a larger role in determining targeted treatments for specific types of epilepsy, a complete understanding of various medications is needed. Additionally, access to several of these medications can be limited in the United States and are especially limited globally. All these …

Trβ Activation Confers At2-To-At1 Cell Differentiation And Anti-Fibrosis During Lung Repair Via Klf2 And Cebpa, Xin Pan, Lan Wang, Juntang Yang, Yingge Li, Min Xu, Chenxi Liang, Lulu Liu, Zhongzheng Li, Cong Xia, Jiaojiao Pang, Mengyuan Wang, Meng Li, Saiya Guo, Peishuo Yan, Chen Ding, Ivan O Rosas, Guoying Yu

Faculty, Staff and Students Publications

Aberrant repair underlies the pathogenesis of pulmonary fibrosis while effective strategies to convert fibrosis to normal regeneration are scarce. Here, we found that thyroid hormone is decreased in multiple models of lung injury but is essential for lung regeneration. Moreover, thyroid hormone receptor α (TRα) promotes cell proliferation, while TRβ fuels cell maturation in lung regeneration. Using a specific TRβ agonist, sobetirome, we demonstrate that the anti-fibrotic effects of thyroid hormone mainly rely on TRβ in mice. Cellularly, TRβ activation enhances alveolar type-2 (AT2) cell differentiation into AT1 cell and constrains AT2 cell hyperplasia. Molecularly, TRβ activation directly regulates the …

Genomics Of Natural Populations: Gene Conversion Events Reveal Selected Genes Within The Inversions Of Drosophila Pseudoobscura, Stephen W Schaeffer, Stephen Richards, Zachary L Fuller

Faculty, Staff and Students Publications

When adaptive phenotypic variation or quantitative trait loci map within an inverted segment of a chromosome, researchers often despair because the suppression of crossing over will prevent the discovery of selective target genes that established the rearrangement. If an inversion polymorphism is old enough, then the accumulation of gene conversion tracts offers the promise that quantitative trait loci or selected loci within inversions can be mapped. The inversion polymorphism of Drosophila pseudoobscura is a model system to show that gene conversion analysis is a useful tool for mapping selected loci within inversions. D. pseudoobscura has over 30 different chromosomal arrangements …

Sars-Cov-2 Vaccine Improved Hemostasis Of A Patient With Protein S Deficiency: A Case Report, Mohammad A. Mohammad, Alaa Malik, Lekha Thangada, Diana Polanía-Villanueva, Jovanny Zabaleta, Rinku Majumder

School of Medicine Faculty Publications

A 16-year-old patient, while an infant, incurred right-sided hemiparesis and had difficulty breast feeding. She was later diagnosed with a neonatal stroke and her genetic testing showed a missense mutation in her PROS1 (Protein S) gene. Both her grandfather and father, but not her mother, had hereditary Protein S (PS) deficiency. The patient was not prescribed any mediation due to her young age but was frequently checked by her physician. The patient’s plasma was first collected at the age of 13, and the isolated plasma from the patient and her father were analyzed by aPTT, thrombin generation, and enzyme-linked immunosorbent …

Multiregional Transcriptomic Profiling Provides Improved Prognostic Insight In Localized Non-Small Cell Lung Cancer, Chenyang Li, Thinh T Nguyen, Jian-Rong Li, Xingzhi Song, Junya Fujimoto, Latasha Little, Curtis Gumb, Chi-Wan B Chow, Ignacio I Wistuba, Andrew P Futreal, Jianhua Zhang, Shawna M Hubert, John V Heymach, Jia Wu, Christopher I Amos, Jianjun Zhang, Chao Cheng

Faculty, Staff and Student Publications

Lung Cancer remains the leading cause of cancer deaths in the USA and worldwide. Non-small cell lung cancer (NSCLC) harbors high transcriptomic intratumor heterogeneity (RNA-ITH) that limits the reproducibility of expression-based prognostic models. In this study, we used multiregional RNA-seq data (880 tumor samples from 350 individuals) from both public (TRACERx) and internal (MDAMPLC) cohorts to investigate the effect of RNA-ITH on prognosis in localized NSCLC at the gene, signature, and tumor microenvironment levels. At the gene level, the maximal expression of hazardous genes (expression negatively associated with survival) but the minimal expression of protective genes (expression positively associated with …

Pre-Procedural Topical Antisepsis In The Neonate: A Systematic Review Evaluating Risk Factors For Skin Injury, Carly Mulinda, Sana Suhail, Bronwyn Sutherland, Christine T Lauren, Raegan D Hunt

Library Staff Publications

BACKGROUND: Pre-procedural antisepsis is a critical component of hospital-acquired infection prevention in the neonatal intensive care unit (NICU). However, broadly utilized topical antiseptic agents pose an elevated risk of disruption to neonatal skin integrity, and evidence-based guidelines are lacking. This systematic review of the literature sought to assess and characterize the predisposing risk factors for and types of neonatal skin injury from topical antiseptic agents.

METHODS: A systematic search of Medline Ovid, Embase, Web of Science, CINAHL, and Cochrane Library was conducted, including academic literature providing data on neonatal skin injuries related to topical antisepsis in the NICU.

RESULTS: A …

The History Of Chromosomal Instability In Genome-Doubled Tumors, Toby M Baker, Siqi Lai, Andrew R Lynch, Tom Lesluyes, Haixi Yan, Huw A Ogilvie, Annelien Verfaillie, Stefan Dentro, Amy L Bowes, Nischalan Pillay, Adrienne M Flanagan, Charles Swanton, Paul T Spellman, Maxime Tarabichi, Peter Van Loo

Faculty, Staff and Student Publications

Tumors frequently display high chromosomal instability and contain multiple copies of genomic regions. Here, we describe Gain Route Identification and Timing In Cancer (GRITIC), a generic method for timing genomic gains leading to complex copy number states, using single-sample bulk whole-genome sequencing data. By applying GRITIC to 6,091 tumors, we found that non-parsimonious evolution is frequent in the formation of complex copy number states in genome-doubled tumors. We measured chromosomal instability before and after genome duplication in human tumors and found that late genome doubling was followed by an increase in the rate of copy number gain. Copy number gains …

Biologic And Clinical Analysis Of Childhood Gamma Delta T-All Identifies Lmo2/Stag2 Rearrangements As Extremely High Risk, Shunsuke Kimura, Chun Shik Park, Lindsey E Montefiori, Ilaria Iacobucci, Petri Pölönen, Qingsong Gao, Elizabeth D Arnold, Andishe Attarbaschi, Anthony Brown, Barbara Buldini, Kenneth J Caldwell, Yunchao Chang, Chelsey Chen, Cheng Cheng, Zhongshan Cheng, John Choi, Valentino Conter, Kristine R Crews, Hester A De Groot-Kruseman, Takao Deguchi, Mariko Eguchi, Hannah E Muhle, Sarah Elitzur, Gabriele Escherich, Burgess B Freeman, Zhaohui Gu, Katie Han, Keizo Horibe, Toshihiko Imamura, Sima Jeha, Motohiro Kato, Kean H Chiew, Tanya Khan, Michal Kicinski, Stefan Köhrer, Steven M Kornblau, Rishi S Kotecha, Chi-Kong Li, Yen-Chun Liu, Franco Locatelli, Selina M Luger, Elisabeth M Paietta, Atsushi Manabe, Hanne V Marquart, Riccardo Masetti, Mellissa Maybury, Pauline Mazilier, Jules P P Meijerink, Sharnise Mitchell, Takako Miyamura, Andrew S Moore, Koichi Oshima, Katarzyna Pawinska-Wasikowska, Rob Pieters, Mollie S Prater, Shondra M Pruett-Miller, Ching-Hon Pui, Chunxu Qu, Michaela Reiterova, Noemi Reyes, Kathryn G Roberts, Jacob M Rowe, Atsushi Sato, Kjeld Schmiegelow, Martin Schrappe, Shuhong Shen, Szymon Skoczeń, Orietta Spinelli, Jan Stary, Michael Svaton, Masatoshi Takagi, Junko Takita, Yanjing Tang, David T Teachey, Paul G Thomas, Daisuke Tomizawa, Jan Trka, Elena Varotto, Tiffaney L Vincent, Jun J Yang, Allen E J Yeoh, Yinmei Zhou, Martin Zimmermann, Hiroto Inaba, Charles G Mullighan

Faculty, Staff and Student Publications

Acute lymphoblastic leukemia expressing the gamma delta T-cell receptor (γδ T-ALL) is a poorly understood disease. We studied 200 children with γδ T-ALL from 13 clinical study groups to understand the clinical and genetic features of this disease. We found age and genetic drivers were significantly associated with outcome. γδ T-ALL diagnosed in children under 3 years of age was extremely high-risk and enriched for genetic alterations that result in both LMO2 activation and STAG2 inactivation. Mechanistically, using patient samples and isogenic cell lines, we show that inactivation of STAG2 profoundly perturbs chromatin organization by altering enhancer-promoter looping, resulting in …

Tissue-Agnostic Targeting Of Neurotrophic Tyrosine Receptor Kinase Fusions: Current Approvals And Future Directions, Mohamed A Gouda, Kyaw Z Thein, David S Hong

Faculty, Staff and Student Publications

NTRK fusions are oncogenic drivers for multiple tumor types. Therefore, the development of selective tropomyosin receptor kinase (TRK) inhibitors, including larotrectinib and entrectinib, has been transformative in the context of clinical management, given the high rates of responses to these drugs, including intracranial responses in patients with brain metastases. Given their promising activity in pan-cancer cohorts, larotrectinib and entrectinib received U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval for tissue-agnostic indications in patients with advanced solid tumors harboring NTRK fusions. The safety profiles for both drugs are quite manageable, although neurotoxicity driven by the on-target inhibition …

Cd28 Costimulation Augments Car Signaling In Nk Cells Via The Lck/Cd3Ζ/Zap70 Signaling Axis, Sunil Acharya, Rafet Basar, May Daher, Hind Rafei, Ping Li, Nadima Uprety, Emily Ensley, Mayra Shanley, Bijender Kumar, Pinaki P Banerjee, Luciana Melo Garcia, Paul Lin, Vakul Mohanty, Kun H Kim, Xianli Jiang, Yuchen Pan, Ye Li, Bin Liu, Ana K Nunez Cortes, Chenyu Zhang, Mohsen Fathi, Ali Rezvan, Melisa J Montalvo, Sophia L Cha, Francia Reyes-Silva, Rejeena Shrestha, Xingliang Guo, Kiran Kundu, Alexander Biederstädt, Luis Muniz-Feliciano, Gary M Deyter, Mecit Kaplan, Xin R Jiang, Enli Liu, Antrix Jain, Janos Roszik, Natalie W Fowlkes, Luisa M Solis Soto, Maria G Raso, Joseph D Khoury, Pei Lin, Francisco Vega, Navin Varadarajan, Ken Chen, David Marin, Elizabeth J Shpall, Katayoun Rezvani

Faculty, Staff and Student Publications

Multiple factors in the design of a chimeric antigen receptor (CAR) influence CAR T-cell activity, with costimulatory signals being a key component. Yet, the impact of costimulatory domains on the downstream signaling and subsequent functionality of CAR-engineered natural killer (NK) cells remains largely unexplored. Here, we evaluated the impact of various costimulatory domains on CAR-NK cell activity, using a CD70-targeting CAR. We found that CD28, a costimulatory molecule not inherently present in mature NK cells, significantly enhanced the antitumor efficacy and long-term cytotoxicity of CAR-NK cells both in vitro and in multiple xenograft models of hematologic and solid tumors. Mechanistically, …

Multi-Ancestry Gwas Meta-Analyses Of Lung Cancer Reveal Susceptibility Loci And Elucidate Smoking-Independent Genetic Risk, Bryan R Gorman, Sun-Gou Ji, Michael Francis, Anoop K Sendamarai, Yunling Shi, Poornima Devineni, Uma Saxena, Elizabeth Partan, Andrea K Devito, Jinyoung Byun, Younghun Han, Xiangjun Xiao, Don D Sin, Wim Timens, Jennifer Moser, Sumitra Muralidhar, Rachel Ramoni, Rayjean J Hung, James D Mckay, Yohan Bossé, Ryan Sun, Christopher I Amos, Va Million Veteran Program, Saiju Pyarajan

Faculty, Staff and Student Publications

Lung cancer remains the leading cause of cancer mortality, despite declining smoking rates. Previous lung cancer GWAS have identified numerous loci, but separating the genetic risks of lung cancer and smoking behavioral susceptibility remains challenging. Here, we perform multi-ancestry GWAS meta-analyses of lung cancer using the Million Veteran Program cohort (approximately 95% male cases) and a previous study of European-ancestry individuals, jointly comprising 42,102 cases and 181,270 controls, followed by replication in an independent cohort of 19,404 cases and 17,378 controls. We then carry out conditional meta-analyses on cigarettes per day and identify two novel, replicated loci, including the 19p13.11 …

Identification Of An Ionic Mechanism For Erα-Mediated Rapid Excitation In Neurons, Meng Yu, Na Yin, Bing Feng, Peiyu Gao, Kaifan Yu, Hesong Liu, Hailan Liu, Yongxiang Li, Olivia Z Ginnard, Kristine M Conde, Mengjie Wang, Xing Fang, Longlong Tu, Jonathan C Bean, Qingzhuo Liu, Yue Deng, Yuxue Yang, Junying Han, Sanika V Jossy, Megan L Burt, Huey Zhong Wong, Yongjie Yang, Benjamin R Arenkiel, Yang He, Shaodong Guo, Pierre Gourdy, Jean-Francois Arnal, Francoise Lenfant, Zhao Wang, Chunmei Wang, Yanlin He, Yong Xu

Faculty, Staff and Students Publications

The major female ovarian hormone, 17β-estradiol (E2), can alter neuronal excitability within milliseconds to regulate a variety of physiological processes. Estrogen receptor-α (ERα), classically known as a nuclear receptor, exists as a membrane-bound receptor to mediate this rapid action of E2, but the ionic mechanisms remain unclear. Here, we show that a membrane channel protein, chloride intracellular channel protein-1 (Clic1), can physically interact with ERα with a preference to the membrane-bound ERα. Clic1-mediated currents can be enhanced by E2 and reduced by its depletion. In addition, Clic1 currents are required to mediate the E2-induced rapid excitations in multiple brain ERα …

Terminal Differentiation Precedes Functional Circuit Integration In The Peduncle Neurons In Regenerating Hydra Vulgaris, Alondra Escobar, Soonyoung Kim, Abby S Primack, Guillaume Duret, Celina E Juliano, Jacob T Robinson

Faculty, Staff and Students Publications

Understanding how neural circuits are regenerated following injury is a fundamental question in neuroscience. Hydra is a powerful model for studying this process because it has a simple neural circuit structure, significant and reproducible regenerative abilities, and established methods for creating transgenics with cell-type-specific expression. While Hydra is a long-standing model for regeneration and development, little is known about how neural activity and behavior is restored following significant injury. In this study, we ask if regenerating neurons terminally differentiate prior to reforming functional neural circuits, or if neural circuits regenerate first and then guide the constituent naive cells toward their …

Default Mode Network Electrophysiological Dynamics And Causal Role In Creative Thinking, Eleonora Bartoli, Ethan Devara, Huy Q Dang, Rikki Rabinovich, Raissa K Mathura, Adrish Anand, Bailey R Pascuzzi, Joshua Adkinson, Yoed N Kenett, Kelly R Bijanki, Sameer A Sheth, Ben Shofty

Faculty, Staff and Students Publications

The default mode network (DMN) is a widely distributed, intrinsic brain network thought to play a crucial role in internally directed cognition. The present study employs stereo-EEG in 13 human patients, obtaining high resolution neural recordings across multiple canonical DMN regions during two processes that have been associated with creative thinking: spontaneous and divergent thought. We probe these two DMN-associated higher cognitive functions through mind wandering and alternate uses tasks, respectively. Our results reveal DMN recruitment during both tasks, as well as a task-specific dissociation in spatiotemporal response dynamics. When compared to the fronto-parietal network, DMN activity was characterized by …