Medical Specialties Commons^™

Single-Cell Sequencing Of Ascites Fluid Illustrates Heterogeneity And Therapy-Induced Evolution During Gastric Cancer Peritoneal Metastasis, Xuan-Zhang Huang, Min-Jiao Pang, Jia-Yi Li, Han-Yu Chen, Jing-Xu Sun, Yong-Xi Song, Hong-Jie Ni, Shi-Yu Ye, Shi Bai, Teng-Hui Li, Xin-Yu Wang, Jing-Yuan Lu, Jin-Jia Yang, Xun Sun, Jason C Mills, Zhi-Feng Miao, Zhen-Ning Wang

Faculty, Staff and Students Publications

Peritoneal metastasis is the leading cause of death for gastrointestinal cancers. The native and therapy-induced ascites ecosystems are not fully understood. Here, we characterize single-cell transcriptomes of 191,987 ascites cancer/immune cells from 35 patients with/without gastric cancer peritoneal metastasis (GCPM). During GCPM progression, an increase is seen of monocyte-like dendritic cells (DCs) that are pro-angiogenic with reduced antigen-presenting capacity and correlate with poor gastric cancer (GC) prognosis. We also describe the evolution of monocyte-like DCs and regulatory and proliferative T cells following therapy. Moreover, we track GC evolution, identifying high-plasticity GC clusters that exhibit a propensity to shift to a …

Ambient Oxygen Levels Regulate Intestinal Dysbiosis And Gvhd Severity After Allogeneic Stem Cell Transplantation, Keisuke Seike, Anders Kiledal, Hideaki Fujiwara, Israel Henig, Marina Burgos Da Silva, Marcel R M Van Den Brink, Robert Hein, Matthew Hoostal, Chen Liu, Katherine Oravecz-Wilson, Emma Lauder, Lu Li, Yaping Sun, Thomas M Schmidt, Yatrik M Shah, Robert R Jenq, Gregory Dick, Pavan Reddy

Faculty, Staff and Student Publications

The severity of T cell-mediated gastrointestinal (GI) diseases such as graft-versus-host disease (GVHD) and inflammatory bowel diseases correlates with a decrease in the diversity of the host gut microbiome composition characterized by loss of obligate anaerobic commensals. The mechanisms underpinning these changes in the microbial structure remain unknown. Here, we show in multiple specific pathogen-free (SPF), gnotobiotic, and germ-free murine models of GI GVHD that the initiation of the intestinal damage by the pathogenic T cells altered ambient oxygen levels in the GI tract and caused dysbiosis. The change in oxygen levels contributed to the severity of intestinal pathology in …

Harnessing Transcriptionally Driven Chromosomal Instability Adaptation To Target Therapy-Refractory Lethal Prostate Cancer., Brittiny Dhital, Sandra Santasusagna, Perumalraja Kirthika, Michael Xu, Peiyao Li, Marc Carceles-Cordon, Rajesh K. Soni, Zhuoning Li, Ronald C. Hendrickson, Matthew J. Schiewer, William K. Kelly, Cora N. Sternberg, Jun Luo, Amaia Lujambio, Carlos Cordon-Cardo, Monica Alvarez-Fernandez, Marcos Malumbres, Haojie Huang, Adam Ertel, Josep Domingo-Domenech, Veronica Rodriguez-Bravo

Kimmel Cancer Center Papers, Presentations, and Grand Rounds

Metastatic prostate cancer (PCa) inevitably acquires resistance to standard therapy preceding lethality. Here, we unveil a chromosomal instability (CIN) tolerance mechanism as a therapeutic vulnerability of therapy-refractory lethal PCa. Through genomic and transcriptomic analysis of patient datasets, we find that castration and chemotherapy-resistant tumors display the highest CIN and mitotic kinase levels. Functional genomics screening coupled with quantitative phosphoproteomics identify MASTL kinase as a survival vulnerability specific of chemotherapy-resistant PCa cells. Mechanistically, MASTL upregulation is driven by transcriptional rewiring mechanisms involving the non-canonical transcription factors androgen receptor splice variant 7 and E2F7 in a circuitry that restrains deleterious CIN and …

Survival Improvement For Patients With Metastatic Colorectal Cancer Over Twenty Years, Fadl A Zeineddine, Mohammad A Zeineddine, Abdelrahman Yousef, Yue Gu, Saikat Chowdhury, Arvind Dasari, Ryan W Huey, Benny Johnson, Bryan Kee, Michael S Lee, Maria Pia Morelli, Van K Morris, Michael J Overman, Christine Parseghian, Kanwal Raghav, Jason Willis, Robert A Wolff, Yoshikuni Kawaguchi, Jean-Nicolas Vauthey, Ryan Sun, Scott Kopetz, John Paul Shen

Faculty, Staff and Student Publications

Over the past two decades of successive clinical trials in metastatic colorectal cancer (CRC), the median overall survival of both control and experimental arms has steadily improved. However, the incremental change in survival for metastatic CRC patients not treated on trial has not yet been quantified. We performed a retrospective review of 1420 patients with de novo metastatic CRC who received their primary treatment at the University of Texas M.D. Anderson Cancer Center (UTMDACC) from 2004 through 2019. Median OS was roughly stable for patients diagnosed between 2004 and 2012 (22.6 months) but since has steadily improved for those diagnosed …

Computational Investigation Of A Series Of Small Molecules As Potential Compounds For Lysyl Hydroxylase-2 (Lh2) Inhibition, Yazdan Maghsoud, Erik Antonio Vázquez-Montelongo, Xudong Yang, Chengwen Liu, Zhifeng Jing, Juhoon Lee, Matthew Harger, Ally K Smith, Miguel Espinoza, Hou-Fu Guo, Jonathan M Kurie, Kevin N Dalby, Pengyu Ren, G Andrés Cisneros

Faculty, Staff and Student Publications

The catalytic function of lysyl hydroxylase-2 (LH2), a member of the Fe(II)/αKG-dependent oxygenase superfamily, is to catalyze the hydroxylation of lysine to hydroxylysine in collagen, resulting in stable hydroxylysine aldehyde-derived collagen cross-links (HLCCs). Reports show that high amounts of LH2 lead to the accumulation of HLCCs, causing fibrosis and specific types of cancer metastasis. Some members of the Fe(II)/αKG-dependent family have also been reported to have intramolecular O

Rna Profiling Of Human Dorsal Root Ganglia Reveals Sex Differences In Mechanisms Promoting Neuropathic Pain, Pradipta R Ray, Stephanie Shiers, James P Caruso, Diana Tavares-Ferreira, Ishwarya Sankaranarayanan, Megan L Uhelski, Yan Li, Robert Y North, Claudio Tatsui, Gregory Dussor, Michael D Burton, Patrick M Dougherty, Theodore J Price

Faculty, Staff and Student Publications

Neuropathic pain is a leading cause of high-impact pain, is often disabling and is poorly managed by current therapeutics. Here we focused on a unique group of neuropathic pain patients undergoing thoracic vertebrectomy where the dorsal root ganglia is removed as part of the surgery allowing for molecular characterization and identification of mechanistic drivers of neuropathic pain independently of preclinical models. Our goal was to quantify whole transcriptome RNA abundances using RNA-seq in pain-associated human dorsal root ganglia from these patients, allowing comprehensive identification of molecular changes in these samples by contrasting them with non-pain-associated dorsal root ganglia. We sequenced …

Cd70 Is A Therapeutic Target Upregulated In Emt-Associated Egfr Tyrosine Kinase Inhibitor Resistance, Monique B Nilsson, Yan Yang, Simon Heeke, Sonia A Patel, Alissa Poteete, Hibiki Udagawa, Yasir Y Elamin, Cesar A Moran, Yukie Kashima, Thiruvengadam Arumugam, Xiaoxing Yu, Xiaoyang Ren, Lixia Diao, Li Shen, Qi Wang, Minying Zhang, Jacqulyne P Robichaux, Chunhua Shi, Allyson N Pfeil, Hai Tran, Don L Gibbons, Jason Bock, Jing Wang, John D Minna, Susumu S Kobayashi, Xiuning Le, John V Heymach

Faculty, Staff and Student Publications

Effective therapeutic strategies are needed for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations that acquire resistance to EGFR tyrosine kinase inhibitors (TKIs) mediated by epithelial-to-mesenchymal transition (EMT). We investigate cell surface proteins that could be targeted by antibody-based or adoptive cell therapy approaches and identify CD70 as being highly upregulated in EMT-associated resistance. Moreover, CD70 upregulation is an early event in the evolution of resistance and occurs in drug-tolerant persister cells (DTPCs). CD70 promotes cell survival and invasiveness, and stimulation of CD70 triggers signal transduction pathways known to be re-activated with acquired TKI resistance. …

Cell-Membrane-Coated Nanoparticles For Targeted Drug Delivery To The Brain For The Treatment Of Neurological Diseases, Jianzhuang Li, Yanhao Wei, Chunlin Zhang, Rentang Bi, Yanmei Qiu, Yanan Li, Bo Hu

Faculty, Staff and Student Publications

Neurological diseases (NDs) are a significant cause of disability and death in the global population. However, effective treatments still need to be improved for most NDs. In recent years, cell-membrane-coated nanoparticles (CMCNPs) as drug-targeting delivery systems have become a research hotspot. Such a membrane-derived, nano drug-delivery system not only contributes to avoiding immune clearance but also endows nanoparticles (NPs) with various cellular and functional mimicries. This review article first provides an overview of the function and mechanism of single/hybrid cell-membrane-derived NPs. Then, we highlight the application and safety of CMCNPs in NDs. Finally, we discuss the challenges and opportunities in …

Visualization Of Preimplantation Uterine Fluid Absorption In Mice Using Alexa Fluor™ 488 Hydrazide†, Yuehuan Li, Taylor Elijah Martin, Jonathan Matthew Hancock, Rong Li, Suvitha Viswanathan, John P Lydon, Yi Zheng, Xiaoqin Ye

Faculty, Staff and Students Publications

Uterine fluid plays important roles in supporting early pregnancy events and its timely absorption is critical for embryo implantation. In mice, its volume is maximum on day 0.5 post-coitum (D0.5) and approaches minimum upon embryo attachment ~D4.0. Its secretion and absorption in ovariectomized rodents were shown to be promoted by estrogen and progesterone (P4), respectively. The temporal mechanisms in preimplantation uterine fluid absorption remain to be elucidated. We have established an approach using intraluminally injected Alexa Fluor™ 488 Hydrazide (AH) in preimplantation control (RhoAf/f) and P4-deficient RhoAf/fPgrCre/+ mice. In control mice, bulk entry (seen as smeared cellular staining) via uterine …

Evaluation Of Genetic Alterations In Hereditary Cancer Susceptibility Genes In The Ashkenazi Jewish Women Community Of Mexico, Clara Estela Díaz-Velásquez, Rina Gitler, Adriana Antoniano, Ronny Kershenovich Sefchovich, Aldo Hugo De La Cruz-Montoya, Héctor Martínez-Gregorio, Ernesto Arturo Rojas-Jiménez, Ricardo Cortez Cardoso Penha, Luis Ignacio Terrazas, Talia Wegman-Ostrosky, Ephrat Levi-Lahad, Jovanny Zabaleta, Sandra Perdomo, Felipe Vaca-Paniagua

School of Medicine Faculty Publications

Background: Individuals of Ashkenazi Jewish ancestry have been identified as having higher prevalence of specific pathogenic variants associated with susceptibility to specific rare and chronic diseases. In Mexico, the prevalence and composition of rare cancer predisposing germline variants in Ashkenazi Jewish individuals has not been evaluated. Aim and methods: We aimed to evaluate the prevalence of pathogenic variants by massive parallel sequencing in a panel of 143 cancer-predisposing genes in 341 women from the Ashkenazi Jewish community of Mexico, who were contacted and invited to participate in the study through the ALMA Foundation for Cancer Reconstruction. Pre- and posttest genetic …

In Vivo Gene Delivery Into Mouse Mammary Epithelial Cells Through Mammary Intraductal Injection, Wen Bu, Yi Li

Faculty, Staff and Students Publications

Mouse mammary glands comprise ductal trees, which are lined by epithelial cells and have one opening at the tip of each nipple. The epithelial cells play a major role in mammary gland function and are the origin of most mammary tumors. Introducing genes of interest into mouse mammary epithelial cells is a critical step in evaluating gene function in epithelial cells and generating mouse mammary tumor models. This goal can be accomplished through the intraductal injection of a viral vector carrying the genes of interest into the mouse mammary ductal tree. The injected virus subsequently infects mammary epithelial cells, bringing …

Dual-Specificity Phosphatases 22-Deficient T Cells Contribute To The Pathogenesis Of Ankylosing Spondylitis, Ming-Han Chen, Huai-Chia Chuang, Yi-Chen Yeh, Chung-Tei Chou, Tse-Hua Tan

Children’s Nutrition Research Center Staff Publications

Background: Dual-specificity phosphatases (DUSPs) can dephosphorylate both tyrosine and serine/threonine residues of their substrates and regulate T cell-mediated immunity and autoimmunity. The aim of this study was to investigate the potential roles of DUSPs in ankylosing spondylitis (AS).

Methods: Sixty AS patients and 45 healthy controls were enrolled in this study. Associations of gene expression of 23 DUSPs in peripheral T cells with inflammatory cytokine gene expression and disease activity of AS were analyzed. Finally, we investigated whether the characteristics of AS are developed in DUSP-knockout mice.

Results: The mRNA levels of DUSP4, DUSP5, DUSP6, DUSP7, and DUSP14 in peripheral …

Phase Ib Study Of Telisotuzumab Vedotin In Combination With Erlotinib In Patients With C-Met Protein-Expressing Non-Small-Cell Lung Cancer, D Ross Camidge, Fabrice Barlesi, Jonathan W Goldman, Daniel Morgensztern, Rebecca Heist, Everett Vokes, Alex Spira, Eric Angevin, Wu-Chou Su, David S Hong, John H Strickler, Monica Motwani, Martin Dunbar, Apurvasena Parikh, Elysa Noon, Vincent Blot, Jun Wu, Karen Kelly

Faculty, Staff and Student Publications

Purpose: Overexpression of c-Met protein and epidermal growth factor receptor (EGFR) mutations can co-occur in non-small-cell lung cancer (NSCLC), providing strong rationale for dual targeting. Telisotuzumab vedotin (Teliso-V), a first-in-class antibody-drug conjugate targeting c-Met, has shown a tolerable safety profile and antitumor activity as monotherapy. Herein, we report the results of a phase Ib study (ClinicalTrials.gov identifier: NCT02099058) evaluating Teliso-V plus erlotinib, an EGFR tyrosine kinase inhibitor (TKI), in patients with c-Met-positive (+) NSCLC.

Patients and methods: This study evaluated Teliso-V (2.7 mg/kg once every 21 days) plus erlotinib (150 mg once daily) in adult patients (age …

Associations Of Financial Toxicity With Symptoms And Unplanned Healthcare Utilization Among Cancer Patients Taking Oral Chemotherapy At Home: A Prospective Observational Study, Yongfeng Chen, Zhenxiang Chen, Haiyun Jin, Yanrong Chen, Jinbing Bai, Guifen Fu

Faculty, Staff and Student Publications

Background: Cancer patients with financial toxicity experience psychological distress and often miss medical appointments and quit treatments early, which could be a barrier to the effective management of oral chemotherapy drugs at home. This study explores whether financial toxicity predicts symptoms and unplanned healthcare utilization among cancer patients taking oral chemotherapy at home, which will contribute to the safe management of oral chemotherapy.

Methods: Data in this study was from a prospective observational study, which was conducted between October 2018 and December 2019. 151 patients completed the Comprehensive Score for Financial Toxicity at discharge and completed the MD Anderson Symptom …

Deep Learning For Detecting And Elucidating Human T-Cell Leukemia Virus Type 1 Integration In The Human Genome, Haodong Xu, Johnathan Jia, Hyun-Hwan Jeong, Zhongming Zhao

Faculty, Staff and Student Publications

Human T-cell leukemia virus type 1 (HTLV-1), a retrovirus, is the causative agent for adult T cell leukemia/lymphoma and many other human diseases. Accurate and high throughput detection of HTLV-1 virus integration sites (VISs) across the host genomes plays a crucial role in the prevention and treatment of HTLV-1-associated diseases. Here, we developed DeepHTLV, the first deep learning framework for VIS prediction de novo from genome sequence, motif discovery, and cis-regulatory factor identification. We demonstrated the high accuracy of DeepHTLV with more efficient and interpretive feature representations. Decoding the informative features captured by DeepHTLV resulted in eight representative clusters …

Micrornas And Gene Regulatory Networks Related To Cleft Lip And Palate, Chihiro Iwaya, Akiko Suzuki, Junichi Iwata

Faculty, Staff and Student Publications

Cleft lip and palate is one of the most common congenital birth defects and has a complex etiology. Either genetic or environmental factors, or both, are involved at various degrees, and the type and severity of clefts vary. One of the longstanding questions is how environmental factors lead to craniofacial developmental anomalies. Recent studies highlight non-coding RNAs as potential epigenetic regulators in cleft lip and palate. In this review, we will discuss microRNAs, a type of small non-coding RNAs that can simultaneously regulate expression of many downstream target genes, as a causative mechanism of cleft lip and palate in humans …

Health Benefits And Cost-Effectiveness Of Children's Oncology Group Breast Cancer Screening Guidelines For Chest-Irradiated Hodgkin Lymphoma Survivors, F Lennie Wong, Janie M Lee, Wendy M Leisenring, Joseph P Neglia, Rebecca M Howell, Susan A Smith, Kevin C Oeffinger, Chaya S Moskowitz, Tara O Henderson, Ann Mertens, Paul C Nathan, Yutaka Yasui, Wendy Landier, Gregory T Armstrong, Leslie L Robison, Smita Bhatia

Faculty, Staff and Student Publications

Purpose: To evaluate the outcomes and cost-effectiveness of the Children's Oncology Group Guideline recommendation for breast cancer (BC) screening using mammography (MAM) and breast magnetic resonance imaging (MRI) in female chest-irradiated childhood Hodgkin lymphoma (HL) survivors. Digital breast tomosynthesis (DBT), increasingly replacing MAM in practice, was also examined.

Methods: Life years (LYs), quality-adjusted LYs (QALYs), BC mortality, health care costs, and false-positive screen frequencies of undergoing annual MAM, DBT, MRI, MAM + MRI, and DBT + MRI from age 25 to 74 years were estimated by microsimulation. BC risks and non-BC mortality were estimated from female 5-year survivors of …

Fgl2-Targeting T Cells Exhibit Antitumor Effects On Glioblastoma And Recruit Tumor-Specific Brain-Resident Memory T Cells, Qingnan Zhao, Jiemiao Hu, Lingyuan Kong, Shan Jiang, Xiangjun Tian, Jing Wang, Rintaro Hashizume, Zhiliang Jia, Natalie Wall Fowlkes, Jun Yan, Xueqing Xia, Sofia F Yi, Long Hoang Dao, David Masopust, Amy B Heimberger, Shulin Li

Faculty, Staff and Student Publications

Although tissue-resident memory T (TRM) cells specific for previously encountered pathogens have been characterized, the induction and recruitment of brain TRM cells following immune therapy has not been observed in the context of glioblastoma. Here, we show that T cells expressing fibrinogen-like 2 (FGL2)–specific single-chain variable fragments (T-αFGL2) can induce tumor-specific CD8+ TRM cells that prevent glioblastoma recurrence. These CD8+ TRM cells display a highly expanded T cell receptor repertoire distinct from that found in peripheral tissue. When adoptively transferred to the brains of either immunocompetent or T cell-deficient naïve mice, these CD8+ TRM cells reject glioma cells. Mechanistically, T-αFGL2 …

A Phase Ib/Ii Study Of Lenvatinib And Pembrolizumab In Advanced Endometrial Carcinoma (Study 111/Keynote-146): Long-Term Efficacy And Safety Update, Vicky Makker, Carol Aghajanian, Allen L Cohn, Margarita Romeo, Raquel Bratos, Marcia S Brose, Mark Messing, Lea Dutta, Corina E Dutcus, Jie Huang, Emmett V Schmidt, Robert Orlowski, Matthew H Taylor

Faculty, Staff and Student Publications

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The open-label phase Ib/II Study 111/KEYNOTE-146 of daily lenvatinib 20 mg plus pembrolizumab 200 mg once every 3 weeks showed promising efficacy and tolerable safety in patients with previously treated advanced endometrial carcinoma (EC; primary data cutoff …

Editorial: Precision Medicine In Obstetrics: Pregnancy Complication, Serena Bertozzi, Bruna Corradetti, Arrigo Fruscalzo, Ambrogio P Londero

Faculty, Staff and Students Publications

No abstract provided.

Early Restrictive Or Liberal Fluid Management For Sepsis-Induced Hypotension, Nathan I Shapiro, Ivor S Douglas, Roy G Brower, Samuel M Brown, Matthew C Exline, Adit A Ginde, Michelle N Gong, Colin K Grissom, Douglas Hayden, Catherine L Hough, Weixing Huang, Theodore J Iwashyna, Alan E Jones, Akram Khan, Poying Lai, Kathleen D Liu, Chadwick D Miller, Katherine Oldmixon, Pauline K Park, Todd W Rice, Nancy Ringwood, Matthew W Semler, Jay S Steingrub, Daniel Talmor, B Taylor Thompson, Donald M Yealy, Wesley H Self

Faculty, Staff and Student Publications

BACKGROUND: Intravenous fluids and vasopressor agents are commonly used in early resuscitation of patients with sepsis, but comparative data for prioritizing their delivery are limited.

METHODS: In an unblinded superiority trial conducted at 60 U.S. centers, we randomly assigned patients to either a restrictive fluid strategy (prioritizing vasopressors and lower intravenous fluid volumes) or a liberal fluid strategy (prioritizing higher volumes of intravenous fluids before vasopressor use) for a 24-hour period. Randomization occurred within 4 hours after a patient met the criteria for sepsis-induced hypotension refractory to initial treatment with 1 to 3 liters of intravenous fluid. We hypothesized that …

Splicing Factor Srsf1 Deficiency In The Liver Triggers Nash-Like Pathology And Cell Death, Waqar Arif, Bhoomika Mathur, Michael F Saikali, Ullas V Chembazhi, Katelyn Toohill, You Jin Song, Qinyu Hao, Saman Karimi, Steven M Blue, Brian A Yee, Eric L Van Nostrand, Sushant Bangru, Grace Guzman, Gene W Yeo, Kannanganattu V Prasanth, Sayeepriyadarshini Anakk, Carolyn L Cummins, Auinash Kalsotra

Faculty, Staff and Students Publications

Regulation of RNA processing contributes profoundly to tissue development and physiology. Here, we report that serine-arginine-rich splicing factor 1 (SRSF1) is essential for hepatocyte function and survival. Although SRSF1 is mainly known for its many roles in mRNA metabolism, it is also crucial for maintaining genome stability. We show that acute liver damage in the setting of targeted SRSF1 deletion in mice is associated with the excessive formation of deleterious RNA-DNA hybrids (R-loops), which induce DNA damage. Combining hepatocyte-specific transcriptome, proteome, and RNA binding analyses, we demonstrate that widespread genotoxic stress following SRSF1 depletion results in global inhibition of mRNA …

North American Blastic Plasmacytoid Dendritic Cell Neoplasm Consortium: Position On Standards Of Care And Areas Of Need, Naveen Pemmaraju, Hagop Kantarjian, Kendra Sweet, Eunice Wang, Jayastu Senapati, Nathaniel R Wilson, Marina Konopleva, Arthur E Frankel, Vikas Gupta, Ruben Mesa, Matthew Ulrickson, Edward Gorak, Sumeet Bhatia, Tulin Budak-Alpdogan, James Mason, Maria Teresa Garcia-Romero, Norma Lopez-Santiago, Gabriela Cesarman-Maus, Pankit Vachhani, Sangmin Lee, Vijaya Raj Bhatt, William Blum, Roland B Walter, Dale Bixby, Ivana Gojo, Madeleine Duvic, Raajit K Rampal, Marcos De Lima, James Foran, Amir T Fathi, Aric Cameron Hall, Meagan A Jacoby, Jeffrey Lancet, Gabriel Mannis, Anthony S Stein, Alice Mims, David Rizzieri, Rebecca Olin, Alexander Perl, Gary Schiller, Paul Shami, Richard M Stone, Stephen Strickland, Matthew J Wieduwilt, Naval Daver, Farhad Ravandi, Sumithira Vasu, Monica Guzman, Gail J Roboz, Joseph Khoury, Muzaffar Qazilbash, Phyu P Aung, Branko Cuglievan, Yazan Madanat, Mohamed A Kharfan-Dabaja, Anna Pawlowska, Justin Taylor, Martin Tallman, Prajwal Dhakal, Andrew A Lane

Faculty, Staff and Student Publications

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with historically poor outcomes and no worldwide consensus treatment approach. Unique among most hematologic malignancies for its frequent cutaneous involvement, BPDCN can also invade other extramedullary compartments, including the central nervous system. Generally affecting older adults, many patients are unfit to receive intensive chemotherapy, and although hematopoietic stem cell transplantation is preferred for younger, fit individuals, not all are eligible. One recent therapeutic breakthrough is that all BPDCNs express CD123 (IL3Rα) and that this accessible surface marker can be pharmacologically targeted. The first-in-class agent for BPDCN, tagraxofusp, which targets …

The Landscape Of Immunotherapy For Retroperitoneal Sarcoma, Alicia A Gingrich, Elise F Nassif, Christina L Roland, Emily Z Keung

Faculty, Staff and Student Publications

Significant multidisciplinary scientific effort has been undertaken to understand the heterogeneous family of neoplasms that comprise soft tissue sarcomas. Within this family of neoplasms, outcomes for retroperitoneal sarcomas (RPS) are currently limited given a lack of effective therapies. In this review, we focus on immunotherapy and its relationship with the common RPS histologic subtypes. Although initial outcomes for RPS patients with immune checkpoint inhibition alone have been somewhat disappointing, subsequent analyses on histologies, the tumor microenvironment, sarcoma immune class, tumor infiltrating lymphocytes and genetic analysis for tumor mutational burden have yielded insight into the interplay between sarcomas and immunotherapy. Such …

Author Correction: Common Variants In Alzheimer’S Disease And Risk Stratification By Polygenic Risk Scores, Itziar De Rojas, Sonia Moreno-Grau, Niccolo Tesi, Benjamin Grenier-Boley, Victor Andrade, Iris E Jansen, Nancy L Pedersen, Najada Stringa, Anna Zettergren, Isabel Hernández, Laura Montrreal, Carmen Antúnez, Anna Antonell, Rick M Tankard, Joshua C Bis, Rebecca Sims, Céline Bellenguez, Inés Quintela, Antonio González-Perez, Miguel Calero, Emilio Franco-Macías, Juan Macías, Rafael Blesa, Laura Cervera-Carles, Manuel Menéndez-González, Ana Frank-García, Jose Luís Royo, Fermin Moreno, Raquel Huerto Vilas, Miquel Baquero, Mónica Diez-Fairen, Carmen Lage, Sebastián García-Madrona, Pablo García-González, Emilio Alarcón-Martín, Sergi Valero, Oscar Sotolongo-Grau, Abbe Ullgren, Adam C Naj, Afina W Lemstra, Alba Benaque, Alba Pérez-Cordón, Alberto Benussi, Alberto Rábano, Alessandro Padovani, Alessio Squassina, Alexandre De Mendonça, Alfonso Arias Pastor, Almar A L Kok, Alun Meggy, Ana Belén Pastor, Ana Espinosa, Anaïs Corma-Gómez, Angel Martín Montes, Ángela Sanabria, Anita L Destefano, Anja Schneider, Annakaisa Haapasalo, Anne Kinhult Ståhlbom, Anne Tybjærg-Hansen, Annette M Hartmann, Annika Spottke, Arturo Corbatón-Anchuelo, Arvid Rongve, Barbara Borroni, Beatrice Arosio, Benedetta Nacmias, Børge G Nordestgaard, Brian W Kunkle, Camille Charbonnier, Carla Abdelnour, Carlo Masullo, Carmen Martínez Rodríguez, Carmen Muñoz-Fernandez, Carole Dufouil, Caroline Graff, Catarina B Ferreira, Caterina Chillotti, Chandra A Reynolds, Chiara Fenoglio, Christine Van Broeckhoven, Christopher Clark, Claudia Pisanu, Claudia L Satizabal, Clive Holmes, Dolores Buiza-Rueda, Dag Aarsland, Dan Rujescu, Daniel Alcolea, Daniela Galimberti, David Wallon, Davide Seripa, Edna Grünblatt, Efthimios Dardiotis, Emrah Düzel, Elio Scarpini, Elisa Conti, Elisa Rubino, Ellen Gelpi, Eloy Rodriguez-Rodriguez, Emmanuelle Duron, Eric Boerwinkle, Evelyn Ferri, Fabrizio Tagliavini, Fahri Küçükali, Florence Pasquier, Florentino Sanchez-Garcia, Francesca Mangialasche, Frank Jessen, Gaël Nicolas, Geir Selbæk, Gemma Ortega, Geneviève Chêne, Georgios Hadjigeorgiou, Giacomina Rossi, Gianfranco Spalletta, Giorgio Giaccone, Giulia Grande, Giuliano Binetti, Goran Papenberg, Harald Hampel, Henri Bailly, Henrik Zetterberg, Hilkka Soininen, Ida K Karlsson, Ignacio Alvarez, Ildebrando Appollonio, Ina Giegling, Ingmar Skoog, Ingvild Saltvedt, Innocenzo Rainero, Irene Rosas Allende, Jakub Hort, Janine Diehl-Schmid, Jasper Van Dongen, Jean-Sebastien Vidal, Jenni Lehtisalo, Jens Wiltfang, Jesper Qvist Thomassen, Johannes Kornhuber, Jonathan L Haines, Jonathan Vogelgsang, Juan A Pineda, Juan Fortea, Julius Popp, Jürgen Deckert, Katharina Buerger, Kevin Morgan, Klaus Fließbach, Kristel Sleegers, Laura Molina-Porcel, Lena Kilander, Leonie Weinhold, Lindsay A Farrer, Li-San Wang, Luca Kleineidam, Lucia Farotti, Lucilla Parnetti, Lucio Tremolizzo, Lucrezia Hausner, Luisa Benussi, Lutz Froelich, M Arfan Ikram, M Candida Deniz-Naranjo, Magda Tsolaki, Maitée Rosende-Roca, Malin Löwenmark, Marc Hulsman, Marco Spallazzi, Margaret A Pericak-Vance, Margaret Esiri, María Bernal Sánchez-Arjona, Maria Carolina Dalmasso, María Teresa Martínez-Larrad, Marina Arcaro, Markus M Nöthen, Marta Fernández-Fuertes, Martin Dichgans, Martin Ingelsson, Martin J Herrmann, Martin Scherer, Martin Vyhnalek, Mary H Kosmidis, Mary Yannakoulia, Matthias Schmid, Michael Ewers, Michael T Heneka, Michael Wagner, Michela Scamosci, Miia Kivipelto, Mikko Hiltunen, Miren Zulaica, Montserrat Alegret, Myriam Fornage, Natalia Roberto, Natasja M Van Schoor, Nazib M Seidu, Nerisa Banaj, Nicola J Armstrong, Nikolaos Scarmeas, Norbert Scherbaum, Oliver Goldhardt, Oliver Hanon, Oliver Peters, Olivia Anna Skrobot, Olivier Quenez, Ondrej Lerch, Paola Bossù, Paolo Caffarra, Paolo Dionigi Rossi, Paraskevi Sakka, Patrizia Mecocci, Per Hoffmann, Peter A Holmans, Peter Fischer, Peter Riederer, Qiong Yang, Rachel Marshall, Rajesh N Kalaria, Richard Mayeux, Rik Vandenberghe, Roberta Cecchetti, Roberta Ghidoni, Ruth Frikke-Schmidt, Sandro Sorbi, Sara Hägg, Sebastiaan Engelborghs, Seppo Helisalmi, Sigrid Botne Sando, Silke Kern, Silvana Archetti, Silvia Boschi, Silvia Fostinelli, Silvia Gil, Silvia Mendoza, Simon Mead, Simona Ciccone, Srdjan Djurovic, Stefanie Heilmann-Heimbach, Steffi Riedel-Heller, Teemu Kuulasmaa, Teodoro Del Ser, Thibaud Lebouvier, Thomas Polak, Tiia Ngandu, Timo Grimmer, Valentina Bessi, Valentina Escott-Price, Vilmantas Giedraitis, Vincent Deramecourt, Wolfgang Maier, Xueqiu Jian, Yolande A L Pijnenburg, Eadb Contributors, Gr@Ace Study Group, Degesco Consortium, Igap (Adgc, Charge, Eadi, Gerad), Pgc-Alz Consortia, Patrick Gavin Kehoe, Guillermo Garcia-Ribas, Pascual Sánchez-Juan, Pau Pastor, Jordi Pérez-Tur, Gerard Piñol-Ripoll, Adolfo Lopez De Munain, Jose María García-Alberca, María J Bullido, Victoria Álvarez, Alberto Lleó, Luis M Real, Pablo Mir, Miguel Medina, Philip Scheltens, Henne Holstege, Marta Marquié, María Eugenia Sáez, Ángel Carracedo, Philippe Amouyel, Gerard D Schellenberg, Julie Williams, Sudha Seshadri, Cornelia M Van Duijn, Karen A Mather, Raquel Sánchez-Valle, Manuel Serrano-Ríos, Adelina Orellana, Lluís Tárraga, Kaj Blennow, Martijn Huisman, Ole A Andreassen, Danielle Posthuma, Jordi Clarimón, Mercè Boada, Wiesje M Van Der Flier, Alfredo Ramirez, Jean-Charles Lambert, Sven J Van Der Lee, Agustín Ruiz

Faculty, Staff and Students Publications

This corrects the article "Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores" in volume 12, 3417.

Novel Pathogenic Mutations Identified From Whole-Genome Sequencing In Unsolved Cases Of Patients Affected With Inherited Retinal Diseases, Hafiz Muhammad Jafar Hussain, Meng Wang, Austin Huang, Ryan Schmidt, Xinye Qian, Paul Yang, Molly Marra, Yumei Li, Mark E Pennesi, Rui Chen

Faculty, Staff and Students Publications

Inherited retinal diseases (IRDs) are a diverse set of visual disorders that collectively represent a major cause of early-onset blindness. With the reduction in sequencing costs in recent years, whole-genome sequencing (WGS) is being used more frequently, particularly when targeted gene panels and whole-exome sequencing (WES) fail to detect pathogenic mutations in patients. In this study, we performed mutation screens using WGS for a cohort of 311 IRD patients whose mutations were undetermined. A total of nine putative pathogenic mutations in six IRD patients were identified, including six novel mutations. Among them, four were deep intronic mutations that affected mRNA …

Discovery Of Highly Potent And Bmpr2-Selective Kinase Inhibitors Using Dna-Encoded Chemical Library Screening, Ram K Modukuri, Diana Monsivais, Feng Li, Murugesan Palaniappan, Kurt M Bohren, Zhi Tan, Angela F Ku, Yong Wang, Chandrashekhar Madasu, Jian-Yuan Li, Suni Tang, Gabriella Miklossy, Stephen S Palmer, Damian W Young, Martin M Matzuk

Faculty, Staff and Students Publications

The discovery of monokinase-selective inhibitors for patients is challenging because the 500+ kinases encoded by the human genome share highly conserved catalytic domains. Until now, no selective inhibitors unique for a single transforming growth factor β (TGFβ) family transmembrane receptor kinase, including bone morphogenetic protein receptor type 2 (BMPR2), have been reported. This dearth of receptor-specific kinase inhibitors hinders therapeutic options for skeletal defects and cancer as a result of an overactivated BMP signaling pathway. By screening 4.17 billion “unbiased” and “kinase-biased” DNA-encoded chemical library molecules, we identified hits CDD-1115 and CDD-1431, respectively, that were low-nanomolar selective kinase inhibitors of …

An Updated Classification Of Meditation Methods Using Principles Of Taxonomy And Systematics, Jonathan D. Nash, Andrew B. Newberg

Marcus Institute of Integrative Health Faculty Papers

This paper revisits the proposal for the classification of meditation methods which we introduced in our initial 2013 publication, “Toward a Universal Taxonomy and Definition of Meditation”. At that time, we advanced the thesis that meditation methods could be effectively segregated into three orthogonal categories by integrating the taxonomic principle of functional essentialism and the paradigm of Affect and Cognition; and we presented relevant research findings which supported that assertion. This iteration expands upon those theoretical and methodological elements by articulating a more comprehensive Three Tier Classification System which accounts for the full range of meditation methods; and demonstrates how …

Efficacy And Clinicogenomic Correlates Of Response To Immune Checkpoint Inhibitors Alone Or With Chemotherapy In Non-Small Cell Lung Cancer, Lingzhi Hong, Muhammad Aminu, Shenduo Li, Xuetao Lu, Milena Petranovic, Maliazurina B Saad, Pingjun Chen, Kang Qin, Susan Varghese, Waree Rinsurongkawong, Vadeerat Rinsurongkawong, Amy Spelman, Yasir Y Elamin, Marcelo V Negrao, Ferdinandos Skoulidis, Carl M Gay, Tina Cascone, Saumil J Gandhi, Steven H Lin, Percy P Lee, Brett W Carter, Carol C Wu, Mara B Antonoff, Boris Sepesi, Jeff Lewis, Don L Gibbons, Ara A Vaporciyan, Xiuning Le, J Jack Lee, Sinchita Roy-Chowdhuri, Mark J Routbort, Justin F Gainor, John V Heymach, Yanyan Lou, Jia Wu, Jianjun Zhang, Natalie I Vokes

Faculty, Staff and Student Publications

The role of combination chemotherapy with immune checkpoint inhibitors (ICI) (ICI-chemo) over ICI monotherapy (ICI-mono) in non-small cell lung cancer (NSCLC) remains underexplored. In this retrospective study of 1133 NSCLC patients, treatment with ICI-mono vs ICI-chemo associate with higher rates of early progression, but similar long-term progression-free and overall survival. Sequential vs concurrent ICI and chemotherapy have similar long-term survival, suggesting no synergism from combination therapy. Integrative modeling identified PD-L1, disease burden (Stage IVb; liver metastases), and STK11 and JAK2 alterations as features associate with a higher likelihood of early progression on ICI-mono. CDKN2A alterations associate with worse long-term outcomes …

Endogenous Mirna-Based Innate-Immunity Against Sars-Cov-2 Invasion Of The Brain, Walter J. Lukiw, Aileen I. Pogue

School of Medicine Faculty Publications

The severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19, possesses an unusually large positive-sense, single-stranded viral RNA (ssvRNA) genome of about ~29,903 nucleotides (nt). In many respects, this ssvRNA resembles a very large, polycistronic messenger RNA (mRNA) possessing a 5′-methyl cap (m7GpppN), a 3′- and 5′-untranslated region (3′-UTR, 5′-UTR), and a poly-adenylated (poly-A+) tail. As such, the SARS-CoV-2 ssvRNA is susceptible to targeting by small non-coding RNA (sncRNA) and/or microRNA (miRNA), as well as neutralization and/or inhibition of its infectivity via the human body’s natural complement of about ~2650 miRNA species. Depending on host cell and tissue …