Genetic Phenomena Commons^™

Autologous T Cell Therapy For Mage-A4+ Solid Cancers In Hla-A*02+ Patients: A Phase 1 Trial, David S Hong, Brian A Van Tine, Swethajit Biswas, Cheryl Mcalpine, Melissa L Johnson, Anthony J Olszanski, Jeffrey M Clarke, Dejka Araujo, George R Blumenschein, Partow Kebriaei, Quan Lin, Alex J Tipping, Joseph P Sanderson, Ruoxi Wang, Trupti Trivedi, Thejo Annareddy, Jane Bai, Stavros Rafail, Amy Sun, Lilliam Fernandes, Jean-Marc Navenot, Frederic D Bushman, John K Everett, Derin Karadeniz, Robyn Broad, Martin Isabelle, Revashnee Naidoo, Natalie Bath, Gareth Betts, Zohar Wolchinsky, Dzmitry G Batrakou, Erin Van Winkle, Erica Elefant, Armin Ghobadi, Amanda Cashen, Anne Grand'maison, Philip Mccarthy, Paula M Fracasso, Elliot Norry, Dennis Williams, Mihaela Druta, David A Liebner, Kunle Odunsi, Marcus O Butler

Faculty, Staff and Student Publications

Affinity-optimized T cell receptors can enhance the potency of adoptive T cell therapy. Afamitresgene autoleucel (afami-cel) is a human leukocyte antigen-restricted autologous T cell therapy targeting melanoma-associated antigen A4 (MAGE-A4), a cancer/testis antigen expressed at varying levels in multiple solid tumors. We conducted a multicenter, dose-escalation, phase 1 trial in patients with relapsed/refractory metastatic solid tumors expressing MAGE-A4, including synovial sarcoma (SS), ovarian cancer and head and neck cancer ( NCT03132922 ). The primary endpoint was safety, and the secondary efficacy endpoints included overall response rate (ORR) and duration of response. All patients (N = 38, nine tumor types) experienced …

Stem Cell Theory Of Cancer: Origin Of Metastasis And Sub-Clonality, Shi-Ming Tu, Cesar Moran, William Norton, Niki M Zacharias

Faculty, Staff and Student Publications

Metastasis may be the secret weapon cancer uses to dominate and subjugate, to persist and prevail. However, it is no longer a secret when we realize that a stem cell has the same ways and means to fulfill its own omnipotence and accomplish its own omnipresence… and when we realize that a cancer cell has its own version of stem-ness origin and stem-like nature. In this perspective, we discuss whether stem-ness enables metastasis or mutations drive metastasis. We ponder about low-grade versus high-grade tumors and about primary versus metastatic tumors. We wonder about stochasticity and hierarchy in the genesis and …

Glial Cell-Specific Contribution Of Pkr-Like Er Kinase (Perk) In Neuroinflammation And Behavior, Anirudhya Lahiri

Graduate Theses, Dissertations, and Problem Reports (ETD)

Neurological disorders such as multiple sclerosis (MS) are a major public health concern in the US, with no available therapeutic cure. Chronic neuroinflammation and aberrant proteostasis in the central nervous system (CNS) are the major hallmarks of neurological diseases. Endoplasmic Reticulum (ER) is a major cellular organelle involved in protein synthesis, folding and maturation of various secretory and transmembrane proteins. Pathophysiological stressors such as trauma and infection result in misfolded protein accumulation in the endoplasmic reticulum (ER) lumen, which results in ER stress. To regain proteostasis (protein homeostasis), cells activate the unfolded protein response (UPR). UPR is an evolutionarily conserved …

A Rapid, Low-Cost, And Highly Sensitive Sars-Cov-2 Diagnostic Based On Whole-Genome Sequencing, Per A Adastra, Neva C Durand, Namita Mitra, Saul Godinez Pulido, Ragini Mahajan, Alyssa Blackburn, Zane L Colaric, Joshua W M Theisen, David Weisz, Olga Dudchenko, Andreas Gnirke, Suhas S P Rao, Parwinder Kaur, Erez Lieberman Aiden, Aviva Presser Aiden

Faculty, Staff and Students Publications

Early detection of SARS-CoV-2 infection is key to managing the current global pandemic, as evidence shows the virus is most contagious on or before symptom onset. Here, we introduce a low-cost, high-throughput method for diagnosing and studying SARS-CoV-2 infection. Dubbed Pathogen-Oriented Low-Cost Assembly & Re-Sequencing (POLAR), this method amplifies the entirety of the SARS-CoV-2 genome. This contrasts with typical RT-PCR-based diagnostic tests, which amplify only a few loci. To achieve this goal, we combine a SARS-CoV-2 enrichment method developed by the ARTIC Network (https://artic.network/) with short-read DNA sequencing and de novo genome assembly. Using this method, we can reliably ( …

The Role Of The Nlrp3 Inflammasome In Alzheimer's Disease, Ethan S. Terman

Undergraduate Research Posters

This study examines the consequences of Alzheimer’s in rat and mice test subjects. The goal is to identify the effects of certain NLRP3 inhibiting drugs and to see if there are any noticeable effects in regards to impeding the pathological development of Alzheimer’s disease. The results are visualized by implementing the immunohistochemical process to identify neurodegeneration in the brain and to assess the expression levels of amyloid beta as an indicator of Alzheimer’s pathology. Other tests are also conducted on these transgenic mice to gauge cognitive functioning levels during the onset of their disease, those being behavior tests, but not …

Concurrent Mutations In Sf3b1 And Phf6 In Myeloid Neoplasms, Zhuang Zuo, L Jeffrey Medeiros, Sofia Garces, Mark J Routbort, Chi Young Ok, Sanam Loghavi, Rashmi Kanagal-Shamanna, Fatima Zahra Jelloul, Guillermo Garcia-Manero, Kelly S Chien, Keyur P Patel, Rajyalakshmi Luthra, C Cameron Yin

Faculty, Staff and Student Publications

It has been reported that gene mutations in SF3B1 and PHF6 are mutually exclusive. However, this observation has never been rigorously assessed. We report the clinicopathologic and molecular genetic features of 21 cases of myeloid neoplasms with double mutations in SF3B1 and PHF6, including 9 (43%) with myelodysplastic syndrome, 5 (24%) with acute myeloid leukemia, 4 (19%) with myeloproliferative neoplasms, and 3 (14%) with myelodysplastic/myeloproliferative neoplasms. Multilineage dysplasia with ring sideroblasts, increased blasts, and myelofibrosis are common morphologic findings. All cases but one had diploid or non-complex karyotypes. SF3B1 mutations were detected in the first analysis of all the …

A Phase Ii Randomized Double Blinded Trial Evaluating The Efficacy Of Curcumin With Pre-Operative Chemoradiation For Rectal Cancer, Jillian R Gunther, Awalpreet S Chadha, Sushovan Guha, Gottumukkala S Raju, Dipen M Maru, Mark F Munsell, Yan Jiang, Peiying Yang, Edd Felix, Marilyn Clemons, Geena George Mathew, Pankaj K Singh, John M Skibber, Miguel A Rodriguez-Bigas, George J Chang, Cathy Eng, Marc E Delclos, Christopher H Crane, Prajnan Das, Sunil Krishnan

Faculty, Staff and Student Publications

Background: In vivo studies demonstrate that curcumin increases radioresponse of colorectal cancers. To demonstrate efficacy in humans, we performed a randomized double-blind study of locally advanced rectal cancer (LARC) patients receiving pre-operative chemoradiation therapy (CRT) ± curcumin. We used pathologic complete response (pCR) rate as a surrogate for clinical outcome.

Methods: From 2008-2010, LARC patients were randomized to placebo/curcumin in a 1:2 ratio. Patients received CRT [50.4 gray in 28 fractions; capecitabine (825 mg/m2 twice daily)] followed by surgery. Curcumin (4 grams orally, twice daily) or placebo was given throughout CRT and 6 weeks afterward. Toxicity was monitored weekly. Blood …

Airway Mucus Dysfunction In Covid-19, Burton F Dickey, Jichao Chen, R Stokes Peebles

Faculty, Staff and Student Publications

No abstract provided.

Development Of A Distributed International Patient Data Registry For Hairy Cell Leukemia, Leslie A Andritsos, Mirela Anghelina, Jasmine Neal, James S Blachly, Puneet Mathur, Omkar Lele, Claire Dearden, Sunil Iyengar, Matthew Cross, Clive S Zent, Kerry A Rogers, Narendranath Epperla, Gerard Lozanski, Christopher C Oakes, Eric Kraut, Amy S Ruppert, Qiuhong Zhao, Seema A Bhat, Francesco Forconi, Versha Banerji, Sasanka Handunnetti, Constantine S Tam, John F Seymour, Monica Else, Robert J Kreitman, Alan Saven, Timothy Call, Sameer A Parikh, Farhad Ravandi, James B Johnston, Enrico Tiacci, Xavier Troussard, Martin S Tallman, Sascha Dietrich, Tamar Tadmor, Alessandro Gozzetti, Pier Luigi Zinzani, Tadeusz Robak, Graeme Quest, Judit Demeter, Kanti Rai, Soledad A Fernandez, Michael Grever

Faculty, Staff and Student Publications

Hairy cell leukemia (HCL) is a rare lymphoproliferative disorder, comprising only 2% of all leukemias. The Hairy Cell Leukemia Foundation (HCLF) has developed a patient data registry to enable investigators to better study the clinical features, treatment outcomes, and complications of patients with HCL. This system utilizes a centralized registry architecture. Patients are enrolled at HCL Centers of Excellence (COE) or via a web-based portal. All data are de-identified, which reduces regulatory burden and increases opportunities for data access and re-use. To date, 579 patients have been enrolled in the registry. Efforts are underway to engage additional COE's to expand …

Radiomics In Abdominopelvic Solid-Organ Oncologic Imaging: Current Status, Xiaoyang Liu, Mohamed G Elbanan, Antonio Luna, Masoom A Haider, Andrew D Smith, Carl F Sabottke, Bradley M Spieler, Baris Turkbey, David Fuentes, Ahmed Moawad, Serageldin Kamel, Natally Horvat, Khaled M Elsayes

Faculty, Staff and Student Publications

Radiomics is the process of extraction of high-throughput quantitative imaging features from medical images. These features represent noninvasive quantitative biomarkers that go beyond the traditional imaging features visible to the human eye. This article first reviews the steps of the radiomics pipeline, including image acquisition, ROI selection and image segmentation, image preprocessing, feature extraction, feature selection, and model development and application. Current evidence for the application of radiomics in abdominopelvic solid-organ cancers is then reviewed. Applications including diagnosis, subtype determination, treatment response assessment, and outcome prediction are explored within the context of hepatobiliary and pancreatic cancer, renal cell carcinoma, prostate …

Impact Of Molecular Sequence Data Completeness On Hiv Cluster Detection And A Network Science Approach To Enhance Detection, Sepideh Mazrouee, Camden J Hallmark, Ricardo Mora, Natascha Del Vecchio, Rocio Carrasco Hernandez, Michelle Carr, Marlene Mcneese, Kayo Fujimoto, Joel O Wertheim

Faculty, Staff and Student Publications

Detection of viral transmission clusters using molecular epidemiology is critical to the response pillar of the Ending the HIV Epidemic initiative. Here, we studied whether inference with an incomplete dataset would influence the accuracy of the reconstructed molecular transmission network. We analyzed viral sequence data available from ~ 13,000 individuals with diagnosed HIV (2012-2019) from Houston Health Department surveillance data with 53% completeness (n = 6852 individuals with sequences). We extracted random subsamples and compared the resulting reconstructed networks versus the full-size network. Increasing simulated completeness was associated with an increase in the number of detected clusters. We also subsampled …

Sars-Cov-2 Incubation Period According To Vaccination Status During The Fifth Covid-19 Wave In A Tertiary-Care Center In Spain: A Cohort Study, Jordi Cortés Martínez, Daewoo Pak, Gabriela Abelenda-Alonso, Klaus Langohr, Jing Ning, Alexander Rombauts, Mireia Colom, Yu Shen, Guadalupe Gómez Melis

Faculty, Staff and Student Publications

Background: The incubation period of an infectious disease is defined as the elapsed time between the exposure to the pathogen and the onset of symptoms. Although both the mRNA-based and the adenoviral vector-based vaccines have shown to be effective, there have been raising concerns regarding possible decreases in vaccine effectiveness for new variants and variations in the incubation period.

Methods: We conducted a unicentric observational study at the Hospital Universitari de Bellvitge, Barcelona, using a structured telephone survey performed by trained interviewers to estimate the incubation period of the SARS-CoV-2 Delta variant in a cohort of Spanish hospitalized patients. The …

Clinical Exome Sequencing Uncovers A High Frequency Of Mendelian Disorders In Infants With Stroke: A Retrospective Analysis, Runjun D Kumar, Linyan Meng, Pengfei Liu, Christina Y Miyake, Kim C Worley, Weimin Bi, Seema R Lalani

Faculty, Staff and Students Publications

Background:

Stroke causes significant disability and is a common cause of death worldwide. Previous studies have estimated that 1-5% of stroke is attributable to monogenic etiologies. We set out to assess the utility of clinical exome sequencing (ES) in the evaluation of stroke.

Methods:

We retrospectively analyzed 124 individuals who received ES at the Baylor Genetics reference lab between 2012 and 2021 who had stroke as a major part of their reported phenotype.

Results:

Ages ranged from 10 days to 69 years. 8.9% of the cohort received a diagnosis, including 25% of infants less than 1 year old; an additional …

First-In-Human Study Of An Ox40 (Ivuxolimab) And 4-1bb (Utomilumab) Agonistic Antibody Combination In Patients With Advanced Solid Tumors, Omid Hamid, Alberto A Chiappori, John A Thompson, Toshihiko Doi, Siwen Hu-Lieskovan, Ferry A L M Eskens, Willeke Ros, Adi Diab, Jean-Philippe Spano, Naiyer A Rizvi, Jeffrey S Wasser, Eric Angevin, Patrick A Ott, Alison Forgie, Wenjing Yang, Cen Guo, Jeffrey Chou, Anthony B El-Khoueiry

Faculty, Staff and Student Publications

Background: Ivuxolimab (PF-04518600) and utomilumab (PF-05082566) are humanized agonistic IgG2 monoclonal antibodies against OX40 and 4-1BB, respectively. This first-in-human, multicenter, open-label, phase I, dose-escalation/dose-expansion study explored safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of ivuxolimab+utomilumab in patients with advanced solid tumors.

Methods: Dose-escalation: patients with advanced bladder, gastric, or cervical cancer, melanoma, head and neck squamous cell carcinoma, or non-small cell lung cancer (NSCLC) who were unresponsive to available therapies, had no standard therapy available or declined standard therapy were enrolled into five dose cohorts: ivuxolimab (0.1-3 mg/kg every 2 weeks (Q2W)) intravenously plus utomilumab (20 or 100 mg every …

Genome-Wide Association Analyses Of Physical Activity And Sedentary Behavior Provide Insights Into Underlying Mechanisms And Roles In Disease Prevention, Zhe Wang, Andrew Emmerich, Nicolas J Pillon, Tim Moore, Daiane Hemerich, Marilyn C Cornelis, Eugenia Mazzaferro, Siacia Broos, Tarunveer S Ahluwalia, Traci M Bartz, Amy R Bentley, Lawrence F Bielak, Mike Chong, Audrey Y Chu, Diane Berry, Rajkumar Dorajoo, Nicole D Dueker, Elisa Kasbohm, Bjarke Feenstra, Mary F Feitosa, Christian Gieger, Mariaelisa Graff, Leanne M Hall, Toomas Haller, Fernando P Hartwig, David A Hillis, Ville Huikari, Nancy Heard-Costa, Christina Holzapfel, Anne U Jackson, Åsa Johansson, Anja Moltke Jørgensen, Marika A Kaakinen, Robert Karlsson, Kathleen F Kerr, Boram Kim, Chantal M Koolhaas, Zoltan Kutalik, Vasiliki Lagou, Penelope A Lind, Mattias Lorentzon, Leo-Pekka Lyytikäinen, Massimo Mangino, Christoph Metzendorf, Kristine R Monroe, Alexander Pacolet, Louis Pérusse, Rene Pool, Rebecca C Richmond, Natalia V Rivera, Sebastien Robiou-Du-Pont, Katharina E Schraut, Christina-Alexandra Schulz, Heather M Stringham, Toshiko Tanaka, Alexander Teumer, Constance Turman, Peter J Van Der Most, Mathias Vanmunster, Frank J A Van Rooij, Jana V Van Vliet-Ostaptchouk, Xiaoshuai Zhang, Jing-Hua Zhao, Wei Zhao, Zhanna Balkhiyarova, Marie N Balslev-Harder, Sebastian E Baumeister, John Beilby, John Blangero, Dorret I Boomsma, Soren Brage, Peter S Braund, Jennifer A Brody, Marcel Bruinenberg, Ulf Ekelund, Ching-Ti Liu, John W Cole, Francis S Collins, L Adrienne Cupples, Tõnu Esko, Stefan Enroth, Jessica D Faul, Lindsay Fernandez-Rhodes, Alison E Fohner, Oscar H Franco, Tessel E Galesloot, Scott D Gordon, Niels Grarup, Catharina A Hartman, Gerardo Heiss, Jennie Hui, Thomas Illig, Russell Jago, Alan James, Peter K Joshi, Taeyeong Jung, Mika Kähönen, Tuomas O Kilpeläinen, Woon-Puay Koh, Ivana Kolcic, Peter P Kraft, Johanna Kuusisto, Lenore J Launer, Aihua Li, Allan Linneberg, Jian'an Luan, Pedro Marques Vidal, Sarah E Medland, Yuri Milaneschi, Arden Moscati, Bill Musk, Christopher P Nelson, Ilja M Nolte, Nancy L Pedersen, Annette Peters, Patricia A Peyser, Christine Power, Olli T Raitakari, Mägi Reedik, Alex P Reiner, Paul M Ridker, Igor Rudan, Kathy Ryan, Mark A Sarzynski, Laura J Scott, Robert A Scott, Stephen Sidney, Kristin Siggeirsdottir, Albert V Smith, Jennifer A Smith, Emily Sonestedt, Marin Strøm, E Shyong Tai, Koon K Teo, Barbara Thorand, Anke Tönjes, Angelo Tremblay, Andre G Uitterlinden, Jagadish Vangipurapu, Natasja Van Schoor, Uwe Völker, Gonneke Willemsen, Kayleen Williams, Quenna Wong, Huichun Xu, Kristin L Young, Jian Min Yuan, M Carola Zillikens, Alan B Zonderman, Adam Ameur, Stefania Bandinelli, Joshua C Bis, Michael Boehnke, Claude Bouchard, Daniel I Chasman, George Davey Smith, Eco J C De Geus, Louise Deldicque, Marcus Dörr, Michele K Evans, Luigi Ferrucci, Myriam Fornage, Caroline Fox, Theodore Garland, Vilmundur Gudnason, Ulf Gyllensten, Torben Hansen, Caroline Hayward, Bernardo L Horta, Elina Hyppönen, Marjo-Riitta Jarvelin, W Craig Johnson, Sharon L R Kardia, Lambertus A Kiemeney, Markku Laakso, Claudia Langenberg, Terho Lehtimäki, Loic Le Marchand, Patrik K E Magnusson, Nicholas G Martin, Mads Melbye, Andres Metspalu, David Meyre, Kari E North, Claes Ohlsson, Albertine J Oldehinkel, Marju Orho-Melander, Guillaume Pare, Taesung Park, Oluf Pedersen, Brenda W J H Penninx, Tune H Pers, Ozren Polasek, Inga Prokopenko, Charles N Rotimi, Nilesh J Samani, Xueling Sim, Harold Snieder, Thorkild I A Sørensen, Tim D Spector, Nicholas J Timpson, Rob M Van Dam, Nathalie Van Der Velde, Cornelia M Van Duijn, Peter Vollenweider, Henry Völzke, Trudy Voortman, Gérard Waeber, Nicholas J Wareham, David R Weir, Heinz-Erich Wichmann, James F Wilson, Andrea L Hevener, Anna Krook, Juleen R Zierath, Martine A I Thomis, Ruth J F Loos, Marcel Den Hoed

Faculty, Staff and Student Publications

Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle …

Pure Erythroid Leukemia Is Characterized By Biallelic Tp53 Inactivation And Abnormal P53 Expression Patterns In De Novo And Secondary Cases, Hong Fang, Sa A Wang, Joseph D Khoury, Siba El Hussein, Do Hwan Kim, Mehrnoosh Tashakori, Zhenya Tang, Shaoying Li, Zhihong Hu, Fatima Zahra Jelloul, Keyur P Patel, Timothy J Mcdonnell, Tapan Kadia, L Jeffrey Medeiros, Wei Wang

Faculty, Staff and Student Publications

No abstract provided.

Muscle And Adipose Tissue Segmentations At The Third Cervical Vertebral Level In Patients With Head And Neck Cancer, Kareem A Wahid, Brennan Olson, Rishab Jain, Aaron J Grossberg, Dina El-Habashy, Cem Dede, Vivian Salama, Moamen Abobakr, Abdallah S R Mohamed, Renjie He, Joel Jaskari, Jaakko Sahlsten, Kimmo Kaski, Clifton D Fuller, Mohamed A Naser

Faculty, Staff and Student Publications

The accurate determination of sarcopenia is critical for disease management in patients with head and neck cancer (HNC). Quantitative determination of sarcopenia is currently dependent on manually-generated segmentations of skeletal muscle derived from computed tomography (CT) cross-sectional imaging. This has prompted the increasing utilization of machine learning models for automated sarcopenia determination. However, extant datasets currently do not provide the necessary manually-generated skeletal muscle segmentations at the C3 vertebral level needed for building these models. In this data descriptor, a set of 394 HNC patients were selected from The Cancer Imaging Archive, and their skeletal muscle and adipose tissue was …

Advances In Head And Neck Cancer Pain, Y Ye, D D Jensen, C T Viet, H L Pan, W M Campana, M Amit, M D Boada

Faculty, Staff and Student Publications

Head and neck cancer (HNC) affects over 890,000 people annually worldwide and has a mortality rate of 50%. Aside from poor survival, HNC pain impairs eating, drinking, and talking in patients, severely reducing quality of life. Different pain phenotype in patients (allodynia, hyperalgesia, and spontaneous pain) results from a combination of anatomical, histopathological, and molecular differences between cancers. Poor pathologic features (e.g., perineural invasion, lymph node metastasis) are associated with increased pain. The use of syngeneic/immunocompetent animal models, as well as a new mouse model of perineural invasion, provides novel insights into the pathobiology of HNC pain. Glial and immune …

A Large-Scale Genome-Wide Gene-Gene Interaction Study Of Lung Cancer Susceptibility In Europeans With A Trans-Ethnic Validation In Asians, Ruyang Zhang, Sipeng Shen, Yongyue Wei, Ying Zhu, Yi Li, Jiajin Chen, Jinxing Guan, Zoucheng Pan, Yuzhuo Wang, Meng Zhu, Junxing Xie, Xiangjun Xiao, Dakai Zhu, Yafang Li, Demetrios Albanes, Maria Teresa Landi, Neil E Caporaso, Stephen Lam, Adonina Tardon, Chu Chen, Stig E Bojesen, Mattias Johansson, Angela Risch, Heike Bickeböller, H-Erich Wichmann, Gadi Rennert, Susanne Arnold, Paul Brennan, James D Mckay, John K Field, Sanjay S Shete, Loic Le Marchand, Geoffrey Liu, Angeline S Andrew, Lambertus A Kiemeney, Shan Zienolddiny-Narui, Annelie Behndig, Mikael Johansson, Angela Cox, Philip Lazarus, Matthew B Schabath, Melinda C Aldrich, Juncheng Dai, Hongxia Ma, Yang Zhao, Zhibin Hu, Rayjean J Hung, Christopher I Amos, Hongbing Shen, Feng Chen, David C Christiani

Faculty, Staff and Students Publications

INTRODUCTION: Although genome-wide association studies have been conducted to investigate genetic variation of lung tumorigenesis, little is known about gene-gene (G × G) interactions that may influence the risk of non-small cell lung cancer (NSCLC).

METHODS: Leveraging a total of 445,221 European-descent participants from the International Lung Cancer Consortium OncoArray project, Transdisciplinary Research in Cancer of the Lung and UK Biobank, we performed a large-scale genome-wide G × G interaction study on European NSCLC risk by a series of analyses. First, we used BiForce to evaluate and rank more than 58 billion G × G interactions from 340,958 single-nucleotide polymorphisms …

Whole Genome Sequence Association Analysis Of Fasting Glucose And Fasting Insulin Levels In Diverse Cohorts From The Nhlbi Topmed Program, Daniel Dicorpo, Sheila M. Gaynor, Emily M. Russell, Kenneth E. Westerman, Laura M. Raffield, Marcio Almeida, Juan M. Peralta, John Blangero, Joanne E. Curran, Ravindranath Duggirala

School of Medicine Publications

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI’s Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well …

Pneumonitis After Immune Checkpoint Inhibitor Therapies In Patients With Acute Myeloid Leukemia: A Retrospective Cohort Study, Ajay Sheshadri, Alberto A Goizueta, Vickie R Shannon, David London, Guillermo Garcia-Manero, Hagop M Kantarjian, Farhad Ravandi-Kashani, Tapan M Kadia, Marina Y Konopleva, Courtney D Dinardo, Sherry Pierce, Abdulrazzak Zarifa, Aya A Albittar, Linda L Zhong, Fechukwu O Akhmedzhanov, Muhammad H Arain, Mansour Alfayez, Ahmad Alotaibi, Mehmet Altan, Aung Naing, Tito R Mendoza, Myrna C B Godoy, Girish Shroff, Sang T Kim, Saadia A Faiz, Dimitrios P Kontoyiannis, Fareed Khawaja, Kristofer Jennings, Naval G Daver

Faculty, Staff and Student Publications

Background: Immune checkpoint inhibitors (ICI), combined with hypomethylating agents, can be used to treat acute myeloid leukemia (AML), but this strategy results in a high rate of pneumonitis. The authors sought to determine risk factors for pneumonitis development and whether pneumonitis increased mortality.

Methods: The authors conducted a retrospective review of 258 AML patients who received ICI-containing regimens from 2016 to 2018. A multidisciplinary adjudication committee diagnosed pneumonia and pneumonitis by reviewing symptoms, imaging, microbiology, and response to therapies. To measure risk factors for pneumonitis and mortality, multivariate Cox proportional hazards models were constructed. Pneumonia, pneumonitis, and disease progression were …

Synthetic Essentiality Of Tryptophan 2,3-Dioxygenase 2 In Apc-Mutated Colorectal Cancer, Rumi Lee, Jiexi Li, Jun Li, Chang-Jiun Wu, Shan Jiang, Wen-Hao Hsu, Deepavali Chakravarti, Peiwen Chen, Kyle A Labella, Jing Li, Denise J Spring, Di Zhao, Y Alan Wang, Ronald A Depinho

Faculty, Staff and Student Publications

Inactivation of adenomatous polyposis coli (APC) is common across many cancer types and serves as a critical initiating event in most sporadic colorectal cancers. APC deficiency activates WNT signaling, which remains an elusive target for cancer therapy, prompting us to apply the synthetic essentiality framework to identify druggable vulnerabilities for APC-deficient cancers. Tryptophan 2,3-dioxygenase 2 (TDO2) was identified as a synthetic essential effector of APC-deficient colorectal cancer. Mechanistically, APC deficiency results in the TCF4/β-catenin-mediated upregulation of TDO2 gene transcription. TDO2 in turn activates the Kyn-AhR pathway, which increases glycolysis to drive anabolic cancer cell growth and CXCL5 secretion to recruit …

Prediction Of Survival With Intensive Chemotherapy In Acute Myeloid Leukemia, Koji Sasaki, Farhad Ravandi, Tapan Kadia, Courtney Dinardo, Gautam Borthakur, Nicholas Short, Nitin Jain, Naval Daver, Elias Jabbour, Guillermo Garcia-Manero, Joseph Khoury, Sergej Konoplev, Sanam Loghavi, Keyur Patel, Guillermo Montalban-Bravo, Lucia Masarova, Marina Konopleva, Hagop Kantarjian

Faculty, Staff and Student Publications

Progress with intensive chemotherapy and supportive care measures has improved survival in newly diagnosed acute myeloid leukemia (AML). Predicting outcome helps in treatment decision making. We analyzed survival as the treatment endpoint in 3728 patients with newly diagnosed AML treated with intensive chemotherapy from 1980 to 2021. We divided the total study group (3:1 basis) into a training (n = 2790) and a validation group (n = 938). The associations between survival and 27 characteristics were investigated. In the training cohort, the multivariate analysis identified 12 consistent adverse prognostic variables independently associated with worse survival: older age, therapy-related myeloid neoplasm, …

Mice Lacking Wnt9a Or Wnt4 Are Prone To Develop Spontaneous Osteoarthritis With Age And Display Alteration In Either The Trabecular Or Cortical Bone Compartment, Stefan Teufel, Lena Wolff, Ulrich König, Akio Kobayashi, Richard Behringer, Christine Hartmann

Faculty, Staff and Student Publications

Osteoarthritis (OA) is a common degenerative disease of the joint, with a complex multifactorial not yet fully understood etiology. Over the past years, the Wnt signaling pathway has been implicated in osteoarthritis. In a recent genomewide association study (GWAS), the chromosomal location on chromosome 1, linked to the Wnt3a-Wnt9a gene locus, was identified as the most significant locus associated with a thumb osteoarthritis endophenotype. Previously, it was shown that WNT9a is involved in maintaining synovial cell identity in the elbow joint during embryogenesis. Here, we report that the conditional loss of Wnt9a in the Prx1-Cre expressing limb mesenchyme or Prg4-CreER …

Lenalidomide Enhances Cd23car T Cell Therapy In Chronic Lymphocytic Leukemia, Sarah Tettamanti, Maria Caterina Rotiroti, Greta Maria Paola Giordano Attianese, Silvia Arcangeli, Ronghua Zhang, Priyanka Banerjee, Giovanni Galletti, Sheighlah Mcmanus, Massimiliano Mazza, Fabio Nicolini, Giovanni Martinelli, Cristina Ivan, Tania Veliz Rodriguez, Federica Barbaglio, Lydia Scarfò, Maurilio Ponzoni, William Wierda, Varsha Gandhi, Michael Keating, Andrea Biondi, Federico Caligaris-Cappio, Ettore Biagi, Paolo Ghia, Maria Teresa Sabrina Bertilaccio

Faculty, Staff and Student Publications

Chimeric antigen receptors (CAR)-modified T cells are an emerging therapeutic tool for chronic lymphocytic leukemia (CLL). However, in patients with CLL, well-known T-cell defects and the inhibitory properties of the tumor microenvironment (TME) hinder the efficacy of CAR T cells. We explored a novel approach combining CARs with lenalidomide, an immunomodulatory drug that tempers the immunosuppressive activity of the CLL TME. T cells from patients with CLL were engineered to express a CAR specific for CD23, a promising target antigen. Lenalidomide maintained the in vitro effector functions of CD23.CAR+ T cells effector functions in terms of antigen-specific cytotoxicity, cytokine release …

Activating Connexin43 Gap Junctions Primes Adipose Tissue For Therapeutic Intervention, Yi Zhu, Na Li, Mingyang Huang, Xi Chen, Yu A An, Jianping Li, Shangang Zhao, Jan-Bernd Funcke, Jianhong Cao, Zhenyan He, Qingzhang Zhu, Zhuzhen Zhang, Zhao V Wang, Lin Xu, Kevin W Williams, Chien Li, Kevin Grove, Philipp E Scherer

Faculty, Staff and Students Publications

Adipose tissue is a promising target for treating obesity and metabolic diseases. However, pharmacological agents usually fail to effectively engage adipocytes due to their extraordinarily large size and insufficient vascularization, especially in obese subjects. We have previously shown that during cold exposure, connexin43 (Cx43) gap junctions are induced and activated to connect neighboring adipocytes to share limited sympathetic neuronal input amongst multiple cells. We reason the same mechanism may be leveraged to improve the efficacy of various pharmacological agents that target adipose tissue. Using an adipose tissue-specific Cx43 overexpression mouse model, we demonstrate effectiveness in connecting adipocytes to augment metabolic …

Decoding The Pitx2-Controlled Genetic Network In Atrial Fibrillation, Jeffrey D Steimle, Francisco J Grisanti Canozo, Minjun Park, Zachary A Kadow, Md Abul Hassan Samee, James F Martin

Faculty, Staff and Students Publications

Atrial fibrillation (AF), the most common sustained cardiac arrhythmia and a major risk factor for stroke, often arises through ectopic electrical impulses derived from the pulmonary veins (PVs). Sequence variants in enhancers controlling expression of the transcription factor PITX2, which is expressed in the cardiomyocytes (CMs) of the PV and left atrium (LA), have been implicated in AF predisposition. Single nuclei multiomic profiling of RNA and analysis of chromatin accessibility combined with spectral clustering uncovered distinct PV- and LA-enriched CM cell states. Pitx2-mutant PV and LA CMs exhibited gene expression changes consistent with cardiac dysfunction through cell type-distinct, PITX2-directed, cis-regulatory …

Utility Of The Motivation To Change Lifestyle And Health Behaviors For Dementia Risk Reduction Scale (Mclhb-Drr) Based On A North American Sample, Angelina E. Witbeck

Dissertations

As the population ages, the prevalence rates of dementia continue to increase. Without a cure or promising treatment for dementia, the best course of lowering the prevalence rates of dementia is through preventative measures. Through an electronic survey, the study utilized the MCLHB-DRR scale to determine whether (1) gender, age, educational background, and socioeconomic status will impact the motivational factors to change lifestyle and health behaviors to reduce the risk of developing dementia and (2) direct experiences with individuals that have a dementia diagnosis are likely to impact one's motivational factors to change lifestyle and health behaviors to reduce the …

Knowledge-Based Planning For The Radiation Therapy Treatment Plan Quality Assurance For Patients With Head And Neck Cancer, Wenhua Cao, Mary Gronberg, Adenike Olanrewaju, Thomas Whitaker, Karen Hoffman, Carlos Cardenas, Adam Garden, Heath Skinner, Beth Beadle, Laurence Court

Faculty, Staff and Student Publications

This study aimed to investigate the feasibility of using a knowledge-based planning technique to detect poor quality VMAT plans for patients with head and neck cancer. We created two dose-volume histogram (DVH) prediction models using a commercial knowledge-based planning system (RapidPlan, Varian Medical Systems, Palo Alto, CA) from plans generated by manual planning (MP) and automated planning (AP) approaches. DVHs were predicted for evaluation cohort 1 (EC1) of 25 patients and compared with achieved DVHs of MP and AP plans to evaluate prediction accuracy. Additionally, we predicted DVHs for evaluation cohort 2 (EC2) of 25 patients for which we intentionally …

A Phase 1 Trial Of 8-Chloro-Adenosine In Relapsed/Refractory Acute Myeloid Leukemia: An Evaluation Of Safety And Pharmacokinetics, Rong Chen, Yuling Chen, Ping Xiong, Daniella Zheleva, David Blake, Michael J Keating, William G Wierda, William Plunkett

Faculty, Staff and Student Publications

Fadraciclib (CYC065) is a second-generation aminopurine CDK2/9 inhibitor with increased potency and selectivity toward CDK2 and CDK9 compared to seliciclib (R-roscovitine). In chronic lymphocytic leukemia (CLL), a disease that depends on the over-expression of anti-apoptotic proteins for its survival, inhibition of CDK9 by fadraciclib reduced phosphorylation of the C-terminal domain of RNA polymerase II and blocked transcription in vitro; these actions depleted the intrinsically short-lived anti-apoptotic protein Mcl-1 and induced apoptosis. While the simulated bone marrow and lymph node microenvironments induced Mcl-1 expression and protected CLL cells from apoptosis, these conditions did not prolong the turnover rate of Mcl-1, and …