Medical Genetics Commons^™

Prmt7 Ablation Stimulates Anti-Tumor Immunity And Sensitizes Melanoma To Immune Checkpoint Blockade, Nivine Srour, Oscar D Villarreal, Swanand Hardikar, Zhenbao Yu, Samuel Preston, Wilson H Miller, Magdelena M Szewczyk, Dalia Barsyte-Lovejoy, Han Xu, Taiping Chen, Sonia V Del Rincón, Stéphane Richard

Faculty, Staff and Student Publications

Despite the success of immune checkpoint inhibitor (ICI) therapy for cancer, resistance and relapse are frequent. Combination therapies are expected to enhance response rates and overcome this resistance. Herein, we report that combining PRMT7 inhibition with ICI therapy induces a strong anti-tumor T cell immunity and restrains tumor growth in vivo by increasing immune cell infiltration. PRMT7-deficient B16.F10 melanoma exhibits increased expression of genes in the interferon pathway, antigen presentation, and chemokine signaling. PRMT7 deficiency or inhibition with SGC3027 in B16.F10 melanoma results in reduced DNMT expression, loss of DNA methylation in the regulatory regions of endogenous retroviral elements (ERVs) …

Blinatumomab Maintenance After Allogeneic Hematopoietic Cell Transplantation For B-Lineage Acute Lymphoblastic Leukemia, Mahmoud R Gaballa, Pinaki Banerjee, Denái R Milton, Xianli Jiang, Christina Ganesh, Sajad Khazal, Vandana Nandivada, Sanjida Islam, Mecit Kaplan, May Daher, Rafet Basar, Amin Alousi, Rohtesh Mehta, Gheath Alatrash, Issa Khouri, Betul Oran, David Marin, Uday Popat, Amanda Olson, Priti Tewari, Nitin Jain, Elias Jabbour, Farhad Ravandi, Hagop Kantarjian, Ken Chen, Richard Champlin, Elizabeth Shpall, Katayoun Rezvani, Partow Kebriaei

Faculty, Staff and Student Publications

Patients with B-lineage acute lymphoblastic leukemia (ALL) are at high-risk for relapse after allogeneic hematopoietic cell transplantation (HCT). We conducted a single-center phase 2 study evaluating the feasibility of 4 cycles of blinatumomab administered every 3 months during the first year after HCT in an effort to mitigate relapse in high-risk ALL patients. Twenty-one of 23 enrolled patients received at least 1 cycle of blinatumomab and were included in the analysis. The median time from HCT to the first cycle of blinatumomab was 78 days (range, 44 to 105). Twelve patients (57%) completed all 4 treatment cycles. Neutropenia was the …

Micrornas In Leukemias: A Clinically Annotated Compendium, Aleksander Turk, George A Calin, Tanja Kunej

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Leukemias are a group of malignancies of the blood and bone marrow. Multiple types of leukemia are known, however reliable treatments have not been developed for most leukemia types. Furthermore, even relatively reliable treatments can result in relapses. MicroRNAs (miRNAs) are a class of short, noncoding RNAs responsible for epigenetic regulation of gene expression and have been proposed as a source of potential novel therapeutic targets for leukemias. In order to identify central miRNAs for leukemia, we conducted data synthesis using two databases: miRTarBase and DISNOR. A total of 137 unique miRNAs associated with 16 types of leukemia were retrieved …

Precision Dosimetry In Yttrium-90 Radioembolization Through Ct Imaging Of Radiopaque Microspheres In A Rabbit Liver Model, E Courtney Henry, Matthew Strugari, George Mawko, Kimberly Brewer, David Liu, Andrew C Gordon, Jeffrey N Bryan, Charles Maitz, James J Karnia, Robert Abraham, S Cheenu Kappadath, Alasdair Syme

Faculty, Staff and Student Publications

Purpose: To perform precision dosimetry in yttrium-90 radioembolization through CT imaging of radiopaque microspheres in a rabbit liver model and to compare extracted dose metrics to those produced from conventional PET-based dosimetry.

Materials and methods: A CT calibration phantom was designed containing posts with nominal microsphere concentrations of 0.5 mg/mL, 5.0 mg/mL, and 25.0 mg/mL. The mean Hounsfield unit was extracted from the post volumes to generate a calibration curve to relate Hounsfield units to microsphere concentration. A nominal bolus of 40 mg of microspheres was administered to the livers of eight rabbits, followed by PET/CT imaging. A CT-based activity …

Fusionai, A Dna-Sequence-Based Deep Learning Protocol Reduces The False Positives Of Human Fusion Gene Prediction, Pora Kim, Hua Tan, Jiajia Liu, Himansu Kumar, Xiaobo Zhou

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Even though there were many tool developments of fusion gene prediction from NGS data, too many false positives are still an issue. Wise use of the genomic features around the fusion gene breakpoints will be helpful to identify reliable fusion genes efficiently. For this aim, we developed FusionAI, a deep learning pipeline predicting human fusion gene breakpoints from DNA sequence. FusionAI is freely available via https://compbio.uth.edu/FusionGDB2/FusionAI. For complete details on the use and execution of this protocol, please refer to Kim et al. (2021b).

Synergy Of Venetoclax And 8-Chloro-Adenosine In Aml: The Interplay Of Rrna Inhibition And Fatty Acid Metabolism, Dinh Hoa Hoang, Corey Morales, Ivan Rodriguez Rodriguez, Melissa Valerio, Jiamin Guo, Min-Hsuan Chen, Xiwei Wu, David Horne, Varsha Gandhi, Lisa S Chen, Bin Zhang, Vinod Pullarkat, Steven T Rosen, Guido Marcucci, Ralf Buettner, Le Xuan Truong Nguyen

Faculty, Staff and Student Publications

It is known that 8-chloro-adenosine (8-Cl-Ado) is a novel RNA-directed nucleoside analog that targets leukemic stem cells (LSCs). In a phase I clinical trial with 8-Cl-Ado in patients with refractory or relapsed (R/R) AML, we observed encouraging but short-lived clinical responses, likely due to intrinsic mechanisms of LSC resistance. LSC homeostasis depends on amino acid-driven and/or fatty acid oxidation (FAO)-driven oxidative phosphorylation (OXPHOS) for survival. We recently reported that 8-Cl-Ado and the BCL-2-selective inhibitor venetoclax (VEN) synergistically inhibit FAO and OXPHOS in LSCs, thereby suppressing acute myeloid leukemia (AML) growth in vitro and in vivo. Herein, we report that 8-Cl-Ado …

Blood-Based Biomarker Panel For Personalized Lung Cancer Risk Assessment, Johannes F Fahrmann, Tracey Marsh, Ehsan Irajizad, Nikul Patel, Eunice Murage, Jody Vykoukal, Jennifer B Dennison, Kim-Anh Do, Edwin Ostrin, Margaret R Spitz, Stephen Lam, Sanjay Shete, Rafael Meza, Martin C Tammemägi, Ziding Feng, Samir M Hanash

Faculty, Staff and Student Publications

Purpose: To investigate whether a panel of circulating protein biomarkers would improve risk assessment for lung cancer screening in combination with a risk model on the basis of participant characteristics.

Methods: A blinded validation study was performed using prostate lung colorectal ovarian (PLCO) Cancer Screening Trial data and biospecimens to evaluate the performance of a four-marker protein panel (4MP) consisting of the precursor form of surfactant protein B, cancer antigen 125, carcinoembryonic antigen, and cytokeratin-19 fragment in combination with a lung cancer risk prediction model (PLCOm2012) compared with current US Preventive Services Task Force (USPSTF) screening criteria. The 4MP was …

Measurable Residual Disease Response And Prognosis In Treatment-Naïve Acute Myeloid Leukemia With Venetoclax And Azacitidine, Keith W Pratz, Brian A Jonas, Vinod Pullarkat, Christian Recher, Andre C Schuh, Michael J Thirman, Jacqueline S Garcia, Courtney D Dinardo, Vladimir Vorobyev, Nicola S Fracchiolla, Su-Peng Yeh, Jun Ho Jang, Muhit Ozcan, Kazuhito Yamamoto, Arpad Illes, Ying Zhou, Monique Dail, Brenda Chyla, Jalaja Potluri, Hartmut Döhner

Faculty, Staff and Student Publications

PURPOSE: There is limited evidence on the clinical utility of monitoring measurable residual disease (MRD) in patients with acute myeloid leukemia treated with lower-intensity therapy. Herein, we explored the outcomes of patients treated with venetoclax and azacitidine who achieved composite complete remission (CRc; complete remission + complete remission with incomplete hematologic recovery) and MRD < 10

METHODS: The patients included in this report were treated with venetoclax and azacitidine. Bone marrow aspirate samples for multiparametric flow cytometry assessments were collected for central analysis at baseline, end of cycle 1, and every three cycles thereafter. MRD-negative response was defined as < 1 residual blast per 1,000 leukocytes (< 10

RESULTS: One hundred …

Chromosomal Imbalances Detected Via Rna-Sequencing In 28 Cancers, Zuhal Ozcan, Francis A San Lucas, Justin W Wong, Kyle Chang, Konrad H Stopsack, Jerry Fowler, Yasminka A Jakubek, Paul Scheet

Faculty, Staff and Student Publications

Motivation: RNA-sequencing (RNA-seq) of tumor tissue is typically only used to measure gene expression. Here, we present a statistical approach that leverages existing RNA-seq data to also detect somatic copy number alterations (SCNAs), a pervasive phenomenon in human cancers, without a need to sequence the corresponding DNA.

Results: We present an analysis of 4942 participant samples from 28 cancers in The Cancer Genome Atlas (TCGA), demonstrating robust detection of SCNAs from RNA-seq. Using genotype imputation and haplotype information, our RNA-based method had a median sensitivity of 85% to detect SCNAs defined by DNA analysis, at high specificity (∼95%). As an …

The Impact Of Radiation Dose To Heart Substructures On Major Coronary Events And Patient Survival After Chemoradiation Therapy For Esophageal Cancer, Xin Wang, Nicolas L Palaskas, Brian P Hobbs, Jun-Ichi Abe, Kevin T Nead, Syed Wamique Yusuf, Joerg Hermann, Anita Deswal, Steven H Lin

Faculty, Staff and Student Publications

Simple Summary

Whether it is necessary to evaluate the radiation exposure of cardiac substructures when making radiotherapy plans is one of the current research hotspots. In this cohort study of 355 patients with esophageal cancer, the radiation dose to key coronary substructures such as the left anterior descending artery V30_Gy and mean left main coronary artery was closely associated with major coronary events and overall patient survival, and showed better predictive value than the mean heart dose or heart V30_Gy recommended by current guidelines. Our findings suggest that, in addition to the whole heart, key coronary substructures should …

Long-Term Survival Following Definitive Radiation Therapy For Recurrence Or Oligometastases In Gynecological Malignancies: A Landmark Analysis, Kelsey L Corrigan, Alison Yoder, Brian De, Lilie Lin, Anuja Jhingran, Melissa M Joyner, Patricia J Eifel, Lauren E Colbert, Karen H Lu, Ann H Klopp

Faculty, Staff and Student Publications

Objective: Radiation therapy (RT) may improve outcomes for patients with oligometastatic cancer. We sought to determine if there are long-term survivors treated with definitive RT for recurrent or oligometastatic gynecological cancer (ROMGC), and to evaluate the clinical and disease characteristics of these patients.

Methods: We performed a landmark analysis in 48 patients with ROMGC who survived for ≥5 years following definitive RT of their metastasis. Patient characteristics were extracted from the medical record. DFS was modeled using the Kaplan-Meier method.

Results: This cohort included 20 patients (42%) with ovarian cancer, 16 (33%) with endometrial cancer, 11 (23%) with cervical cancer, …

Peripheral And Central Kynurenine Pathway Abnormalities In Major Depression, Elisabeth R Paul, Lilly Schwieler, Sophie Erhardt, Sandra Boda, Ada Trepci, Robin Kämpe, Anna Asratian, Lovisa Holm, Adam Yngve, Robert Dantzer, Markus Heilig, J Paul Hamilton, Martin Samuelsson

Faculty, Staff and Student Publications

Considerable data relate major depressive disorder (MDD) with aberrant immune system functioning. Pro-inflammatory cytokines facilitate metabolism of tryptophan along the kynurenine pathway (KP) putatively resulting in reduced neuroprotective and increased neurotoxic KP metabolites in MDD, in addition to modulating metabolic and immune function. This central nervous system hypothesis has, however, only been tested in the periphery. Here, we measured KP-metabolite levels in both plasma and cerebrospinal fluid (CSF) of depressed patients (n = 63/36 respectively) and healthy controls (n = 48/33). Further, we assessed the relation between KP abnormalities and brain-structure volumes, as well as body mass index (BMI), an …

Characterization Of Patient-Derived Bone Marrow Human Mesenchymal Stem Cells As Oncolytic Virus Carriers For The Treatment Of Glioblastoma, Yuzaburo Shimizu, Joy Gumin, Feng Gao, Anwar Hossain, Elizabeth J Shpall, Akihide Kondo, Brittany C Parker Kerrigan, Jing Yang, Daniel Ledbetter, Juan Fueyo, Candelaria Gomez-Manzano, Frederick F Lang

Faculty, Staff and Student Publications

Objective: Delta-24-RGD is an oncolytic adenovirus that is capable of replicating in and killing human glioma cells. Although intratumoral delivery of Delta-24-RGD can be effective, systemic delivery would improve its clinical application. Bone marrow-derived human mesenchymal stem cells (BM-hMSCs) obtained from healthy donors have been investigated as virus carriers. However, it is unclear whether BM-hMSCs can be derived from glioma patients previously treated with marrow-toxic chemotherapy or whether such BM-hMSCs can deliver oncolytic viruses effectively. Herein, the authors undertook a prospective clinical trial to determine the feasibility of obtaining BM-hMSCs from patients with recurrent malignant glioma who were previously exposed …

Local Treatment Of A Pediatric Osteosarcoma Model With A 4-1bbl Armed Oncolytic Adenovirus Results In An Antitumor Effect And Leads To Immune Memory, Naiara Martinez-Velez, Virginia Laspidea, Marta Zalacain, Sara Labiano, Marc García-Moure, Montse Puigdelloses, Lucía Marrodan, Marisol Gonzalez-Huarriz, Guillermo Herrador, Daniel De La Nava, Iker Ausejo-Mauleon, Juan Fueyo, Candelaria Gomez-Manzano, Ana Patiño-García, Marta M Alonso

Faculty, Staff and Student Publications

Osteosarcoma is an aggressive bone tumor occurring primarily in pediatric patients. Despite years of intensive research, the outcomes of patients with metastatic disease or those who do not respond to therapy have remained poor and have not changed in the last 30 years. Oncolytic virotherapy is becoming a reality to treat local and metastatic tumors while maintaining a favorable safety profile. Delta-24-ACT is a replicative oncolytic adenovirus engineered to selectively target cancer cells and to potentiate immune responses through expression of the immune costimulatory ligand 4-1BB. This work aimed to assess the antisarcoma effect of Delta-24-ACT. MTS and replication assays …

Identification Of A Novel Microdeletion Causative Of Nance-Horan Syndrome, Mariana Lopez Martinolich, Hope Northrup, Pedro Mancias, Paul Hillman, Kavya Rao, Kate Mowrey

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BACKGROUND: Nance-Horan syndrome (NHS) is a rare X-linked genetic disorder characterized by ophthalmologic and dental anomalies as well as dysmorphic facies. The clinical phenotype in males includes congenital cataracts, vision loss, microcornea, nystagmus, microphthalmia, glaucoma, screwdriver blade-shaped incisors, supernumerary maxillary incisors, diastema, delays, intellectual disability, and dysmorphic facies. With the evolution of array-CGH technology, a total of five kindreds with NHS have been reported in the medical literature with microdeletions encompassing the NHS gene rather than sequencing variants.

METHODS: The patient is a 19-year-old male born to non-consanguineous parents with a past medical history of bilateral congenital cataracts, nystagmus, poor …

Assessing The Contribution Of Rare Variants To Complex Trait Heritability From Whole-Genome Sequence Data, Pierrick Wainschtein, Deepti Jain, Zhili Zheng, Topmed Anthropometry Working Group, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, L Adrienne Cupples, Aladdin H Shadyab, Barbara Mcknight, Benjamin M Shoemaker, Braxton D Mitchell, Bruce M Psaty, Charles Kooperberg, Ching-Ti Liu, Christine M Albert, Dan Roden, Daniel I Chasman, Dawood Darbar, Donald M Lloyd-Jones, Donna K Arnett, Elizabeth A Regan, Eric Boerwinkle, Jerome I Rotter, Jeffrey R O'Connell, Lisa R Yanek, Mariza De Andrade, Matthew A Allison, Merry-Lynn N Mcdonald, Mina K Chung, Myriam Fornage, Nathalie Chami, Nicholas L Smith, Patrick T Ellinor, Ramachandran S Vasan, Rasika A Mathias, Ruth J F Loos, Stephen S Rich, Steven A Lubitz, Susan R Heckbert, Susan Redline, Xiuqing Guo, Y -D Ida Chen, Cecelia A Laurie, Ryan D Hernandez, Stephen T Mcgarvey, Michael E Goddard, Cathy C Laurie, Kari E North, Leslie A Lange, Bruce S Weir, Loic Yengo, Jian Yang, Peter M Visscher

Faculty, Staff and Student Publications

Analyses of data from genome-wide association studies on unrelated individuals have shown that, for human traits and diseases, approximately one-third to two-thirds of heritability is captured by common SNPs. However, it is not known whether the remaining heritability is due to the imperfect tagging of causal variants by common SNPs, in particular whether the causal variants are rare, or whether it is overestimated due to bias in inference from pedigree data. Here we estimated heritability for height and body mass index (BMI) from whole-genome sequence data on 25,465 unrelated individuals of European ancestry. The estimated heritability was 0.68 (standard error …

Targeting Mitochondrial Respiration And The Bcl2 Family In High-Grade Myc-Associated B-Cell Lymphoma, Giulio Donati, Micol Ravà, Marco Filipuzzi, Paola Nicoli, Laura Cassina, Alessandro Verrecchia, Mirko Doni, Simona Rodighiero, Federica Parodi, Alessandra Boletta, Christopher P Vellano, Joseph R Marszalek, Giulio F Draetta, Bruno Amati

Faculty, Staff and Student Publications

Multiple molecular features, such as activation of specific oncogenes (e.g., MYC, BCL2) or a variety of gene expression signatures, have been associated with disease course in diffuse large B-cell lymphoma (DLBCL), although their relationships and implications for targeted therapy remain to be fully unraveled. We report that MYC activity is closely correlated with-and most likely a driver of-gene signatures related to oxidative phosphorylation (OxPhos) in DLBCL, pointing to OxPhos enzymes, in particular mitochondrial electron transport chain (ETC) complexes, as possible therapeutic targets in high-grade MYC-associated lymphomas. In our experiments, indeed, MYC sensitized B cells to the ETC complex I inhibitor …

Monitoring Malignant T-Cell Clones By Direct Tcr Expression Assay In Patients With Leukemic Cutaneous T-Cell Lymphoma During Extracorporeal Photopheresis, Xiao Ni, Sourindra Maiti, Alissa Redko, Pedram Bijani, Madeleine Duvic

Faculty, Staff and Student Publications

Background/purpose: Accurate assessment of malignant T-cell clones in patients with leukemic cutaneous T-cell lymphoma (L-CTCL) is crucial for diagnosis, treatment, and monitoring disease. Although multiple approaches to quantitate malignant T-cell clones have been reported, a cost-effective assay with broad coverage is not available. We report a NanoString-nCounter-Technology-based direct TCR expression assay (DTEA) that was previously developed to quantify both TCR-Vα and TCR-Vβ usages after adoptive immunotherapy. This study was performed to test the effectiveness of DTEA in assessing malignant T-cell clones in L-CTCL patients.

Methods: Total RNAs extracted from peripheral blood mononuclear cells of patients before starting extracorporeal photopheresis (ECP) …

Dose Accumulation Of Daily Adaptive Plans To Decide Optimal Plan Adaptation Strategy For Head-And-Neck Patients Treated With Mr-Linac, Shin Yun Lim, Alan Tran, Anh Ngoc Kieu Tran, Angela Sobremonte, Clifton D Fuller, Lori Simmons, Jinzhong Yang

Faculty, Staff and Student Publications

Advances in magnetic resonance linear accelerators (MR-Linacs) allow for superior visualization of soft tissue to guide online adaptive replanning for precise radiotherapy delivery. Elekta Unity MR-Linacs (Elekta AB, Stockholm, Sweden) provides 2 plan adaptation approaches, adapt-to-position (ATP), plan reoptimization based on the reference CT with the iso-shift measured from daily MR scans, and adapt-to-shape (ATS), full plan reoptimization based on the re-contoured daily MR scans. Our study aims to close the gap in knowledge regarding the use of the ATP technique in the treatment of head and neck (HN) cancers through the analysis of accumulated dose of daily ATP plans …

Stem Cell Architecture Drives Myelodysplastic Syndrome Progression And Predicts Response To Venetoclax-Based Therapy, Irene Ganan-Gomez, Hui Yang, Feiyang Ma, Guillermo Montalban-Bravo, Natthakan Thongon, Valentina Marchica, Guillaume Richard-Carpentier, Kelly Chien, Ganiraju Manyam, Feng Wang, Ana Alfonso, Shuaitong Chen, Caleb Class, Rashmi Kanagal-Shamanna, Justin P Ingram, Yamini Ogoti, Ashley Rose, Sanam Loghavi, Pamela Lockyer, Benedetta Cambo, Muharrem Muftuoglu, Sarah Schneider, Vera Adema, Michael Mclellan, John Garza, Matteo Marchesini, Nicola Giuliani, Matteo Pellegrini, Jing Wang, Jason Walker, Ziyi Li, Koichi Takahashi, Joel D Leverson, Carlos Bueso-Ramos, Michael Andreeff, Karen Clise-Dwyer, Guillermo Garcia-Manero, Simona Colla

Faculty, Staff and Student Publications

Myelodysplastic syndromes (MDS) are heterogeneous neoplastic disorders of hematopoietic stem cells (HSCs). The current standard of care for patients with MDS is hypomethylating agent (HMA)-based therapy; however, almost 50% of MDS patients fail HMA therapy and progress to acute myeloid leukemia, facing a dismal prognosis due to lack of approved second-line treatment options. As cancer stem cells are the seeds of disease progression, we investigated the biological properties of the MDS HSCs that drive disease evolution, seeking to uncover vulnerabilities that could be therapeutically exploited. Through integrative molecular profiling of HSCs and progenitor cells in large patient cohorts, we found …

Accounting For Egfr Mutations In Epidemiologic Analyses Of Non-Small Cell Lung Cancers: Examples Based On The International Lung Cancer Consortium Data, Sabine Schmid, Mei Jiang, M Catherine Brown, Aline Fares, Miguel Garcia, Joelle Soriano, Mei Dong, Sera Thomas, Takashi Kohno, Leticia Ferro Leal, Nancy Diao, Juntao Xie, Zhichao Wang, David Zaridze, Ivana Holcatova, Jolanta Lissowska, Beata Świątkowska, Dana Mates, Milan Savic, Angela S Wenzlaff, Curtis C Harris, Neil E Caporaso, Hongxia Ma, Guillermo Fernandez-Tardon, Matthew J Barnett, Gary Goodman, Michael P A Davies, Mónica Pérez-Ríos, Fiona Taylor, Eric J Duell, Ben Schoettker, Hermann Brenner, Angeline Andrew, Angela Cox, Alberto Ruano-Ravina, John K Field, Loic Le Marchand, Ying Wang, Chu Chen, Adonina Tardon, Sanjay Shete, Matthew B Schabath, Hongbing Shen, Maria Teresa Landi, Brid M Ryan, Ann G Schwartz, Lihong Qi, Lori C Sakoda, Paul Brennan, Ping Yang, Jie Zhang, David C Christiani, Rui Manuel Reis, Kouya Shiraishi, Rayjean J Hung, Wei Xu, Geoffrey Liu

Faculty, Staff and Student Publications

Background: Somatic EGFR mutations define a subset of non-small cell lung cancers (NSCLC) that have clinical impact on NSCLC risk and outcome. However, EGFR-mutation-status is often missing in epidemiologic datasets. We developed and tested pragmatic approaches to account for EGFR-mutation-status based on variables commonly included in epidemiologic datasets and evaluated the clinical utility of these approaches.

Methods: Through analysis of the International Lung Cancer Consortium (ILCCO) epidemiologic datasets, we developed a regression model for EGFR-status; we then applied a clinical-restriction approach using the optimal cut-point, and a second epidemiologic, multiple imputation approach to ILCCO survival analyses that did and did …

Subtype-Specific And Co-Occurring Genetic Alterations In B-Cell Non-Hodgkin Lymphoma, Man Chun John Ma, Saber Tadros, Alyssa Bouska, Tayla Heavican, Haopeng Yang, Qing Deng, Dalia Moore, Ariz Akhter, Keenan Hartert, Neeraj Jain, Jordan Showell, Sreejoyee Ghosh, Lesley Street, Marta Davidson, Christopher Carey, Joshua Tobin, Deepak Perumal, Julie M Vose, Matthew A Lunning, Aliyah R Sohani, Benjamin J Chen, Shannon Buckley, Loretta J Nastoupil, R Eric Davis, Jason R Westin, Nathan H Fowler, Samir Parekh, Maher Gandhi, Sattva Neelapu, Douglas Stewart, Kapil Bhalla, Javeed Iqbal, Timothy Greiner, Scott J Rodig, Adnan Mansoor, Michael R Green

Faculty, Staff and Student Publications

B-cell non-Hodgkin lymphoma (B-NHL) encompasses multiple clinically and phenotypically distinct subtypes of malignancy with unique molecular etiologies. Common subtypes of B-NHL, such as diffuse large B-cell lymphoma, have been comprehensively interrogated at the genomic level, but rarer subtypes, such as mantle cell lymphoma, remain less extensively characterized. Furthermore, multiple B-NHL subtypes have thus far not been comprehensively compared using the same methodology to identify conserved or subtype-specific patterns of genomic alterations. Here, we employed a large targeted hybrid-capture sequencing approach encompassing 380 genes to interrogate the genomic landscapes of 685 B-NHL tumors at high depth, including diffuse large B-cell lymphoma, …

Inhibition Of Calcium-Triggered Secretion By Hydrocarbon-Stapled Peptides, Ying Lai, Giorgio Fois, Jose R Flores, Michael J Tuvim, Qiangjun Zhou, Kailu Yang, Jeremy Leitz, John Peters, Yunxiang Zhang, Richard A Pfuetzner, Luis Esquivies, Philip Jones, Manfred Frick, Burton F Dickey, Axel T Brunger

Faculty, Staff and Student Publications

Membrane fusion triggered by Ca2+ is orchestrated by a conserved set of proteins to mediate synaptic neurotransmitter release, mucin secretion and other regulated exocytic processes1-4. For neurotransmitter release, the Ca2+ sensitivity is introduced by interactions between the Ca2+ sensor synaptotagmin and the SNARE complex5, and sequence conservation and functional studies suggest that this mechanism is also conserved for mucin secretion6. Disruption of Ca2+-triggered membrane fusion by a pharmacological agent would have therapeutic value for mucus hypersecretion as it is the major cause of airway obstruction in the pathophysiology of respiratory viral infection, asthma, chronic obstructive pulmonary disease and cystic fibrosis7-11. …

Current State And Future Directions Of Genomic Medicine In Aortic Dissection: A Path To Prevention And Personalized Care, Alana C Cecchi, Madeline Drake, Chrisanne Campos, Jake Howitt, Jonathan Medina, Scott M Damrauer, Sherene Shalhub, Dianna M Milewicz, Aortic Dissection Collaborative

Faculty, Staff and Student Publications

Aortic dissection confers high mortality and morbidity rates despite advances in treatment, impacts quality of life, and contributes immense burden to the healthcare system globally. Efforts to prevent aortic dissection through screening and management of modifiable risk factors and early detection of aneurysms should incorporate genomic information, as it is integral to stratifying risk. However, effective integration of genomic-guided risk assessment into clinical practice will require addressing implementation barriers that currently permeate our healthcare systems. The Aortic Dissection Collaborative was established to define aortic dissection research priorities through patient engagement. Using a collaborative patient-centered feedback model, our Genomic Medicine Working …

Methyl-Lysine Readers Phf20 And Phf20l1 Define Two Distinct Gene Expression-Regulating Nsl Complexes, Hieu T Van, Peter R Harkins, Avni Patel, Abhinav K Jain, Yue Lu, Mark T Bedford, Margarida A Santos

Faculty, Staff and Student Publications

The methyl-lysine readers plant homeodomain finger protein 20 (PHF20) and its homolog PHF20-like protein 1 (PHF20L1) are known components of the nonspecific lethal (NSL) complex that regulates gene expression through its histone acetyltransferase activity. In the current model, both PHF homologs coexist in the same NSL complex, although this was not formally tested; nor have the functions of PHF20 and PHF20L1 regarding NSL complex integrity and transcriptional regulation been investigated. Here, we perform an in-depth biochemical and functional characterization of PHF20 and PHF20L1 in the context of the NSL complex. Using mass spectrometry, genome-wide chromatin analysis, and protein-domain mapping, we …

Current Surgical Indications For Non-Small-Cell Lung Cancer, Nathaniel Deboever, Kyle G Mitchell, Hope A Feldman, Tina Cascone, Boris Sepesi

Faculty, Staff and Student Publications

With recent strides made within the field of thoracic oncology, the management of NSCLC is evolving rapidly. Careful patient selection and timing of multi-modality therapy to permit the optimization of therapeutic benefit must be pursued. While chemotherapy and radiotherapy continue to have a role in the management of lung cancer, surgical therapy remains an essential component of lung cancer treatment in early, locally and regionally advanced, as well as in selected, cases of metastatic disease. Recent and most impactful advances in the treatment of lung cancer relate to the advent of immunotherapy and targeted therapy, molecular profiling, and predictive biomarker …

Safety And Activity Of Pembrolizumab In Combination With Rituximab In Relapsed Or Refractory Follicular Lymphoma, Loretta J Nastoupil, Collin K Chin, Jason R Westin, Nathan H Fowler, Felipe Samaniego, Xiaoyun Cheng, Man Chun John Ma, Zhiqiang Wang, Fuliang Chu, Ly Dsouza, Chizobam Obi, Jennifer Mims, Lei Feng, Shouhao Zhou, Michael Green, Richard Eric Davis, Sattva S Neelapu

Faculty, Staff and Student Publications

PD-1 blockade enhances the function of antitumor T cells and antibody-dependent, cell-mediated cytotoxicity (ADCC) of NK cells. In a single-center, open-label, phase 2 trial, we tested the combination of pembrolizumab, an anti-PD-1 monoclonal antibody, and rituximab, an anti-CD20 monoclonal antibody that induces ADCC, in 30 patients with follicular lymphoma (FL) with rituximab-sensitive disease who had relapsed after ≥1 prior therapy. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 16 cycles, and rituximab was given at 375 mg/m2 IV weekly for 4 weeks in cycle 1 only. The most common grade 3/4 adverse events (AEs) were …

Crare Coding Variants In Rcn3 Are Associated With Blood Pressure, Karen Y He, Tanika N Kelly, Heming Wang, Jingjing Liang, Luke Zhu, Brian E Cade, Themistocles L Assimes, Lewis C Becker, Amber L Beitelshees, Lawrence F Bielak, Adam P Bress, Jennifer A Brody, Yen-Pei Christy Chang, Yi-Cheng Chang, Paul S De Vries, Ravindranath Duggirala, Ervin R Fox, Nora Franceschini, Anna L Furniss, Yan Gao, Xiuqing Guo, Jeffrey Haessler, Yi-Jen Hung, Shih-Jen Hwang, Marguerite Ryan Irvin, Rita R Kalyani, Ching-Ti Liu, Chunyu Liu, Lisa Warsinger Martin, May E Montasser, Paul M Muntner, Stanford Mwasongwe, Take Naseri, Walter Palmas, Muagututi'a Sefuiva Reupena, Kenneth M Rice, Wayne H-H Sheu, Daichi Shimbo, Jennifer A Smith, Beverly M Snively, Lisa R Yanek, Wei Zhao, John Blangero, Eric Boerwinkle, Yii-Der Ida Chen, Adolfo Correa, L Adrienne Cupples, Joanne E Curran, Myriam Fornage, Jiang He, Lifang Hou, Robert C Kaplan, Sharon L R Kardia, Eimear E Kenny, Charles Kooperberg, Donald Lloyd-Jones, Ruth J F Loos, Rasika A Mathias, Stephen T Mcgarvey, Braxton D Mitchell, Kari E North, Patricia A Peyser, Bruce M Psaty, Laura M Raffield, D C Rao, Susan Redline, Alex P Reiner, Stephen S Rich, Jerome I Rotter, Kent D Taylor, Russell Tracy, Ramachandran S Vasan, Samoan Obesity, Lifestyle And Genetic Adaptations Study (Olaga) Group, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Alanna C Morrison, Daniel Levy, Aravinda Chakravarti, Donna K Arnett, Xiaofeng Zhu

Faculty, Staff and Student Publications

BACKGROUND: While large genome-wide association studies have identified nearly one thousand loci associated with variation in blood pressure, rare variant identification is still a challenge. In family-based cohorts, genome-wide linkage scans have been successful in identifying rare genetic variants for blood pressure. This study aims to identify low frequency and rare genetic variants within previously reported linkage regions on chromosomes 1 and 19 in African American families from the Trans-Omics for Precision Medicine (TOPMed) program. Genetic association analyses weighted by linkage evidence were completed with whole genome sequencing data within and across TOPMed ancestral groups consisting of 60,388 individuals of …

Feasibility Of Administering Human Pancreatic Cancer Chemotherapy In A Spontaneous Pancreatic Cancer Mouse Model, Abagail M Delahoussaye, Joseph Abi Jaoude, Morgan Green, Tara N Fujimoto, Jessica Molkentine, Carolina J Garcia Garcia, Jason P Gay, Ningping Feng, Joseph Marszalek, Natalie Fowlkes, Cullen M Taniguchi

Faculty, Staff and Student Publications

Background: Both modified FOLFIRINOX (mFFX) and gemcitabine/nab-paclitaxel chemotherapy regimens have been shown to improve clinical outcomes in patients with pancreatic cancer, and are often used interchangeably as the standard of care. Preclinical studies often do not use these regimens, since administering these multiagent approaches can be difficult. In this study, we assessed the feasibility of administering these two chemotherapy regimens in spontaneous pancreatic tumors using KPC mice with the ultimate goal of advancing preclinical studies.

Methods: KPC mice were created by breeding KrasLSL-G12D/+ to Trp53fl/fl;Ptf1αCre/+, resulting in KrasLSL-G12D/+;p53fl/+;Ptf1αCre/+ mice. At 14 weeks of age, mice were palpated for spontaneous tumor …

Spatial Transcriptomics Of Dorsal Root Ganglia Identifies Molecular Signatures Of Human Nociceptors, Diana Tavares-Ferreira, Stephanie Shiers, Pradipta R Ray, Andi Wangzhou, Vivekanand Jeevakumar, Ishwarya Sankaranarayanan, Anna M Cervantes, Jeffrey C Reese, Alexander Chamessian, Bryan A Copits, Patrick M Dougherty, Robert W Gereau, Michael D Burton, Gregory Dussor, Theodore J Price

Faculty, Staff and Student Publications

Nociceptors are specialized sensory neurons that detect damaging or potentially damaging stimuli and are found in the dorsal root ganglia (DRG) and trigeminal ganglia. These neurons are critical for the generation of neuronal signals that ultimately create the perception of pain. Nociceptors are also primary targets for treating acute and chronic pain. Single-cell transcriptomics on mouse nociceptors has transformed our understanding of pain mechanisms. We sought to generate equivalent information for human nociceptors with the goal of identifying transcriptomic signatures of nociceptors, identifying species differences and potential drug targets. We used spatial transcriptomics to molecularly characterize transcriptomes of single DRG …