Medical Specialties Commons^™

Acupuncture Treatment For Post-Stroke Depression: Intestinal Microbiota And Its Role, Hailun Jiang, Shizhe Deng, Jieying Zhang, Junjie Chen, Boxuan Li, Weiming Zhu, Menglong Zhang, Chao Zhang, Zhihong Meng

Faculty, Staff and Student Publications

Stroke-induced depression is a common complication and an important risk factor for disability. Besides psychiatric symptoms, depressed patients may also exhibit a variety of gastrointestinal symptoms, and even take gastrointestinal symptoms as the primary reason for medical treatment. It is well documented that stress may disrupt the balance of the gut microbiome in patients suffering from post-stroke depression (PSD), and that disruption of the gut microbiome is closely related to the severity of the condition in depressed patients. Therefore, maintaining the balance of intestinal microbiota can be the focus of research on the mechanism of acupuncture in the treatment of …

Conjugation's Toolkit: The Roles Of Nonstructural Proteins In Bacterial Sex, Matthew B Cooke, Christophe Herman

Faculty, Staff and Students Publications

Bacterial conjugation, a form of horizontal gene transfer, relies on a type 4 secretion system (T4SS) and a set of nonstructural genes that are closely linked. These nonstructural genes aid in the mobile lifestyle of conjugative elements but are not part of the T4SS apparatus for conjugative transfer, such as the membrane pore and relaxosome, or the plasmid maintenance and replication machineries. While these nonstructural genes are not essential for conjugation, they assist in core conjugative functions and mitigate the cellular burden on the host. This review compiles and categorizes known functions of nonstructural genes by the stage of conjugation …

Pd-L1 + Macrophages Are Associated With Favorable Features In Primary Mediastinal (Thymic) Large B-Cell Lymphoma, Raphael E Steiner, Edwin R Parra, Francisco Vega, Lei Feng, Jason R Westin, Sattva S Neelapu, Paolo Strati, Michael R Green, Christopher R Flowers, Luisa M Solis, Ignacio I Wistuba, Sairah Ahmed, Ranjit Nair, Fredrick B Hagemeister, Mansoor Noorani, Mario L Marques-Piubelli

Faculty, Staff and Student Publications

Primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is a rare, aggressive subtype of non-Hodgkin lymphoma and has a complex inflammatory microenvironment. Although most patients can be cured with standard-of-care immunochemotherapy, patients who have disease relapse have an unfavorable prognosis. Pre-treatment prognostic biomarkers in PMBCL are needed. In this retrospective study, we analyzed the clinical features and outcomes of PMBCL patients and their association with immune cell subpopulations identified by multiplex immunofluorescence at initial diagnosis. Two different antibody panels were used to assess macrophages in tissue biopsy specimens collected before the initiation of induction therapy. Twelve PMBCL patients, including five patients …

Dna Damage Response-Related Proteins Are Prognostic For Outcome In Both Adult And Pediatric Acute Myelogenous Leukemia Patients: Samples From Adults And From Children Enrolled In A Children's Oncology Group Study, Stefan E Hubner, Eduardo S De Camargo Magalhães, Fieke W Hoff, Brandon D Brown, Yihua Qiu, Terzah M Horton, Steven M Kornblau

Faculty, Staff and Student Publications

The survival of malignant leukemic cells is dependent on DNA damage repair (DDR) signaling. Reverse Phase Protein Array (RPPA) data sets were assembled using diagnostic samples from 810 adult and 500 pediatric acute myelogenous leukemia (AML) patients and were probed with 412 and 296 strictly validated antibodies, respectively, including those detecting the expression of proteins directly involved in DDR. Unbiased hierarchical clustering identified strong recurrent DDR protein expression patterns in both adult and pediatric AML. Globally, DDR expression was associated with gene mutational statuses and was prognostic for outcomes including overall survival (OS), relapse rate, and remission duration (RD). In …

Multicenter Phase Ii Trial Of The Wee1 Inhibitor Adavosertib In Refractory Solid Tumors Harboring, Siqing Fu, Shuyang Yao, Yuan Yuan, Rebecca A Previs, Anthony D Elias, Richard D Carvajal, Thomas J George, Ying Yuan, Lihou Yu, Shannon N Westin, Yan Xing, Ecaterina E Dumbrava, Daniel D Karp, Sarina A Piha-Paul, Apostolia M Tsimberidou, Jordi Rodon Ahnert, Naoko Takebe, Karen Lu, Khandan Keyomarsi, Funda Meric-Bernstam

Faculty, Staff and Student Publications

PURPOSE: Preclinical cancer models harboring

PATIENTS AND METHODS: Patients aged ≥ 18 years with measurable disease and refractory solid tumors harboring

RESULTS: Thirty patients were enrolled. The median follow-up duration was 9.9 months. Eight patients had partial responses (PRs), and three had stable disease (SD) ≥ 6 months, with an ORR of 27% (95% CI, 12 to 46), a SD ≥ 6 months/PR rate of 37% (95% CI, 20 to 56), a median progression-free survival duration of 4.1 months (95% CI, 1.8 to 6.4), and a median overall survival duration of 9.9 months (95% CI, 4.8 to 15). Fourteen patients …

A First-In-Human Phase I Study Of Milademetan, An Mdm2 Inhibitor, In Patients With Advanced Liposarcoma, Solid Tumors, Or Lymphomas, Mrinal M Gounder, Todd M Bauer, Gary K Schwartz, Amy M Weise, Patricia Lorusso, Prasanna Kumar, Ben Tao, Ying Hong, Parul Patel, Yasong Lu, Arnaud Lesegretain, Vijaya G Tirunagaru, Feng Xu, Robert C Doebele, David S Hong

Faculty, Staff and Student Publications

Purpose: This study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of milademetan, a small-molecule murine double minute-2 (MDM2) inhibitor, in patients with advanced cancers.

Patients and methods: In this first-in-human phase I study, patients with advanced solid tumors or lymphomas received milademetan orally once daily as extended/continuous (days 1-21 or 1-28 every 28 days) or intermittent (days 1-7, or days 1-3 and 15-17 every 28 days) schedules. The primary objective was to determine the recommended phase II dose and schedule. Secondary objectives included tumor response according to standard evaluation criteria. Predefined analyses by tumor type were performed. Safety and …

Cognitive Sparing In Proton Versus Photon Radiotherapy For Pediatric Brain Tumor Is Associated With White Matter Integrity: An Exploratory Study, Lisa E Mash, Lisa S Kahalley, Kimberly P Raghubar, Naomi J Goodrich-Hunsaker, Tracy J Abildskov, Luz A De Leon, Marianne Macleod, Heather Stancel, Kelley Parsons, Brian Biekman, Nilesh K Desai, David R Grosshans, Arnold C Paulino, Zili D Chu, William E Whitehead, Mehmet Fatih Okcu, Murali Chintagumpala, Elisabeth A Wilde

Faculty, Staff and Student Publications

Radiotherapy for pediatric brain tumors is associated with reduced white matter structural integrity and neurocognitive decline. Superior cognitive outcomes have been reported following proton radiotherapy (PRT) compared to photon radiotherapy (XRT), presumably due to improved sparing of normal brain tissue. This exploratory study examined the relationship between white matter change and late cognitive effects in pediatric brain tumor survivors treated with XRT versus PRT. Pediatric brain tumor survivors treated with XRT (

Protocols For Single-Cell Rna-Seq And Spatial Gene Expression Integration And Interactive Visualization, Surbhi Sona, Matthew Bradley, Angela H Ting

Faculty, Staff and Student Publications

There is a wealth of software that utilizes single-cell RNA-seq (scRNA-seq) data to deconvolve spatial transcriptomic spots, which currently are not yet at single-cell resolution. Here we provide protocols for implementing Seurat and Giotto packages to elucidate cell-type distribution in our example human ureter scRNA-seq dataset. We also describe how to create a stand-alone interactive web application using Seurat libraries to visualize and share our results. For complete details on the use and execution of this protocol, please refer to Fink et al. (2022).

A Mast Cell-Thermoregulatory Neuron Circuit Axis Regulates Hypothermia In Anaphylaxis, Chunjing Bao, Ouyang Chen, Huaxin Sheng, Jeffrey Zhang, Yikai Luo, Byron W Hayes, Han Liang, Wolfgang Liedtke, Ru-Rong Ji, Soman N Abraham

Faculty, Staff and Student Publications

IgE-mediated anaphylaxis is an acute life-threatening systemic reaction to allergens, including certain foods and venoms. Anaphylaxis is triggered when blood-borne allergens activate IgE-bound perivascular mast cells (MCs) throughout the body, causing an extensive systemic release of MC mediators. Through precipitating vasodilatation and vascular leakage, these mediators are believed to trigger a sharp drop in blood pressure in humans and in core body temperature in animals. We report that the IgE/MC-mediated drop in body temperature in mice associated with anaphylaxis also requires the body's thermoregulatory neural circuit. This circuit is activated when granule-borne chymase from MCs is deposited on proximal TRPV1+ …

Comparison Of Four Clinical Prognostic Scores In Patients With Advanced Gastric And Esophageal Cancer, Lucy X Ma, Osvaldo Espin-Garcia, Yvonne Bach, Hiroko Aoyama, Michael J Allen, Xin Wang, Gail E Darling, Jonathan Yeung, Carol J Swallow, Savtaj Brar, Patrick Veit-Haibach, Sangeetha Kalimuthu, Rebecca Wong, Eric X Chen, Grainne M O'Kane, Raymond W Jang, Elena Elimova

Faculty, Staff and Student Publications

Background: Prognostic scores that can identify patients at risk for early death are needed to aid treatment decision-making and patient selection for clinical trials. We compared the accuracy of four scores to predict early death (within 90 days) and overall survival (OS) in patients with metastatic gastric and esophageal (GE) cancer.

Methods: Advanced GE cancer patients receiving first-line systemic therapy were included. Prognostic risks were calculated using: Royal Marsden Hospital (RMH), MD Anderson Cancer Centre (MDACC), Gustave Roussy Immune (GRIm-Score), and MD Anderson Immune Checkpoint Inhibitor (MDA-ICI) scores. Overall survival (OS) was estimated using the Kaplan-Meier method. Cox proportional hazards …

Apkcs Role In Neuroblastoma Cell Signaling Cascades And Implications Of Apkcs Inhibitors As Potential Therapeutics, Sloan Breedy

USF Tampa Graduate Theses and Dissertations

Neuroblastoma (NB) is a cancer that develops in the neuroblasts. It is the most common cancer in children under the age of 1 year, accounting for approximately 6% of all cancers. The prognosis of NB is linked to both age and degree of cell differentiation. This results in a range of survival rates for patients, with outcomes ranging from recurrence and mortality to high survival rates and tumor regression. Our previous work indicated that PKC-ι promotes cell proliferation in NB cells through the PKC-ι/Cdk7/Cdk2 cascade. We report on two atypical protein kinase inhibitors as potential therapeutic candidates against BE(2)-C and …

A Differentiation Roadmap Of Murine Placentation At Single-Cell Resolution, Xiangxiang Jiang, Yue Wang, Zhenyu Xiao, Long Yan, Shanshan Guo, Yiming Wang, Hao Wu, Xuehan Zhao, Xiaoyin Lu, Hongmei Wang

Faculty, Staff and Student Publications

The placenta is one of the most important yet least understood organs. Due to the limitations of conventional research approaches, we are still far from a comprehensive understanding of mouse placentation, especially regarding the differentiation of trophoblast lineages at the early developmental stage. To decipher cell compositions and developmental processes, we systematically profile the single-cell transcriptomes of trophoblast cells from extraembryonic tissues (embryonic day 7.5 (E7.5) and E8.5) and placentae (E9.5-E14.5) at one-day intervals. We identify distinct trophoblast cell types during mouse placentation, including unreported progenitor cells and intermediate precursor cells. An updated differentiation roadmap of mouse trophoblast lineages is …

Ferroptosis Hijacking By Mycobacterium Tuberculosis, Boyi Gan

Faculty, Staff and Student Publications

A recent study from Nature Communications reveals that Mycobacterium tuberculosis can hijack epigenetic machinery in host cells and induce host cell ferroptosis, which promotes pathogen pathogenicity and spread. These findings also suggest new therapeutic strategies to treat tuberculosis.

How Erastin Assassinates Cells By Ferroptosis Revealed, Boyi Gan

Faculty, Staff and Student Publications

No abstract provided.

Esrage-Expressing Ohsv Enhances Anti-Tumor Efficacy By Inhibition Of Endothelial Cell Activation, Jessica Swanner, Ji Seon Shim, Kimberly A Rivera-Caraballo, Karina Vázquez-Arreguín, Bangxing Hong, Alberto J Bueso-Perez, Tae Jin Lee, Yeshavanth Kumar Banasavadi-Siddegowda, Balveen Kaur, Ji Young Yoo

Faculty, Staff and Student Publications

High-mobility group box 1 (HMGB1) is a damage-associated molecular pattern (DAMP) molecule that plays an important role in inflammation and tumorigenesis. Receptor for advanced glycation end products (RAGE) is one of the major receptors to which extracellular HMGB1 binds to mediate its activity. RAGE is highly expressed on the endothelial cells (ECs) and regulates endothelial permeability during inflammation. Here, we introduced the endogenous secretory form of RAGE (esRAGE) as a decoy receptor for RAGE ligands into an oncolytic herpes simplex virus 1 (oHSV) (OVesRAGE), which, upon release, can function to block RAGE signaling. OVesRAGE significantly decreased phosphorylation of MEK1/2 and …

Factors Associated With Open Access Publishing Costs In Oncology Journals: Cross-Sectional Observational Study, Alex Koong, Ulysses Grant Gardner, Jason Burton, Caleb Stewart, Petria Thompson, Clifton David Fuller, Ethan Bernard Ludmir, Michael Kevin Rooney

Faculty, Staff and Student Publications

Background: Open access (OA) publishing represents an exciting opportunity to facilitate the dissemination of scientific information to global audiences. However, OA publishing is often associated with significant article processing charges (APCs) for authors, which may thus serve as a barrier to publication.

Objective: In this observational cohort study, we aimed to characterize the landscape of OA publishing in oncology and, further, identify characteristics of oncology journals that are predictive of APCs.

Methods: We identified oncology journals using the SCImago Journal & Country Rank database. All journals with an OA publication option and APC data openly available were included. We searched …

Venetoclax And Idasanutlin In Relapsed/Refractory Aml: A Nonrandomized, Open-Label Phase 1b Trial, Naval G Daver, Monique Dail, Jacqueline S Garcia, Brian A Jonas, Karen W L Yee, Kevin R Kelly, Norbert Vey, Sarit Assouline, Gail J Roboz, Stefania Paolini, Daniel A Pollyea, Agostino Tafuri, Joseph M Brandwein, Arnaud Pigneux, Bayard L Powell, Pierre Fenaux, Rebecca L Olin, Giuseppe Visani, Giovanni Martinelli, Maika Onishi, Jue Wang, Weize Huang, Cherie Green, Marion G Ott, Wan-Jen Hong, Marina Y Konopleva, Michael Andreeff

Faculty, Staff and Student Publications

This phase 1b trial (NCT02670044) evaluated venetoclax-idasanutlin in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) ineligible for cytotoxic chemotherapy. Two-dimensional dose escalation (DE, n = 50) was performed for venetoclax daily with idasanutlin on days 1 to 5 in 28-day cycles, followed by dosing schedule optimization (n = 6) to evaluate reduced venetoclax schedules (21-/14-day dosing). Common adverse events (occurring in ≥40% of patients) included diarrhea (87.3% of patients), nausea (74.5%), vomiting (52.7%), hypokalemia (50.9%), and febrile neutropenia (45.5%). During DE, across all doses, composite complete remission (CRc; CR + CR with incomplete blood count recovery + CR with …

The Evolution Of Acute Lymphoblastic Leukemia Research And Therapy At Md Anderson Over Four Decades, Elias Jabbour, Nicholas J Short, Nitin Jain, Fadi G Haddad, Mary Alma Welch, Farhad Ravandi, Hagop Kantarjian

Faculty, Staff and Student Publications

Progress in the research and therapy of adult acute lymphoblastic leukemia (ALL) is accelerating. This analysis summarizes the data derived from the clinical trials conducted at MD Anderson between 1985 and 2022 across ALL subtypes. In Philadelphia chromosome-positive ALL, the addition of BCR::ABL1 tyrosine kinase inhibitors (TKIs) to intensive chemotherapy since 2000, improved outcomes. More recently, a chemotherapy-free regimen with blinatumomab and ponatinib resulted in a complete molecular remission rate of 85% and an estimated 3-year survival rate of 90%, potentially reducing the role of, and need for allogeneic stem cell transplantation (SCT) in remission. In younger patients with pre-B …

Animal Models And Their Role In Imaging-Assisted Co-Clinical Trials, Donna M Peehl, Cristian T Badea, Thomas L Chenevert, Heike E Daldrup-Link, Li Ding, Lacey E Dobrolecki, A Mcgarry Houghton, Paul E Kinahan, John Kurhanewicz, Michael T Lewis, Shunqiang Li, Gary D Luker, Cynthia X Ma, H Charles Manning, Yvonne M Mowery, Peter J O'Dwyer, Robia G Pautler, Mark A Rosen, Raheleh Roudi, Brian D Ross, Kooresh I Shoghi, Renuka Sriram, Moshe Talpaz, Richard L Wahl, Rong Zhou

Faculty, Staff and Student Publications

The availability of high-fidelity animal models for oncology research has grown enormously in recent years, enabling preclinical studies relevant to prevention, diagnosis, and treatment of cancer to be undertaken. This has led to increased opportunities to conduct co-clinical trials, which are studies on patients that are carried out parallel to or sequentially with animal models of cancer that mirror the biology of the patients' tumors. Patient-derived xenografts (PDX) and genetically engineered mouse models (GEMM) are considered to be the models that best represent human disease and have high translational value. Notably, one element of co-clinical trials that still needs significant …

Fresh Produce As A Potential Vector And Reservoir For Human Bacterial Pathogens: Revealing The Ambiguity Of Interaction And Transmission, Ahmed Esmael, Rashad R. Al-Hindi, Raed S. Albiheyri, Mona G. Alharbi, Amani A. R. Filimban, Mazen S. Alseghayer, Abdulaziz M. Almaneea, Meshari Ahmed Alhadlaq, Jumaa Ayubu, Addisu D. Teklemariam

Nebraska Center for Virology: Faculty Publications

The consumer demand for fresh produce (vegetables and fruits) has considerably increased since the 1980s for more nutritious foods and healthier life practices, particularly in developed countries. Currently, several foodborne outbreaks have been linked to fresh produce. The global rise in fresh produce associated with human infections may be due to the use of wastewater or any contaminated water for the cultivation of fruits and vegetables, the firm attachment of the foodborne pathogens on the plant surface, and the internalization of these agents deep inside the tissue of the plant, poor disinfection practices and human consumption of raw fresh produce. …

Safety Of Nivolumab Added To Chemoradiation Therapy Platforms For Intermediate And High-Risk Locoregionally Advanced Head And Neck Squamous Cell Carcinoma: Rtog Foundation 3504, Maura L Gillison, Robert L Ferris, Jonathan Harris, A Dimitrios Colevas, Loren K Mell, Christina Kong, Richard C Jordan, Kevin L Moore, Minh-Tam Truong, Claudia Kirsch, Arnab Chakravarti, Dukagjin M Blakaj, David A Clump, James P Ohr, John F Deeken, Michael F Gensheimer, Nabil F Saba, Jennifer A Dorth, David I Rosenthal, Rom S Leidner, Randall J Kimple, Mitchell Machtay, Walter J Curran, Pedro Torres-Saavedra, Quynh Thu Le

Faculty, Staff and Student Publications

PURPOSE: Programmed death-1 immune checkpoint blockade improves survival of patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), but the benefits of addition to (chemo)radiation for newly diagnosed patients with HNSCC remain unknown.

METHODS AND MATERIALS: We evaluated the safety of nivolumab concomitant with 70 Gy intensity modulated radiation therapy and weekly cisplatin (arm 1), every 3-week cisplatin (arm 2), cetuximab (arm 3), or alone for platinum-ineligible patients (arm 4) in newly diagnosed intermediate- or high-risk locoregionally advanced HNSCC. Patients received nivolumab from 2 weeks prior to radiation therapy until 3 months post-radiation therapy. The primary endpoint was dose-limiting …

The Alpha7 Integrin Subunit In Astrocytes Promotes Endothelial Blood-Brain Barrier Integrity, Zhihua Chen, Jack R Kelly, John E Morales, Raymond C Sun, Arpan De, Dean J Burkin, Joseph H Mccarty

Faculty, Staff and Student Publications

The blood-brain barrier (BBB) is a vascular endothelial cell boundary that partitions the circulation from the central nervous system to promote normal brain health. We have a limited understanding of how the BBB is formed during development and maintained in adulthood. We used quantitative transcriptional profiling to investigate whether specific adhesion molecules are involved in BBB functions, with an emphasis on understanding how astrocytes interact with endothelial cells. Our results reveal a striking enrichment of multiple genes encoding laminin subunits as well as the laminin receptor gene Itga7, which encodes the alpha7 integrin subunit, in astrocytes. Genetic ablation of Itga7 …

Sequential Targeting Of Retinoblastoma And Dna Synthesis Pathways Is A Therapeutic Strategy For Sarcomas That Can Be Monitored In Real Time, Tuyen Duong Thanh Nguyen, Yan Wang, Tuyen N Bui, Rossana Lazcano, Davis R Ingram, Min Yi, Varshini Vakulabharanam, Linjie Luo, Marc A Pina, Cansu Karakas, Mi Li, Nicole M Kettner, Neeta Somaiah, Peter J Hougton, Osama Mawlawi, Alexander J Lazar, Kelly K Hunt, Khandan Keyomarsi

Faculty, Staff and Student Publications

Treatment strategies with a strong scientific rationale based on specific biomarkers are needed to improve outcomes in patients with advanced sarcomas. Suppression of cell cycle progression through reactivation of the tumor suppressor retinoblastoma (Rb) using CDK4/6 inhibitors is a potential avenue for novel targeted therapies in sarcomas that harbor intact Rb signaling. Here, we evaluated combination treatment strategies (sequential and concomitant) with the CDK4/6 inhibitor abemacicib to identify optimal combination strategies. Expression of Rb was examined in 1043 sarcoma tumor specimens, and 50% were found to be Rb-positive. Using in vitro and in vivo models, an effective 2-step sequential combination …

Etnk1 Mutation Occurs In A Wide Spectrum Of Myeloid Neoplasms And Is Not Specific For Atypical Chronic Myeloid Leukemia, Wen Shuai, Zhuang Zuo, Nianyi Li, Sofia Garces, Fatima Zahra Jelloul, Chi Young Ok, Shaoying Li, Jie Xu, M James You, Wei Wang, Catherine Rehder, Elias J Jabbour, Keyur P Patel, L Jeffrey Medeiros, C Cameron Yin

Faculty, Staff and Student Publications

Background: ETNK1 mutation has been suggested as a useful tool to support the diagnosis of atypical chronic myeloid leukemia. ETNK1 mutations, however, occur in other myeloid neoplasms.

Methods: The authors assessed the clinicopathologic and molecular genetic features of 80 ETNK1-mutated myeloid neoplasms.

Results: Thirty-seven neoplasms (46%) were classified as myelodysplastic syndrome, 17 (21%) were classified as myelodysplastic/myeloproliferative neoplasm, 14 (18%) were classified as acute myeloid leukemia, and 12 (15%) were classified as myeloproliferative neoplasm. ETNK1 mutations were detected at the first test in 96% of patients, suggesting that ETNK1 mutation is an early event in pathogenesis. ETNK1 mutations represented the …

Kdm6a Loss Triggers An Epigenetic Switch That Disrupts Urothelial Differentiation And Drives Cell Proliferation In Bladder Cancer, Hong Qiu, Vladimir Makarov, Jennifer K Bolzenius, Angela Halstead, Yvonne Parker, Allen Wang, Gopakumar V Iyer, Hannah Wise, Daniel Kim, Varna Thayaparan, Daniel J Lindner, Georges-Pascal Haber, Angela H Ting, Bing Ren, Timothy A Chan, Vivek Arora, David B Solit, Byron H Lee

Faculty, Staff and Student Publications

Disruption of KDM6A, a histone lysine demethylase, is one of the most common somatic alternations in bladder cancer. Insights into how KDM6A mutations affect the epigenetic landscape to promote carcinogenesis could help reveal potential new treatment approaches. Here, we demonstrated that KDM6A loss triggers an epigenetic switch that disrupts urothelial differentiation and induces a neoplastic state characterized by increased cell proliferation. In bladder cancer cells with intact KDM6A, FOXA1 interacted with KDM6A to activate genes instructing urothelial differentiation. KDM6A-deficient cells displayed simultaneous loss of FOXA1 target binding and genome-wide redistribution of the bZIP transcription factor ATF3, which in turn repressed …

Sequential Targeting Of Retinoblastoma And Dna Synthesis Pathways Is A Therapeutic Strategy For Sarcomas That Can Be Monitored In Real Time, Tuyen Duong Thanh Nguyen, Yan Wang, Tuyen N Bui, Rossana Lazcano, Davis R Ingram, Min Yi, Varshini Vakulabharanam, Linjie Luo, Marc A Pina, Cansu Karakas, Mi Li, Nicole M Kettner, Neeta Somaiah, Peter J Hougton, Osama Mawlawi, Alexander J Lazar, Kelly K Hunt, Khandan Keyomarsi

Faculty, Staff and Student Publications

Treatment strategies with a strong scientific rationale based on specific biomarkers are needed to improve outcomes in patients with advanced sarcomas. Suppression of cell-cycle progression through reactivation of the tumor suppressor retinoblastoma (Rb) using CDK4/6 inhibitors is a potential avenue for novel targeted therapies in sarcomas that harbor intact Rb signaling. Here, we evaluated combination treatment strategies (sequential and concomitant) with the CDK4/6 inhibitor abemacicib to identify optimal combination strategies. Expression of Rb was examined in 1,043 sarcoma tumor specimens, and 50% were found to be Rb-positive. Using in vitro and in vivo models, an effective two-step sequential combination strategy …

T-Cell Receptor Repertoire Sequencing In The Era Of Cancer Immunotherapy, Meredith L Frank, Kaylene Lu, Can Erdogan, Yi Han, Jian Hu, Tao Wang, John V Heymach, Jianjun Zhang, Alexandre Reuben

Faculty, Staff and Student Publications

T cells are integral components of the adaptive immune system, and their responses are mediated by unique T-cell receptors (TCR) that recognize specific antigens from a variety of biological contexts. As a result, analyzing the T-cell repertoire offers a better understanding of immune responses and of diseases like cancer. Next-generation sequencing technologies have greatly enabled the high-throughput analysis of the TCR repertoire. On the basis of our extensive experience in the field from the past decade, we provide an overview of TCR sequencing, from the initial library preparation steps to sequencing and analysis methods and finally to functional validation techniques. …

Genetic Architecture Of Spatial Electrical Biomarkers For Cardiac Arrhythmia And Relationship With Cardiovascular Disease, William J Young, Jeffrey Haessler, Jan-Walter Benjamins, Linda Repetto, Jie Yao, Aaron Isaacs, Andrew R Harper, Julia Ramirez, Sophie Garnier, Stefan Van Duijvenboden, Antoine R Baldassari, Maria Pina Concas, Thuyvy Duong, Luisa Foco, Jonas L Isaksen, Hao Mei, Raymond Noordam, Casia Nursyifa, Anne Richmond, Meddly L Santolalla, Colleen M Sitlani, Negin Soroush, Sébastien Thériault, Stella Trompet, Stefanie Aeschbacher, Fariba Ahmadizar, Alvaro Alonso, Jennifer A Brody, Archie Campbell, Adolfo Correa, Dawood Darbar, Antonio De Luca, Jean-François Deleuze, Christina Ellervik, Christian Fuchsberger, Anuj Goel, Christopher Grace, Xiuqing Guo, Torben Hansen, Susan R Heckbert, Rebecca D Jackson, Jan A Kors, Maria Fernanda Lima-Costa, Allan Linneberg, Peter W Macfarlane, Alanna C Morrison, Pau Navarro, David J Porteous, Peter P Pramstaller, Alexander P Reiner, Lorenz Risch, Ulrich Schotten, Xia Shen, Gianfranco Sinagra, Elsayed Z Soliman, Monika Stoll, Eduardo Tarazona-Santos, Andrew Tinker, Katerina Trajanoska, Eric Villard, Helen R Warren, Eric A Whitsel, Kerri L Wiggins, Dan E Arking, Christy L Avery, David Conen, Giorgia Girotto, Niels Grarup, Caroline Hayward, J Wouter Jukema, Dennis O Mook-Kanamori, Morten Salling Olesen, Sandosh Padmanabhan, Bruce M Psaty, Cristian Pattaro, Antonio Luiz P Ribeiro, Jerome I Rotter, Bruno H Stricker, Pim Van Der Harst, Cornelia M Van Duijn, Niek Verweij, James G Wilson, Michele Orini, Philippe Charron, Hugh Watkins, Charles Kooperberg, Henry J Lin, James F Wilson, Jørgen K Kanters, Nona Sotoodehnia, Borbala Mifsud, Pier D Lambiase, Larisa G Tereshchenko, Patricia B Munroe

Faculty, Staff and Student Publications

The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic …

Use Of Dual Genomic Sequencing To Screen Mitochondrial Diseases In Pediatrics: A Retrospective Analysis, Teng-Hui Wu, Jing Peng, Li Yang, Yan-Hui Chen, Xiu-Lan Lu, Jiao-Tian Huang, Jie-Yu You, Wen-Xian Ou-Yang, Yue-Yu Sun, Yi-Nan Xue, Xiao Mao, Hui-Ming Yan, Rong-Na Ren, Jing Xie, Zhi-Heng Chen, Victor-Wei Zhang, Gui-Zhen Lyu, Fang He

Children’s Nutrition Research Center Staff Publications

Mitochondrial diseases (MDs) were a large group multisystem disorders, attributable in part to the dual genomic control. The advent of massively sequencing has improved diagnostic rates and speed, and was increasingly being used as a first-line diagnostic test. Paediatric patients (aged <  18 years) who underwent dual genomic sequencing were enrolled in this retrospective multicentre study. We evaluated the mitochondrial disease criteria (MDC) and molecular diagnostic yield of dual genomic sequencing. Causative variants were identified in 177 out of 503 (35.2%) patients using dual genomic sequencing. Forty-six patients (9.1%) had mitochondria-related variants, including 25 patients with nuclear DNA (nDNA) variants, 15 with mitochondrial DNA (mtDNA) variants, and six with dual genomic variants (MT-ND6 and POLG; MT-ND5 and RARS2; MT-TL1 and NARS2; MT-CO2 and NDUFS1; MT-CYB and SMARCA2; and CHRNA4 and MT-CO3). Based on the MDC, 15.2% of the patients with mitochondria-related variants were classified as "unlikely to have mitochondrial disorder". Moreover, 4.5% of the patients with non-mitochondria-related variants and 1.43% with negative genetic tests, were classified as "probably having mitochondrial disorder". Dual genomic sequencing in suspected MDs provided a more comprehensive and accurate diagnosis for pediatric patients, especially for patients with dual genomic variants.

Renal Cell Carcinoma Unclassified With Medullary Phenotype In A Patient With Neurofibromatosis Type 2, Sanila Sarkar, Whitney Throckmorton, Racheal Bingham, Pavlos Msaouel, Giannicola Genovese, John Slopis, Priya Rao, Zsila Sadighi, Cynthia E Herzog

Faculty, Staff and Student Publications

We present, to our knowledge, the first reported case of germline neurofibromatosis Type 2 (NF2) associated with renal cell carcinoma unclassified with medullary phenotype (RCCU-MP) with somatic loss by immunohistochemistry of the SMARCB1 tumor suppressor gene located centromeric to NF2 on chromosome 22q. Our patient is a 15-year-old with germline neurofibromatosis Type 2 (NF2) confirmed by pathogenic mutation of c.-854-??46+??deletion. Her NF2 history is positive for a right optic nerve sheath meningioma, CNIII schwannoma requiring radiation therapy and post gross total resection of right frontotemporal anaplastic meningioma followed by radiation. At age 15 she developed new onset weight loss and …