Medical Specialties Commons^™

Genomic Determinants Of Response And Resistance To Inotuzumab Ozogamicin In B-Cell All, Yaqi Zhao, Nicholas J Short, Hagop M Kantarjian, Ti-Cheng Chang, Pankaj S Ghate, Chunxu Qu, Walid Macaron, Nitin Jain, Beenu Thakral, Aaron H Phillips, Joseph Khoury, Guillermo Garcia-Manero, Wenchao Zhang, Yiping Fan, Hui Yang, Rebecca S Garris, Lewis F Nasr, Richard W Kriwacki, Kathryn G Roberts, Marina Konopleva, Elias J Jabbour, Charles G Mullighan

Faculty, Staff and Student Publications

Inotuzumab ozogamicin (InO) is an antibody-drug conjugate that delivers calicheamicin to CD22-expressing cells. In a retrospective cohort of InO-treated patients with B-cell acute lymphoblastic leukemia, we sought to understand the genomic determinants of the response and resistance to InO. Pre- and post-InO-treated patient samples were analyzed by whole genome, exome, and/or transcriptome sequencing. Acquired CD22 mutations were observed in 11% (3/27) of post-InO-relapsed tumor samples, but not in refractory samples (0/16). There were multiple CD22 mutations per sample and the mechanisms of CD22 escape included epitope loss (protein truncation and destabilization) and epitope alteration. Two CD22 mutant cases were post-InO …

Controlled Delivery Of Rosuvastatin Or Rapamycin Through Electrospun Bismuth Nanoparticle-Infused Perivascular Wraps Promotes Arteriovenous Fistula Maturation, Allan John R Barcena, Joy Vanessa D Perez, Marvin R Bernardino, Erin Marie D San Valentin, Jossana A Damasco, Carleigh Klusman, Benjamin Martin, Karem A Court, Biana Godin, Gino Canlas, Natalie Fowlkes, Richard R Bouchard, Jizhong Cheng, Steven Y Huang, Marites P Melancon

Faculty, Staff and Student Publications

In the context of arteriovenous fistula (AVF) failure, local delivery enables the release of higher concentrations of drugs that can suppress neointimal hyperplasia (NIH) while reducing systemic adverse effects. However, the radiolucency of polymeric delivery systems hinders long-term in vivo surveillance of safety and efficacy. We hypothesize that using a radiopaque perivascular wrap to deliver anti-NIH drugs could enhance AVF maturation. Through electrospinning, we fabricated multifunctional perivascular polycaprolactone (PCL) wraps loaded with bismuth nanoparticles (BiNPs) for enhanced radiologic visibility and drugs that can attenuate NIH—rosuvastatin (Rosu) and rapamycin (Rapa). The following groups were tested onto the AVFs of a total …

Improving Laboratory Animal Genetic Reporting: Lag-R Guidelines, Lydia Teboul, James Amos-Landgraf, Fernando J Benavides, Marie-Christine Birling, Steve D M Brown, Elizabeth Bryda, Rosie Bunton-Stasyshyn, Hsian-Jean Chin, Martina Crispo, Fabien Delerue, Michael Dobbie, Craig L Franklin, Ernst-Martin Fuchtbauer, Xiang Gao, Christelle Golzio, Rebecca Haffner, Yann Hérault, Martin Hrabe De Angelis, Kevin C Kent Lloyd, Terry R Magnuson, Lluis Montoliu, Stephen A Murray, Ki-Hoan Nam, Lauryl M J Nutter, Eric Pailhoux, Fernando Pardo Manuel De Villena, Kevin Peterson, Laura Reinholdt, Radislav Sedlacek, Je Kyung Seong, Toshihiko Shiroishi, Cynthia Smith, Toru Takeo, Louise Tinsley, Jean-Luc Vilotte, Søren Warming, Sara Wells, C Bruce Whitelaw, Atsushi Yoshiki, Asian Mouse Mutagenesis Resource Association, Celphedia Infrastructure, Infrafrontier Consortium, International Mammalian Genome Society, International Mouse Phenotyping Consortium, International Society For Transgenic Technologies, Mutant Mouse Resource And Research Centers, Phenomics Australia, Rrrc- Rat Resource And Research Center, Guillaume Pavlovic

Faculty, Staff and Student Publications

The biomedical research community addresses reproducibility challenges in animal studies through standardized nomenclature, improved experimental design, transparent reporting, data sharing, and centralized repositories. The ARRIVE guidelines outline documentation standards for laboratory animals in experiments, but genetic information is often incomplete. To remedy this, we propose the Laboratory Animal Genetic Reporting (LAG-R) framework. LAG-R aims to document animals' genetic makeup in scientific publications, providing essential details for replication and appropriate model use. While verifying complete genetic compositions may be impractical, better reporting and validation efforts enhance reliability of research. LAG-R standardization will bolster reproducibility, peer review, and overall scientific rigor.

Post-Immunotherapy Ctla-4 Ig Treatment Improves Antitumor Efficacy, Stephen Mok, Didem Ağaç Çobanoğlu, Huey Liu, James J Mancuso, James P Allison

Faculty, Staff and Student Publications

Immune checkpoint therapies (ICT) improve overall survival of patients with cancer but may cause immune-related adverse events (irAEs) such as myocarditis. Cytotoxic T lymphocyte-associated antigen 4 immunoglobulin fusion protein (CTLA-4 Ig), an inhibitor of T cell costimulation through CD28, reverses irAEs in animal models. However, concerns exist about potentially compromising antitumor response of ICT. In mouse tumor models, we administered CTLA-4 Ig 1) concomitantly with ICT or 2) after ICT completion. Concomitant treatment reduced antitumor efficacy, while post-ICT administration improved efficacy without affecting frequency and function of CD8 T cells. The improved response was independent of the ICT used, whether …

Loss Of The Dna Repair Gene Rnase H2 Identifies A Unique Subset Of Ddr-Deficient Leiomyosarcomas, Michael S Nakazawa, Ian M Silverman, Victoria Rimkunas, Artur Veloso, Dominik Glodzik, Adrienne Johnson, Toshiro K Ohsumi, Shreyaskumar R Patel, Anthony P Conley, Christina L Roland, Pamela T Soliman, Hannah C Beird, Chia-Chin Wu, Davis R Ingram, Rossana Lazcano, Dawon Song, Khalida M Wani, Alexander J Lazar, Timothy A Yap, Wei-Lien Wang, J Andrew Livingston

Faculty, Staff and Student Publications

Targeting the DNA damage response (DDR) pathway is an emerging therapeutic approach for leiomyosarcoma (LMS), and loss of RNase H2, a DDR pathway member, is a potentially actionable alteration for DDR-targeted treatments. Therefore, we designed a protein- and genomic-based RNase H2 screening assay to determine its prevalence and prognostic significance. Using a selective RNase H2 antibody on a pan-tumor microarray (TMA), RNase H2 loss was more common in LMS (11.5%, 9/78) than across all tumors (3.8%, 32/843). In a separate LMS cohort, RNase H2 deficiency was confirmed in uterine LMS (U-LMS, 21%, 23/108) and soft-tissue LMS (ST-LMS; 30%, 39/102). In …

Inhibition Of Malt1 And Bcl2 Induces Synergistic Antitumor Activity In Models Of B-Cell Lymphoma, Joshua P Plotnik, Adam E Richardson, Haopeng Yang, Estela Rojas, Velitchka Bontcheva, Colleen Dowell, Sydney Parsons, Ashley Wilson, Vida Ravanmehr, Christine Will, Paul Jung, Haizhong Zhu, Sarathy Karunan Partha, Sanjay C Panchal, Raghuveer Singh Mali, Frederick J Kohlhapp, Ryan A Mcclure, Cyril Y Ramathal, Mariam D George, Manisha Jhala, Nathaniel L Elsen, Wei Qiu, Russell A Judge, Chin Pan, Anthony Mastracchio, Jared Henderson, Jonathan A Meulbroek, Michael R Green, William N Pappano

Faculty, Staff and Student Publications

The activated B cell (ABC) subset of diffuse large B-cell lymphoma (DLBCL) is characterized by chronic B-cell receptor signaling and associated with poor outcomes when treated with standard therapy. In ABC-DLBCL, MALT1 is a core enzyme that is constitutively activated by stimulation of the B-cell receptor or gain-of-function mutations in upstream components of the signaling pathway, making it an attractive therapeutic target. We discovered a novel small-molecule inhibitor, ABBV-MALT1, that potently shuts down B-cell signaling selectively in ABC-DLBCL preclinical models leading to potent cell growth and xenograft inhibition. We also identified a rational combination partner for ABBV-MALT1 in the BCL2 …

Assessment Of Patient-Derived Xenograft Growth And Antitumor Activity: The Nci Pdxnet Consensus Recommendations, Funda Meric-Bernstam, Michael W Lloyd, Soner Koc, Yvonne A Evrard, Lisa M Mcshane, Michael T Lewis, Kurt W Evans, Dali Li, Lawrence Rubinstein, Alana Welm, Dennis A Dean, Anuj Srivastava, Jeffrey W Grover, Min J Ha, Huiqin Chen, Xuelin Huang, Kaushik Varadarajan, Jing Wang, Jack A Roth, Bryan Welm, Ramaswamy Govinden, Li Ding, Salma Kaochar, Nicholas Mitsiades, Luis Carvajal-Carmona, Meenhard Herylyn, Michael A Davies, Geoffrey I Shapiro, Ryan Fields, Jose G Trevino, Joshua C Harrell, Nci Pdxnet Consortium, James H Doroshow, Jeffrey H Chuang, Jeffrey A Moscow

Faculty, Staff and Student Publications

Although patient-derived xenografts (PDX) are commonly used for preclinical modeling in cancer research, a standard approach to in vivo tumor growth analysis and assessment of antitumor activity is lacking, complicating the comparison of different studies and determination of whether a PDX experiment has produced evidence needed to consider a new therapy promising. We present consensus recommendations for assessment of PDX growth and antitumor activity, providing public access to a suite of tools for in vivo growth analyses. We expect that harmonizing PDX study design and analysis and assessing a suite of analytical tools will enhance information exchange and facilitate identification …

Ultrapotent Broadly Neutralizing Human-Llama Bispecific Antibodies Against Hiv-1, Jianliang Xu, Tongqing Zhou, Krisha Mckee, Baoshan Zhang, Cuiping Liu, Alexandra F Nazzari, Amarendra Pegu, Chen-Hsiang Shen, Jordan E Becker, Michael F Bender, Payton Chan, Anita Changela, Ridhi Chaudhary, Xuejun Chen, Tal Einav, Young Do Kwon, Bob C Lin, Mark K Louder, Jonah S Merriam, Nicholas C Morano, Sijy O'Dell, Adam S Olia, Reda Rawi, Ryan S Roark, Tyler Stephens, I-Ting Teng, Emily Tourtellott-Fogt, Shuishu Wang, Eun Sung Yang, Lawrence Shapiro, Yaroslav Tsybovsky, Nicole A Doria-Rose, Rafael Casellas, Peter D Kwong

Faculty, Staff and Student Publications

Broadly neutralizing antibodies are proposed as therapeutic and prophylactic agents against HIV‐1, but their potency and breadth are less than optimal. This study describes the immunization of a llama with the prefusion‐stabilized HIV‐1 envelope (Env) trimer, BG505 DS‐SOSIP, and the identification and improvement of potent neutralizing nanobodies recognizing the CD4‐binding site (CD4bs) of vulnerability. Two of the vaccine‐elicited CD4bs‐targeting nanobodies, G36 and R27, when engineered into a triple tandem format with llama IgG2a‐hinge region and human IgG1‐constant region (G36×3‐IgG2a and R27×3‐IgG2a), neutralized 96% of a multiclade 208‐strain panel at geometric mean IC80s of 0.314 and 0.033 µg mL−1, respectively. Cryo‐EM …

Effect Of Medicaid Expansion On Cancer Treatment And Survival Among Medicaid Beneficiaries And The Uninsured, Kristin M Primm, Hui Zhao, Naomi N Adjei, Charlotte C Sun, Alen Haas, Larissa A Meyer, Shine Chang

Faculty, Staff and Student Publications

BACKGROUND: The Affordable Care Act expanded Medicaid coverage for people with low income in the United States. Expanded insurance coverage could promote more timely access to cancer treatment, which could improve overall survival (OS), yet the long-term effects of Medicaid expansion (ME) remain unknown. We evaluated whether ME was associated with improved timely treatment initiation (TTI) and 3-year OS among patients with breast, cervical, colon, and lung cancers who were affected by the policy.

METHODS: Medicaid-insured or uninsured patients aged 40-64 with stage I-III breast, cervical, colon, or non-small cell lung cancer within the National Cancer Database (NCDB). A difference-in-differences …

Identification Of Immune-Associated Biomarkers Of Diabetes Nephropathy Tubulointerstitial Injury Based On Machine Learning: A Bioinformatics Multi-Chip Integrated Analysis, Lin Wang, Jiaming Su, Zhongjie Liu, Shaowei Ding, Yaotan Li, Baoluo Hou, Yuxin Hu, Zhaoxi Dong, Jingyi Tang, Hongfang Liu, Weijing Liu

Faculty, Staff and Student Publications

BACKGROUND: Diabetic nephropathy (DN) is a major microvascular complication of diabetes and has become the leading cause of end-stage renal disease worldwide. A considerable number of DN patients have experienced irreversible end-stage renal disease progression due to the inability to diagnose the disease early. Therefore, reliable biomarkers that are helpful for early diagnosis and treatment are identified. The migration of immune cells to the kidney is considered to be a key step in the progression of DN-related vascular injury. Therefore, finding markers in this process may be more helpful for the early diagnosis and progression prediction of DN.

METHODS: The …

A Deep Catalogue Of Protein-Coding Variation In 983,578 Individuals, Kathie Y Sun, Xiaodong Bai, Siying Chen, Suying Bao, Chuanyi Zhang, Manav Kapoor, Joshua Backman, Tyler Joseph, Evan Maxwell, George Mitra, Alexander Gorovits, Adam Mansfield, Boris Boutkov, Sujit Gokhale, Lukas Habegger, Anthony Marcketta, Adam E Locke, Liron Ganel, Alicia Hawes, Michael D Kessler, Deepika Sharma, Jeffrey Staples, Jonas Bovijn, Sahar Gelfman, Alessandro Di Gioia, Veera M Rajagopal, Alexander Lopez, Jennifer Rico Varela, Jesús Alegre-Díaz, Jaime Berumen, Roberto Tapia-Conyer, Pablo Kuri-Morales, Jason Torres, Jonathan Emberson, Rory Collins, Regeneron Genetics Center, Rgc-Me Cohort Partners; Michael Cantor, Michael Cantor, Timothy Thornton, Hyun Min Kang, John D Overton, Alan R Shuldiner, M Laura Cremona, Mona Nafde, Aris Baras, Gonçalo Abecasis, Jonathan Marchini, Jeffrey G Reid, William Salerno, Suganthi Balasubramanian

Faculty, Staff and Student Publications

Rare coding variants that substantially affect function provide insights into the biology of a gene1-3. However, ascertaining the frequency of such variants requires large sample sizes4-8. Here we present a catalogue of human protein-coding variation, derived from exome sequencing of 983,578 individuals across diverse populations. In total, 23% of the Regeneron Genetics Center Million Exome (RGC-ME) data come from individuals of African, East Asian, Indigenous American, Middle Eastern and South Asian ancestry. The catalogue includes more than 10.4 million missense and 1.1 million predicted loss-of-function (pLOF) variants. We identify individuals with rare biallelic pLOF variants in 4,848 genes, 1,751 of …

Targeting Of Cyp2e1 By Mirnas In Alcohol-Induced Intestine Injury, Hyejin Mun, Sungyul Lee, Suyoung Choi, Ji-Hoon Jeong, Seungbeom Ko, Yoo Lim Chun, Benjamin Deaton, Clay T Yeager, Audrey Boyette, Juliana Palmera, London Newman, Ping Zhou, Soona Shin, Dong-Chan Kim, Cari A Sagum, Mark T Bedford, Young-Kook Kim, Jaeyul Kwon, Junyang Jung, Jeong Ho Chang, Je-Hyun Yoon

Faculty, Staff and Student Publications

Although binge alcohol-induced gut leakage has been studied extensively in the context of reactive oxygen species-mediated signaling, it was recently revealed that post-transcriptional regulation plays an essential role as well. Ethanol (EtOH)-inducible cytochrome P450-2E1 (CYP2E1), a key enzyme in EtOH metabolism, promotes alcohol-induced hepatic steatosis and inflammatory liver disease, at least in part by mediating changes in intestinal permeability. For instance, gut leakage and elevated intestinal permeability to endotoxins have been shown to be regulated by enhancing CYP2E1 mRNA and CYP2E1 protein levels. Although it is understood that EtOH promotes CYP2E1 induction and activation, the mechanisms that regulate CYP2E1 expression …

Change In Trust In Us Government Health Agencies For Cancer Information In The Covid-19 Era, Onyema G Chido-Amajuoyi, Rajesh Talluri, Henry K Onyeaka, Itunu Sokale, Gideon T Dosunmu, Noelle Loconte, Sanjay Shete

Faculty, Staff and Student Publications

This cross-sectional study assesses changes in levels of public trust in US government health agencies providing cancer information.

Machine Learning Identifies Prognostic Subtypes Of The Tumor Microenvironment Of Nsclc, Duo Yu, Michael J Kane, Eugene J Koay, Ignacio I Wistuba, Brian P Hobbs

Faculty, Staff and Student Publications

The tumor microenvironment (TME) plays a fundamental role in tumorigenesis, tumor progression, and anti-cancer immunity potential of emerging cancer therapeutics. Understanding inter-patient TME heterogeneity, however, remains a challenge to efficient drug development. This article applies recent advances in machine learning (ML) for survival analysis to a retrospective study of NSCLC patients who received definitive surgical resection and immune pathology following surgery. ML methods are compared for their effectiveness in identifying prognostic subtypes. Six survival models, including Cox regression and five survival machine learning methods, were calibrated and applied to predict survival for NSCLC patients based on PD-L1 expression, CD3 expression, …

Mutation Order In Acute Myeloid Leukemia Identifies Uncommon Patterns Of Evolution And Illuminates Phenotypic Heterogeneity, Matthew Schwede, Katharina Jahn, Jack Kuipers, Linde A Miles, Robert L Bowman, Troy Robinson, Ken Furudate, Hidetaka Uryu, Tomoyuki Tanaka, Yuya Sasaki, Asiri Ediriwickrema, Brooks Benard, Andrew J Gentles, Ross Levine, Niko Beerenwinkel, Koichi Takahashi, Ravindra Majeti

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) has a poor prognosis and a heterogeneous mutation landscape. Although common mutations are well-studied, little research has characterized how the sequence of mutations relates to clinical features. Using published, single-cell DNA sequencing data from three institutions, we compared clonal evolution patterns in AML to patient characteristics, disease phenotype, and outcomes. Mutation trees, which represent the order of select mutations, were created for 207 patients from targeted panel sequencing data using 1 639 162 cells, 823 mutations, and 275 samples. In 224 distinct orderings of mutated genes, mutations related to DNA methylation typically preceded those related to …

Epigenetic Regulation Of Heart Failure, Manisha Deogharia, Priyatansh Gurha

Faculty, Staff and Student Publications

Purpose of review: The studies on chromatin-modifying enzymes and how they respond to different stimuli within the cell have revolutionized our understanding of epigenetics. In this review, we provide an overview of the recent studies on epigenetic mechanisms implicated in heart failure.

Recent findings: We focus on the major mechanisms and the conceptual advances in epigenetics as evidenced by studies in humans and mouse models of heart failure. The significance of epigenetic modifications and the enzymes that catalyze them is also discussed. New findings from the studies of histone lysine demethylases demonstrate their significance in regulating fetal gene expression, as …

50-Nm Gas-Filled Protein Nanostructures To Enable The Access Of Lymphatic Cells By Ultrasound Technologies, Qionghua Shen, Zongru Li, Yixian Wang, Matthew D Meyer, Marc T De Guzman, Janie C Lim, Han Xiao, Richard R Bouchard, George J Lu

Faculty, Staff and Student Publications

Ultrasound imaging and ultrasound-mediated gene and drug delivery are rapidly advancing diagnostic and therapeutic methods; however, their use is often limited by the need for microbubbles, which cannot transverse many biological barriers due to their large size. Here, the authors introduce 50-nm gas-filled protein nanostructures derived from genetically engineered gas vesicles(GVs) that are referred to as

Neighborhood-Level Social Determinants Of Health Burden Among Adolescent And Young Adult Cancer Patients And Impact On Overall Survival, Elizabeth R Rodriguez, Tori Tonn, Midhat Jafry, Sairah Ahmed, Branko Cuglievan, J Andrew Livingston, Christopher R Flowers, Gregory J Aune, Karen H Albritton, Michael E Roth, Qian Xiao, Michelle A T Hildebrandt

Faculty, Staff and Student Publications

BACKGROUND: Neighborhood socioeconomic deprivation has been linked to adverse health outcomes, yet it is unclear whether neighborhood-level social determinants of health (SDOH) measures affect overall survival in adolescent and young adult patients with cancer.

METHODS: This study used a diverse cohort of adolescent and young adult patients with cancer (N = 10 261) seen at MD Anderson Cancer Center. Zip codes were linked to Area Deprivation Index (ADI) values, a validated neighborhood-level SDOH measure, with higher ADI values representing worse SDOH.

RESULTS: ADI was statistically significantly worse (P < .050) for Black (61.7) and Hispanic (65.3) patients than for White patients (51.2). Analysis of ADI by cancer type showed statistically significant differences, mainly driven by worse ADI in patients with cervical cancer (62.3) than with other cancers. In multivariable models including sex, age at diagnosis, cancer diagnosis, and race and ethnicity, risk of shorter survival for people residing in neighborhoods with the least favorable ADI quartile was greater than for individuals in the most favorable ADI quartile (hazard ratio = 1.09, 95% confidence interval = 1.00 to 1.19, P = .043).

CONCLUSION: Adolescent and young adult patients with cancer and the worst ADI …

Radiation Dose Attenuation Using Radpad In Cath Lab For Primary And Secondary Operators – Radar-Cath Study, Sandeepan Saha, Aditya Kapoor, Kamlesh Raut, Arpita Katheria, Harshit Khare, Ankit Sahu, Roopali Khanna, Sudeep Kumar, Naveen Garg, Satyendra Tewari

Faculty, Staff and Student Publications

BACKGROUND: Radiation injury is an important concern for interventional cardiologists and needs to be addressed. RADPAD is a radiation protection drape that has been shown to reduce the radiation exposure of the primary operator (PO). While Indian data on radiation exposure of the PO in the cath lab are scarce, the exposure of the secondary operator (SO) is even less well studied.

AIMS: The aim of this study was to evaluate the efficacy of RADPAD drapes in reducing radiation doses in the cath lab for the primary as well as the secondary operator.

METHODS: A total of 160 patients (40 …

Eus-Guided Hydrogel Injection To Separate Pancreatic Head Carcinoma From Duodenum For Enhanced Radiotherapy: Multi-Site Feasibility Study, Manoop S Bhutani, Amol K Narang, Kai Ding, Brenna Casey, Kumar Krishnan, Eugene J Koay, Theodore S Hong, Joseph M Herman, Kristen H Griffin, Eun Ji Shin

Faculty, Staff and Student Publications

Background and study aims The proximity of a pancreas head tumor to the duodenum often limits delivery of an ablative dose of radiation therapy. This study evaluated the feasibility and safety of using an injectable polyethylene glycol (PEG) hydrogel between the head of the pancreas and duodenum.

Patients and methods In a multi-site feasibility cohort study of patients with localized pancreatic cancer, PEG hydrogel was injected under endoscopic ultrasound guidance to temporarily position the duodenum away from the pancreas. Procedure characteristics were recorded, including hydrogel volume and space created. Patients were monitored for adverse events (AEs) and radiotherapy toxicity.

Results …

Sequencing Of Kaposi’S Sarcoma Herpesvirus (Kshv) Genomes From Persons Of Diverse Ethnicities And Provenances With Kshv-Associated Diseases Demonstrate Multiple Infections, Novel Polymorphisms, And Low Intra-Host Variance, Vickie A Marshall, Elena M Cornejo Castro, Charles A Goodman, Nazzarena Labo, Isabella Liu, Nicholas C Fisher, Kyle N Moore, Ananthakrishnan Nair, Taina Immonen, Brandon F Keele, Mark N Polizzotto, Thomas S Uldrick, Yunxiang Mu, Tanuja Saswat, Laurie T Krug, Kevin M Mcbride, Kathryn Lurain, Ramya Ramaswami, Robert Yarchoan, Denise Whitby

Faculty, Staff and Student Publications

Recently published near full-length KSHV genomes from a Cameroon Kaposi sarcoma case-control study showed strong evidence of viral recombination and mixed infections, but no sequence variations associated with disease. Using the same methodology, an additional 102 KSHV genomes from 76 individuals with KSHV-associated diseases have been sequenced. Diagnoses comprise all KSHV-associated diseases (KAD): Kaposi sarcoma (KS), primary effusion lymphoma (PEL), KSHV-associated large cell lymphoma (KSHV-LCL), a type of multicentric Castleman disease (KSHV-MCD), and KSHV inflammatory cytokine syndrome (KICS). Participants originated from 22 different countries, providing the opportunity to obtain new near full-length sequences of a wide diversity of KSHV genomes. …

Ccr2+ Monocytes Promote White Matter Injury And Cognitive Dysfunction After Myocardial Infarction, Edward B Thorp, Mallory Filipp, Maria Dima, Chunfeng Tan, Matthew Feinstein, Brian Popko, Matthew Deberge

Faculty, Staff and Student Publications

Survivors of myocardial infarction are at increased risk for vascular dementia. Neuroinflammation has been implicated in the pathogenesis of vascular dementia, yet little is known about the cellular and molecular mediators of neuroinflammation after myocardial infarction. Using a mouse model of myocardial infarction coupled with flow cytometric analyses and immunohistochemistry, we discovered increased monocyte abundance in the brain after myocardial infarction, which was associated with increases in brain-resident perivascular macrophages and microglia. Myeloid cell recruitment and activation was also observed in post-mortem brains of humans that died after myocardial infarction. Spatial and single cell transcriptomic profiling of brain-resident myeloid cells …

Exploring The Landscape Of Somatic Asxl2 Mutations In Myeloid Neoplasms: Frequency And Clinical Implications, Tareq Abuasab, Gautam Borthakur, Rashmi Kanagal-Shamanna, Lucia Masarova, Keyur Patel, Koichi Takahashi, Prithviraj Bose, John Villarreal, Sherry Pierce, Tapan Kadia, Guillermo Garcia-Manero, Nicholas J Short, Courtney Dinardo, Naval Daver, Farhad Ravandi, Hagop Kantarjian, Srdan Verstovsek, Musa Yilmaz

Faculty, Staff and Student Publications

No abstract provided.

Author Correction: The Evolution Of Lung Cancer And Impact Of Subclonal Selection In Tracerx, Alexander M Frankell, Michelle Dietzen, Maise Al Bakir, Emilia L Lim, Takahiro Karasaki, Sophia Ward, Selvaraju Veeriah, Emma Colliver, Ariana Huebner, Abigail Bunkum, Mark S Hill, Kristiana Grigoriadis, David A Moore, James R M Black, Wing Kin Liu, Kerstin Thol, Oriol Pich, Thomas B K Watkins, Cristina Naceur-Lombardelli, Daniel E Cook, Roberto Salgado, Gareth A Wilson, Chris Bailey, Mihaela Angelova, Robert Bentham, Carlos Martínez-Ruiz, Christopher Abbosh, Andrew G Nicholson, John Le Quesne, Dhruva Biswas, Rachel Rosenthal, Clare Puttick, Sonya Hessey, Claudia Lee, Paulina Prymas, Antonia Toncheva, Jon Smith, Wei Xing, Jerome Nicod, Gillian Price, Keith M Kerr, Babu Naidu, Gary Middleton, Kevin G Blyth, Dean A Fennell, Martin D Forster, Siow Ming Lee, Mary Falzon, Madeleine Hewish, Michael J Shackcloth, Eric Lim, Sarah Benafif, Peter Russell, Ekaterini Boleti, Matthew G Krebs, Jason F Lester, Dionysis Papadatos-Pastos, Tanya Ahmad, Ricky M Thakrar, David Lawrence, Neal Navani, Sam M Janes, Caroline Dive, Fiona H Blackhall, Yvonne Summers, Judith Cave, Teresa Marafioti, Javier Herrero, Sergio A Quezada, Karl S Peggs, Roland F Schwarz, Peter Van Loo, Daniël M Miedema, Nicolai J Birkbak, Crispin T Hiley, Allan Hackshaw, Simone Zaccaria, Tracerx Consortium, Mariam Jamal-Hanjani, Nicholas Mcgranahan, Charles Swanton

Faculty, Staff and Student Publications

No abstract provided.

Automated Quantification Of Measurable Residual Disease In Chronic Lymphocytic Leukemia Using An Artificial Intelligence-Assisted Workflow, Alexandre Bazinet, Alan Wang, Xinmei Li, Fuli Jia, Huan Mo, Wei Wang, Sa A Wang

Faculty, Staff and Student Publications

Detection of measurable residual disease (MRD) in chronic lymphocytic leukemia (CLL) is an important prognostic marker. The most common CLL MRD method in current use is multiparameter flow cytometry, but availability is limited by the need for expert manual analysis. Automated analysis has the potential to expand access to CLL MRD testing. We evaluated the performance of an artificial intelligence (AI)-assisted multiparameter flow cytometry (MFC) workflow for CLL MRD. We randomly selected 113 CLL MRD FCS files and divided them into training and validation sets. The training set (n = 41) was gated by expert manual analysis and used to …

Optimization And Validation Of Multi-Echo, Multi-Contrast Sage Acquisition In Fmri, Elizabeth G Keeling, Maurizio Bergamino, Sudarshan Ragunathan, C Chad Quarles, Allen T Newton, Ashley M Stokes

Faculty, Staff and Student Publications

The purpose of this study was to optimize and validate a multi-contrast, multi-echo fMRI method using a combined spin- and gradient-echo (SAGE) acquisition. It was hypothesized that SAGE-based blood oxygen level-dependent (BOLD) functional MRI (fMRI) will improve sensitivity and spatial specificity while reducing signal dropout. SAGE-fMRI data were acquired with five echoes (2 gradient-echoes, 2 asymmetric spin-echoes, and 1 spin-echo) across 12 protocols with varying acceleration factors, and temporal SNR (tSNR) was assessed. The optimized protocol was then implemented in working memory and vision tasks in 15 healthy subjects. Task-based analysis was performed using individual echoes, quantitative dynamic relaxation times …

Behavioral Therapies Targeting Reward Mechanisms In Substance Use Disorders, Margaret C Wardle, Heather E Webber, Jin H Yoon, Angela M Heads, Angela L Stotts, Scott D Lane, Joy M Schmitz

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Behavioral therapies are considered best practices in the treatment of substance use disorders (SUD) and used as first-line approaches for SUDs without FDA-approved pharmacotherapies. Decades of research on the neuroscience of drug reward and addiction have informed the development of current leading behavioral therapies that, while differing in focus and technique, have in common the overarching goal of shifting reward responding away from drug and toward natural non-drug rewards. This review begins by describing key neurobiological processes of reward in addiction, followed by a description of how various behavioral therapies address specific reward processes. Based on this review, a conceptual …

Mitochondrial Health, Physical Functioning, And Daily Affect: Bioenergetic Mechanisms Of Dementia Caregiver Well-Being, E Lydia Wu-Chung, Luis D Medina, Jensine Paoletti-Hatcher, Vincent Lai, Jennifer M Stinson, Itee Mahant, Paul E Schulz, Cobi J Heijnen, Christopher P Fagundes

Faculty, Staff and Student Publications

Objective: Chronic stress adversely affects mental and physical well-being. However, health outcomes vary among people experiencing the same stressor. Individual differences in physical and emotional well-being may depend on mitochondrial biology, as energy production is crucial for stress regulation. This study investigated whether mitochondrial respiratory capacity corresponds to individual differences in dementia spousal caregivers' mental and physical health.

Methods: Spousal caregivers of individuals with Alzheimer's disease and related dementias ( N = 102, mean age = 71, 78% female, 83% White) provided peripheral blood samples and completed self-report questionnaires on quality of life, caregiver burden, and a 7-day affect scale. …

Hairy Cell Leukemia Variant And Who Classification Correspondence Re: 5th Edition Who Classification Haematolymphoid Tumors: Lymphoid Neoplasms, Michael Grever, Leslie Andritsos, Mirela Anghelina, Evgeny Arons, Versha Banerji, Jacqueline Barrientos, Seema A Bhat, James Blachly, Alessandro Broccoli, Timothy Call, Claire Dearden, Sascha Dietrich, Monica Else, Narendranath Epperla, Andrei Fagarasanu, Brunangelo Falini, Francesco Forconi, Alessandro Gozzetti, Paul Hampel, David J Hermel, Sunil Iyengar, James B Johnston, Gunnar Juliusson, Robert J Kreitman, Francesco Lauria, Gerard Lozanski, Christopher C Oakes, Sameer A Parikh, Jae Park, Graeme Quest, Kanti Rai, Farhad Ravandi, Tadeusz Robak, Kerry A Rogers, Alan Saven, John F Seymour, Tamar Tadmor, Martin S Tallman, Constantine S Tam, Enrico Tiacci, Xavier Troussard, Bernhard Wörmann, Clive S Zent, Thorsten Zenz, Pier Luigi Zinzani

Faculty, Staff and Student Publications

No abstract provided.

A Bayesian Latent-Subgroup Platform Design For Dose Optimization, Rongji Mu, Xiaojiang Zhan, Rui Sammi Tang, Ying Yuan

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The US Food and Drug Administration launched Project Optimus to reform the dose optimization and dose selection paradigm in oncology drug development, calling for the paradigm shift from finding the maximum tolerated dose to the identification of optimal biological dose (OBD). Motivated by a real-world drug development program, we propose a master-protocol-based platform trial design to simultaneously identify OBDs of a new drug, combined with standards of care or other novel agents, in multiple indications. We propose a Bayesian latent subgroup model to accommodate the treatment heterogeneity across indications, and employ Bayesian hierarchical models to borrow information within subgroups. At …